Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Pegasys is indicated for the treatment of hepatitis B envelope antigen (HBeAg)-positive or HBeAgnegative chronic hepatitis B (CHB) in adult patients with compensated liver disease and evidence of viral replication, increased alanine aminotransferase (ALT) and histologically verified liver inflammation and/or fibrosis (see sections 4.4 and 5.1).
Pegasys is indicated for the treatment of HBeAg-positive CHB in non-cirrhotic children and adolescents 3 years of age and older with evidence of viral replication and persistently elevated serum ALT levels. With respect to the decision to initiate treatment in paediatric patients see sections 4.2, 4.4 and 5.1.
Pegasys is indicated in combination with other medicinal products, for the treatment of chronic hepatitis C (CHC) in patients with compensated liver disease (see sections 4.2, 4.4 and 5.1).
For hepatitis C virus (HCV) genotype specific activity, see sections 4.2 and 5.1.
Pegasys in combination with ribavirin is indicated for the treatment of CHC in treatment-naïve children and adolescents 5 years of age and older who are positive for serum HCV-RNA.
When deciding to initiate treatment in childhood, it is important to consider growth inhibition induced by combination therapy. The reversibility of growth inhibition is uncertain. The decision to treat should be made on a case by case basis (see section 4.4).
Treatment should be initiated only by a physician experienced in the treatment of patients with hepatitis B or C.
Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Pegasys.
Monotherapy for hepatitis C should only be considered in case of contraindication to other medicinal products.
The recommended dosage and duration of Pegasys for both HBeAg-positive and HBeAg-negative CHB is 180 micrograms once weekly for 48 weeks. For information on predictive values for ontreatment response, see section 5.1.
The recommended dose for Pegasys is 180 micrograms once weekly given in combination with oral ribavirin or as monotherapy.
The dose of ribavirin to be used in combination with Pegasys is given in Table 1.
The ribavirin dose should be administered with food.
The duration of combination therapy with ribavirin for CHC depends on viral genotype. Patients infected with HCV genotype 1 who have detectable HCV RNA at week 4 regardless of pre-treatment viral load should receive 48 weeks of therapy.
Treatment for 24 weeks may be considered in patients infected with:
who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24. However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration (see section 5.1). In these patients, tolerability to combination therapy and additional prognostic factors such as degree of fibrosis should be taken into account when deciding on treatment duration. Shortening the treatment duration in patients with genotype 1 and high viral load (HVL) (>800, 000 IU/ml) at baseline who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24 should be considered with even more caution since the limited data available suggest that this may significantly negatively impact the sustained virologic response.
Patients infected with HCV genotype 2 or 3 who have detectable HCV RNA at week 4, regardless of pre-treatment viral load should receive 24 weeks of therapy. Treatment for only 16 weeks may be considered in selected patients infected with genotype 2 or 3 with LVL (≤800,000 IU/ml) at baseline who become HCV negative by week 4 of treatment and remains HCV negative by week 16. Overall 16 weeks of treatment may be associated with a lower chance of response and is associated with a higher risk of relapse than a 24-week treatment duration (see section 5.1). In these patients, tolerability to combination therapy and the presence of additional clinical or prognostic factors such as degree of fibrosis should be taken into account when considering deviations from standard 24 weeks treatment duration. Shortening the treatment duration in patients infected with genotype 2 or 3 with HVL (>800,000 IU/ml) at baseline who become HCV negative by week 4 should be considered with more caution as this may significantly negatively impact the sustained virological response (see Table 1).
Available data for patients infected with genotype 5 or 6 are limited; therefore combination treatment with 1,000/1,200 mg of ribavirin for 48 weeks is recommended.
Table 1. Dosing recommendations for combination therapy for adult patients with chronic hepatitis C:
| Genotype | Pegasys dose | Ribavirin dose | Duration |
|---|---|---|---|
| Genotype 1 LVL with RVR* | 180 micrograms | <75 kg = 1000 mg, ≥75 kg = 1200 mg | 24 weeks or 48 weeks |
| Genotype 1 ΗVL with RVR* | 180 micrograms | <75 kg = 1000 mg, ≥75 kg = 1200 mg | 48 weeks |
| Genotype 4 with RVR* | 180 micrograms | <75 kg = 1000 mg, ≥75 kg = 1200 mg | 24 weeks ή 48 weeks |
| Genotype 1 or 4 without RVR* | 180 micrograms | <75 kg = 1000 mg, ≥75 kg = 1200 mg | 48 weeks |
| Genotype 2 or 3 without RVR** | 180 micrograms | 800 mg | 24 weeks |
| Genotype 2 or 3 LVL with RVR** | 180 micrograms | 800 mga | 16 weeksa or 24 weeks |
| Genotype 2 or 3 ΗVL with RVR** | 180 micrograms | 800 mg | 24 weeks |
* RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24
** RVR = rapid viral response (HCV RNA negative) by week 4 LVL = ≤800,000 IU/ml; HVL = >800,000 IU/ml
a It is presently not clear whether a higher dose of ribavirin (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.
The ultimate clinical impact of a shortened initial treatment of 16 weeks instead of 24 weeks is unknown, taking into account the need for re-treating non-responding and relapsing patients.
The recommended duration of Pegasys monotherapy is 48 weeks.
The recommended dose of Pegasys in combination with ribavirin is 180 mcg once weekly by subcutaneous administration. For patients <75 kg and 75 kg, 1000 mg daily and 1200 mg daily of ribavirin, respectively, and regardless of genotype, should be administered. Patients who have detectable virus at week 12 should stop therapy. The recommended total duration of therapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment with peginterferon and ribavirin are considered for treatment, the recommended total duration of therapy is 72 weeks (see section 5.1).
The recommended dosage for Pegasys, alone or in combination with ribavirin, is 180 micrograms once weekly subcutaneously for 48 weeks. For patients infected with HCV genotype 1 <75 kg and ≥75 kg, 1000 mg daily and 1200 mg daily of ribavirin, respectively, should be administered. Patients infected with HCV genotypes other than genotype 1 should receive 800 mg daily of ribavirin. A duration of therapy less than 48 weeks has not been adequately studied.
Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Pegasys.
Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of HCV RNA has been shown to be predictive for sustained response (see Tables 2 and 13).
Table 2. Predictive value of week 12 virological response at the recommended dosing regimen while on Pegasys combination therapy in adult patients with chronic hepatitis C:
| Genotype | Negative | Positive | ||||
|---|---|---|---|---|---|---|
| No response by week 12 | No sustained response | Predictive Value | Response by week 12 | Sustained response | Predictive Value | |
| Genotype 1 (N=569) | 102 | 97 | 95% (97/102) | 467 | 271 | 58% (271/467) |
| Genotype 2 and 3 (N=96) | 3 | 3 | 100% (3/3) | 93 | 81 | 87% (81/93) |
The negative predictive value for sustained response in patients treated with Pegasys in monotherapy was 98%.
A similar negative predictive value has been observed in HIV-HCV co-infected patients treated with Pegasys monotherapy or in combination with ribavirin (100% (130/130) or 98% (83/85), respectively). Positive predictive values of 45% (50/110) and 70% (59/84) were observed for genotype 1 and genotype ⅔ HIV-HCV co-infected patients receiving combination therapy.
In non-responder patients re-treated for 48 or 72 weeks, viral suppression at week 12 (undetectable HCV RNA defined as <50 IU/ml) has been shown to be predictive for sustained virological response. The probabilities of not achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was not achieved at week 12 were 96% (363 of 380) and 96% (324 of 339), respectively. The probabilities of achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was achieved at week 12 were 35% (20 of 57) and 57% (57 of 100), respectively.
Where dose adjustment is required for moderate to severe adverse reactions (clinical and/or laboratory) initial dose reduction to 135 micrograms is generally adequate for adult patients. In some cases, dose reduction to 90 micrograms or 45 micrograms is necessary. Dose increases to or towards the original dose may be considered when the adverse reaction abates (see sections 4.4 and 4.8).
For adults, dose reduction is recommended if the absolute neutrophil count (ANC) is 500 to <750 cells/mm³. For patients with ANC <500 cells/mm³ treatment should be suspended until ANC values return to >1000 cells/mm³. Therapy should initially be re-instituted at 90 micrograms Pegasys and the neutrophil count monitored.
Dose reduction to 90 micrograms is recommended if the platelet count is 25,000 to <50,000 cells/mm³. Treatment discontinuation is recommended when platelet count decreases to levels <25,000 cells/mm³.
Specific recommendations for management of treatment-emergent anaemia in adults are as follows: ribavirin should be reduced to 600 milligrams/day (200 milligrams in the morning and 400 milligrams in the evening) if either of the following apply: (1) a patient without significant cardiovascular disease experiences a fall in haemoglobin to <10 g/dl and ≥8.5 g/dl, or (2) a patient with stable cardiovascular disease experiences a fall in haemoglobin by ≥2 g/dl during any 4 weeks of treatment. A return to original dosing is not recommended. Ribavirin should be discontinued if either of the following applies: (1) a patient without significant cardiovascular disease experiences a fall in haemoglobin confirmed to <8.5 g/dl; (2) a patient with stable cardiovascular disease maintains a haemoglobin value <12 g/dl despite 4 weeks on a reduced dose. If the abnormality is reversed, ribavirin may be restarted at 600 milligrams daily, and further increased to 800 milligrams daily at the discretion of the treating physician. A return to original dosing is not recommended.
Table 3. Dose adjustment for adverse reactions in adult patients (for further guidance see also text above):
| Reduce ribavirin to 600 mg | Withhold ribavirin | Reduce Pegasys to 135/90/45 micrograms | Withhold Pegasys | Discontinue combination | |
| Absolute Neutrophil Count | 500 to <750 cells/mm³ | <500 cells/mm³ | |||
| Platelet Countν | 25.000 to <50.000 cells/mm³ | <25.000 cells/mm³ | |||
| Haemoglobin – no cardiac disease | <10 g/dl, and ≥8,5 g/dl | <8,5 g/dl | |||
| Haemoglobin – stable cardiac disease | decrease ≥2 g/dl during any 4 weeks | <12 g/dl despite 4 weeks at reduced dose |
In case of intolerance to ribavirin, Pegasys monotherapy should be continued.
For CHB patients, transient flares of ALT levels sometimes exceeding 10x ULN are not uncommon, and may reflect immune clearance. Treatment should normally not be initiated if ALT is >10x ULN. Consideration should be given to continuing treatment with more frequent monitoring of liver function during ALT flares. If the Pegasys dose is reduced or withheld, therapy can be restored once the flare is subsiding (see section 4.4).
No dose adjustment is required for adult patients with mild or moderate renal impairment. A reduced dose of 135 mcg once weekly is recommended in adult patients with severe renal impairment or end stage renal disease (see section 5.2). Regardless of the starting dose or degree of renal impairment, patients should be monitored and appropriate dose reductions of Pegasys during the course of therapy should be made in the event of adverse reactions.
In patients with compensated cirrhosis (e.g., Child-Pugh A), Pegasys has been shown to be effective and safe. Pegasys has not been evaluated in patients with decompensated cirrhosis (e.g., Child-Pugh B or C or bleeding oesophageal varices) (see section 4.3).
The Child-Pugh classification divides patients into groups A, B, and C, or “Mild”, “Moderate” and “Severe” corresponding to scores of 5-6, 7-9 and 10-15, respectively.
Modified Assessment:
| Assessment | Degree of abnormality | Score |
|---|---|---|
| Encephalopathy | None | 1 |
| Grade 1-2 | 2 | |
| Grade 3-4* | 3 | |
| Ascites | Absent | 1 |
| Slight | 2 | |
| Moderate | 3 | |
| S-Bilirubi (mg/dl) | <2 | 1 |
| 2.0-3 | 2 | |
| >3 | 3 | |
| (SI unit = μmol/l) | <34 | 1 |
| 34-51 | 2 | |
| >51 | 3 | |
| S-Albumin (g/dl) | >3.5 | 1 |
| 3.5-2.8 | 2 | |
| <2.8 | 3 | |
| INR | <1.7 | 1 |
| 1.7-2.3 | 2 | |
| >2.3 | 3 |
* Grading according to Trey, Burns and Saunders (1966)
Pegasys is contraindicated in neonates and young children up to 3 years old due to the excipient benzyl alcohol (see sections 4.3 and 4.4).
It is recommended that Pegasys pre-filled syringes be used for paediatric patients. The Pegasys prefilled pens do not allow for appropriate adjustment of dosing in these patients. Patients who initiate treatment prior to their 18th birthday should maintain paediatric dosing through the completion of therapy.
The posology of Pegasys in paediatric patients is based on the Body Surface Area (BSA). To calculate BSA, it is recommended to use Mosteller’s equation:
The recommended duration of therapy is 48 weeks in patients with CHB. Before initiating therapy for CHB, persistently elevated serum ALT levels should have been documented. The response rate was lower in patients with no to minimal increase in ALT level at baseline (see Section 5.1).
The duration of treatment with Pegasys in combination with ribavirin in paediatric patients with CHC depends on viral genotype. Patients infected with viral genotypes 2 or 3 should receive 24 weeks of treatment, while patients infected with any other genotype should receive 48 weeks of therapy. Patients who still have detectable levels of HCV-RNA despite an initial 24 weeks of therapy, should discontinue therapy, as it is unlikely they will be able to achieve a sustained virological response with continued therapy.
For children and adolescents aged 3 to 17 years with CHB and having a BSA greater than 0.54 m² and for children and adolescents aged 5 to 17 years with CHC and having a BSA greater than 0.71 m², the recommended doses for Pegasys are provided in Table 4.
Table 4. Pegasys dosing recommendations for paediatric patients with chronic hepatitis B and chronic hepatitis C:
| Body Surface Area (BSA) range (m²) | Weekly dose (mcg) | |
|---|---|---|
| CHC | CHB | |
| 0.71-0.74 | 0.54-0.74 | 65 |
| 0.75-1.08 | 90 | |
| 1.09-1.51 | 135 | |
| >1.51 | 180 | |
For paediatric patients, based on toxicities, up to three levels of dose modification can be made before dose interruption or discontinuation is considered (see Table 5).
Table 5. Pegasys dose modification recommendations in paediatric patients with chronic hepatitis B or chronic hepatitis C:
| Starting dose (mcg) | 1 level reduction (mcg) | 2 level reduction (mcg) | 3 level reduction (mcg) |
|---|---|---|---|
| 65 | 45 | 30 | 20 |
| 90 | 65 | 45 | 20 |
| 135 | 90 | 65 | 30 |
| 180 | 135 | 90 | 45 |
Recommendations for dose modifications of Pegasys for toxicities in the CHB and CHC paediatric populations are presented in Table 6.
Table 6. Pegasys dose modification recommendations for toxicities in paediatric patients with chronic hepatitis B or chronic hepatitis C:
| Toxicity | Pegasys Dose Modification |
|---|---|
| Neutropenia | 500 to <750 cells/mm³: Immediate 1 level adjustment. |
| 250 to <500 cells/mm³: interrupt dosing until ≥1000 cells/mm³, then resume dose with 2 level adjustments and monitor. | |
| <250 cells/mm³ (or febrile neutropenia): discontinue treatment. | |
| Thrombocytopenia | Platelet 25.000 to <50.000 cells/mm³: 2 level adjustment. |
| Platelet <25.000 cells/mm³: discontinue treatment. | |
| Increased alanine aminotransferase (ALT) | For persistent or increasing elevations ≥5 but <10 x ULN, reduce dose with a 1 level adjustment and monitor weekly ALT level to ensure it is stable or decreasing. |
| For persistent ALT values ≥10 x ULN discontinue treatment. |
For children and adolescents aged 5 to 17 years with CHC, the recommended dose of ribavirin is based on the patient’s body weight, with a target dose of 15 mg/kg/day, divided in two daily doses. For children and adolescents 23 kg or greater, a dosing schedule using 200 mg ribavirin tablets is provided in Table 7. Patients and caregivers must not attempt to break the 200 mg tablets.
Table 7. Ribavirin dosing recommendations for paediatric patients with chronic hepatitis C aged 5 to 17 years:
| Body weight kg (lbs) | Ribavirin daily dose (Approx. 15 mg/kg/day) | Ribavirin number of tablets |
|---|---|---|
| 23–33 (51-73) | 400 mg/day | 1 × 200 mg tablets A.M. |
| 1 × 200 mg tablets P.M. | ||
| 34–46 (75-101) | 600 mg/day | 1 × 200 mg tablets A.M. |
| 2 × 200 mg tablets P.M. | ||
| 47–59 (103-131) | 800 mg/day | 2 × 200 mg tablets A.M. |
| 2 × 200 mg tablets P.M. | ||
| 60–74 (132-163) | 1000 mg/day | 2 × 200 mg tablets A.M. |
| 3 × 200 mg tablets P.M. | ||
| ≥75 (>165) | 1200 mg/day | 3 × 200 mg tablets A.M. |
| 3 × 200 mg tablets P.M. |
It is important to note that ribavirin should never be given as monotherapy. Unless otherwise noted, the management of all other toxicities should follow the adult recommendations.
In paediatric patients, ribavirin treatment-associated toxicities, such as treatment-emergent anaemia, will be managed by reduction of the full dose. The dose reduction levels are provided in Table 8.
Table 8. Ribavirin dose modification recommendations in paediatric patients with chronic hepatitis C:
| Full dose (Approx. 15 mg/kg/day) | One step dose modification (Approx. 7.5 mg/kg/day) | Ribavirin number of tablets |
|---|---|---|
| 400 mg/day | 200 mg/day | 1 × 200 mg tablets A.M. |
| 600 mg/day | 400 mg/day | 1 × 200 mg tablets A.M. |
| 1 × 200 mg mg tablets P.M. | ||
| 800 mg/day | 400 mg/day | 1 × 200 mg tablets A.M. |
| 1 × 200 mg mg tablets P.M. | ||
| 1000 mg/day | 600 mg/day | 1 × 200 mg tablets A.M. |
| 2 × 200 mg mg tablets P.M. | ||
| 1200 mg/day | 600 mg/day | 1 × 200 mg tablets A.M. |
| 2 × 200 mg mg tablets P.M. |
There is limited experience with Pegasys in treating paediatric patients with CHC aged 3 to 5 years, or who have failed to be adequately treated previously. There are no data in paediatric patients coinfected with HCV/HIV or with renal impairment.
Pegasys is administered subcutaneously in the abdomen or thigh. Exposure to Pegasys was decreased in studies following administration of Pegasys in the arm (see section 5.2).
Pegasys is designed for administration by the patient or carer. Each syringe should be used by one person only and is for single use.
Appropriate training is recommended for non-healthcare professionals administering this medicinal product. The “Instructions for the User”, provided in the carton, must be followed carefully by the patient.
Overdoses involving between two injections on consecutive days (instead of weekly interval) up to daily injections for 1 week (i.e., 1260 micrograms/week) have been reported. None of these patients experienced unusual, serious or treatment-limiting events. Weekly doses of up to 540 and 630 micrograms have been administered in renal cell carcinoma and chronic myelogenous leukaemia clinical trials, respectively. Dose limiting toxicities were fatigue, elevated liver enzymes, neutropenia and thrombocytopenia, consistent with interferon therapy.
Pegasys 90 micrograms solution for injection in pre-filled syringe: 3 years.
Pegasys 135 micrograms solution for injection in pre-filled syringe: 4 years.
Pegasys 180 micrograms solution for injection in pre-filled syringe: 4 years.
Store in a refrigerator (2°C-8°C). Do not freeze.
Keep the pre-filled syringe in the outer carton in order to protect from light.
0.5 ml of solution for injection in pre-filled syringe (siliconised Type I glass) with a plunger stopper and tip cap (butyl rubber laminated on the product facing side with fluororesin) with a needle.
Pegasys 90 micrograms solution for injection in pre-filled syringe: The syringe is labeled with graduations corresponding to doses of 90 mcg, 65 mcg, 45 mcg, 30 mcg, 20 mcg and 10 mcg. Available in packs of 1 pre-filled syringe.
Pegasys 135 micrograms solution for injection in pre-filled syringe: The syringe is labeled with graduations corresponding to doses of 135 mcg, 90 mcg and 45 mcg. Available in packs of 1, 4 or a multipack of 12 (2 packs of 6) pre-filled syringes. Not all pack-sizes may be marketed.
Pegasys 180 micrograms solution for injection in pre-filled syringe: The syringe is labeled with graduations corresponding to doses of 180 mcg, 135 mcg and 90 mcg. Available in packs of 1, 4 or a multipack of 12 (2 packs of 6) pre-filled syringes. Not all pack-sizes may be marketed.
The solution for injection is for single use only. It should be inspected visually for particulate matter and discoloration before administration.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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