English
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

ViraferonPeg (peginterferon alfa-2b) – Summary of product characteristics - L03AB10

Updated on site: 10-Oct-2017

Medication nameViraferonPeg
ATC CodeL03AB10
Substancepeginterferon alfa-2b
ManufacturerMerck Sharp

1.NAME OF THE MEDICINAL PRODUCT

PegIntron 50 micrograms powder and solvent for solution for injection

PegIntron 80 micrograms powder and solvent for solution for injection

PegIntron 100 micrograms powder and solvent for solution for injection

PegIntron 120 micrograms powder and solvent for solution for injection

PegIntron 150 micrograms powder and solvent for solution for injection

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

PegIntron 50 micrograms powder and solvent for solution for injection

Each vial contains 50 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each vial provides 50 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

PegIntron 80 micrograms powder and solvent for solution for injection

Each vial contains 80 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each vial provides 80 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

PegIntron 100 micrograms powder and solvent for solution for injection

Each vial contains 100 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each vial provides 100 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

PegIntron 120 micrograms powder and solvent for solution for injection

Each vial contains 120 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each vial provides 120 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

PegIntron 150 micrograms powder and solvent for solution for injection

Each vial contains 150 micrograms of peginterferon alfa-2b as measured on a protein basis.

Each vial provides 150 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

The active substance is a covalent conjugate of recombinant interferon alfa-2b* with monomethoxy polyethylene glycol. The potency of this product should not be compared to that of another pegylated or non-pegylated protein of the same therapeutic class (see section 5.1).

*produced by rDNA technology in E. coli cells harbouring a genetically engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.

Excipients with known effect:

Each vial contains 40 mg of sucrose per 0.5 ml.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

White powder.

Clear and colourless solvent.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Adults (tritherapy)

PegIntron in combination with ribavirin and boceprevir (tritherapy) is indicated for the treatment of

chronic hepatitis C (CHC) genotype 1 infection in adult patients (18 years of age and older) with compensated liver disease who are previously untreated or who have failed previous therapy (see section 5.1).

Please refer to the ribavirin and boceprevir Summary of Product Characteristics (SmPCs) when PegIntron is to be used in combination with these medicines.

Adults (bitherapy and monotherapy)

PegIntron is indicated for the treatment of adult patients (18 years of age and older) with CHC who are positive for hepatitis C virus RNA (HCV-RNA), including patients with compensated cirrhosis and/or co-infected with clinically stable HIV (see section 4.4).

PegIntron in combination with ribavirin (bitherapy) is indicated for the treatment of CHC infection in adult patients who are previously untreated including patients with clinically stable HIV co-infection and in adult patients who have failed previous treatment with interferon alpha (pegylated or nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy (see section 5.1).

Interferon monotherapy, including PegIntron, is indicated mainly in case of intolerance or contraindication to ribavirin.

Please refer to the ribavirin SmPC when PegIntron is to be used in combination with ribavirin.

Paediatric population (bitherapy)

PegIntron is indicated in a combination regimen with ribavirin for the treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C, previously untreated, without liver decompensation, and who are positive for HCV-RNA.

When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case basis (see section 4.4).

Please refer to the ribavirin SmPC for capsules or oral solution when PegIntron is to be used in combination with ribavirin.

4.2Posology and method of administration

Treatment should be initiated and monitored only by a physician experienced in the management of patients with hepatitis C.

Posology

PegIntron should be administered as a once weekly subcutaneous injection. The dose administered in adults depends on whether it is used in combination therapy (bitherapy or tritherapy) or as monotherapy.

PegIntron combination therapy (bitherapy or tritherapy)

Bitherapy (PegIntron with ribavirin): applies to all adult and paediatric patients 3 years of age and older.

Tritherapy (PegIntron with ribavirin and boceprevir): applies to adult patients with genotype 1 CHC.

Adults – Dose to be administered

PegIntron 1.5 micrograms/kg/week in combination with ribavirin capsules.

The intended dose of 1.5 g/kg of PegIntron to be used in combination with ribavirin may be delivered in weight categories with the PegIntron strengths according to Table 1. Ribavirin capsules are to be administered orally each day in two divided doses with food (morning and evening).

Table 1

Dosing for combination therapy*

 

 

Body weight

PegIntron

Ribavirin capsules

(kg)

 

PegIntron strength

Administer once

Total daily

Number of

 

 

( g/0.5 ml)

weekly

ribavirin dose

capsules

 

 

 

(ml)

(mg)

(200 mg)

< 40

 

0.5

4a

40-50

 

0.4

4a

51-64

 

0.5

4a

65-75

 

0.5

1,000

5b

76-80

 

0.5

1,000

5b

81-85

 

0.5

1,200

6c

86-105

 

0.5

1,200

6c

> 105

 

0.5

1,400

7d

a:2 morning, 2 evening

b:2 morning, 3 evening

c:3 morning, 3 evening

d:3 morning, 4 evening

* Refer to the SmPC of boceprevir for details about the dose of boceprevir to be administered in tritherapy.

Adults - Duration of treatment – Naïve patients

Tritherapy: Refer to the SmPC for boceprevir.

Bitherapy: Predictability of sustained virological response - Patients infected with virus genotype 1 who fail to achieve undetectable HCV-RNA or demonstrate adequate virological response at week 4 or 12 are highly unlikely to become sustained virological responders and should be evaluated for discontinuation (see also section 5.1).

Genotype 1:

-Patients who have undetectable HCV-RNA at treatment week 12, treatment should be continued for another nine month period (i.e., a total of 48 weeks).

-Patients with detectable but ≥ 2 log decrease in HCV-RNA level from baseline at treatment week 12 should be reassessed at treatment week 24 and, if HCV-RNA is undetectable, they should continue with full course of therapy (i.e. a total of 48 weeks). However, if HCV-RNA is still detectable at treatment week 24, discontinuation of therapy should be considered.

-In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml) who become HCV-RNA negative at treatment week 4 and remain HCV-RNA negative at week 24, the treatment could either be stopped after this 24 week treatment course or pursued for an additional 24 weeks (i.e. overall 48 weeks treatment duration). 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).

Genotypes 2 or 3:

It is recommended that all patients be treated with bitherapy for 24 weeks, except for HCV/HIV co-infected patients who should receive 48 weeks of treatment.

Genotype 4:

In general, patients infected with genotype 4 are considered harder to treat and limited study data (n=66) indicate they are compatible with a duration of treatment with bitherapy as for genotype 1.

Adults - Duration of treatment - HCV/HIV co-infection

Bitherapy: The recommended duration of treatment for HCV/HIV co-infected patients is 48 weeks with bitherapy, regardless of genotype.

Predictability of response and non-response in HCV/HIV co-infection - 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. The negative predictive value for sustained response in HCV/HIV co-infected patients treated with PegIntron in combination with ribavirin was 99 % (67/68;

Study 1) (see section 5.1). A positive predictive value of 50 % (52/104; Study 1) was observed for HCV/HIV co-infected patients receiving bitherapy.

Adults - Duration of treatment - Retreatment

Tritherapy: Refer to the SmPC for boceprevir.

Bitherapy: Predictability of sustained virological response - All patients, irrespective of genotype, who have demonstrated serum HCV-RNA below the limits of detection at week 12 should receive

48 weeks of bitherapy. Retreated patients who fail to achieve virological response (i.e. HCV-RNA below the limits of detection) at week 12 are unlikely to become sustained virological responders after 48 weeks of therapy (see also section 5.1).

Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not been studied with pegylated interferon alfa-2b and ribavirin combination therapy.

Paediatric population (bitherapy only) – Dose to be administered

Dosing for children 3 years of age and older and adolescent patients is determined by body surface area for PegIntron and by body weight for ribavirin. The recommended dose of PegIntron is

60 g/m2/week subcutaneously in combination with ribavirin 15 mg/kg/day orally in two divided doses with food (morning and evening).

Paediatric population (bitherapy only) - Duration of treatment

Genotype 1:

The recommended duration of treatment with bitherapy is 1 year. By extrapolation from clinical data on combination therapy with standard interferon in paediatric patients (negative predictive value 96 % for interferon alfa–2b/ribavirin), patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders. Therefore, it is recommended that children and adolescent patients receiving PegIntron/ribavirin combination

be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment or if they have detectable HCV-RNA at treatment week 24.

Genotype 2 or 3:

The recommended duration of treatment with bitherapy is 24 weeks.

Genotype 4:

Only 5 children and adolescents with Genotype 4 were treated in the PegIntron/ribavirin clinical trial. The recommended duration of treatment with bitherapy is 1 year. It is recommended that children and adolescent patients receiving PegIntron/ribavirin combination be discontinued

from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment or if they have detectable HCV-RNA at treatment week 24.

PegIntron monotherapy – Adults Dose to be administered

As monotherapy the PegIntron regimen is 0.5 or 1.0 g/kg/week. The lowest PegIntron strength available is 50 g/0.5 ml; therefore for patients prescribed 0.5 g/kg/week, doses must be adjusted by volume as shown in Table 2. For the 1.0 g/kg dose, similar volume adjustments can be made or alternate strengths can be used as shown in Table 2. PegIntron monotherapy was not studied in HCV/HIV co-infected patients.

Table 2

Monotherapy dosing

 

 

 

 

 

0.5 g/kg

1.0 g/kg

Body weight

PegIntron

Administer once

PegIntron

Administer once

(kg)

 

strength

weekly

strength

weekly

 

 

( g/0.5 ml)

(ml)

( g/0.5 ml)

(ml)

30-35

 

50*

0.15

0.2

36-45

 

0.2

0.4

46-56

 

0.25

0.5

57-72

 

0.2

0.4

73-88

 

0.4

0.5

89-106

0.5

0.5

107-120**

0.4

0.5

Minimum delivery for pen is 0.2 ml.

*Must use vial.

**For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes.

Duration of treatment

For patients who exhibit virological response at week 12, treatment should be continued for at least another three-month period (i.e., a total of six months). The decision to extend therapy to one year of treatment should be based on prognostic factors (e.g., genotype, age > 40 years, male gender, bridging fibrosis).

Dose modification for all patients (monotherapy and combination therapy)

If severe adverse reactions or laboratory abnormalities develop during treatment with PegIntron monotherapy or combination therapy, the dosages of PegIntron and/or ribavirin must be modified as appropriate, until the adverse reactions abate. Dose reduction of boceprevir is not recommended. Boceprevir must not be administered in the absence of PegIntron and ribavirin.

As adherence might be of importance for outcome of therapy, the dose of PegIntron and ribavirin should be kept as close as possible to the recommended standard dose. Guidelines were developed in clinical trials for dose modification.

Combination therapy dose reduction guidelines

Table 2a Dose modification guidelines for combination therapy based on laboratory parameters

Laboratory values

Reduce only ribavirin

Reduce only PegIntron

Discontinue

 

daily dose (see note 1)

dose (see note 2) if:

combination therapy

 

if:

 

if:

Haemoglobin

≥ 8.5 g/dl, and

-

< 8.5 g/dl

 

< 10 g/dl

 

 

Adults: Haemoglobin

2 g/dl decrease in haemoglobin during any

 

in Patients with history

< 12 g/dl after four

of stable cardiac

four week period during treatment

weeks of dose

disease

(permanent dose reduction)

reduction

Children and

 

 

 

adolescents: not

 

 

 

applicable

 

 

 

Leukocytes

-

≥ 1.0 x 109/l, and

< 1.0 x 109/l

 

 

< 1.5 x 109/l

 

Neutrophils

-

≥ 0.5 x 109/l, and

< 0.5 x 109/l

 

 

< 0.75 x 109/l

 

Platelets

-

≥ 25 x 109/l, and

< 25 x 109/l (adults)

 

 

< 50 x 109/l (adults)

< 50 x 109/l (children

 

 

≥ 50 x 109/l, and

and adolescents)

 

 

<70 x 109/l (children and

 

 

 

adolescents)

 

Bilirubin – direct

-

-

2.5 x ULN*

Bilirubin - indirect

> 5 mg/dl

-

> 4 mg/dl

 

 

 

(for > 4 weeks)

Serum Creatinine

-

-

> 2.0 mg/dl

Creatinine Clearance

-

-

Discontinue ribavirin

 

 

 

if CrCL < 50ml/min

Laboratory values

Reduce only ribavirin

Reduce only PegIntron

Discontinue

 

daily dose (see note 1)

dose (see note 2) if:

combination therapy

 

if:

 

if:

Alanine

-

-

2 x baseline and

aminotransferase

 

 

> 10 x ULN*

(ALT)

 

 

 

or

 

 

2 x baseline and

Aspartate

 

 

> 10 x ULN*

aminotransferase

 

 

 

(AST)

 

 

 

*Upper limit of normal

Note 1: In adult patients 1st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to

600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.

In children and adolescent patients 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dose reduction of ribavirin is to 8 mg/kg/day.

Note 2: In adult patients 1st dose reduction of PegIntron is to 1 µg/kg/week. If needed, 2nd dose reduction of PegIntron is to 0.5 µg/kg/week. For patients on PegIntron monotherapy: refer to monotherapy dose reduction guidelines section for dose reduction.

In children and adolescent patients 1st dose reduction of PegIntron is to 40 g/m2/week, 2nd dose reduction of PegIntron is to 20 g/m2/week.

Dose reduction of PegIntron in adults may be accomplished by reducing the prescribed volume or by utilizing a lower dose strength as shown in Table 2b. Dose reduction of PegIntron in children and adolescents is accomplished by modifying the recommended dose in a two-step process from the original starting dose of 60 g/m2/week, to 40 g/m2/week, then to 20 g/m2/week, if needed.

Table 2b Two-step dose reduction of PegIntron in combination therapy in adults

First dose reduction to PegIntron 1 µg/kg

 

Second dose reduction to PegIntron 0.5 µg/kg

Body

PegIntron

Amount of

 

Volume of

Body

PegIntron

Amount of

Volume of

weight(kg)

strength

PegIntron

 

PegIntron

weight

strength

PegIntron

PegIntron

 

( g/0.5 ml)

to

 

to

(kg)

( g/0.5 ml)

to

to

 

 

administer

 

administer

 

 

administer

administer

 

 

(µg)

 

(ml)

 

 

(µg)

(ml)

< 40

 

0.35

< 40

0.2

40 – 50

 

0.2

40 – 50

0.25

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

51 – 64

 

0.35

51 – 64

0.2

 

 

 

 

 

 

 

65 – 75

 

0.35

65 – 75

0.35

 

 

 

 

 

 

 

 

 

 

 

76 – 85

 

0.5

76 – 85

0.2

 

 

 

 

 

 

 

 

86 - 105

 

0.4

86 – 105

0.5

 

 

 

 

 

 

 

 

 

> 105

 

0.35

> 105

0.4

 

 

 

 

 

 

 

 

 

 

 

 

PegIntron monotherapy dose reduction guidelines in adults

Dose modification guidelines for adult patients who use PegIntron monotherapy are shown in

Table 3a.

Table 3a Dose modification guidelines for PegIntron monotherapy in adults based on laboratory parameters

Laboratory values

Reduce PegIntron

Discontinue PegIntron if:

 

to one-half dose if:

 

Neutrophils

≥ 0.5 x 109/l, and < 0.75 x 109/l

< 0.5 x 109/l

Platelets

≥ 25 x 109/l, and < 50 x 109/l

< 25 x 109/l

For adult patients who use 0.5 g/kg PegIntron monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half as shown in Table 3b.

Table 3b Reduced PegIntron dose (0.25 g/kg) for the 0.5 g/kg monotherapy regimen in adults

Body weight

PegIntron strength

Amount of PegIntron to

Volume of PegIntron to

(kg)

( g/0.5 ml)

administer

Administer

 

 

( g)

(ml)

30-35

50*

0.08

36-45

50*

0.1

46-56

50*

0.13

57-72

80*

0.1

73-88

0.2

89-106

0.25

107-120**

0.2

Minimum delivery for pen is 0.2 ml.

*Must use vial.

**For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes.

For adult patients who use 1.0 g/kg PegIntron monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half or by utilizing a lower dose strength as shown in

Table 3c.

Table 3c Reduced PegIntron dose (0.5 g/kg) for the 1.0 g/kg monotherapy regimen in adults

Body weight

PegIntron

Amount of

Volume of

(kg)

strength

PegIntron to

PegIntron to

 

( g/0.5 ml)

administer

administer

 

 

( g)

(ml)

30-35

50*

0.15

36-45

0.20

46-56

0.25

57-72

0.2

73-88

0.4

89-106

0.5

107-120**

0.4

Minimum delivery for pen is 0.2 ml.

*Must use vial.

**For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes.

Special populations

Renal impairment Monotherapy

PegIntron should be used with caution in patients with moderate to severe renal impairment. In patients with moderate renal dysfunction (creatinine clearance 30-50 ml/minute), the starting dose of PegIntron should be reduced by 25 %. Patients with severe renal dysfunction (creatinine clearance

15-29 ml/minute) should have the starting dose of PegIntron reduced by 50 %. Data are not available for the use of PegIntron in patients with creatinine clearance < 15 ml/minute (see section 5.2). Patients with severe renal impairment, including those on hemodialysis, should be closely monitored. If renal function decreases during treatment, PegIntron therapy should be discontinued.

Combination therapy

Patients with creatinine clearance < 50 ml/minute must not be treated with PegIntron in combination with ribavirin (see ribavirin SmPC). When administered in combination therapy, patients with impaired renal function should be more carefully monitored with respect to the development of anaemia.

Hepatic impairment

The safety and efficacy of PegIntron therapy has not been evaluated in patients with severe hepatic dysfunction, therefore PegIntron must not be used for these patients.

Elderly ( 65 years of age)

There are no apparent age-related effects on the pharmacokinetics of PegIntron. Data from elderly patients treated with a single dose of PegIntron suggest no alteration in PegIntron dose is necessary based on age (see section 5.2).

Paediatric population

PegIntron can be used in combination with ribavirin in paediatric patients 3 years of age and older.

Method of administration

PegIntron should be administered as a subcutaneous injection. For special handling information see section 6.6. Patients may self-inject PegIntron if their physician determines that it is appropriate and with medical follow-up as necessary.

4.3Contraindications

-Hypersensitivity to the active substance or to any interferon or to any of the excipients listed in section 6.1;

-A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months (see section 4.4);

-Severe, debilitating medical conditions;

-Autoimmune hepatitis or a history of autoimmune disease;

-Severe hepatic dysfunction or decompensated cirrhosis of the liver;

-Pre-existing thyroid disease unless it can be controlled with conventional treatment;

-Epilepsy and/or compromised central nervous system (CNS) function;

-HCV/HIV patients with cirrhosis and a Child-Pugh score ≥ 6.

-Combination of PegIntron with telbivudine.

Paediatric population

-Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicidal attempt.

Combination therapy

Also see SmPCs for ribavirin and boceprevir if PegIntron is to be administered in combination therapy in patients with chronic hepatitis C.

4.4Special 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 PegIntron therapy, 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 or homicidal ideation is identified, it is recommended that treatment with PegIntron be discontinued, and the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions

If treatment with peginterferon alfa-2b is judged necessary in adult 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.

- The use of PegIntron in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Among children and adolescents treated with interferon alfa-2b in combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult patients, children and adolescents experienced other psychiatric adverse events (e.g. depression, emotional lability, and somnolence).

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 ages 3 through 17 years, weight loss and growth inhibition were common. Long-term data available in children treated with the combination therapy of pegylated interferon/ribavirin are indicative of substantial growth retardation. Thirty two percent (30/94) of subjects demonstrated > 15 percentile decrease in height-for-age percentile 5 years after completion of therapy (see sections 4.8 and 5.1).

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, that resulted in reduced height in some patients.

-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. Although data are limited, no evidence of long-term effects on sexual maturation was noted in the 5-year observational follow-up study.

More significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses for oncology indications. While these effects are generally reversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high doses of interferon alpha.

All patients in the selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (i.e. patients with genotype 2 and 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.

Acute hypersensitivity

Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely during interferon alfa-2b therapy. If such a reaction develops during treatment with PegIntron, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

Cardiovascular system

As with interferon alfa-2b, adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, receiving PegIntron therapy require close monitoring. It is recommended that patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of PegIntron therapy. There are no data in children or adolescents with a history of cardiac disease.

Hepatic Failure

PegIntron increases the risk of hepatic decompensation and death in patients with cirrhosis. As with all interferons, discontinue treatment with PegIntron in patients who develop prolongation of coagulation markers which might indicate liver decompensation. Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Pyrexia

While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out.

Hydration

Adequate hydration must be maintained in patients undergoing PegIntron therapy since hypotension related to fluid depletion has been seen in some patients treated with alpha interferons. Fluid replacement may be necessary.

Pulmonary changes

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients. Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.

Autoimmune disease

The development of auto-antibodies and autoimmune disorders has been reported during treatment with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 4.4 Thyroid changes and section 4.8).

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Ocular changes

Ophthalmologic disorders, including retinal haemorrhages, retinal exudates, serous retinal detachment, and retinal artery or vein occlusion have been reported in rare instances after treatment with alpha interferons (see section 4.8). All patients should have a baseline eye examination. Any patient complaining of ocular symptoms, including loss of visual acuity or visual field must have a prompt and complete eye examination. Periodic visual examinations are recommended during PegIntron therapy, particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of PegIntron should be considered in patients who develop new or worsening ophthalmological disorders.

Thyroid changes

Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21 % of children treated with PegIntron/ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another approximately 2 % had a transient decrease below the lower limit of normal. Prior to initiation of PegIntron therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Determine TSH levels if, during the course of therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, PegIntron treatment may be continued if TSH levels can be maintained in the normal range by medicine. Children and adolescents should be monitored every

3 months for evidence of thyroid dysfunction (e.g. TSH).

Metabolic disturbances

Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.

HCV/HIV Co-infection

Mitochondrial toxicity and lactic acidosis

Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding PegIntron and ribavirin to HAART therapy (see ribavirin SmPC).

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

Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentration.

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed.

Haematological abnormalities in HCV/HIV co-infected patients

HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and HAART may be at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia and anaemia) compared to HCV mono-infected patients. Although, the majority of them could be managed by dose reduction, close monitoring of haematological parameters should be undertaken in this population of patients (see section 4.2 and below “Laboratory tests” and section 4.8).

Patients treated with PegIntron and ribavirin combination therapy and zidovudine are at increased risk of developing anaemia and therefore the concomitant use of this combination with zidovudine is not recommended (see section 4.5).

Patients with low CD4 counts

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

patients with low CD4 counts.

Please refer to the respective SmPCs 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 PegIntron and ribavirin.

HCV/HBV Coinfection

Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co- infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation appears to be low.

All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; patients co-infected with hepatitis B and C must then be monitored and managed according to current clinical guidelines.

Dental and periodontal disorders

Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving PegIntron and ribavirin 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 PegIntron and ribavirin. 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.

Organ transplant recipients

The safety and efficacy of PegIntron alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. Preliminary data indicate that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported.

Other

Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of PegIntron in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.

Laboratory tests

Standard haematologic tests, blood chemistry and a test of thyroid function must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of PegIntron therapy are:

 

Platelets

100,000/mm3

 

Neutrophil count

1,500/mm3

 

TSH level

must be within normal limits

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2).

Long term maintenance monotherapy

It has been demonstrated in a clinical study that peginterferon alfa-2b at low-dose (0.5 μg/kg/week) is not effective in long term maintenance monotherapy (for a mean duration of 2.5 years) for the prevention of disease progression in non responders with compensated cirrhosis. No statistically significant effect on the time to development of the first clinical event (liver decompensation, hepatocellular carcinoma, death and/or liver transplantation) was observed as compared to the absence of treatment. PegIntron should therefore not be used as long term maintenance monotherapy.

Important information about some of the ingredients of PegIntron

Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially "sodium-free".

4.5Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Telbivudine

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SmPC). Moreover, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Therefore, the combination of PegIntron with telbivudine is contraindicated (see section 4.3).

Methadone

In patients with chronic hepatitis C that were on stable methadone maintenance therapy and naïve to peginterferon alfa-2b, addition of 1.5 microgram/kg/week of PegIntron subcutaneously for 4 weeks increased R-methadone AUC by approximately 15 % (95 % Cl for AUC ratio estimate 103 – 128 %). The clinical significance of this finding is unknown; however, patients should be monitored for signs and symptoms of increased sedative effect, as well as respiratory depression. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.

Effect of Peginterferon alfa-2b on Co-administered Medicines

The potential interaction of peginterferon alfa-2b (PegIntron) on substrates of metabolic enzymes was evaluated in 3 multiple-dose clinical pharmacology studies. In these studies, the effects of multiple-dose regimens of peginterferon alfa-2b (PegIntron) were investigated in Hepatitis C subjects (1.5 mcg/week) or healthy subjects (1 mcg/week or 3 mcg/week) (Table 4). A clinically significant pharmacokinetic interaction was not observed between peginterferon alfa-2b (PegIntron) and tolbutamide, midazolam or dapsone; therefore, no dosing adjustment is necessary when peginterferon alfa-2b (PegIntron) is administered with medicines metabolized by CYP2C9, CYP3A4 and N-acetyltransferase. Concomitant administration of peginterferon alfa-2b (PegIntron) with caffeine or desipramine modestly increased the exposure of caffeine and desipramine. When patients are administered PegIntron with medications metabolized by CYP1A2 or CYP2D6, the extent of the decrease in cytochrome P 450 activity is unlikely to have a clinical impact, except with medicines which have a narrow therapeutic margin (Table 5).

Table 4Effect of Peginterferon alfa-2b on Co-administered Medicines

 

 

 

Geometric Mean Ratio (Ratio

 

 

 

with/without peginterferon

Co-administered

Dose of

Study Population

alfa-2b)

 

Medicine

peginterferon

 

AUC

Cmax

 

alfa-2b

 

(90% CI)

(90% CI)

Caffeine

1.5 mcg/kg/week

Chronic Hepatitis

1.39

1.02

(CYP1A2 substrate)

(4 weeks)

C Subjects (N=22)

(1.27, 1.51)

(0.95, 1.09)

 

1 mcg/kg/week

Healthy Subjects

1.18

1.12

 

(4 weeks)

(N=24)

(1.07, 1.31)

(1.05, 1.19)

 

3 mcg/kg/week

Healthy Subjects

1.36

1.16

 

(2 weeks)

(N=13)

(1.25, 1.49)

(1.10, 1.24)

Tolbutamide

1.5 mcg/kg/week

Chronic Hepatitis

1.1#

NA

(CYP2C9 substrate)

(4 weeks)

C Subjects (N=22)

(0.94, 1.28)

 

 

1 mcg/kg/week

Healthy Subjects

0.90#

NA

 

(4 weeks)

(N=24)

(0.81, 1.00)

 

 

3 mcg/kg/week

Healthy Subjects

0.95

0.99

 

(2 weeks)

(N=13)

(0.89, 1.01)

(0.92, 1.07)

 

 

 

Geometric Mean Ratio (Ratio

 

 

 

with/without peginterferon

Co-administered

Dose of

Study Population

alfa-2b)

 

Medicine

peginterferon

 

AUC

Cmax

 

alfa-2b

 

(90% CI)

(90% CI)

Dextromethorphan

1.5 mcg/kg/week

Chronic Hepatitis

0.96##

NA

hydrobromide

(4 weeks)

C Subjects (N=22)

(0.73, 1.26)

 

(CYP2D6 and

1 mcg/kg/week

Healthy Subjects

2.03#

NA

CYP3A substrate)

(4 weeks)

(N=24)

(1.55, 2.67)

 

Desipramine

3 mcg/kg/week

Healthy Subjects

1.30

1.08

(CYP2D6 substrate)

(2 weeks)

(N=13)

(1.18, 1.43)

(1.00, 1.16)

Midazolam

1.5 mcg/kg/week

Chronic Hepatitis

1.07

1.12

(CYP3A4 substrate)

(4 weeks)

C Subjects (N=24)

(0.91, 1.25)

(0.94, 1.33)

 

1 mcg/kg/week

Healthy Subjects

1.07

1.33

 

(4 weeks)

(N=24)

(0.99, 1.16)

(1.15, 1.53)

 

3 mcg/kg/week

Healthy Subjects

1.18

1.24

 

(2 weeks)

(N=13)

(1.06, 1.32)

(1.07, 1.43)

Dapsone

1.5 mcg/kg/week

Chronic Hepatitis

1.05

1.03

(N-acetyltransferase

(4 weeks)

C Subjects (N=24)

(1.02, 1.08)

(1.00, 1.06)

substrate)

 

 

 

 

# Calculated from urine data collected over an interval of 48-hours ## Calculated from urine data collected over an interval of 24-hours

Table 5 Precautions for co-administration (PegIntron should be administered with care when co-administered with the following medicines)

Medicines

Signs, Symptoms, and Treatment

Mechanism and Risk Factors

Theophylline

Co-administration of theophylline

Metabolism of theophylline is

 

with the product (PegIntron) may

suppressed by inhibitory action of

 

increase the blood concentrations of

the product (PegIntron) on

 

theophylline. Careful

CYP1A2.

 

co-administration of theophylline

 

 

with the product (PegIntron) is

 

 

recommended. Package inserts of

 

 

theophylline should be referred to

 

 

when co-administering with the

 

 

product (PegIntron)

 

Thioridazine

Co-administration of thioridazine

Metabolism of thioridazine is

 

with the product (PegIntron) may

suppressed by inhibitory action of

 

increase the blood concentrations of

the product (PegIntron) on

 

thioridazine. Careful

CYP2D6.

 

co-administration of thioridazine

 

 

with the product (PegIntron) is

 

 

recommended. Package inserts of

 

 

thioridazine should be referred to

 

 

when co-administering with the

 

 

product (PegIntron)

 

Theophylline,

Elevation of blood concentrations

Metabolism of other medicines in

Antipyrine,

of these medicines has been

the liver may be suppressed.

Warfarin

reported when administered in

 

 

combination with other interferon

 

 

preparations and therefore care

 

 

should be taken.

 

Medicines

Signs, Symptoms, and Treatment

Mechanism and Risk Factors

Zidovudine

When administered in combination

Mechanism of action is unknown,

 

with other interferon preparations,

but it is considered that both

 

suppressive effect on bone marrow

medicines have bone marrow

 

function may be strengthened and

depressive effects.

 

aggravation of blood cell reduction

 

 

such as white blood cells decreased

 

 

may occur.

 

Immuno-suppressive

When administered in combination

It is considered that graft rejection

therapy

with other interferon preparations,

reactions may be induced.

 

effect of immunosuppressive

 

 

therapy may be weakened in

 

 

transplant (kidney, bone marrow,

 

 

etc.) patients.

 

No pharmacokinetic interactions were noted between PegIntron and ribavirin in a multiple-dose pharmacokinetic study.

HCV/HIV Co-infection

Nucleoside analogues

Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see ribavirin SmPC).

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 anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine-induced anaemia.

4.6Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

PegIntron is recommended for use in fertile women only when they are using effective contraception during the treatment.

Combination therapy with ribavirin

Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking PegIntron in combination with ribavirin. Females of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SmPC).

Pregnancy

There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Interferon alfa-2b has been shown to be abortifacient in primates. PegIntron is likely to also cause this effect.

The potential risk in humans is unknown. PegIntron is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin

Ribavirin causes serious birth defects when administered during pregnancy, therefore ribavirin therapy is contraindicated in women who are pregnant.

Breast-feeding

It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding should be discontinued prior to initiation of treatment.

Fertility

There are no data available regarding potential effects of PegIntron treatment on male or female fertility.

4.7Effects on ability to drive and use machines

Patients who develop fatigue, somnolence or confusion during treatment with PegIntron are cautioned to avoid driving or operating machines.

4.8Undesirable effects

Adults

Tritherapy

Refer to the SmPC for boceprevir.

Bitherapy and monotherapy Summary of the safety profile

The most common treatment-related adverse reactions reported during clinical trials with PegIntron in combination with ribavirin in adults, seen in more than half of the study subjects, were fatigue, headache, and injection site reaction. Additional adverse reactions reported in more than 25 % of subjects included nausea, chills, insomnia, anaemia, pyrexia, myalgia, asthenia, pain, alopecia, anorexia, weight decreased, depression, rash and irritability. The most frequently reported adverse reactions were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy. Fatigue, alopecia, pruritus, nausea, anorexia, weight decreased, irritability and insomnia occur at a notably lower rate in patients treated with PegIntron monotherapy compared to those treated with combination therapy (see Table 6).

Tabulated summary of adverse reactions

The following treatment-related adverse reactions were reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including PegIntron monotherapy or PegIntron/ribavirin. These reactions are listed in table 6 by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data).

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

Table 6 Adverse reactions reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including PegIntron monotherapy or PegIntron + ribavirin

Infections and infestations

Very common:

Viral infection*, pharyngitis*

Common:

Bacterial infection (including sepsis), fungal infection, influenza, upper

 

respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media,

 

rhinitis

Uncommon:

Injection site infection, lower respiratory tract infection

 

 

Not known:

Hepatitis B reactivation in HCV/HBV co-infected patients

 

 

Blood and lymphatic system disorders

Very common:

Anaemia, neutropenia

Common:

Haemolytic anaemia, leukopenia, thrombocytopenia, lymphadenopathy

Very rare:

Aplastic anaemia

Not known:

Aplasia pure red cell

Immune system disorders

Uncommon:

Drug hypersensitivity

 

 

Rare:

Sarcoidosis

 

 

Not known:

Acute hypersensitivity reactions including angioedema, anaphylaxis and

 

anaphylactic reactions including anaphylactic shock, idiopathic

 

thrombocytopenic purpura, thrombotic thrombocytopenic purpura, systemic

 

lupus erythematosus

 

 

Endocrine disorders

 

Common:

Hypothyroidism, hyperthyroidism

Metabolism and nutrition disorders

Very common:

Anorexia

 

 

Common:

Hypocalcemia, hyperuricemia, dehydration, increased appetite

 

 

Uncommon:

Diabetes mellitus, hypertriglyceridaemia

 

 

Rare:

Diabetic ketoacidosis

 

 

Psychiatric disorders

 

Very common:

Depression, anxiety*, emotional lability*, concentration impaired, insomnia

 

 

Common:

Aggression, agitation, anger, mood altered, abnormal behaviour,

 

nervousness, sleep disorder, libido decreased, apathy, abnormal dreams,

 

crying

Uncommon:

Suicide, suicide attempt, suicidal ideation, psychosis, hallucination, panic

 

attack

Rare:

Bipolar disorders

Not known:

Homicidal ideation, mania

Nervous system disorders

Very common:

Headache, dizziness

Common:

Amnesia, memory impairment, syncope, migraine, ataxia, confusion,

 

neuralgia, paraesthesia, hypoaesthesia, hyperaesthesia, hypertonia,

 

somnolence, disturbance in attention, tremor, dysgeusia

 

 

Uncommon:

Neuropathy, neuropathy peripheral

Rare:

Convulsion

Very rare:

Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy

 

 

Not known:

Facial palsy, mononeuropathies

 

 

Eye disorders

 

Common:

Visual disturbance, vision blurred, photophobia, conjunctivitis, eye

 

irritation, lacrimal disorder, eye pain, dry eye

Uncommon:

Retinal exudates

 

 

Rare:

Loss of visual acuity or visual fields, retinal haemorrhage, retinopathy,

 

retinal artery occlusion, retinal vein occlusion, optic neuritis, papilloedema,

 

macular oedema

Not known:

Serous retinal detachment

Ear and labyrinth disorders

Common:

Hearing impaired/loss, tinnitus, vertigo

Uncommon

Ear pain

Cardiac disorders

 

Common:

Palpitations, tachycardia

Uncommon:

Myocardial infarction

Rare:

Congestive heart failure, cardiomyopathy, arrhythmia, pericarditis

Very rare:

Cardiac ischaemia

Not known:

Pericardial effusion

Vascular disorders

 

Common:

Hypotension, hypertension, flushing

Rare:

Vasculitis

Respiratory, thoracic and mediastinal disorders

Very common:

Dyspnoea*, cough*

Common:

Dysphonia, epistaxis, respiratory disorder, respiratory tract congestion,

 

sinus congestion, nasal congestion, rhinorrhea, increased upper airway

 

secretion, pharyngolaryngeal pain

Very rare:

Interstitial lung disease

Not known:

Pulmonary fibrosis, pulmonary arterial hypertension#

Gastrointestinal disorders

Very common:

Vomiting*, nausea, abdominal pain, diarrhoea, dry mouth*

Common:

Dyspepsia, gastroesophageal reflux disease, stomatitis, mouth ulceration,

 

glossodynia, gingival bleeding, constipation, flatulence, haemorrhoids,

 

cheilitis, abdominal distension, gingivitis, glossitis, tooth disorder

 

 

Uncommon:

Pancreatitis, oral pain

 

 

Rare:

Colitis ischaemic

 

 

Very rare:

Colitis ulcerative

Not known

Tongue pigmentation

Hepatobiliary disorders

 

Common:

Hyperbilirubinemia, hepatomegaly

Skin and subcutaneous tissue disorders

Very common:

Alopecia, pruritus*, dry skin*, rash*

Common:

Psoriasis, photosensitivity reaction, rash maculo-papular, dermatitis,

 

erythematous rash, eczema, night sweats, hyperhidrosis, acne, furuncle,

 

erythema, urticaria, abnormal hair texture, nail disorder

Rare:

Cutaneous sarcoidosis

Very rare:

Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

 

 

Musculoskeletal and connective tissue disorders

Very common:

Myalgia, arthralgia, musculoskeletal pain

Common:

Arthritis, back pain, muscle spasms, pain in extremity

Uncommon:

Bone pain, muscle weakness

Rare:

Rhabdomyolysis, myositis, rheumatoid arthritis

Renal and urinary disorders

 

 

Common:

Micturition frequency, polyuria, urine abnormality

Rare:

Renal failure, renal insufficiency

Reproductive system and breast disorders

Common:

Amenorrhoea, breast pain, menorrhagia, menstrual disorder, ovarian

 

disorder, vaginal disorder, sexual dysfunction, prostatitis, erectile

 

dysfunction

General disorders and administration site conditions

Very common:

Injection site reaction*, injection site inflammation, fatigue, asthenia,

 

irritability, chills, pyrexia, influenza like illness, pain

 

 

Common:

Chest pain, chest discomfort, injection site pain, malaise, face oedema,

 

oedema peripheral, feeling abnormal, thirst

Rare:

Injection site necrosis

Investigations

 

 

 

Very common:

Weight decreased

*These adverse reactions were common (≥1/100 to < 1/10) in clinical trials in patients treated with PegIntron monotherapy.

#Class label for interferon products, see below Pulmonary arterial hypertension.

Description of selected adverse reactions in adults

Most cases of neutropenia and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with the recommended doses of PegIntron in combination with ribavirin (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]).

In a clinical trial, approximately 1.2 % of patients treated with PegIntron or interferon alfa-2b in combination with ribavirin reported life-threatening psychiatric events during treatment. These events included suicidal ideation and attempted suicide (see section 4.4).

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients without prior evidence of cardiac disease.

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). Events were reported at various time points typically several months after starting treatment with interferon alfa.

Ophthalmological disorders that have been reported rarely with alpha interferons include retinopathies (including macular oedema), retinal haemorrhages, retinal artery or vein occlusion, retinal exudates, loss of visual acuity or visual field, optic neuritis, and papilloedema (see section 4.4).

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies and Vogt-Koyanagi-Harada syndrome (see also section 4.4).

HCV/HIV co-infected patients

Summary of the safety profile

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

Description of selected adverse reactions Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated ribavirin for co-HCV infection (see section 4.4).

Laboratory values for HCV/HIV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving PegIntron in combination with ribavirin when compared to patients receiving interferon alfa-2b in combination with ribavirin. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 %

(8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) of patients receiving PegIntron in combination with ribavirin. Anaemia (hemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with PegIntron in combination with ribavirin.

CD4 lymphocytes decrease

Treatment with PegIntron in combination with ribavirin 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 PegIntron in combination with ribavirin had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N= 25) are available in co-infected patients with CD4+ cell counts < 200/µl (see section 4.4).

Please refer to the respective SmPCs 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 PegIntron in combination with ribavirin.

Paediatric population

Summary of the safety profile

In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of PegIntron and ribavirin, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with PegIntron and ribavirin, growth inhibition was observed that resulted in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and height percentile were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3rd percentile in 70 % of the patients).

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still of 3 percentiles and 7 percentiles respectively, and 20 % of the children continued to have inhibited growth (growth velocity < 3rd percentile). Ninety-four of 107 subjects enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow- up among subjects treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and

9.0 percentiles, respectively. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40 % of subjects (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of the 5 year long-term follow-up compared to pre-treatment baseline percentile. Eleven percent of subjects (5/46) treated for 24 weeks and 13 % of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight- for-age percentiles decreased 1.3 and 5.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy (see section 4.4).

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia

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

Tabulated summary of adverse reactions

The following treatment-related adverse reactions were reported in the study in children and adolescent patients treated with PegIntron in combination with ribavirin. These reactions are listed in Table 7 by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 7 Adverse reactions very commonly, commonly and uncommonly reported in the clinical trial in children and adolescent patients treated with PegIntron in combination with ribavirin

Infections and infestations

Common:

Fungal infection, influenza, oral herpes, otitis media, pharyngitis

 

streptococcal, nasopharyngitis, sinusitis

Uncommon:

Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis, urinary tract

 

infection, gastroenteritis

Blood and lymphatic system disorders

 

 

Very common:

Anaemia, leucopenia, neutropenia

Common:

Thrombocytopenia, lymphadenopathy

Endocrine disorders

 

Common:

Hypothyroidism

Metabolism and nutrition disorders

Very common:

Anorexia, decreased appetite

 

 

Psychiatric disorders

 

Common:

Suicidal ideation§, suicide attempt§, depression, aggression, affect lability,

 

anger, agitation, anxiety, mood altered, restlessness, nervousness, insomnia

 

 

Uncommon:

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

Nervous system disorders

Very common:

Headache, dizziness

Common:

Dysgeusia, syncope, disturbance in attention, somnolence, poor quality

 

sleep

 

 

Uncommon:

Neuralgia, lethargy, paraesthesia, hypoaesthesia, psychomotor

 

hyperactivity, tremor

Eye disorders

 

Common:

Eye pain

Uncommon:

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

 

 

Ear and labyrinth disorders

Common:

Vertigo

Cardiac disorders

 

Common:

Palpitations, tachycardia

Vascular disorders

 

Common:

Flushing

Uncommon:

Hypotension, pallor

Respiratory, thoracic and mediastinal disorders

Common:

Cough, epistaxis, pharyngolaryngeal pain

 

 

Uncommon:

Wheezing, nasal discomfort, rhinorrhoea

Gastrointestinal disorders

Very common:

Abdominal pain, abdominal pain upper, vomiting, nausea

Common:

Diarrhoea, aphthous stomatitis, cheilosis, mouth ulceration, stomach

 

discomfort, oral pain

 

 

Uncommon:

Dyspepsia, gingivitis

 

 

Hepatobiliary disorders

 

Uncommon:

Hepatomegaly

Skin and subcutaneous tissue disorders

Very common:

Alopecia, dry skin

Common:

Pruritus, rash, rash erythematous, eczema, acne, erythema

 

 

Uncommon:

Photosensitivity reaction, rash maculo-papular, skin exfoliation,

 

pigmentation disorder, dermatitis atopic, skin discolouration

Musculoskeletal and connective tissue disorders

Very common:

Myalgia, arthralgia

Common:

Musculoskeletal pain, pain in extremity, back pain

Uncommon:

Muscle contracture, muscle twitching

Renal and urinary disorders

 

 

Uncommon:

Proteinuria

Reproductive system and breast disorders

Uncommon:

Female: Dysmenorrhoea

 

 

General disorders and administration site conditions

Very common:Injection site erythema, fatigue, pyrexia, rigors, influenza-like illness, asthenia, pain, malaise, irritability

Common:

Injection site reaction, injection site pruritus, injection site rash injection

 

site dryness, injection site pain, feeling cold

Uncommon:

Chest pain, chest discomfort, facial pain

Investigations

 

 

 

Very common:

Growth rate decrease (height and/or weight decrease for age)

Common:

Blood thyroid stimulating hormone increased, thyroglobulin increased

Uncommon:

Anti-thyroid antibody positive

Injury and poisoning

Uncommon:Contusion

§class effect of interferon-alfa containing products – reported with standard interferon therapy in adult and paediatric patients; with PegIntron reported in adult patients.

Description of selected adverse reactions in children and adolescents

Most of the changes in laboratory values in the PegIntron/ribavirin clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2). While changes in laboratory values were observed in some patients treated with PegIntron used in combination with ribavirin in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.

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.

4.9Overdose

Doses up to 10.5 times the intended dose have been reported. The maximum daily dose reported is 1,200 µg for one day. In general, the adverse events seen in overdose cases involving PegIntron are consistent with the known safety profile for PegIntron; however, the severity of the events may be increased. Standard methods to increase elimination of the medicinal product, e.g., dialysis, have not been shown to be useful. No specific antidote for PegIntron is available; therefore, symptomatic

treatment and close observation of the patient are recommended in cases of overdose. If available, prescribers are advised to consult with a poison control centre (PCC).

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB10.

Recombinant interferon alfa-2b is covalently conjugated with monomethoxy polyethylene glycol at an average degree of substitution of 1 mole of polymer/mole of protein. The average molecular mass is approximately 31,300 daltons of which the protein moiety constitutes approximately 19,300.

Mechanism of action

In vitro and in vivo studies suggest that the biological activity of PegIntron is derived from its interferon alfa-2b moiety.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Studies with other interferons have demonstrated species specificity. However, certain monkey species, e.g., Rhesus monkeys are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.

Once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that this process, at least in part, is responsible for the various cellular responses to interferon, including inhibition of virus replication in virus- infected cells, suppression of cell proliferation and such immunomodulating activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities may contribute to interferon’s therapeutic effects.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are unable to leave the cell.

Pharmacodynamic effects

PegIntron pharmacodynamics were assessed in a rising single-dose trial in healthy subjects by examining changes in oral temperature, concentrations of effector proteins such as serum neopterin and 2’5’- oligoadenylate synthetase (2’5’-OAS), as well as white cell and neutrophil counts. Subjects treated with PegIntron showed mild dose-related elevations in body temperature. Following single doses of PegIntron between 0.25 and 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-related manner. Neutrophil and white cell count reductions at the end of week 4 correlated with the dose of PegIntron.

Clinical efficacy and safety – Adults

Tritherapy with PegIntron, ribavirin and boceprevir

Refer to the SmPC for boceprevir.

Monotherapy with PegIntron and bitherapy with PegIntron and ribavirin Naïve patients

Two pivotal trials have been conducted, one (C/I97-010) with PegIntron monotherapy; the other (C/I98-580) with PegIntron in combination with ribavirin. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction (PCR) assay (> 30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

In the PegIntron monotherapy trial, a total of 916 naïve chronic hepatitis C patients were treated with PegIntron (0.5, 1.0 or 1.5 micrograms/kg/week) for one year with a follow-up period of six months. In addition, 303 patients received interferon alfa-2b (3 million International Units [MIU] three times a week) as a comparator. This study showed that PegIntron was superior to interferon alfa-2b (Table 8).

In the PegIntron combination trial, 1,530 naïve patients were treated for one year with one of the following combination regimens:

-PegIntron (1.5 micrograms/kg/week) + ribavirin (800 mg/day), (n = 511).

-PegIntron (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) + ribavirin (1,000/1,200 mg/day), (n = 514).

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

In this trial, the combination of PegIntron (1.5 micrograms/kg/week) and ribavirin was significantly more effective than the combination of interferon alfa-2b and ribavirin (Table 8), particularly in patients infected with Genotype 1 (Table 9). Sustained response was assessed by the response rate six months after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of ribavirin administered in combination with PegIntron or interferon alfa-2b. In those patients that received

> 10.6 mg/kg ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received 10.6 mg/kg ribavirin (Table 9), while response rates in patients that received > 13.2 mg/kg ribavirin were even higher.

Table 8

Sustained virological response (% patients HCV negative)

 

 

 

 

 

PegIntron monotherapy

PegIntron + ribavirin

Treatment regimen

 

P 1.5

P 1.0

P 0.5

I

P 1.5/R

P 0.5/R

I/R

Number of patients

 

Response at end of treatment

 

49 %

41 %

33 %

24 %

65 %

56 %

54 %

Sustained response

 

23 %*

25 %

18 %

12 %

54 %**

47 %

47 %

P 1.5

PegIntron 1.5 micrograms/kg

 

 

 

 

 

 

P 1.0

PegIntron 1.0 microgram/kg

 

 

 

 

 

 

P 0.5

PegIntron 0.5 microgram/kg

 

 

 

 

 

 

I

Interferon alfa-2b 3 MIU

 

 

 

 

 

 

 

P 1.5/R

PegIntron (1.5 micrograms/kg) + ribavirin (800 mg)

 

 

 

 

P 0.5/R

PegIntron (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg)

 

 

 

I/R

Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg)

 

 

 

 

*

p < 0.001 P 1.5 vs. I

 

 

 

 

 

 

 

**p = 0.0143 P 1.5/R vs. I/R

Table 9 Sustained response rates with PegIntron + ribavirin (by ribavirin dose, genotype and viral load)

HCV Genotype

Ribavirin dose

P 1.5/R

P 0.5/R

I/R

 

(mg/kg)

 

 

 

All Genotypes

All

54 %

47 %

47 %

 

10.6

50 %

41 %

27 %

 

> 10.6

61 %

48 %

47 %

Genotype 1

All

42 %

34 %

33 %

 

10.6

38 %

25 %

20 %

 

> 10.6

48 %

34 %

34 %

Genotype 1

All

73 %

51 %

45 %

600,000 IU/ml

10.6

74 %

25 %

33 %

 

> 10.6

71 %

52 %

45 %

Genotype 1

All

30 %

27 %

29 %

> 600,000 IU/ml

10.6

27 %

25 %

17 %

 

> 10.6

37 %

27 %

29 %

HCV Genotype

Ribavirin dose

P 1.5/R

P 0.5/R

I/R

 

 

(mg/kg)

 

 

 

All

82 %

80 %

79 %

 

 

10.6

79 %

73 %

50 %

 

 

> 10.6

88 %

80 %

80 %

P 1.5/R

PegIntron (1.5 micrograms/kg) + ribavirin (800 mg)

 

 

P 0.5/R

PegIntron (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg)

 

 

I/R

Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg)

 

 

In the PegIntron monotherapy study, the Quality of Life was generally less affected by

0.5 microgram/kg of PegIntron than by either 1.0 microgram/kg of PegIntron once weekly or 3 MIU of interferon alfa-2b three times a week.

In a separate trial, 224 patients with genotype 2 or 3 received PegIntron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with ribavirin 800 mg –1,400 mg p.o. for 6 months (based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose) (Table 10). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).

Table 10 Virologic response at end of treatment, Sustained Virologic Response and relapse by HCV Genotype and viral load*

 

PegIntron 1.5 g/kg once weekly plus Ribavirin 800-1,400 mg/day

 

End of treatment

Sustained Virologic Response

Relapse

 

response

 

 

All subjects

94 % (211/224)

81 % (182/224)

12 % (27/224)

HCV 2

100 % (42/42)

93 % (39/42)

7 % (3/42)

600,000 IU/ml

100 % (20/20)

95 % (19/20)

5 % (1/20)

> 600,000 IU/ml

100 % (22/22)

91 % (20/22)

9 % (2/22)

HCV 3

93 % (169/182)

79 % (143/182)

14 % (24/166)

600,000 IU/ml

93 % (92/99)

86 % (85/99)

8 % (7/91)

> 600,000 IU/ml

93 % (77/83)

70 % (58/83)

23 % (17/75)

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window was considered to be a non-responder at week 24 of follow-up.

The 6 month treatment duration in this trial was better tolerated than one year of treatment in the pivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %.

In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml) received PegIntron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. The overall sustained response rate after a 24-week treatment duration was 50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis (n=49) and prospectively confirmed (n=48).

Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two PegIntron/ribavirin regimens [PegIntron 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both in combination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] and peginterferon alfa- 2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 11).

Table 11 Virologic response at treatment week 12, end of treatment response, relapse rate *and Sustained Virologic Response (SVR)

Treatment group

 

% (number) of patients

 

 

PegIntron 1.5 µg/kg +

PegIntron 1 µg/kg +

peginterferon alfa-2a

 

ribavirin

ribavirin

180 µg + ribavirin

Undetectable HCV-

 

 

 

RNA at treatment

40 (407/1,019)

36 (366/1,016)

45 (466/1,035)

week 12

 

 

 

End of treatment

53 (542/1,019)

49 (500/1,016)

64 (667/1,035)

response

 

 

 

Relapse

24 (123/523)

20 (95/475)

32 (193/612)

SVR

40 (406/1,019)

38 (386/1,016)

41 (423/1,035)

SVR in patients with

 

 

 

undetectable HCV-

81 (328/407)

83 (303/366)

74 (344/466)

RNA at treatment

 

 

 

week 12

 

 

 

* (HCV-RNA PCR assay, with

a lower limit of quantitation of 27

IU/ml)

 

Lack of early virologic response by Treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from baseline) was a criterion for discontinuation of treatment.

In all three treatment groups, sustained virologic response rates were similar. In patients of African American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with PegIntron (1.5 µg/kg)/ribavirin combination therapy resulted in a higher sustained virologic response rate compared to PegIntron 1 µg/kg dose. At the PegIntron 1.5 µg/kg plus ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml, and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse rate was 24 %.

Predictability of sustained virological response – Naïve patients: Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels of HCV-RNA. Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have been shown to be predictive for sustained response (Table 12).

Table 12 Predictive value of in-treatment Virologic Response while on PegIntron 1.5 µg/kg/ribavirin 800-1,400 mg combination therapy

 

 

Negative

 

 

Positive

 

 

No

 

 

 

 

 

 

response

 

 

Response

 

 

 

at

No

Negative

at

 

Positive

 

treatment

sustained

predictive

treatment

Sustained

predictive

 

week

response

value

week

response

value

Genotype 1*

 

 

 

 

 

 

By week 4***

 

 

 

 

 

 

(n=950)

 

 

 

 

 

 

HCV-RNA negative

65 %

92 %

 

 

 

(539/834)

 

 

(107/116)

HCV-RNA negative

95 %

54 %

or

 

 

(210/220)

 

 

(392/730)

≥ 1 log decrease

 

 

 

 

 

 

in viral load

 

 

 

 

 

 

 

 

 

 

 

 

 

By week 12***

 

 

 

 

 

 

(n=915)

 

 

 

 

 

 

HCV-RNA negative

85 %

81 %

 

 

 

(433/508)

 

 

(328/407)

 

 

Negative

 

 

Positive

 

 

No

 

 

 

 

 

 

response

 

 

Response

 

 

 

at

No

Negative

at

 

Positive

 

treatment

sustained

predictive

treatment

Sustained

predictive

 

week

response

value

week

response

value

HCV-RNA negative

N/A

57 %

or

 

 

 

 

 

(402/709)

≥ 2 log decrease in

 

 

 

 

 

 

viral load

 

 

 

 

 

 

Genotype 2, 3**

 

 

 

 

 

 

 

 

 

 

 

 

 

By week 12

 

 

 

 

 

 

(n= 215)

 

 

 

 

 

 

HCV-RNA negative

50 %

83 %

or

 

 

(1/2)

 

 

(177/213)

≥ 2 log decrease in

 

 

 

 

 

 

viral load

 

 

 

 

 

 

*Genotype 1 receive 48 weeks treatment **Genotype 2, 3 receive 24 weeks treatment

***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 or week 12.

These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2log10 decrease from baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2log10 from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

The negative predictive value for sustained response in patients treated with PegIntron in monotherapy was 98 %.

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 13. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either PegIntron (1.5 µg/kg/week) plus ribavirin (800 mg/day) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800 mg/day) for

48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either PegIntron (100 or 150 µg/week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load

< 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

Table 13 Sustained virological response based on genotype after PegIntron in combination with Ribavirin in HCV/HIV Co-infected patients

 

 

Study 11

 

 

Study 22

 

 

 

 

 

PegIntron

Interferon

 

 

PegIntron

Interferon

 

(100 or

alfa-2b

 

 

(1.5 µg/kg/

alfa-2b

 

150c µg/week)

(3 MIU TIW)

 

 

week) +

(3 MIU TIW) +

 

+ ribavirin

+ ribavirin

 

 

ribavirin

ribavirin

p

(800-

(800-

p

 

(800 mg)

(800 mg)

valuea

1,200 mg)d

1,200 mg)d

valueb

All

27 % (56/205)

20 % (41/205)

0.047

44 % (23/52)

21 % (9/43)

0.017

Genotype 1,

17 % (21/125)

6 % (8/129)

0.006

38 % (12/32)

7 % (2/27)

0.007

 

 

 

 

 

 

Genotype 2,

44 % (35/80)

43 % (33/76)

0.88

53 % (10/19)

47 % (7/15)

0.730

 

 

 

 

 

 

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

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

b:p value based on chi-square test.

c:subjects < 75 kg received 100 µg/week PegIntron and subjects ≥ 75 kg received 150 µg/week PegIntron.

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

1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848. 2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

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

PegIntron/ribavirin retreatment of prior treatment failures

In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with PegIntron,

1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of treatment).

Patients who were HCV-RNA negative at treatment week 12 continued treatment for 48 weeks and were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV-RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable HCV-RNA at 24 weeks post-treatment (Table 14).

Table 14

Rates of response to retreatment in prior treatment failures

 

 

 

 

 

Patients with undetectable HCV–RNA

 

 

 

 

 

at treatment week 12 and SVR upon retreatment

 

 

 

 

 

 

 

 

 

 

 

Overall

 

 

interferon alpha/ribavirin

peginterferon alpha/ribavirin

population*

 

 

Response

SVR % (n/N)

Response

SVR % (n/N)

SVR % (n/N)

 

 

week 12 %

99% CI

week 12 %

99% CI

99 % CI

 

 

(n/N)

 

 

(n/N)

 

 

 

 

Overall

 

38.6

59.4

 

31.5

 

50.4

 

21.7

 

 

 

(549/1,423)

(326/549)

(272/863)

(137/272)

(497/2,293)

 

 

 

54.0,64.8

 

 

42.6, 58.2

19.5, 23.9

Prior response

 

 

 

 

 

 

 

 

 

Relapse

 

67.7 (203/300)

59.6

 

58.1

 

52.5

 

37.7 (243/645)

 

 

 

(121/203)

(200/344)

(105/200)

32.8, 42.6

 

 

 

50.7, 68.5

 

 

43.4, 61.6

 

 

59.7 (129/216)

51.2

(66/129)

48.6

 

44.3

(54/122)

28.6

(134/468)

 

 

 

39.8, 62.5

(122/251)

32.7, 55.8

23.3, 34.0

88.9 (72/81)

73.6

(53/72)

83.7

(77/92)

64.9

(50/77)

61.3

(106/173)

 

 

 

(60.2, 87.0)

 

 

50.9, 78.9

51.7, 70.8

NR

 

28.6 (258/903)

57.0

 

12.4

(59/476)

44.1

(26/59)

13.6

 

 

 

 

(147/258)

 

 

27.4, 60.7

(188/1,385)

 

 

 

49.0, 64.9

 

 

 

 

11.2, 15.9

23.0 (182/790)

51.6

(94/182)

9.9 (44/446)

38.6

(17/44)

9.9 (123/1,242)

 

 

 

42.1, 61.2

 

 

19.7, 57.5

7.7, 12.1

67.9 (74/109)

70.3

(52/74)

53.6

(15/28)

60.0

(9/15)

46.0

(63/137)

 

 

 

56.6, 84.0

 

 

27.4, 92.6

35.0, 57.0

Genotype

 

 

 

 

 

 

 

 

 

 

 

30.2

51.3

 

23.0

 

42.6

(69/162)

14.6

 

 

 

(343/1,135)

(176/343)

(162/704)

32.6, 52.6

(270/1,846)

 

 

 

44.4, 58.3

 

 

 

 

12.5, 16.7

 

77.1 (185/240)

73.0

 

75.6

(96/127)

63.5

(61/96)

55.3

(203/367)

 

 

 

(135/185)

 

 

50.9, 76.2

48.6, 62.0

 

 

 

64.6, 81.4

 

 

 

 

 

 

 

42.5 (17/40)

70.6

(12/17)

44.4

(12/27)

50.0

(6/12)

28.4

(19/67)

 

 

 

42.1, 99.1

 

 

12.8, 87.2

14.2, 42.5

METAVIR

 

 

 

 

 

 

 

 

 

 

Fibrosis score

 

 

 

 

 

 

 

 

 

F2

 

46.0 (193/420)

66.8

 

33.6

(78/232)

57.7

(45/78)

29.2

(191/653)

 

 

 

(129/193)

 

 

43.3, 72.1

24.7, 33.8

 

 

 

58.1, 75.6

 

 

 

 

 

 

F3

 

38.0 (163/429)

62.6

 

32.4

(78/241)

51.3

(40/78)

21.9

(147/672)

 

 

 

(102/163)

 

 

36.7, 65.9

17.8, 26.0

 

 

 

52.8, 72.3

 

 

 

 

 

 

F4

 

33.6 (192/572)

49.5

(95/192)

29.7

 

44.8

(52/116)

16.5

(159/966)

 

 

 

40.2, 58.8

(116/390)

32.9, 56.7

13.4, 19.5

Baseline Viral

 

 

 

 

 

 

 

 

 

Load

 

 

 

 

 

 

 

 

 

 

HVL

 

32.4 (280/864)

56.1

 

26.5

 

41.4

(63/152)

16.6

 

(>600,000 IU/ml)

 

(157/280)

(152/573)

31.2, 51.7

(239/1,441)

 

 

 

48.4, 63.7

 

 

 

 

14.1, 19.1

LVL

 

48.3 (269/557)

62.8

 

41.0

 

61.0

(72/118)

30.2

(256/848)

(≤600,000 IU/ml)

 

(169/269)

(118/288)

49.5, 72.6

26.1, 34.2

 

 

 

55.2, 70.4

 

 

 

 

 

 

NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment. Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory *Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed.

Overall, approximately 36 % (821/2,286) of patients had undetectable plasma HCV-RNA levels at week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In this subgroup, there was a 56 % (463/823) sustained virological response rate. For patients with prior failure on therapy with nonpegylated interferon or pegylated interferon and negative at week 12, the sustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log viral reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patients the SVR was 12 %.

Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a week 12 response to retreatment than non-responders to nonpegylated interferon alpha/ribavirin

(12.4 % vs. 28.6 %). However, if a week 12 response was achieved, there was little difference in SVR regardless of prior treatment or prior response.

Long-term efficacy data-Adults

A large long-term follow-up study enrolled 567 patients after treatment in a prior study with PegIntron (with or without ribavirin). The purpose of the study was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. 327 patients completed at least 5 years of long-term follow-up and only 3 out of 366 sustained responders relapsed during the study.

The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 99 %

(95 % CI: 98-100 %). SVR after treatment of chronic HCV with PegIntron (with or without ribavirin) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical “cure” from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

Clinical efficacy and safety – paediatric population

Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were enrolled in a multicentre trial and treated with ribavirin 15 mg/kg per day plus PegIntron 60 g/m2 once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 %

< 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of PegIntron with ribavirin needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 15.

Table 15 Sustained virological response rates (na,b (%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects n = 107

 

24 weeks

48 weeks

All Genotypes

26/27 (96 %)

44/80 (55 %)

Genotype 1

-

38/72 (53 %)

Genotype 2

14/15 (93 %)

-

Genotype 3c

12/12 (100 %)

2/3 (67 %)

Genotype 4

-

4/5 (80 %)

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

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

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

Long-term efficacy data - paediatric population

A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirin

treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustained responders completed the study. No paediatric subjects with SVR had relapsed during the 5 years of follow-up.

5.2Pharmacokinetic properties

PegIntron is a well characterized polyethylene glycol-modified (“pegylated”) derivative of interferon alfa-2b and is predominantly composed of monopegylated species. The plasma half-life of PegIntron is prolonged compared with nonpegylated interferon alfa-2b. PegIntron has a potential to depegylate to free interferon alfa-2b. The biologic activity of the pegylated isomers is qualitatively similar, but weaker than free interferon alfa-2b.

Following subcutaneous administration, maximal serum concentrations occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours post-dose.

PegIntron Cmax and AUC measurements increase in a dose-related manner. Mean apparent volume of distribution is 0.99 l/kg.

Upon multiple dosing, there is an accumulation of immunoreactive interferons. There is, however, only a modest increase in biologic activity as measured by a bioassay.

Mean (SD) PegIntron elimination half-life is approximately 40 hours (13.3 hours), with apparent clearance of 22.0 ml/hr/kg. The mechanisms involved in clearance of interferons in man have not yet been fully elucidated. However, renal elimination may account for a minority (approximately 30 %) of PegIntron apparent clearance.

Renal impairment

Renal clearance appears to account for 30 % of total clearance of PegIntron. In a single dose study (1.0 microgram/kg) in patients with impaired renal function, Cmax, AUC, and half-life increased in relation to the degree of renal impairment.

Following multiple dosing of PegIntron (1.0 microgram/kg subcutaneously administered every week for four weeks) the clearance of PegIntron is reduced by a mean of 17 % in patients with moderate renal impairment (creatinine clearance 30-49 ml/minute) and by a mean of 44 % in patients with severe renal impairment (creatinine clearance 15-29 ml/minute) compared to subjects with normal renal function. Based on single dose data, clearance was similar in patients with severe renal impairment not on dialysis and in patients who were receiving hemodialysis. The dose of PegIntron for monotherapy should be reduced in patients with moderate or severe renal impairment (see sections 4.2 and 4.4). Patients with creatinine clearance < 50 ml/minute must not be treated with PegIntron in combination with ribavirin (bitherapy or tritherapy) (see section 4.3).

Because of marked inter-subject variability in interferon pharmacokinetics, it is recommended that patients with severe renal impairment be closely monitored during treatment with PegIntron (see section 4.2)

Hepatic impairment

The pharmacokinetics of PegIntron have not been evaluated in patients with severe hepatic dysfunction.

Elderly ( 65 years of age)

The pharmacokinetics of PegIntron following a single subcutaneous dose of 1.0 microgram/kg were not affected by age. The data suggest that no alteration in PegIntron dosage is necessary based on advancing age.

Paediatric population

Multiple-dose pharmacokinetic properties for PegIntron and ribavirin (capsules and oral solution) in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study.

In children and adolescent patients receiving body surface area-adjusted dosing of PegIntron at

60 g/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 g/kg/week.

Interferon neutralising factors

Interferon neutralising factor assays were performed on serum samples of patients who received PegIntron in the clinical trial. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors in patients who received

PegIntron 0.5 micrograms/kg is 1.1 %.

Transfer into seminal fluid

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

5.3Preclinical safety data

PegIntron

Adverse events not observed in clinical trials were not seen in toxicity studies in monkeys. These studies were limited to four weeks due to the appearance of anti-interferon antibodies in most monkeys.

Reproduction studies of PegIntron have not been performed. Interferon alfa-2b has been shown to be an abortifacient in primates. PegIntron is likely to also cause this effect. Effects on fertility have not been determined. It is not known whether the components of this medicinal product are excreted into experimental animal or human milk (see section 4.6 for relevant human data on pregnancy and lactation). PegIntron showed no genotoxic potential.

The relative non-toxicity of monomethoxy-polyethylene glycol (mPEG), which is liberated from PegIntron by metabolism in vivo has been demonstrated in preclinical acute and subchronic toxicity studies in rodents and monkeys, standard embryo-foetal development studies and in in vitro mutagenicity assays.

PegIntron plus ribavirin

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

No studies have been conducted in juvenile animals to examine the effects of treatment with PegIntron on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin (see section 5.3 of Rebetol SmPC if PegIntron is to be administered in combination with ribavirin).

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Powder

Disodium phosphate, anhydrous

Sodium dihydrogen phosphate dihydrate

Sucrose

Polysorbate 80

Solvent

Water for injections

6.2Incompatibilities

This medicinal product should only be reconstituted with the solvent provided (see section 6.6). In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3Shelf life

Before reconstitution 3 years.

After reconstitution

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8ºC.

From a microbiological point of view, the product is to be used immediately. If not used immediately, in- use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C.

6.4Special precautions for storage

Store in a refrigerator (2°C - 8°C).

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5Nature and contents of container

The powder is contained in a 2 ml vial (Type I flint glass) with a butyl rubber stopper in an aluminium flip-off seal with a polypropylene bonnet. The solvent is presented in a 2 ml ampoule (Type I flint glass).

PegIntron is supplied as:

-1 vial of powder for solution for injection and 1 ampoule of solvent for parenteral use;

-1 vial of powder for solution for injection, 1 ampoule of solvent for parenteral use, 1 injection syringe, 2 injection needles and 1 cleansing swab;

-4 vials of powder for solution for injection and 4 ampoules of solvent for parenteral use;

-4 vials of powder for solution for injection, 4 ampoules of solvent for parenteral use, 4 injection syringes, 8 injection needles and 4 cleansing swabs;

-6 vials of powder for solution for injection and 6 ampoules of solvent for parenteral use.

-12 vials of powder for solution for injection, 12 ampoules of solvent for parenteral use, 12 injection syringes, 24 injection needles and 12 cleansing swabs.

Not all pack sizes may be marketed.

6.6Special precautions for disposal and other handling

PegIntron 50 micrograms powder and solvent for solution for injection

Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 50 micrograms/0.5 ml.

PegIntron 80 micrograms powder and solvent for solution for injection

Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 80 micrograms/0.5 ml.

PegIntron 100 micrograms powder and solvent for solution for injection

Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 100 micrograms/0.5 ml.

PegIntron 120 micrograms powder and solvent for solution for injection

Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 120 micrograms/0.5 ml.

PegIntron 150 micrograms powder and solvent for solution for injection

Each vial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each vial contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 150 micrograms/0.5 ml.

Using a sterilised injection syringe and injection needle, 0.7 ml of water for injections is injected into the vial of PegIntron. Dissolution of powder is completed by agitating it gently. The appropriate dose can then be withdrawn with a sterilised injection syringe and injected. A complete set of instructions is provided in the Annex to the Package Leaflet.

As for all parenteral medicinal products, the reconstituted solution is to be inspected visually prior to administration. The reconstituted solution should be clear and colourless. If discolouration or particulate matter is present, the reconstituted solution should not be used. Any unused material is to be discarded.

7.MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8.MARKETING AUTHORISATION NUMBERS

PegIntron 50 micrograms powder and solvent for solution for injection

EU/1/00/131/001

EU/1/00/131/002

EU/1/00/131/003

EU/1/00/131/004

EU/1/00/131/005

EU/1/00/131/026

PegIntron 80 micrograms powder and solvent for solution for injection

EU/1/00/131/006

EU/1/00/131/007

EU/1/00/131/008

EU/1/00/131/009

EU/1/00/131/010

EU/1/00/131/027

PegIntron 100 micrograms powder and solvent for solution for injection

EU/1/00/131/011

EU/1/00/131/012

EU/1/00/131/013

EU/1/00/131/014

EU/1/00/131/015

EU/1/00/131/028

PegIntron 120 micrograms powder and solvent for solution for injection

EU/1/00/131/016

EU/1/00/131/017

EU/1/00/131/018

EU/1/00/131/019

EU/1/00/131/020

EU/1/00/131/029

PegIntron 150 micrograms powder and solvent for solution for injection

EU/1/00/131/021

EU/1/00/131/022

EU/1/00/131/023

EU/1/00/131/024

EU/1/00/131/025

EU/1/00/131/030

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 May 2000

Date of latest renewal: 25 May 2010

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the web-site of the European Medicines Agency http://www.ema.europa.eu.

1.NAME OF THE MEDICINAL PRODUCT

PegIntron 50 micrograms powder and solvent for solution for injection in pre-filled pen PegIntron 80 micrograms powder and solvent for solution for injection in pre-filled pen PegIntron 100 micrograms powder and solvent for solution for injection in pre-filled pen PegIntron 120 micrograms powder and solvent for solution for injection in pre-filled pen PegIntron 150 micrograms powder and solvent for solution for injection in pre-filled pen

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

PegIntron 50 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 50 micrograms of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 50 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

PegIntron 80 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 80 micrograms of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 80 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

PegIntron 100 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 100 micrograms of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 100 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

PegIntron 120 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 120 micrograms of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 120 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

PegIntron 150 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen contains 150 micrograms of peginterferon alfa-2b as measured on a protein basis. Each pre-filled pen provides 150 micrograms/0.5 ml of peginterferon alfa-2b when reconstituted as recommended.

The active substance is a covalent conjugate of recombinant interferon alfa-2b* with monomethoxy polyethylene glycol. The potency of this product should not be compared to that of another pegylated or non-pegylated protein of the same therapeutic class (see section 5.1).

*produced by rDNA technology in E. coli cells harbouring a genetically engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.

Excipients with known effect:

Each pre-filled pen contains 40 mg of sucrose per 0.5 ml.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Powder and solvent for solution for injection in pre-filled pen.

White powder.

Clear and colourless solvent.

4.CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults (tritherapy)

PegIntron in combination with ribavirin and boceprevir (tritherapy) is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adult patients (18 years of age and older) with compensated liver disease who are previously untreated or who have failed previous therapy (see section 5.1).

Please refer to the ribavirin and boceprevir Summary of Product Characteristics (SmPCs) when PegIntron is to be used in combination with these medicines.

Adults (bitherapy and monotherapy)

PegIntron is indicated for the treatment of adult patients (18 years of age and older) with CHC who are positive for hepatitis C virus RNA (HCV-RNA), including patients with compensated cirrhosis and/or co-infected with clinically stable HIV (see section 4.4).

PegIntron in combination with ribavirin (bitherapy) is indicated for the treatment of CHC infection in adult patients who are previously untreated including patients with clinically stable HIV co-infection and in adult patients who have failed previous treatment with interferon alpha (pegylated or nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy (see section 5.1).

Interferon monotherapy, including PegIntron, is indicated mainly in case of intolerance or contraindication to ribavirin.

Please refer to the ribavirin SmPC when PegIntron is to be used in combination with ribavirin.

Paediatric population (bitherapy)

PegIntron is indicated in a combination regimen with ribavirin for the treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C, previously untreated, without liver decompensation, and who are positive for HCV-RNA.

When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case basis (see section 4.4).

Please refer to the ribavirin SmPC for capsules or oral solution when PegIntron is to be used in combination with ribavirin.

4.2 Posology and method of administration

Treatment should be initiated and monitored only by a physician experienced in the management of patients with hepatitis C.

Posology

PegIntron should be administered as a once weekly subcutaneous injection. The dose administered in adults depends on whether it is used in combination therapy (bitherapy or tritherapy) or as monotherapy.

PegIntron combination therapy (bitherapy or tritherapy)

Bitherapy (PegIntron with ribavirin): applies to all adult and paediatric patients 3 years of age and older.

Tritherapy (PegIntron with ribavirin and boceprevir): applies to adult patients with genotype 1 CHC.

Adults – Dose to be administered

PegIntron 1.5 micrograms/kg/week in combination with ribavirin capsules.

The intended dose of 1.5 µg/kg of PegIntron to be used in combination with ribavirin may be delivered in weight categories with the PegIntron strengths according to Table 1. Ribavirin capsules are to be administered orally each day in two divided doses with food (morning and evening).

Table 1

Dosing for combination therapy*

 

 

Body weight

PegIntron

Ribavirin capsules

(kg)

 

PegIntron strength

Administer once

Total daily

Number of

 

 

(µg/0.5 ml)

weekly

ribavirin dose

capsules

 

 

 

(ml)

(mg)

(200 mg)

< 40

 

0.5

4a

40-50

 

0.4

4a

51-64

 

0.5

4a

65-75

 

0.5

1,000

5b

76-80

 

0.5

1,000

5b

81-85

 

0.5

1,200

6c

86-105

 

0.5

1,200

6c

> 105

 

0.5

1,400

7d

a:2 morning, 2 evening

b:2 morning, 3 evening

c:3 morning, 3 evening

d:3 morning, 4 evening

* Refer to the SmPC of boceprevir for details about the dose of boceprevir to be administered in tritherapy.

Adults - Duration of treatment – Naïve patients

Tritherapy: Refer to the SmPC for boceprevir.

Bitherapy: Predictability of sustained virological response - Patients infected with virus genotype 1 who fail to achieve undetectable HCV-RNA or demonstrate adequate virological response at week 4 or 12 are highly unlikely to become sustained virological responders and should be evaluated for discontinuation (see also section 5.1).

Genotype 1:

-Patients who have undetectable HCV-RNA at treatment week 12, treatment should be continued for another nine month period (i.e., a total of 48 weeks).

-Patients with detectable but ≥ 2 log decrease in HCV-RNA level from baseline at treatment week 12 should be reassessed at treatment week 24 and, if HCV-RNA is undetectable, they should continue with full course of therapy (i.e. a total of 48 weeks). However, if HCV-RNA is still detectable at treatment week 24, discontinuation of therapy should be considered.

-In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml) who become HCV-RNA negative at treatment week 4 and remain HCV-RNA negative at week 24, the treatment could either be stopped after this 24 week treatment course or pursued for an additional 24 weeks (i.e. overall 48 weeks treatment duration). 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).

Genotypes 2 or 3:

It is recommended that all patients be treated with bitherapy for 24 weeks, except for HCV/HIV co-infected patients who should receive 48 weeks of treatment.

Genotype 4:

In general, patients infected with genotype 4 are considered harder to treat and limited study data (n=66) indicate they are compatible with a duration of treatment with bitherapy as for genotype 1.

Adults - Duration of treatment - HCV/HIV co-infection

Bitherapy: The recommended duration of treatment for HCV/HIV co-infected patients is 48 weeks with bitherapy, regardless of genotype.

Predictability of response and non-response in HCV/HIV co-infection - 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. The negative predictive value for sustained response in HCV/HIV co-infected patients treated with PegIntron in combination with ribavirin was 99 % (67/68; Study 1) (see section 5.1). A positive predictive value of 50 % (52/104; Study 1) was observed for HCV/HIV co-infected patients receiving bitherapy.

Adults - Duration of treatment - Retreatment

Tritherapy: Refer to the SmPC for boceprevir.

Bitherapy: Predictability of sustained virological response - All patients, irrespective of genotype, who have demonstrated serum HCV-RNA below the limits of detection at week 12 should receive

48 weeks of bitherapy. Retreated patients who fail to achieve virological response (i.e. HCV-RNA below the limits of detection) at week 12 are unlikely to become sustained virological responders after 48 weeks of therapy (see also section 5.1).

Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not been studied with pegylated interferon alfa-2b and ribavirin combination therapy.

Paediatric population (bitherapy only) – Dose to be administered

Dosing for children 3 years of age and older and adolescent patients is determined by body surface area for PegIntron and by body weight for ribavirin. The recommended dose of PegIntron is

60 g/m2/week subcutaneously in combination with ribavirin 15 mg/kg/day orally in two divided doses with food (morning and evening).

Paediatric population (bitherapy only) - Duration of treatment

Genotype 1:

The recommended duration of treatment with bitherapy is 1 year. By extrapolation from clinical data on combination therapy with standard interferon in paediatric patients (negative predictive value 96 % for interferon alfa–2b/ribavirin), patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders. Therefore, it is recommended that children and adolescent patients receiving PegIntron/ribavirin combination

be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment or if they have detectable HCV-RNA at treatment week 24.

Genotype 2 or 3:

The recommended duration of treatment with bitherapy is 24 weeks.

Genotype 4:

Only 5 children and adolescents with Genotype 4 were treated in the PegIntron/ribavirin clinical trial. The recommended duration of treatment with bitherapy is 1 year. It is recommended that children and adolescent patients receiving PegIntron/ribavirin combination be discontinued

from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment or if they have detectable HCV-RNA at treatment week 24.

PegIntron monotherapy – Adults Dose to be administered

As monotherapy the PegIntron regimen is 0.5 or 1.0 µg/kg/week. The lowest PegIntron strength available is 50 µg/0.5 ml; therefore for patients prescribed 0.5 µg/kg/week, doses must be adjusted by volume as shown in Table 2. For the 1.0 µg/kg dose, similar volume adjustments can be made or alternate strengths can be used as shown in Table 2. PegIntron monotherapy was not studied in HCV/HIV co-infected patients.

Table 2

Monotherapy dosing

 

 

 

 

 

0.5 µg/kg

1.0 µg/kg

Body weight

PegIntron

Administer once

PegIntron

Administer once

(kg)

 

strength

weekly

strength

weekly

 

 

(µg/0.5 ml)

(ml)

(µg/0.5 ml)

(ml)

30-35

 

50*

0.15

0.2

36-45

 

0.2

0.4

46-56

 

0.25

0.5

57-72

 

0.2

0.4

73-88

 

0.4

0.5

89-106

 

0.5

0.5

107-120**

 

0.4

0.5

Minimum delivery for pen is 0.2 ml.

*Must use vial.

**For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes.

Duration of treatment

For patients who exhibit virological response at week 12, treatment should be continued for at least another three-month period (i.e., a total of six months). The decision to extend therapy to one year of treatment should be based on prognostic factors (e.g., genotype, age > 40 years, male gender, bridging fibrosis).

Dose modification for all patients (monotherapy and combination therapy)

If severe adverse reactions or laboratory abnormalities develop during treatment with PegIntron monotherapy or combination therapy, the dosages of PegIntron and/or ribavirin must be modified as appropriate, until the adverse reactions abate. Dose reduction of boceprevir is not recommended. Boceprevir must not be administered in the absence of PegIntron and ribavirin.

As adherence might be of importance for outcome of therapy, the dose of PegIntron and ribavirin should be kept as close as possible to the recommended standard dose. Guidelines were developed in clinical trials for dose modification.

Combination therapy dose reduction guidelines

Table 2a Dose modification guidelines for combination therapy based on laboratory parameters

Laboratory values

Reduce only ribavirin

Reduce only PegIntron

Discontinue

 

daily dose (see note 1)

dose (see note 2) if:

combination therapy

 

if:

 

if:

Haemoglobin

≥ 8.5 g/dl, and

-

< 8.5 g/dl

 

< 10 g/dl

 

 

Adults: Haemoglobin

2 g/dl decrease in haemoglobin during any

 

in Patients with history

< 12 g/dl after four

of stable cardiac

four week period during treatment

weeks of dose

disease

(permanent dose reduction)

reduction

Children and

 

 

 

adolescents: not

 

 

 

applicable

 

 

 

Leukocytes

-

≥ 1.0 x 109/l, and

< 1.0 x 109/l

 

 

< 1.5 x 109/l

 

Neutrophils

-

≥ 0.5 x 109/l, and

< 0.5 x 109/l

 

 

< 0.75 x 109/l

 

Laboratory values

Reduce only ribavirin

Reduce only PegIntron

Discontinue

 

daily dose (see note 1)

dose (see note 2) if:

combination therapy

 

if:

 

if:

Platelets

-

≥ 25 x 109/l, and

< 25 x 109/l (adults)

 

 

< 50 x 109/l (adults)

< 50 x 109/l (children

 

 

≥ 50 x 109/l, and

and adolescents)

 

 

<70 x 109/l (children and

 

 

 

adolescents)

 

Bilirubin – direct

-

-

2.5 x ULN*

Bilirubin – indirect

> 5 mg/dl

-

> 4 mg/dl

 

 

 

(for > 4 weeks)

Serum Creatinine

-

-

> 2.0 mg/dl

Creatinine Clearance

-

-

Discontinue ribavirin

 

 

 

if CrCL < 50ml/min

Alanine

-

-

2 x baseline and

aminotransferase

 

 

> 10 x ULN*

(ALT)

 

 

 

or

 

 

2 x baseline and

Aspartate

 

 

> 10 x ULN*

aminotransferase

 

 

 

(AST)

 

 

 

*Upper limit of normal

Note 1: In adult patients 1st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to

600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.

In children and adolescent patients 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dose reduction of ribavirin is to 8 mg/kg/day.

Note 2: In adult patients 1st dose reduction of PegIntron is to 1 µg/kg/week. If needed, 2nd dose reduction of PegIntron is to 0.5 µg/kg/week. For patients on PegIntron monotherapy: refer to monotherapy dose reduction guidelines section for dose reduction.

In children and adolescent patients 1st dose reduction of PegIntron is to 40 g/m2/week, 2nd dose reduction of PegIntron is to 20 g/m2/week.

Dose reduction of PegIntron in adults may be accomplished by reducing the prescribed volume or by utilizing a lower dose strength as shown in Table 2b. Dose reduction of PegIntron in children and adolescents is accomplished by modifying the recommended dose in a two-step process from the original starting dose of 60 g/m2/week, to 40 g/m2/week, then to 20 g/m2/week, if needed.

Table 2b Two-step dose reduction of PegIntron in combination therapy in adults

First dose reduction to PegIntron 1 µg/kg

 

Second dose reduction to PegIntron 0.5 µg/kg

Body

PegIntron

Amount of

 

Volume of

Body

PegIntron

Amount of

Volume of

weight

strength

PegIntron

 

PegIntron

weight

strength

PegIntron

PegIntron

(kg)

(µg/0.5 ml)

to

 

to

(kg)

(µg/0.5 ml)

to

to

 

 

administer

 

administer

 

 

administer

administer

 

 

(µg)

 

(ml)

 

 

(µg)

(ml)

< 40

 

0.35

< 40

0.2

40 – 50

 

0.2

40 – 50

0.25

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

51 – 64

 

0.35

51 – 64

0.2

 

 

 

 

 

 

 

65 – 75

 

0.35

65 – 75

0.35

 

 

 

 

 

 

 

 

 

 

 

76 – 85

 

0.5

76 – 85

0.2

 

 

 

 

 

 

 

 

86 - 105

 

0.4

86 – 105

0.5

 

 

 

 

 

 

 

 

 

> 105

 

0.35

> 105

0.4

PegIntron monotherapy dose reduction guidelines in adults

 

 

 

Dose modification guidelines for adult patients who use PegIntron monotherapy are shown in

Table 3a.

Table 3a Dose modification guidelines for PegIntron monotherapy in adults based on laboratory parameters

Laboratory values

Reduce PegIntron

Discontinue PegIntron if:

 

to one-half dose if:

 

Neutrophils

≥ 0.5 x 109/l, and < 0.75 x 109/l

< 0.5 x 109/l

Platelets

≥ 25 x 109/l, and < 50 x 109/l

< 25 x 109/l

For adult patients who use 0.5 g/kg PegIntron monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half as shown in Table 3b.

Table 3b Reduced PegIntron dose (0.25 g/kg) for the 0.5 g/kg monotherapy regimen in adults

Body weight

PegIntron strength

Amount of PegIntron

Volume of PegIntron to

(kg)

( g/0.5 ml)

to administer

administer

 

 

( g)

(ml)

30-35

50*

0.08

36-45

50*

0.1

46-56

50*

0.13

57-72

80*

0.1

73-88

0.2

89-106

0.25

107-120**

0.2

Minimum delivery for pen is 0.2 ml.

*Must use vial.

**For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes.

For adult patients who use 1.0 µg/kg PegIntron monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half or by utilizing a lower dose strength as shown in

Table 3c.

Table 3c Reduced PegIntron dose (0.5 g/kg) for the 1.0 g/kg monotherapy regimen in adults

Body weight

PegIntron

Amount of

Volume of

(kg)

strength

PegIntron to

PegIntron to

 

(µg/0.5 ml)

administer

administer

 

 

( g)

(ml)

30-35

50*

0.15

36-45

0.20

46-56

0.25

57-72

0.2

73-88

0.4

89-106

0.5

107-120**

0.4

Minimum delivery for pen is 0.2 ml.

*Must use vial.

**For patients > 120 kg, the PegIntron dose should be calculated based on the individual patient weight. This may require combinations of various PegIntron dose strengths and volumes.

Special populations

Renal impairment Monotherapy

PegIntron should be used with caution in patients with moderate to severe renal impairment. In patients with moderate renal dysfunction (creatinine clearance 30-50 ml/minute), the starting dose of PegIntron should be reduced by 25 %. Patients with severe renal dysfunction (creatinine clearance

15-29 ml/minute) should have the starting dose of PegIntron reduced by 50 %. Data are not available for the use of PegIntron in patients with creatinine clearance < 15 ml/minute (see section 5.2). Patients with severe renal impairment, including those on hemodialysis, should be closely monitored. If renal function decreases during treatment, PegIntron therapy should be discontinued.

Combination therapy

Patients with creatinine clearance < 50 ml/minute must not be treated with PegIntron in combination with ribavirin (see ribavirin SmPC). When administered in combination therapy, patients with impaired renal function should be more carefully monitored with respect to the development of anaemia.

Hepatic impairment

The safety and efficacy of PegIntron therapy has not been evaluated in patients with severe hepatic dysfunction, therefore PegIntron must not be used for these patients.

Elderly ( 65 years of age)

There are no apparent age-related effects on the pharmacokinetics of PegIntron. Data from elderly patients treated with a single dose of PegIntron suggest no alteration in PegIntron dose is necessary based on age (see section 5.2).

Paediatric population

PegIntron can be used in combination with ribavirin in paediatric patients 3 years of age and older.

Method of administration

PegIntron should be administered as a subcutaneous injection. For special handling information see section 6.6. Patients may self-inject PegIntron if their physician determines that it is appropriate and with medical follow-up as necessary.

4.3 Contraindications

-Hypersensitivity to the active substance or to any interferon or to any of the excipients listed in section 6.1;

-A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months (see section 4.4);

-Severe, debilitating medical conditions;

-Autoimmune hepatitis or a history of autoimmune disease;

-Severe hepatic dysfunction or decompensated cirrhosis of the liver;

-Pre-existing thyroid disease unless it can be controlled with conventional treatment;

-Epilepsy and/or compromised central nervous system (CNS) function;

-HCV/HIV patients with cirrhosis and a Child-Pugh score ≥ 6.

-Combination of PegIntron with telbivudine.

Paediatric population

-Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicidal attempt.

Combination therapy

Also see SmPCs for ribavirin and boceprevir if PegIntron is to be administered in combination therapy in patients with chronic hepatitis C.

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 PegIntron therapy, 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 or homicidal ideation is identified, it is recommended that treatment with PegIntron be discontinued, and the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions

If treatment with peginterferon alfa-2b is judged necessary in adult 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.

- The use of PegIntron in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Among children and adolescents treated with interferon alfa-2b in combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult patients, children and adolescents experienced other psychiatric adverse events (e.g. depression, emotional lability, and somnolence).

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 ages 3 through 17 years, weight loss and growth inhibition were common. Long-term data available in children treated with the combination therapy of pegylated interferon/ribavirin are indicative of substantial growth retardation. Thirty two percent (30/94) of subjects demonstrated > 15 percentile decrease in height-for-age percentile 5 years after completion of therapy (see sections 4.8 and 5.1).

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, that resulted in reduced height in some patients.

-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. Although data are limited, no evidence of long-term effects on sexual maturation was noted in the 5-year observational follow-up study.

More significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses for oncology indications. While these effects are generally reversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high doses of interferon alpha.

All patients in the selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (i.e. patients with genotype 2 and 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.

Acute hypersensitivity

Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely during interferon alfa-2b therapy. If such a reaction develops during treatment with PegIntron, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

Cardiovascular system

As with interferon alfa-2b, adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, receiving PegIntron therapy require close monitoring. It is recommended that patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of PegIntron therapy. There are no data in children or adolescents with a history of cardiac disease.

Hepatic Failure

PegIntron increases the risk of hepatic decompensation and death in patients with cirrhosis. As with all interferons, discontinue treatment with PegIntron in patients who develop prolongation of coagulation markers which might indicate liver decompensation. Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Pyrexia

While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out.

Hydration

Adequate hydration must be maintained in patients undergoing PegIntron therapy since hypotension related to fluid depletion has been seen in some patients treated with alpha interferons. Fluid replacement may be necessary.

Pulmonary changes

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients. Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.

Autoimmune disease

The development of auto-antibodies and autoimmune disorders has been reported during treatment with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 4.4 Thyroid changes and section 4.8).

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Ocular changes

Ophthalmologic disorders, including retinal haemorrhages, retinal exudates, serous retinal detachment, and retinal artery or vein occlusion have been reported in rare instances after treatment with alpha interferons (see section 4.8). All patients should have a baseline eye examination. Any patient complaining of ocular symptoms, including loss of visual acuity or visual field must have a prompt and complete eye examination. Periodic visual examinations are recommended during PegIntron therapy, particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of PegIntron should be considered in patients who develop new or worsening ophthalmological disorders.

Thyroid changes

Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21 % of children treated with PegIntron/ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another approximately 2 % had a transient decrease below the lower limit of normal. Prior to initiation of PegIntron therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Determine TSH levels if, during the course of therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, PegIntron treatment may be continued if TSH levels can be maintained in the normal range by medicine. Children and adolescents should be monitored every

3 months for evidence of thyroid dysfunction (e.g. TSH).

Metabolic disturbances

Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.

HCV/HIV Co-infection

Mitochondrial toxicity and lactic acidosis

Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding PegIntron and ribavirin to HAART therapy (see ribavirin SmPC).

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

Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentration.

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed.

Haematological abnormalities in HCV/HIV co-infected patients

HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and HAART may be at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia and anaemia) compared to HCV mono-infected patients. Although, the majority of them could be managed by dose reduction, close monitoring of haematological parameters should be undertaken in this population of patients (see section 4.2 and below “Laboratory tests” and section 4.8).

Patients treated with PegIntron and ribavirin combination therapy and zidovudine are at increased risk of developing anaemia and therefore the concomitant use of this combination with zidovudine is not recommended (see section 4.5).

Patients with low CD4 counts

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

Please refer to the respective SmPCs 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 PegIntron and ribavirin.

HCV/HBV Coinfection

Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co- infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation appears to be low.

All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; patients co-infected with hepatitis B and C must then be monitored and managed according to current clinical guidelines.

Dental and periodontal disorders

Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving PegIntron and ribavirin 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 PegIntron and ribavirin. 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.

Organ transplant recipients

The safety and efficacy of PegIntron alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. Preliminary data indicate that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported.

Other

Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of PegIntron in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.

Laboratory tests

Standard haematologic tests, blood chemistry and a test of thyroid function must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of PegIntron therapy are:

 

Platelets

100,000/mm3

 

Neutrophil count

1,500/mm3

 

TSH level

must be within normal limits

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2).

Long term maintenance monotherapy

It has been demonstrated in a clinical study that peginterferon alfa-2b at low-dose (0.5 μg/kg/week) is not effective in long term maintenance monotherapy (for a mean duration of 2.5 years) for the prevention of disease progression in non responders with compensated cirrhosis. No statistically significant effect on the time to development of the first clinical event (liver decompensation, hepatocellular carcinoma, death and/or liver transplantation) was observed as compared to the absence of treatment. PegIntron should therefore not be used as long term maintenance monotherapy.

Important information about some of the ingredients of PegIntron

Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially "sodium-free".

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Telbivudine

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SmPC). Moreover, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Therefore, the combination of PegIntron with telbivudine is contraindicated (see section 4.3).

Methadone

In patients with chronic hepatitis C that were on stable methadone maintenance therapy and naïve to peginterferon alfa-2b, addition of 1.5 microgram/kg/week of PegIntron subcutaneously for 4 weeks increased R-methadone AUC by approximately 15 % (95 % Cl for AUC ratio estimate 103 – 128 %). The clinical significance of this finding is unknown; however, patients should be monitored for signs and symptoms of increased sedative effect, as well as respiratory depression. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.

Effect of Peginterferon alfa-2b on Co-administered Medicines

The potential interaction of peginterferon alfa-2b (PegIntron) on substrates of metabolic enzymes was evaluated in 3 multiple-dose clinical pharmacology studies. In these studies, the effects of multiple-dose regimens of peginterferon alfa-2b (PegIntron) were investigated in Hepatitis C subjects (1.5 mcg/week) or healthy subjects (1 mcg/week or 3 mcg/week) (Table 4). A clinically significant pharmacokinetic interaction was not observed between peginterferon alfa-2b (PegIntron) and tolbutamide, midazolam or dapsone; therefore, no dosing adjustment is necessary when peginterferon alfa-2b (PegIntron) is administered with medicines metabolized by CYP2C9, CYP3A4 and N-acetyltransferase. Concomitant administration of peginterferon alfa-2b (PegIntron) with caffeine or

desipramine modestly increased the exposure of caffeine and desipramine. When patients are administered PegIntron with medications metabolized by CYP1A2 or CYP2D6, the extent of the decrease in cytochrome P 450 activity is unlikely to have a clinical impact, except with medicines which have a narrow therapeutic margin (Table 5).

Table 4Effect of Peginterferon alfa-2b on Co-administered Medicines

 

 

 

Geometric Mean Ratio (Ratio

 

 

 

with/without peginterferon

Co-administered

Dose of

Study Population

alfa-2b)

 

Medicine

peginterferon

 

AUC

Cmax

 

alfa-2b

 

(90% CI)

(90% CI)

Caffeine

1.5 mcg/kg/week

Chronic Hepatitis

1.39

1.02

(CYP1A2 substrate)

(4 weeks)

C Subjects (N=22)

(1.27, 1.51)

(0.95, 1.09)

 

1 mcg/kg/week

Healthy Subjects

1.18

1.12

 

(4 weeks)

(N=24)

(1.07, 1.31)

(1.05, 1.19)

 

3 mcg/kg/week

Healthy Subjects

1.36

1.16

 

(2 weeks)

(N=13)

(1.25, 1.49)

(1.10, 1.24)

Tolbutamide

1.5 mcg/kg/week

Chronic Hepatitis

1.1#

NA

(CYP2C9 substrate)

(4 weeks)

C Subjects (N=22)

(0.94, 1.28)

 

 

1 mcg/kg/week

Healthy Subjects

0.90#

NA

 

(4 weeks)

(N=24)

(0.81, 1.00)

 

 

3 mcg/kg/week

Healthy Subjects

0.95

0.99

 

(2 weeks)

(N=13)

(0.89, 1.01)

(0.92, 1.07)

Dextromethorphan

1.5 mcg/kg/week

Chronic Hepatitis

0.96##

NA

hydrobromide

(4 weeks)

C Subjects (N=22)

(0.73, 1.26)

 

(CYP2D6 and

1 mcg/kg/week

Healthy Subjects

2.03#

NA

CYP3A substrate)

(4 weeks)

(N=24)

(1.55, 2.67)

 

Desipramine

3 mcg/kg/week

Healthy Subjects

1.30

1.08

(CYP2D6 substrate)

(2 weeks)

(N=13)

(1.18, 1.43)

(1.00, 1.16)

Midazolam

1.5 mcg/kg/week

Chronic Hepatitis

1.07

1.12

(CYP3A4 substrate)

(4 weeks)

C Subjects (N=24)

(0.91, 1.25)

(0.94, 1.33)

 

1 mcg/kg/week

Healthy Subjects

1.07

1.33

 

(4 weeks)

(N=24)

(0.99, 1.16)

(1.15, 1.53)

 

3 mcg/kg/week

Healthy Subjects

1.18

1.24

 

(2 weeks)

(N=13)

(1.06, 1.32)

(1.07, 1.43)

Dapsone

1.5 mcg/kg/week

Chronic Hepatitis

1.05

1.03

(N-acetyltransferase

(4 weeks)

C Subjects (N=24)

(1.02, 1.08)

(1.00, 1.06)

substrate)

 

 

 

 

# Calculated from urine data collected over an interval of 48-hours ## Calculated from urine data collected over an interval of 24-hours

Table 5

Precautions for co-administration (PegIntron should be administered with care

 

when co-administered with the following medicines)

Medicines

 

Signs, Symptoms, and Treatment

Mechanism and Risk Factors

Theophylline

Co-administration of theophylline

Metabolism of theophylline is

 

 

with the product (PegIntron) may

suppressed by inhibitory action of

 

 

increase the blood concentrations of

the product (PegIntron) on

 

 

theophylline. Careful

CYP1A2.

 

 

co-administration of theophylline

 

 

 

with the product (PegIntron) is

 

 

 

recommended. Package inserts of

 

 

 

theophylline should be referred to

 

 

 

when co-administering with the

 

 

 

product (PegIntron)

 

Thioridazine

Co-administration of thioridazine

Metabolism of thioridazine is

 

 

with the product (PegIntron) may

suppressed by inhibitory action of

 

 

increase the blood concentrations of

the product (PegIntron) on

 

 

thioridazine. Careful

CYP2D6.

 

 

co-administration of thioridazine

 

 

 

with the product (PegIntron) is

 

 

 

recommended. Package inserts of

 

 

 

thioridazine should be referred to

 

 

 

when co-administering with the

 

 

 

product (PegIntron)

 

Theophylline,

Elevation of blood concentrations

Metabolism of other medicines in

Antipyrine,

 

of these medicines has been

the liver may be suppressed.

Warfarin

 

reported when administered in

 

 

 

combination with other interferon

 

 

 

preparations and therefore care

 

 

 

should be taken.

 

Zidovudine

 

When administered in combination

Mechanism of action is unknown,

 

 

with other interferon preparations,

but it is considered that both

 

 

suppressive effect on bone marrow

medicines have bone marrow

 

 

function may be strengthened and

depressive effects.

 

 

aggravation of blood cell reduction

 

 

 

such as white blood cells decreased

 

 

 

may occur.

 

Immuno-suppressive

When administered in combination

It is considered that graft rejection

therapy

 

with other interferon preparations,

reactions may be induced.

 

 

effect of immunosuppressive

 

 

 

therapy may be weakened in

 

 

 

transplant (kidney, bone marrow,

 

 

 

etc.) patients.

 

No pharmacokinetic interactions were noted between PegIntron and ribavirin in a multiple-dose pharmacokinetic study.

HCV/HIV Co-infection

Nucleoside analogues

Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see ribavirin SmPC).

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 anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine-induced anaemia.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

PegIntron is recommended for use in fertile women only when they are using effective contraception during the treatment.

Combination therapy with ribavirin

Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking PegIntron in combination with ribavirin. Females of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SmPC).

Pregnancy

There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Interferon alfa-2b has been shown to be abortifacient in primates. PegIntron is likely to also cause this effect.

The potential risk in humans is unknown. PegIntron is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin

Ribavirin causes serious birth defects when administered during pregnancy, therefore ribavirin therapy is contraindicated in women who are pregnant.

Breast-feeding

It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding should be discontinued prior to initiation of treatment.

Fertility

There are no data available regarding potential effects of PegIntron treatment on male or female fertility.

4.7 Effects on ability to drive and use machines

Patients who develop fatigue, somnolence or confusion during treatment with PegIntron are cautioned to avoid driving or operating machines.

4.8 Undesirable effects

Adults

Tritherapy

Refer to the SmPC for boceprevir.

Bitherapy and monotherapy Summary of the safety profile

The most common treatment-related adverse reactions reported during clinical trials with PegIntron in combination with ribavirin in adults, seen in more than half of the study subjects, were fatigue, headache, and injection site reaction. Additional adverse reactions reported in more than 25 % of subjects included nausea, chills, insomnia, anaemia, pyrexia, myalgia, asthenia, pain, alopecia,

anorexia, weight decreased, depression, rash and irritability. The most frequently reported adverse reactions were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy. Fatigue, alopecia, pruritus, nausea, anorexia, weight decreased, irritability and insomnia occur at a notably lower rate in patients treated with PegIntron monotherapy compared to those treated with combination therapy (see Table 6).

Tabulated summary of adverse reactions

The following treatment-related adverse reactions were reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including PegIntron monotherapy or PegIntron/ribavirin. These reactions are listed in table 6 by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data).

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

Table 6 Adverse reactions reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including PegIntron monotherapy or PegIntron + ribavirin

Infections and infestations

Very common:

Viral infection*, pharyngitis*

Common:

Bacterial infection (including sepsis), fungal infection, influenza, upper

 

respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media,

 

rhinitis

Uncommon:

Injection site infection, lower respiratory tract infection

 

 

Not known:

Hepatitis B reactivation in HCV/HBV co-infected patients

 

 

Blood and lymphatic system disorders

 

 

Very common:

Anaemia, neutropenia

Common:

Haemolytic anaemia, leukopenia, thrombocytopenia, lymphadenopathy

Very rare:

Aplastic anaemia

Not known:

Aplasia pure red cell

Immune system disorders

Uncommon:

Drug hypersensitivity

 

 

Rare:

Sarcoidosis

 

 

Not known:

Acute hypersensitivity reactions including angioedema, anaphylaxis and

 

anaphylactic reactions including anaphylactic shock, idiopathic

 

thrombocytopenic purpura, thrombotic thrombocytopenic purpura, systemic

 

lupus erythematosus

 

 

Endocrine disorders

 

Common:

Hypothyroidism, hyperthyroidism

Metabolism and nutrition disorders

Very common:

Anorexia

 

 

Common:

Hypocalcemia, hyperuricemia, dehydration, increased appetite

 

 

Uncommon:

Diabetes mellitus, hypertriglyceridaemia

 

 

Rare:

Diabetic ketoacidosis

 

 

Psychiatric disorders

 

Very common:

Depression, anxiety*, emotional lability*, concentration impaired, insomnia

 

 

Common:

Aggression, agitation, anger, mood altered, abnormal behaviour,

 

nervousness, sleep disorder, libido decreased, apathy, abnormal dreams,

 

crying

 

 

Uncommon:

Suicide, suicide attempt, suicidal ideation, psychosis, hallucination, panic

 

attack

Rare:

Bipolar disorders

Not known:

Homicidal ideation, mania

Nervous system disorders

Very common:

Headache, dizziness

Common:

Amnesia, memory impairment, syncope, migraine, ataxia, confusion,

 

neuralgia, paraesthesia, hypoaesthesia, hyperaesthesia, hypertonia,

 

somnolence, disturbance in attention, tremor, dysgeusia

 

 

Uncommon:

Neuropathy, neuropathy peripheral

Rare:

Convulsion

Very rare:

Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy

 

 

Not known:

Facial palsy, mononeuropathies

 

 

Eye disorders

 

Common:

Visual disturbance, vision blurred, photophobia, conjunctivitis, eye

 

irritation, lacrimal disorder, eye pain, dry eye

Uncommon:

Retinal exudates

 

 

Rare:

Loss of visual acuity or visual fields, retinal haemorrhage, retinopathy,

 

retinal artery occlusion, retinal vein occlusion, optic neuritis, papilloedema,

 

macular oedema

Not known:

Serous retinal detachment

Ear and labyrinth disorders

Common:

Hearing impaired/loss, tinnitus, vertigo

Uncommon

Ear pain

Cardiac disorders

 

Common:

Palpitations, tachycardia

Uncommon:

Myocardial infarction

Rare:

Congestive heart failure, cardiomyopathy, arrhythmia, pericarditis

Very rare:

Cardiac ischaemia

Not known:

Pericardial effusion

Vascular disorders

 

Common:

Hypotension, hypertension, flushing

Rare:

Vasculitis

Respiratory, thoracic and mediastinal disorders

Very common:

Dyspnoea*, cough*

Common:

Dysphonia, epistaxis, respiratory disorder, respiratory tract congestion,

 

sinus congestion, nasal congestion, rhinorrhea, increased upper airway

 

secretion, pharyngolaryngeal pain

Very rare:

Interstitial lung disease

Not known:

Pulmonary fibrosis, pulmonary arterial hypertension#

Gastrointestinal disorders

Very common:

Vomiting*, nausea, abdominal pain, diarrhoea, dry mouth*

Common:

Dyspepsia, gastroesophageal reflux disease, stomatitis, mouth ulceration,

 

glossodynia, gingival bleeding, constipation, flatulence, haemorrhoids,

 

cheilitis, abdominal distension, gingivitis, glossitis, tooth disorder

 

 

Uncommon:

Pancreatitis, oral pain

 

 

Rare:

Colitis ischaemic

 

 

Very rare:

Colitis ulcerative

Not known

Tongue pigmentation

Hepatobiliary disorders

Common:

Hyperbilirubinemia, hepatomegaly

Skin and subcutaneous tissue disorders

Very common:

Alopecia, pruritus*, dry skin*, rash*

Common:

Psoriasis, photosensitivity reaction, rash maculo-papular, dermatitis,

 

erythematous rash, eczema, night sweats, hyperhidrosis, acne, furuncle,

 

erythema, urticaria, abnormal hair texture, nail disorder

Rare:

Cutaneous sarcoidosis

Very rare:

Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

 

 

Musculoskeletal and connective tissue disorders

Very common:

Myalgia, arthralgia, musculoskeletal pain

Common:

Arthritis, back pain, muscle spasms, pain in extremity

Uncommon:

Bone pain, muscle weakness

Rare:

Rhabdomyolysis, myositis, rheumatoid arthritis

Renal and urinary disorders

 

 

Common:

Micturition frequency, polyuria, urine abnormality

Rare:

Renal failure, renal insufficiency

Reproductive system and breast disorders

Common:

Amenorrhoea, breast pain, menorrhagia, menstrual disorder, ovarian

 

disorder, vaginal disorder, sexual dysfunction, prostatitis, erectile

 

dysfunction

General disorders and administration site conditions

Very common:

Injection site reaction*, injection site inflammation, fatigue, asthenia,

 

irritability, chills, pyrexia, influenza like illness, pain

 

 

Common:

Chest pain, chest discomfort, injection site pain, malaise, face oedema,

 

oedema peripheral, feeling abnormal, thirst

Rare:

Injection site necrosis

Investigations

 

 

 

Very common:

Weight decreased

*These adverse reactions were common (≥1/100 to < 1/10) in clinical trials in patients treated with PegIntron monotherapy.

#Class label for interferon products, see below Pulmonary arterial hypertension.

Description of selected adverse reactions in adults

Most cases of neutropenia and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with the recommended doses of PegIntron in combination with ribavirin (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]).

In a clinical trial, approximately 1.2 % of patients treated with PegIntron or interferon alfa-2b in combination with ribavirin reported life-threatening psychiatric events during treatment. These events included suicidal ideation and attempted suicide (see section 4.4).

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients without prior evidence of cardiac disease.

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). Events were reported at various time points typically several months after starting treatment with interferon alfa.

Ophthalmological disorders that have been reported rarely with alpha interferons include retinopathies (including macular oedema), retinal haemorrhages, retinal artery or vein occlusion, retinal exudates, loss of visual acuity or visual field, optic neuritis, and papilloedema (see section 4.4).

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies and Vogt-Koyanagi-Harada syndrome (see also section 4.4).

HCV/HIV co-infected patients

Summary of the safety profile

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

Description of selected adverse reactions Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated ribavirin for co-HCV infection (see section 4.4).

Laboratory values for HCV/HIV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving PegIntron in combination with ribavirin when compared to patients receiving interferon alfa-2b in combination with ribavirin. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) of patients receiving PegIntron in combination with ribavirin. Anaemia (hemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with PegIntron in combination with ribavirin.

CD4 lymphocytes decrease

Treatment with PegIntron in combination with ribavirin 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 PegIntron in combination with ribavirin had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N= 25) are available in co-infected patients with CD4+ cell counts < 200/µl (see section 4.4).

Please refer to the respective SmPCs 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 PegIntron in combination with ribavirin.

Paediatric population

Summary of the safety profile

In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of PegIntron and ribavirin, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with PegIntron and ribavirin, growth inhibition was observed that resulted in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and height percentile were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3rd percentile in 70 % of the patients).

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still of 3 percentiles and 7 percentiles respectively, and 20 % of the children continued to have inhibited growth (growth velocity < 3rd percentile). Ninety-four of 107 subjects enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow- up among subjects treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and

9.0 percentiles, respectively. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40 % of subjects (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of the 5 year long-term follow-up compared to pre-treatment baseline percentile. Eleven percent of subjects (5/46) treated for 24 weeks and 13 % of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight- for-age percentiles decreased 1.3 and 5.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy (see section 4.4).

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia

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

Tabulated summary of adverse reactions

The following treatment-related adverse reactions were reported in the study in children and adolescent patients treated with PegIntron in combination with ribavirin. These reactions are listed in Table 7 by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 7 Adverse reactions very commonly, commonly and uncommonly reported in the clinical trial in children and adolescent patients treated with PegIntron in combination with ribavirin

Infections and infestations

Common:

Fungal infection, influenza, oral herpes, otitis media, pharyngitis

 

streptococcal, nasopharyngitis, sinusitis

Uncommon:

Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis, urinary tract

 

infection, gastroenteritis

Blood and lymphatic system disorders

 

 

Very common:

Anaemia, leucopenia, neutropenia

Common:

Thrombocytopenia, lymphadenopathy

Endocrine disorders

 

Common:

Hypothyroidism

Metabolism and nutrition disorders

Very common:

Anorexia, decreased appetite

 

 

Psychiatric disorders

Common:

 

Suicidal ideation§, suicide attempt§, depression, aggression, affect lability,

 

 

anger, agitation, anxiety, mood altered, restlessness, nervousness, insomnia

 

 

 

Uncommon:

 

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

Nervous system disorders

Very common:

 

Headache, dizziness

Common:

 

Dysgeusia, syncope, disturbance in attention, somnolence, poor quality

 

 

sleep

 

 

 

Uncommon:

 

Neuralgia, lethargy, paraesthesia, hypoaesthesia, psychomotor

 

 

hyperactivity, tremor

Eye disorders

 

Common:

 

Eye pain

Uncommon:

 

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

 

 

Ear and labyrinth disorders

Common:

 

Vertigo

Cardiac disorders

 

Common:

 

Palpitations, tachycardia

Vascular disorders

 

Common:

 

Flushing

Uncommon:

 

Hypotension, pallor

Respiratory, thoracic and mediastinal disorders

Common:

 

Cough, epistaxis, pharyngolaryngeal pain

 

 

 

Uncommon:

 

Wheezing, nasal discomfort, rhinorrhoea

Gastrointestinal disorders

Very common:

 

Abdominal pain, abdominal pain upper, vomiting, nausea

Common:

 

Diarrhoea, aphthous stomatitis, cheilosis, mouth ulceration, stomach

 

 

discomfort, oral pain

 

 

 

Uncommon:

 

Dyspepsia, gingivitis

 

 

 

Hepatobiliary disorders

 

Uncommon:

 

Hepatomegaly

Skin and subcutaneous tissue disorders

Very common:

 

Alopecia, dry skin

Common:

 

Pruritus, rash, rash erythematous, eczema, acne, erythema

 

 

 

Uncommon:

 

Photosensitivity reaction, rash maculo-papular, skin exfoliation,

 

 

pigmentation disorder, dermatitis atopic, skin discolouration

Musculoskeletal and connective tissue disorders

Very common:

 

Myalgia, arthralgia

Common:

 

Musculoskeletal pain, pain in extremity, back pain

Uncommon:

 

Muscle contracture, muscle twitching

Renal and urinary disorders

Uncommon:

 

Proteinuria

Reproductive system and breast disorders

Uncommon:

 

Female: Dysmenorrhoea

 

 

General disorders and administration site conditions

Very common:

 

Injection site erythema, fatigue, pyrexia, rigors, influenza-like illness,

 

 

asthenia, pain, malaise, irritability

 

 

 

Common:

 

Injection site reaction, injection site pruritus, injection site rash injection

 

 

site dryness, injection site pain, feeling cold

Uncommon:

 

Chest pain, chest discomfort, facial pain

Investigations

Very common:

Growth rate decrease (height and/or weight decrease for age)

Common:

Blood thyroid stimulating hormone increased, thyroglobulin increased

Uncommon:

Anti-thyroid antibody positive

Injury and poisoning

Uncommon:Contusion

§class effect of interferon-alfa containing products – reported with standard interferon therapy in adult and paediatric patients; with PegIntron reported in adult patients.

Description of selected adverse reactions in children and adolescents

Most of the changes in laboratory values in the PegIntron/ribavirin clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2). While changes in laboratory values were observed in some patients treated with PegIntron used in combination with ribavirin in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.

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.

4.9 Overdose

Doses up to 10.5 times the intended dose have been reported. The maximum daily dose reported is 1,200 µg for one day. In general, the adverse events seen in overdose cases involving PegIntron are consistent with the known safety profile for PegIntron; however, the severity of the events may be increased. Standard methods to increase elimination of the medicinal product, e.g., dialysis, have not been shown to be useful. No specific antidote for PegIntron is available; therefore, symptomatic treatment and close observation of the patient are recommended in cases of overdose. If available, prescribers are advised to consult with a poison control centre (PCC).

5.PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB10.

Recombinant interferon alfa-2b is covalently conjugated with monomethoxy polyethylene glycol at an average degree of substitution of 1 mole of polymer/mole of protein. The average molecular mass is approximately 31,300 daltons of which the protein moiety constitutes approximately 19,300.

Mechanism of action

In vitro and in vivo studies suggest that the biological activity of PegIntron is derived from its interferon alfa-2b moiety.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Studies with other interferons have demonstrated species specificity. However, certain monkey species, e.g., Rhesus monkeys are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.

Once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that this process, at least in part, is responsible for the various cellular responses to interferon, including inhibition of virus replication in virus- infected cells, suppression of cell proliferation and such immunomodulating activities as enhancement

of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities may contribute to interferon’s therapeutic effects.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are unable to leave the cell.

Pharmacodynamic effects

PegIntron pharmacodynamics were assessed in a rising single-dose trial in healthy subjects by examining changes in oral temperature, concentrations of effector proteins such as serum neopterin and 2’5’- oligoadenylate synthetase (2’5’-OAS), as well as white cell and neutrophil counts. Subjects treated with PegIntron showed mild dose-related elevations in body temperature. Following single doses of PegIntron between 0.25 and 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-related manner. Neutrophil and white cell count reductions at the end of week 4 correlated with the dose of PegIntron.

Clinical efficacy and safety – Adults

Tritherapy with PegIntron, ribavirin and boceprevir

Refer to the SmPC for boceprevir.

Monotherapy with PegIntron and bitherapy with PegIntron and ribavirin Naïve patients

Two pivotal trials have been conducted, one (C/I97-010) with PegIntron monotherapy; the other (C/I98-580) with PegIntron in combination with ribavirin. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction (PCR) assay (> 30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

In the PegIntron monotherapy trial, a total of 916 naïve chronic hepatitis C patients were treated with PegIntron (0.5, 1.0 or 1.5 micrograms/kg/week) for one year with a follow-up period of six months. In addition, 303 patients received interferon alfa-2b (3 million International Units [MIU] three times a week) as a comparator. This study showed that PegIntron was superior to interferon alfa-2b (Table 8).

In the PegIntron combination trial, 1,530 naïve patients were treated for one year with one of the following combination regimens:

-PegIntron (1.5 micrograms/kg/week) + ribavirin (800 mg/day), (n = 511).

-PegIntron (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) + ribavirin (1,000/1,200 mg/day), (n = 514).

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

In this trial, the combination of PegIntron (1.5 micrograms/kg/week) and ribavirin was significantly more effective than the combination of interferon alfa-2b and ribavirin (Table 8), particularly in patients infected with Genotype 1 (Table 9). Sustained response was assessed by the response rate six months after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of ribavirin administered in combination with PegIntron or interferon alfa-2b. In those patients that received

> 10.6 mg/kg ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received 10.6 mg/kg ribavirin (Table 9), while response rates in patients that received > 13.2 mg/kg ribavirin were even higher.

Table 8

Sustained virological response (% patients HCV negative)

 

 

 

 

 

PegIntron monotherapy

PegIntron + ribavirin

Treatment regimen

 

P 1.5

P 1.0

P 0.5

I

P 1.5/R

P 0.5/R

I/R

Number of patients

 

Response at end of treatment

 

49 %

41 %

33 %

24 %

65 %

56 %

54 %

Sustained response

 

23 %*

25 %

18 %

12 %

54 %**

47 %

47 %

P 1.5

PegIntron 1.5 micrograms/kg

 

 

 

 

 

 

P 1.0

PegIntron 1.0 microgram/kg

 

 

 

 

 

 

P 0.5

PegIntron 0.5 microgram/kg

 

 

 

 

 

 

I

Interferon alfa-2b 3 MIU

 

 

 

 

 

 

 

P 1.5/R

PegIntron (1.5 micrograms/kg) + ribavirin (800 mg)

 

 

 

 

P 0.5/R

PegIntron (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg)

 

 

 

I/R

Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg)

 

 

 

 

*

p < 0.001 P 1.5 vs. I

 

 

 

 

 

 

 

**p = 0.0143 P 1.5/R vs. I/R

Table 9 Sustained response rates with PegIntron + ribavirin (by ribavirin dose, genotype and viral load)

HCV Genotype

Ribavirin dose

P 1.5/R

P 0.5/R

I/R

 

 

(mg/kg)

 

 

 

All Genotypes

All

54 %

47 %

47 %

 

 

≤ 10.6

50 %

41 %

27 %

 

 

> 10.6

61 %

48 %

47 %

Genotype 1

All

42 %

34 %

33 %

 

 

≤ 10.6

38 %

25 %

20 %

 

 

> 10.6

48 %

34 %

34 %

Genotype 1

All

73 %

51 %

45 %

≤ 600,000 IU/ml

≤ 10.6

74 %

25 %

33 %

 

 

> 10.6

71 %

52 %

45 %

Genotype 1

All

30 %

27 %

29 %

> 600,000 IU/ml

≤ 10.6

27 %

25 %

17 %

 

 

> 10.6

37 %

27 %

29 %

All

82 %

80 %

79 %

 

 

≤ 10.6

79 %

73 %

50 %

 

 

> 10.6

88 %

80 %

80 %

P 1.5/R

PegIntron (1.5 micrograms/kg) + ribavirin (800 mg)

 

 

P 0.5/R

PegIntron (1.5 to 0.5 microgram/kg) + ribavirin (1,000/1,200 mg)

 

 

I/R

Interferon alfa-2b (3 MIU) + ribavirin (1,000/1,200 mg)

 

 

In the PegIntron monotherapy study, the Quality of Life was generally less affected by

0.5 microgram/kg of PegIntron than by either 1.0 microgram/kg of PegIntron once weekly or 3 MIU of interferon alfa-2b three times a week.

In a separate trial, 224 patients with genotype 2 or 3 received PegIntron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with ribavirin 800 mg –1,400 mg p.o. for 6 months (based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose) (Table 10). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).

Table 10 Virologic response at end of treatment, Sustained Virologic Response and relapse by HCV Genotype and viral load*

 

PegIntron 1.5 µg/kg once weekly plus Ribavirin 800-1,400 mg/day

 

End of treatment

Sustained Virologic Response

Relapse

 

response

 

 

All subjects

94 % (211/224)

81 % (182/224)

12 % (27/224)

HCV 2

100 % (42/42)

93 % (39/42)

7 % (3/42)

≤ 600,000 IU/ml

100 % (20/20)

95 % (19/20)

5 % (1/20)

> 600,000 IU/ml

100 % (22/22)

91 % (20/22)

9 % (2/22)

HCV 3

93 % (169/182)

79 % (143/182)

14 % (24/166)

≤ 600,000 IU/ml

93 % (92/99)

86 % (85/99)

8 % (7/91)

> 600,000 IU/ml

93 % (77/83)

70 % (58/83)

23 % (17/75)

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window was considered to be a non-responder at week 24 of follow-up.

The 6 month treatment duration in this trial was better tolerated than one year of treatment in the pivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %.

In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml) received PegIntron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. The overall sustained response rate after a 24-week treatment duration was 50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis (n=49) and prospectively confirmed (n=48).

Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two PegIntron/ribavirin regimens [PegIntron 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both in combination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] and

peginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 11).

Table 11 Virologic response at treatment week 12, end of treatment response, relapse rate *and Sustained Virologic Response (SVR)

Treatment group

 

% (number) of patients

 

 

PegIntron 1.5 µg/kg +

 

PegIntron 1 µg/kg +

peginterferon alfa-2a

 

ribavirin

 

ribavirin

180 µg + ribavirin

Undetectable HCV-

 

 

 

 

RNA at treatment

40 (407/1,019)

 

36 (366/1,016)

45 (466/1,035)

week 12

 

 

 

 

End of treatment

53 (542/1,019)

 

49 (500/1,016)

64 (667/1,035)

response

 

 

 

 

 

Relapse

24 (123/523)

 

20 (95/475)

32 (193/612)

SVR

40 (406/1,019)

 

38 (386/1,016)

41 (423/1,035)

 

 

 

 

 

SVR in patients with

 

 

 

 

undetectable HCV-

81 (328/407)

 

83 (303/366)

74 (344/466)

RNA at treatment

 

 

 

 

 

week 12

 

 

 

 

* (HCV-RNA PCR assay, with

a lower limit of quantitation of 27

IU/ml)

 

Lack of early virologic response by Treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from baseline) was a criterion for discontinuation of treatment.

In all three treatment groups, sustained virologic response rates were similar. In patients of African American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with PegIntron (1.5 µg/kg)/ribavirin combination therapy resulted in a higher sustained virologic response rate compared to PegIntron 1 µg/kg dose. At the PegIntron 1.5 µg/kg plus ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml, and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse rate was 24 %.

Predictability of sustained virological response – Naïve patients: Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels of HCV-RNA.Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have been shown to be predictive for sustained response (Table 12).

Table 12 Predictive value of in-treatment Virologic Response while on PegIntron 1.5 µg/kg/ribavirin 800-1,400 mg combination therapy

 

 

Negative

 

 

Positive

 

 

No

 

 

 

 

 

 

response

 

 

Response

 

 

 

at

No

Negative

at

 

Positive

 

treatment

sustained

predictive

treatment

Sustained

predictive

 

week

response

value

week

response

value

Genotype 1*

 

 

 

 

 

 

By week 4***

 

 

 

 

 

 

(n=950)

 

 

 

 

 

 

HCV-RNA negative

65 %

92 %

 

 

 

(539/834)

 

 

(107/116)

HCV-RNA negative

95 %

54 %

or

 

 

(210/220)

 

 

(392/730)

≥ 1 log

 

 

 

 

 

 

decrease in

 

 

 

 

 

 

viral load

 

 

 

 

 

 

By week 12***

 

 

 

 

 

 

(n=915)

 

 

 

 

 

 

HCV-RNA negative

85 %

81 %

 

 

 

(433/508)

 

 

(328/407)

HCV-RNA negative

N/A

57 %

or

 

 

 

 

 

(402/709)

≥ 2 log decrease in

 

 

 

 

 

 

viral load

 

 

 

 

 

 

Genotype 2, 3**

 

 

 

 

 

 

 

 

 

 

 

 

 

By week 12

 

 

 

 

 

 

(n= 215)

 

 

 

 

 

 

HCV-RNA negative

50 %

83 %

or

 

 

(1/2)

 

 

(177/213)

≥ 2 log decrease in

 

 

 

 

 

 

viral load

 

 

 

 

 

 

*Genotype 1 receive 48 weeks treatment **Genotype 2, 3 receive 24 weeks treatment

***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 or week 12.

These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2log10 decrease from baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2log10 from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

The negative predictive value for sustained response in patients treated with PegIntron in monotherapy was 98 %.

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 13. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either PegIntron (1.5 µg/kg/week) plus ribavirin (800 mg/day) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800 mg/day) for

48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either PegIntron (100 or 150 µg/week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or interferon alfa-2b (3 MIU TIW) plus ribavirin (800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load

< 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

Table 13 Sustained virological response based on genotype after PegIntron in combination with Ribavirin in HCV/HIV Co-infected patients

 

 

Study 11

 

 

Study 22

 

 

 

 

 

PegIntron

Interferon

 

 

PegIntron

Interferon

 

(100 or

alfa-2b

 

 

(1.5 µg/kg/

alfa-2b

 

150c µg/week)

(3 MIU TIW)

 

 

week) +

(3 MIU TIW) +

 

+ ribavirin

+ ribavirin

 

 

ribavirin

ribavirin

p

(800-

(800-

p

 

(800 mg)

(800 mg)

valuea

1,200 mg)d

1,200 mg)d

valueb

All

27 % (56/205)

20 % (41/205)

0.047

44 % (23/52)

21 % (9/43)

0.017

Genotype 1,

17 % (21/125)

6 % (8/129)

0.006

38 % (12/32)

7 % (2/27)

0.007

 

 

 

 

 

 

Genotype 2,

44 % (35/80)

43 % (33/76)

0.88

53 % (10/19)

47 % (7/15)

0.730

 

 

 

 

 

 

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

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

b:p value based on chi-square test.

c:subjects < 75 kg received 100 µg/week PegIntron and subjects ≥ 75 kg received 150 µg/week PegIntron.

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

1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848. 2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

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

PegIntron/ribavirin retreatment of prior treatment failures

In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with PegIntron,

1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of treatment).

Patients who were HCV-RNA negative at treatment week 12 continued treatment for 48 weeks and were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV-RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable HCV-RNA at 24 weeks post-treatment (Table 14).

Table 14

Rates of response to retreatment in prior treatment failures

 

 

 

 

Patients with undetectable HCV–RNA

 

 

 

 

 

at treatment week 12 and SVR upon retreatment

 

 

 

 

 

 

 

 

 

 

 

Overall

 

 

interferon alpha/ribavirin

peginterferon alpha/ribavirin

population*

 

 

Response

SVR % (n/N)

Response

SVR % (n/N)

SVR % (n/N)

 

 

week 12 %

99% CI

week 12 %

99% CI

99 % CI

 

 

(n/N)

 

 

(n/N)

 

 

 

 

Overall

 

38.6

59.4

 

31.5

 

50.4

 

21.7

 

 

 

(549/1,423)

(326/549)

(272/863)

(137/272)

(497/2,293)

 

 

 

54.0,64.8

 

 

42.6, 58.2

19.5, 23.9

Prior response

 

 

 

 

 

 

 

 

 

Relapse

 

67.7 (203/300)

59.6

 

58.1

 

52.5

 

37.7

(243/645)

 

 

 

(121/203)

(200/344)

(105/200)

32.8, 42.6

 

 

 

50.7, 68.5

 

 

43.4, 61.6

 

 

59.7 (129/216)

51.2

(66/129)

48.6

 

44.3

(54/122)

28.6

(134/468)

 

 

 

39.8, 62.5

(122/251)

32.7, 55.8

23.3, 34.0

 

 

 

 

 

 

 

 

 

88.9 (72/81)

73.6

(53/72)

83.7

(77/92)

64.9

(50/77)

61.3 (106/173)

 

 

 

(60.2, 87.0)

 

 

50.9, 78.9

51.7, 70.8

NR

 

28.6 (258/903)

57.0

 

12.4

(59/476)

44.1

(26/59)

13.6

 

 

 

 

(147/258)

 

 

27.4, 60.7

(188/1,385)

 

 

 

49.0, 64.9

 

 

 

 

11.2, 15.9

23.0 (182/790)

51.6

(94/182)

9.9 (44/446)

38.6

(17/44)

9.9 (123/1,242)

 

 

 

42.1, 61.2

 

 

19.7, 57.5

7.7, 12.1

67.9 (74/109)

70.3

(52/74)

53.6

(15/28)

60.0

(9/15)

46.0

(63/137)

 

 

 

56.6, 84.0

 

 

27.4, 92.6

35.0, 57.0

Genotype

 

 

 

 

 

 

 

 

 

 

 

30.2

51.3

 

23.0

 

42.6

(69/162)

14.6

 

 

 

(343/1,135)

(176/343)

(162/704)

32.6, 52.6

(270/1,846)

 

 

 

44.4, 58.3

 

 

 

 

12.5, 16.7

 

77.1 (185/240)

73.0

 

75.6

(96/127)

63.5

(61/96)

55.3

(203/367)

 

 

 

(135/185)

 

 

50.9, 76.2

48.6, 62.0

 

 

 

64.6, 81.4

 

 

 

 

 

 

 

42.5 (17/40)

70.6

(12/17)

44.4

(12/27)

50.0

(6/12)

28.4

(19/67)

 

 

 

42.1, 99.1

 

 

12.8, 87.2

14.2, 42.5

METAVIR

 

 

 

 

 

 

 

 

 

 

Fibrosis score

 

 

 

 

 

 

 

 

 

F2

 

46.0 (193/420)

66.8

 

33.6

(78/232)

57.7

(45/78)

29.2

(191/653)

 

 

 

(129/193)

 

 

43.3, 72.1

24.7, 33.8

 

 

 

58.1, 75.6

 

 

 

 

 

 

F3

 

38.0 (163/429)

62.6

 

32.4

(78/241)

51.3

(40/78)

21.9

(147/672)

 

 

 

(102/163)

 

 

36.7, 65.9

17.8, 26.0

 

 

 

52.8, 72.3

 

 

 

 

 

 

F4

 

33.6 (192/572)

49.5

(95/192)

29.7

 

44.8

(52/116)

16.5

(159/966)

 

 

 

40.2, 58.8

(116/390)

32.9, 56.7

13.4, 19.5

 

Patients with undetectable HCV–RNA

 

 

at treatment week 12 and SVR upon retreatment

 

 

 

 

 

 

Overall

 

interferon alpha/ribavirin

peginterferon alpha/ribavirin

population*

 

Response

SVR % (n/N)

Response

SVR % (n/N)

SVR % (n/N)

 

week 12 %

99% CI

week 12 %

99% CI

99 % CI

 

(n/N)

 

(n/N)

 

 

Baseline Viral

 

 

 

 

 

Load

 

 

 

 

 

HVL (>600,000

32.4 (280/864)

56.1

26.5

41.4 (63/152)

16.6

IU/ml)

 

(157/280)

(152/573)

31.2, 51.7

(239/1,441)

 

 

48.4, 63.7

 

 

14.1, 19.1

LVL (≤600,000

48.3 (269/557)

62.8

41.0

61.0 (72/118)

30.2 (256/848)

IU/ml)

 

(169/269)

(118/288)

49.5, 72.6

26.1, 34.2

 

 

55.2, 70.4

 

 

 

NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment. Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory

*Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed.

Overall, approximately 36 % (821/2,286) of patients had undetectable plasma HCV-RNA levels at week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In this subgroup, there was a 56 % (463/823) sustained virological response rate. For patients with prior failure on therapy with nonpegylated interferon or pegylated interferon and negative at week 12, the sustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log viral reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patients the SVR was 12 %.

Non-responders to prior therapy with pegylated interferon alpha/ribavirin were less likely to achieve a week 12 response to retreatment than non-responders to nonpegylated interferon alpha/ribavirin

(12.4 % vs. 28.6 %). However, if a week 12 response was achieved, there was little difference in SVR regardless of prior treatment or prior response.

Long-term efficacy data-Adults

A large long-term follow-up study enrolled 567 patients after treatment in a prior study with PegIntron (with or without ribavirin). The purpose of the study was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. 327 patients completed at least 5 years of long-term follow-up and only 3 out of 366 sustained responders relapsed during the study.

The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 99 %

(95 % CI: 98-100 %). SVR after treatment of chronic HCV with PegIntron (with or without ribavirin) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical “cure” from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

Clinical efficacy and safety – paediatric population

Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were enrolled in a multicentre trial and treated with ribavirin 15 mg/kg per day plus PegIntron 60 g/m2 once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 %

< 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of PegIntron with ribavirin needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 15.

Table 15 Sustained virological response rates (na,b (%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects n = 107

 

24 weeks

48 weeks

All Genotypes

26/27 (96 %)

44/80 (55 %)

Genotype 1

-

38/72 (53 %)

Genotype 2

14/15 (93 %)

-

Genotype 3c

12/12 (100 %)

2/3 (67 %)

Genotype 4

-

4/5 (80 %)

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

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

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

Long-term efficacy data - paediatric population

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

5.2 Pharmacokinetic properties

PegIntron is a well characterized polyethylene glycol-modified (“pegylated”) derivative of interferon alfa-2b and is predominantly composed of monopegylated species. The plasma half-life of PegIntron is prolonged compared with nonpegylated interferon alfa-2b. PegIntron has a potential to depegylate to free interferon alfa-2b. The biologic activity of the pegylated isomers is qualitatively similar, but weaker than free interferon alfa-2b.

Following subcutaneous administration, maximal serum concentrations occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours post-dose.

PegIntron Cmax and AUC measurements increase in a dose-related manner. Mean apparent volume of distribution is 0.99 l/kg.

Upon multiple dosing, there is an accumulation of immunoreactive interferons. There is, however, only a modest increase in biologic activity as measured by a bioassay.

Mean (SD) PegIntron elimination half-life is approximately 40 hours (13.3 hours), with apparent clearance of 22.0 ml/hr/kg. The mechanisms involved in clearance of interferons in man have not yet been fully elucidated. However, renal elimination may account for a minority (approximately 30 %) of PegIntron apparent clearance.

Renal impairment

Renal clearance appears to account for 30 % of total clearance of PegIntron. In a single dose study (1.0 microgram/kg) in patients with impaired renal function, Cmax, AUC, and half-life increased in relation to the degree of renal impairment.

Following multiple dosing of PegIntron (1.0 microgram/kg subcutaneously administered every week for four weeks) the clearance of PegIntron is reduced by a mean of 17 % in patients with moderate renal impairment (creatinine clearance 30-49 ml/minute) and by a mean of 44 % in patients with severe renal impairment (creatinine clearance 15-29 ml/minute) compared to subjects with normal renal function. Based on single dose data, clearance was similar in patients with severe renal impairment not on dialysis and in patients who were receiving hemodialysis. The dose of PegIntron

for monotherapy should be reduced in patients with moderate or severe renal impairment (see sections 4.2 and 4.4). Patients with creatinine clearance < 50 ml/minute must not be treated with PegIntron in combination with ribavirin (bitherapy or tritherapy) (see section 4.3).

Because of marked inter-subject variability in interferon pharmacokinetics, it is recommended that patients with severe renal impairment be closely monitored during treatment with PegIntron (see section 4.2)

Hepatic impairment

The pharmacokinetics of PegIntron have not been evaluated in patients with severe hepatic dysfunction.

Elderly (≥ 65 years of age)

The pharmacokinetics of PegIntron following a single subcutaneous dose of 1.0 microgram/kg were not affected by age. The data suggest that no alteration in PegIntron dosage is necessary based on advancing age.

Paediatric population

Multiple-dose pharmacokinetic properties for PegIntron and ribavirin (capsules and oral solution) in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children and adolescent patients receiving body surface area-adjusted dosing of PegIntron at

60 g/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 g/kg/week.

Interferon neutralising factors

Interferon neutralising factor assays were performed on serum samples of patients who received PegIntron in the clinical trial. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors in patients who received

PegIntron 0.5 micrograms/kg is 1.1 %.

Transfer into seminal fluid

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

5.3 Preclinical safety data

PegIntron

Adverse events not observed in clinical trials were not seen in toxicity studies in monkeys. These studies were limited to four weeks due to the appearance of anti-interferon antibodies in most monkeys.

Reproduction studies of PegIntron have not been performed. Interferon alfa-2b has been shown to be an abortifacient in primates. PegIntron is likely to also cause this effect. Effects on fertility have not been determined. It is not known whether the components of this medicinal product are excreted into experimental animal or human milk (see section 4.6 for relevant human data on pregnancy and lactation). PegIntron showed no genotoxic potential.

The relative non-toxicity of monomethoxy-polyethylene glycol (mPEG), which is liberated from PegIntron by metabolism in vivo has been demonstrated in preclinical acute and subchronic toxicity studies in rodents and monkeys, standard embryo-foetal development studies and in in vitro mutagenicity assays.

PegIntron plus ribavirin

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

No studies have been conducted in juvenile animals to examine the effects of treatment with PegIntron on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin (see section 5.3 of Rebetol SmPC if PegIntron is to be administered in combination with ribavirin).

6.PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder

Disodium phosphate, anhydrous

Sodium dihydrogen phosphate dihydrate

Sucrose

Polysorbate 80

Solvent

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

Before reconstitution 3 years.

After reconstitution

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8ºC.

From a microbiological point of view, the product is to be used immediately. If not used immediately, in- use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C.

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C). Do not freeze.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

The powder and solvent are both contained in a two-chamber cartridge (Type I flint glass) separated by a bromobutyl rubber plunger. The cartridge is sealed at one end with a polypropylene cap containing a bromobutyl rubber liner and at the other end by a bromobutyl rubber plunger.

PegIntron is supplied as:

-1 pre-filled pen (CLEARCLICK) containing powder and solvent for solution for injection, 1 needle ("Push-On Needle"),

2 cleansing swabs;

-4 pre-filled pens (CLEARCLICK) containing powder and solvent for solution for injection,

4 needles ("Push-On Needle"),

8 cleansing swabs;

-12 pre-filled pens (CLEARCLICK) containing powder and solvent for solution for injection, 12 needles ("Push-On Needle"),

24 cleansing swabs.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

PegIntron pre-filled pen is to be removed from the refrigerator before administration to allow the solvent to reach room temperature (not more than 25°C).

PegIntron 50 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 50 micrograms in 0.5 ml.

PegIntron 80 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 80 micrograms in 0.5 ml.

PegIntron 100 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 100 micrograms in 0.5 ml.

PegIntron 120 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 120 micrograms in 0.5 ml.

PegIntron 150 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of PegIntron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and PegIntron powder to ensure delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted solution has a concentration of 150 micrograms in 0.5 ml.

PegIntron is injected subcutaneously after reconstituting the powder as instructed, attaching a needle and setting the prescribed dose. A complete and illustrated set of instructions is provided in the Annex to the Package Leaflet.

As for all parenteral medicinal products, the reconstituted solution is to be inspected visually prior to administration. The reconstituted solution should be clear and colourless. If discolouration or particulate matter is present, the reconstituted solution should not be used. After administering the dose, the PegIntron pre-filled pen and any unused solution contained in it is to be disposed of in accordance with local requirements.

7.MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8.MARKETING AUTHORISATION NUMBERS

PegIntron 50 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/131/031

EU/1/00/131/032

EU/1/00/131/034

PegIntron 80 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/131/035

EU/1/00/131/036

EU/1/00/131/038

PegIntron 100 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/131/039

EU/1/00/131/040

EU/1/00/131/042

PegIntron 120 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/131/043

EU/1/00/131/044

EU/1/00/131/046

PegIntron 150 micrograms powder and solvent for solution for injection in pre-filled pen EU/1/00/131/047

EU/1/00/131/048

EU/1/00/131/050

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 May 2000

Date of latest renewal: 25 May 2010

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the web-site of the European Medicines Agency http://www.ema.europa.eu.

Comments

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
  • Help
  • Get it on Google Play
  • About
  • Info on site by:

  • Presented by RXed.eu

  • 27558

    prescription drugs listed