Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN, Haarlem, The Netherlands
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.
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.
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.
Treatment should be initiated and monitored only by a physician experienced in the management of patients with hepatitis C.
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.
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.
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 (kg) | PegIntron | Ribavirin capsules | ||
|---|---|---|---|---|
| PegIntron strength (μg/0.5 ml) | Administer once weekly (ml) | Total daily ribavirin dose (mg) | Number of capsules (200 mg) | |
| <40 | 50 | 0.5 | 800 | 4a |
| 40-50 | 80 | 0.4 | 800 | 4a |
| 51-64 | 80 | 0.5 | 800 | 4a |
| 65-75 | 100 | 0.5 | 1,000 | 5b |
| 76-80 | 120 | 0.5 | 1,000 | 5b |
| 81-85 | 120 | 0.5 | 1,200 | 6c |
| 86-105 | 150 | 0.5 | 1,200 | 6c |
| >105 | 150 | 0.5 | 1,400 | 7 |
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.
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).
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.
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.
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 μg/m²/week subcutaneously in combination with ribavirin 15 mg/kg/day orally in two divided doses with food (morning and evening).
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 (kg) | PegIntron strength (μg/0.5 ml) | Administer once weekly (ml) | PegIntron strength (μg/0.5 ml) | Administer once weekly (ml) |
| 30-35 | 50* | 0.15 | 80 | 0.2 |
| 36-45 | 50 | 0.2 | 50 | 0.4 |
| 46-56 | 50 | 0.25 | 50 | 0.5 |
| 57-72 | 80 | 0.2 | 80 | 0.4 |
| 73-88 | 50 | 0.4 | 80 | 0.5 |
| 89-106 | 50 | 0.5 | 100 | 0.5 |
| 107-120** | 80 | 0.4 | 120 | 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.
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).
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.
Table 2a. Dose modification guidelines for combination therapy based on laboratory parameters:
| Laboratory values | Reduce only ribavirin daily dose (see note 1) if | Reduce only PegIntron dose (see note 2) if: | Discontinue combination therapy if: |
|---|---|---|---|
| Haemoglobin | ≥8.5 g/dl and <10 g/dl | - | <8.5 g/dl |
| Adults: Haemoglobin in Patients with history of stable cardiac disease | ≥2 g/dl decrease in haemoglobin during any four week period during treatment (permanent dose reduction) | <12 g/dl after four weeks of dose reduction | |
| Children and adolescents: not applicable | |||
| Leukocytes | - | ≥1.0 × 109/l and <1.5 × 109/l | <1.0 × 109/l |
| Neutrophils | - | ≥0.5 × 109/l and <0.75 × 109/l | <0.5 × 109/l |
| Platelets | - | ≥25 × 109/l and <50 × 109/l (adults) | <25 × 109/l (adults) |
| ≥50 × 109/l and <70 × 109/l (children and adolescents) | <50 × 109/l (children and adolescents) | ||
| Bilirubin – direct | - | - | 2.5 x ΑΦΟ* |
| 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 aminotransferase (ALT) or | - | - | 2 x baseline and >10 x ULN* |
| Aspartate aminotransferase (AST) | - | - | 2 x baseline and >10 x ULN* |
* 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 1 st 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 μg/m²/week, 2nd dose reduction of PegIntron is to 20 μg/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 μg/m²/week, to 40 μg/m²/week, then to 20 μg/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 weight (kg) | PegIntron strength (μg/0.5 ml) | Amount of PegIntron to administer (μg) | Volume of PegIntron to administer (ml) | Body weight (kg) | PegIntron strength (μg/0.5 ml) | Amount of PegIntron to administer (μg) | Volume of PegIntron to administer (ml) |
| <40 | 50 | 35 | 0.35 | <40 | 50 | 20 | 0.2 |
| 40–50 | 120 | 48 | 0.2 | 40–50 | 50 | 25 | 0.25 |
| 51–64 | 80 | 56 | 0.35 | 51–64 | 80 | 32 | 0.2 |
| 65–75 | 100 | 70 | 0.35 | 65–75 | 50 | 35 | 0.35 |
| 76–85 | 80 | 80 | 0.5 | 76–85 | 120 | 48 | 0.2 |
| 86-105 | 120 | 96 | 0.4 | 86–105 | 50 | 50 | 0.5 |
| >105 | 150 | 105 | 0.35 | >105 | 80 | 64 | 0.4 |
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 to one-half dose if: | Discontinue PegIntron if: |
|---|---|---|
| Neutrophils | ≥0.5 × 109/l, and <0.75 × 109/l | <0.5 × 109/l |
| Platelets | ≥25 × 109/l, and <50 × 109/l | <25 × 109/l |
For adult patients who use 0.5 μg/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 μg/kg) for the 0.5 μg/kg monotherapy regimen in adults:
| Body weight (kg) | PegIntron strength (μg/0.5 ml) | Amount of PegIntron to administer (μg) | Volume of PegIntron to Administer (ml) |
|---|---|---|---|
| 30-35 | 50* | 8 | 0.08 |
| 36-45 | 50* | 10 | 0.1 |
| 46-56 | 50* | 13 | 0.13 |
| 57-72 | 80* | 16 | 0.1 |
| 73-88 | 50 | 20 | 0.2 |
| 89-106 | 50 | 25 | 0.25 |
| 107-120** | 80 | 32 | 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 μg/kg) for the 1.0 μg/kg monotherapy regimen in adults:
| Body weight (kg) | PegIntron strength (μg/0.5 ml) | Amount of PegIntron to administer (μg) | Volume of PegIntron to administer (ml) |
|---|---|---|---|
| 30-35 | 50* | 15 | 0.15 |
| 36-45 | 50 | 20 | 0.20 |
| 46-56 | 50 | 25 | 0.25 |
| 57-72 | 80 | 32 | 0.2 |
| 73-88 | 50 | 40 | 0.4 |
| 89-106 | 50 | 50 | 0.5 |
| 107-120** | 80 | 64 | 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.
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.
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.
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.
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).
PegIntron can be used in combination with ribavirin in paediatric patients 3 years of age and older.
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.
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).
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, inuse 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.
Store in a refrigerator (2°C-8°C).
For storage conditions of the reconstituted medicinal product, see section 6.3.
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:
Not all pack sizes may be marketed.
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.
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