Medicinal Products

PEGASYS 180 micrograms

Generic drug of the therapeutic class: Gastro-Entero-Hepatology
active ingredients: Peginterferon alfa-2a
Lab: Roche Registration Ltd

Injectable solution
Box of 4 pre-filled 0.5 mL syringes
All forms

Indication

Chronic hepatitis B


Pegasys is indicated for the treatment of HBeAg (HBeAg) positive or negative chronic hepatitis B (HCB) in adults with compensated liver disease with viral replication, elevated ALT and hepatic inflammation and / or histologically proven fibrosis (see sections 4.4 Special warnings and precautions for use and Pharmacodynamic properties).

Chronic hepatitis C


Adult patients

Pegasys is indicated, in combination with other medicinal products, for the treatment of chronic hepatitis C (CCH) in patients with compensated liver disease (see sections 4.2 and 4.2). use and pharmacodynamic properties).


For activity based on hepatitis C virus (HCV) genotype, see sections Posology and method of administration and Pharmacodynamic properties.


Pediatric population aged 5 years and over:

The combination of Pegasys and ribavirin is indicated for the treatment of chronic hepatitis C in children aged 5 years and older and treatment-naive adolescents with ribo-nucleic acid of hepatitis C virus (RNA). -VHC) positive serum.

When it is decided to initiate the treatment in children, it is important to consider an inhibition of growth induced by the association. The reversibility of this inhibition is uncertain. The decision to treat should be made on a case-by-case basis (see section 4.4 Special warnings and precautions for use).

Dosage PEGASYS 180 micrograms Solution for injection Box of 4 0.5 mL pre-filled syringes

Treatment should be initiated only by a physician experienced in the treatment of patients with hepatitis B or C.

Also refer to the Summary of Product Characteristics (SPC) of the drugs used in combination with Pegasys.
Monotherapy in patients with hepatitis C should only be considered if there is a contraindication to another medicine.


Dosage

Chronic hepatitis B adult patients

The recommended dosage and duration of treatment for Pegasys is 180 micrograms once a week for 48 weeks, by subcutaneous injection into the abdomen or thigh, regardless of whether it is HBeAg-positive chronic HBV hepatitis or HBeAg negative.

Chronic hepatitis C - naive adult patients:

The recommended dosage for Pegasys is 180 micrograms once a week, by subcutaneous injection into the abdomen or thigh, in combination with ribavirin or monotherapy.

The dose of ribavirin for use in combination with Pegasys is shown in Table 1.

Ribavirin should be given with food.

Duration of treatment - Pegasys and ribavirin dual therapy

The duration of treatment of chronic hepatitis C with dual therapy in combination with ribavirin depends on the viral genotype. Patients infected with HCV genotype 1 who have a detectable HCV RNA level at week 4, regardless of the initial viral load, should be treated for 48 weeks.

Treatment lasting 24 weeks may be considered in patients infected with:

- a genotype 1 with a low initial viral load (≤ 800 000 IU / ml) or

- a genotype 4

in whom the HCV RNA becomes undetectable at week 4 and remains undetectable at week 24. However, a total treatment duration of 24 weeks may be associated with a higher risk of relapse than a treatment duration of 48 weeks (see section Pharmacodynamic properties ). In these patients, the tolerance of dual therapy and additional prognostic factors such as the degree of fibrosis should be taken into account when determining the duration of treatment. A decrease in the duration of treatment in patients infected with genotype 1 with a high initial viral load (> 800, 000 IU / ml) in whom HCV RNA becomes undetectable at week 4 and remains undetectable at week 24 should be considered with even greater caution since the available data are limited and suggest that this decrease in treatment duration may have a significant negative impact on obtaining a prolonged virological response.

Patients infected with HCV genotype 2 or 3 who have a detectable HCV RNA level at week 4, regardless of the initial viral load, should be treated for 24 weeks. A treatment lasting only 16 weeks can be considered in patients infected with genotype 2 or 3 with a low initial viral load (≤ 800, 000 IU / ml) whose HCV RNA level becomes negative by the week. 4 treatment and remains negative at week 16. A total treatment duration of 16 weeks may be associated with a lower response rate and is associated with a higher risk of relapse than a treatment duration of 24 weeks (see section Pharmacodynamic properties ). In these patients, the tolerance of dual therapy and the presence of additional clinical or prognostic factors, such as the degree of fibrosis, should be taken into account when a change in the standard duration of treatment of 24 weeks is considered. A decrease in the duration of treatment in patients infected with genotype 2 or 3 with a high initial viral load (> 800, 000 IU / ml) whose HCV RNA level becomes negative at week 4 should be considered with more caution because this shorter duration of treatment may have a significant negative impact on obtaining a prolonged virological response (see Table 1).

Available data in patients infected with genotype 5 or 6 are limited. Therefore, dual therapy with 1000/1 200 mg ribavirin for 48 weeks is recommended.

Table 1: Dosing recommendations for the combination in patients infected with HCV

Genotype

Dose of Pegasys

Dose of ribavirin

duration

Genotype 1 low viral load with RVR * 180 micrograms <75 kg = 1000 mg ≥ 75 kg = 1200 mg 24 weeks or 48 weeks
Genotype 1 high viral load 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 or 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 low viral load with RVR ** 180 micrograms

800 mg (a)

16 weeks (a) or

24 weeks
Genotype 2 or 3 high viral load with RVR ** 180 micrograms 800 mg 24 weeks
* RVR = rapid virological response (undetectable HCV RNA) at week 4 and undetectable HCV RNA at week 24 ** RVR = rapid virological response (negative HCV RNA) at week 4 Low viral load = ≤ 800, 000 IU / ml; High viral load => 800, 000 IU / ml

(a) It is not currently known whether a higher dose of ribavirin (eg 1000/1200 mg / day by weight) leads to higher sustained virological response rates than a dose of 800 mg / day, when duration of treatment is reduced to 16 weeks.

The final clinical impact of a decrease in initial treatment duration to 16 weeks instead of 24 weeks, after considering the need to re-treat non-responders and relapsers, is not known .

In monotherapy, the recommended duration of treatment with Pegasys is 48 weeks.

Chronic hepatitis C - adult patients who have been previously treated:

The recommended dosage of Pegasys in combination with ribavirin is 180 micrograms once a week subcutaneously. A dose of 1000 mg / day and 1200 mg / day of ribavirin should be administered to patients weighing <75 kg and ≥ 75 kg, regardless of genotype.

Patients with detectable virus at week 12 should stop treatment.

The total recommended duration of treatment is 48 weeks. If treatment is considered in patients infected with a genotype 1 virus, who have not responded to previous treatment with

pegylated interferon and ribavirin, the recommended total duration of treatment is 72 weeks (see section 5.1 ).


Adult patients co-infected with HIV and HCV

The recommended dosage of Pegasys, alone or in combination with ribavirin, is 180 micrograms once a week for 48 weeks, subcutaneously. A dose of 1000 mg / day and 1200 mg / day of ribavirin should be administered to patients infected with HCV genotype 1 whose weight is <75 kg and ≥ 75 kg, respectively. Patients infected with HCV of genotype 1 genotype should receive 800 mg of ribavirin daily. A treatment duration of less than 48 weeks has not been sufficiently studied.

Duration of treatment when Pegasys is used in combination with other medicines

Also refer to the Summary of Product Characteristics (SPC) for drugs used in combination with Pegasys
Predictive value of getting a response or no response with Pegasys and ribavirin dual therapy - naïve patients
Obtaining an early virologic response at Week 12, defined as a 2-log decrease in viral load or by the non-detection of HCV RNA, has been shown to be predictive of prolonged response (see Tables 2 and 12).

Table 2: Predictive value of virologic response at Week 12 at the recommended dosage when Pegasys is used in combination

Genotype

negative

positive

No answer at week 12 No prolonged response Predictive value Answer to week 12 Extended 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)

In patients treated with Pegasys monotherapy, the predictive value of no prolonged response was 98%.

A similar negative predictive value was observed in patients co-infected with HIV and HCV receiving Pegasys alone or in combination with ribavirin (100% (130/130) and 98% (83/85), respectively). In co-infected patients treated with the combination, positive predictive values ​​of 45% (50/110) and 70% (59/84) were observed for genotypes 1 and 2/3, respectively.

Predictive Value of Obtaining Response or No Response with Pegasys and Ribavirin Dual Therapy - Previously Treated Patients

In non-responder patients re-treated for 48 or 72 weeks, suppression of virus at week 12 (undetectable HCV RNA defined as <50 IU / ml) was predictive of prolonged virologic response. If virus suppression was not achieved by week 12, the odds of not obtaining a sustained virological response with 48 or 72 weeks of treatment were 96% (363 of 380) and 96% (324 of 339), respectively. . If virus suppression was achieved by week 12, the probabilities of obtaining a sustained virological response with 48 or 72 weeks of treatment were 35% (20 of 57) and 57% (57 of 100), respectively.

Dose modification in case of adverse reactions in adult patients

When dosage should be adjusted for moderate to severe adverse reactions (clinical reactions and / or laboratory abnormalities), an initial dose reduction of 135 micrograms is usually sufficient in adult patients. In some cases, a reduction of the dose to 90 micrograms or 45 micrograms is necessary. Dose increases may be considered, possibly returning to the starting dose when adverse reactions have been reduced (see Warnings and Precautions and Adverse Reactions sections).

Hematologic abnormalities (see also Table 3)

In adult patients, a dose reduction is recommended when the number of polymorphonuclear neutrophils becomes <750 / mm 3 . In patients with absolute neutrophils (NAPN) <500 / mm 3, treatment should be suspended until NAPN becomes> 1000 / mm 3 . Treatment with Pegasys may be resumed at a dose of 90 micrograms and the number of neutrophils will be monitored. The recommendations for dose reduction based on NAPN in children are presented in Table 7.

A reduction of the dose to 90 micrograms is recommended if the number of platelets is <50 000 / mm 3 . Stopping treatment is recommended when the number of platelets becomes <25, 000 / mm 3 .

Specific recommendations for the management of treatment-induced anemia in adult patients are as follows: the dose of ribavirin should be reduced to 600 milligrams / day (200 milligrams in the morning and 400 milligrams in the evening) if the one of the following conditions applies:

(1) a patient without significant cardiovascular disease has a decrease in hemoglobin between <10 g / dl and ≥ 8.5 g / dl or (2) a patient with stable cardiovascular disease has a decrease in hemoglobin ≥ 2 g / dl for a period of four consecutive weeks of treatment. It is not recommended to return to the initial dosage. Ribavirin should be discontinued if any of the following conditions apply: (1) a patient without significant cardiovascular disease has a decrease in hemoglobin confirmed to <8.5 g / dl;

(2) a patient with stable cardiovascular disease maintains a hemoglobin <12 g / dl despite 4 weeks at a reduced dose. If the abnormality is corrected, ribavirin can be readministered at 600 milligrams / day and then increased to 800 milligrams / day as decided by the attending physician. It is not recommended to return to the initial dosage.

Table 3: Adjustment of the dose in case of adverse reaction (for more details, see text above)
Reduce the dose of ribavirin to 600 mg Stop ribavirin Reduce the dose of Pegasys to 135/90/45 micrograms Stop Pegasys Stop Pegasys + ribavirin
Absolute number of neutrophils

<750 / mm 3

<500 / mm 3

platelets

<50, 000 / mm 3 > 25, 000 / mm 3

<25, 000 / mm 3

Hemoglobin
- no heart disease

<10 g / dl and ≥ 8.5 g / dl <8.5 g / dl

Hemoglobin
- disease

stable heart
decrease ≥ 2 g / dl for a period of 4 weeks <12 g / dl despite 4 weeks at reduced dose

In case of ribavirin intolerance, Pegasys monotherapy should be continued.

Liver function

Fluctuations in liver test abnormalities are common in patients with chronic hepatitis C. Elevations of ALT above baseline (IT) have been observed in patients treated with Pegasys, including patients with virological response.

In clinical trials for chronic hepatitis C in adult patients, isolated elevations of ALT (≥ 10 x LNS (Upper Normal Limit) or ≥ 2 x TI for patients with an initial ALT ≥ 10 x LNS) were observed in 8 of the 451 patients treated by the association. These rates normalized without the dose being changed. If the increase in ALT is progressive or persistent, the dose should first be reduced to 135 micrograms. If elevation of ALT continues despite dose reduction or is accompanied by increased bilirubin or signs of hepatic decompensation, treatment should be discontinued (see Warnings and Precautions section). employment ). The recommendations for dosage reduction based on ALT levels in children are presented in Table 7.

In patients with chronic hepatitis B, transient hepatic cytolysis, sometimes exceeding 10 times the upper limit of normal for ALT, is not uncommon and may indicate immune clearance. Treatment with Pegasys should not normally be initiated if ALT is greater than 10 x LNS. If treatment is continued, closer monitoring of liver function should be considered during elevations of transaminases. In case of dose reduction or discontinuation of Pegasys, initial therapy may be reinstituted after improvement in ALT (see Warnings and Precautions section ).


Special populations

Elderly

There is no need to adjust the recommended dosage of 180 micrograms once a week if Pegasys treatment is started in elderly patients (see section 5.2 ).

Renal failure

In patients with end-stage renal disease, an initial dose of 135 micrograms should be used (see section 5.2 ). Regardless of the initial dose or degree of renal impairment, patients should be monitored and the dose of Pegasys should be appropriately reduced during treatment in case of adverse reactions.

Hepatic insufficiency

In patients with compensated cirrhosis (ie Child-Pugh A), Pegasys has demonstrated efficacy and good tolerability. Pegasys has not been evaluated in patients with decompensated cirrhosis (ie Child-Pugh B or C or oesophageal hemorrhagic 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 evaluation

Evaluation Degree of anomaly Score
encephalopathy No 1
Grade 1-2 2
Grade 3-4 * 3
ascites Absence 1
Lightweight 2
Moderate 3
Bilirubin (mg / dl) <2 1
2.0 to 3 2
> 3 3
(SI unit = μmol / l) <34 1
34-51 2
> 51 3
Albumin (g / dl) > 3, 5 1
3.5 to 2.8 2
<2.8 3
INR <1.7 1
1.7-2.3 2
> 2, 3 3

* Graduation according to Trey, Burns and Saunders (1966)


Pediatric population

Pegasys is contraindicated in neonates and children up to 3 years of age because of the presence of benzyl alcohol (see sections Contraindications and Warnings and Precautions ).

In children and adolescents aged 5 to 17 years with chronic hepatitis C and with

body surface area (SC) greater than 0.7 m 2, the recommended dosages of Pegasys and ribavirin are shown in Table 4 and Table 5. It is recommended that pre-filled syringes from Pegasys be used for children. Pegasys pre-filled pens do not allow for proper dose adjustment in these patients. Patients who begin treatment before their 18th birthday must maintain the dosage applicable to the pediatric population until the end of treatment.

Pegasys should not be used in children with body surface area (SCC) less than 0.71 m 2 as there are no data available for this population.

To calculate the body surface (SC), it is recommended to use the Mosteller equation:

______________________

Body Area (m 2) = √ (Size (cm) X Weight (Kg))

3600 Processing time

The duration of treatment with Pegasys in combination with ribavirin in children with chronic hepatitis C depends on the viral genotype. Patients infected with viral genotype 2 or 3 must receive 24 weeks of treatment, while patients infected with any other genotype must receive 48 weeks of treatment.

Patients who still have a detectable level of RNA-HCV despite initial 24-week treatment, should discontinue treatment as they are unlikely to be able to achieve prolonged virological response by continuing treatment.

Table 4: Posology Recommendations for Pegasys in Children Aged 5-17 Years

Body Area (SC) (m 2 )

Weekly dose (mcg)
0.71 to 0.74 65
0.75 to 1.08 90
1.09 to 1.51 135
> 1.51 180

For children and adolescents aged 5 to 17 years with chronic hepatitis C, the recommended dose of ribavirin is determined based on the patient's body surface area. The recommended dosage is 15 mg / kg / day divided into two doses per day.

Dosage recommendations for children and adolescents weighing 23 kg or more using 200 mg ribavirin tablets are shown in Table 5. Patients and their caregivers should not attempt to break the 200 mg tablets.


Table 5: Dosing recommendations for ribavirin in children aged 5 to 17 years

Body weight (kg) Daily dose of ribavirin (Approx 15 mg / kg / day) Number of ribavirin tablets
23 - 33 400 mg / day

1 tablet 200 mg in the morning
1 tablet at 200 mg in the evening

34 - 46 600 mg / day

1 tablet 200 mg in the morning

2 tablets at 200 mg in the evening

47 - 59 800 mg / day 2 200 mg tablets in the morning 2 200 mg tablets in the evening
60 - 74 1000 mg / day 2 200 mg tablets in the morning 3 200 mg tablets in the evening
≥ 75 1200 mg / day 3 tablets 200 mg in the morning 3 tablets 200 mg the evening
Dose modification in case of adverse reactions in children

In children, based on the toxicities (see Table 6), a dose modification of up to three levels may be applied before considering interruption or discontinuation of treatment.

Table 6: Change in recommended Pegasys dose in children

Initial dose

(Mcg)

1 step reduction (mcg)

Reduction of

2 steps

(Mcg)

Reduction of

3 steps

(Mcg)

65 45 30 20
90 65 45 20
135 90 65 30
180 135 90 45

In the event of toxicities that may be associated with Pegasys and / or ribavirin, the dose of one or both of the drugs may be reduced. In addition, ribavirin or Pegasys / ribavirin combination may be discontinued. It is important to emphasize that ribavirin should never be used as monotherapy. Dose modification recommendations for Pegasys-specific and pediatric-specific toxicities are presented in Table 7. Unless otherwise noted, action to address all other toxicities should be considered. follow the recommendations applicable to adults.


Table 7: Recommendations for dose modification for children's toxicities

Toxicity

Changing the dose of Pegasys

neutropenia

750-999 cells / mm 3 : 1-2 weeks: immediate reduction of the dose of a plateau; weeks 3-48: no change.

500-749 cells / mm 3 : 1-2 weeks: discontinue treatment until> 750 cells / mm 3 return, then resume treatment with a dose reduction of one step, check once a week during three weeks after that the number of white blood cells is> 750 cells / mm 3 ; weeks 3-48: immediate reduction of the dose of a plateau.

250-499 cells / mm 3 : 1-2 weeks: discontinue treatment until return to> 750 cells / mm 3, then resume treatment with a two dose reduction; weeks 3-48: discontinue treatment until return to> 750 cells / mm 3, then resume treatment with a dose reduction of one step.

<250 cells / mm 3 (or febrile neutropenia): stop treatment.

Increased alanine aminotransferase (ALT) In case of persistent or increasing elevations ≥ 5 but <10 x LNS, reduce the dose by one step and monitor the ALT once a week to ensure that it is stable or decreasing. In case of persistent ALT ≥ 10 x LNS, stop the treatment.

In children, the toxicities associated with ribavirin therapy, such as treatment-induced anemia, will be managed by reducing the total dose. The dose reduction steps are shown in Table 8.

Table 8: Recommendations for changing the dose of ribavirin in children

Total dose

(Approx 15 mg / kg / day)

Changing the dose of a bearing

(Approx 7.5 mg / kg / day)

Number of ribavirin tablets

400 mg / day 200 mg / day 1 tablet 200 mg in the morning
600 mg / day 400 mg / day

1 tablet 200 mg in the morning
1 tablet at 200 mg in the evening

800 mg / day 400 mg / day

1 tablet 200 mg in the morning
1 tablet at 200 mg in the evening

1000 mg / day 600 mg / day

1 tablet 200 mg in the morning

2 tablets at 200 mg in the evening

1200 mg / day 600 mg / day

1 tablet 200 mg in the morning

2 tablets at 200 mg in the evening

There is limited data regarding the use of Pegasys for the treatment of children aged 3 to 5 with hepatitis C or who have not been optimally treated previously. There are no data in children with HCV and HIV or kidney disease.


Administration mode :

Pegasys is given by subcutaneous injection into the abdomen or thigh. Exposure to Pegasys was lower in studies after administration in the arm (see section Pharmacokinetic properties ).

Pegasys is designed to be administered by the patient himself or by his caregiver.

Each syringe must be used by one person and is intended for one use only.

Appropriate training is recommended for non-health professionals administering this medication. The instructions in the leaflet explaining how to administer Pegasys should be carefully followed by the patient.

Against indications

• Hypersensitivity to the active substance, interferons alfa or to any of the ingredients mentioned under Composition

• Autoimmune hepatitis

• Severe hepatic insufficiency or decompensated cirrhosis

• • Severe pre-existing cardiac pathology, including unstable or uncontrolled heart disease in the last six months (see Warnings and Precautions section )

• Patients co-infected with HIV and HCV, with cirrhosis with a Child-Pugh score ≥ 6, unless this is solely due to an elevation of indirect bilirubin caused by drugs such as atazanavir and indinavir

• Association with telbivudine (see section Interactions with other medicinal products and other forms of interaction )

• In newborns and young children up to 3 years old, because of the presence of benzyl alcohol as an excipient (see Warnings and Precautions for Benzyl Alcohol section)

• Children with severe psychiatric disorders or with a history of severe psychiatric disorders including severe depression, suicidal ideation, or attempted suicide.

Pegasys side effects

Summary of the job security profile

Chronic hepatitis C

The frequency and severity of the main adverse reactions with Pegasys are similar to those reported with interferon alfa-2a (see Table 9). The most common adverse reactions with Pegasys 180 micrograms were mostly mild to moderate and did not require dose modification or discontinuation.

Chronic hepatitis B

In clinical trials of 48 weeks of treatment and 24 weeks of follow-up, the safety profile of Pegasys in patients with chronic hepatitis B was similar to that seen in patients with chronic hepatitis C. Except In fever, the frequency of the majority of adverse reactions reported was significantly lower in Pegasys-treated HBV-treated patients compared to HCV-treated patients treated with Pegasys monotherapy (see Table 9). Adverse events occurred in 88% of Pegasys-treated patients, compared to 53% of lamivudine-treated patients alone, while 6% of Pegasys-treated patients and 4% of lamivudine-treated patients experienced serious adverse events during treatment. clinical tests. Adverse events or laboratory abnormalities led 5% of patients to discontinue Pegasys, while less than 1% of patients in the lamivudine arm alone discontinued treatment for these reasons. The percentage of cirrhotic patients who discontinued treatment was similar to that observed in the overall population in each treatment group.

Chronic hepatitis C in non-responder patients at a previous treatment

Overall, the safety profile of Pegasys in combination with ribavirin in non-responder patients in a previous treatment was similar to that of naïve patients. In a clinical study in non-responder patients with previous treatment with pegylated interferon alfa-2b / ribavirin, treated for either 48 weeks or 72 weeks, the frequency of discontinuation of Pegasys treatment and treatment with ribavirin for cause of adverse effects or biological abnormalities was 6% and 7%, respectively in arms 48 weeks and 12% and 13%, respectively in arms 72 weeks. Similarly, for patients with cirrhosis or cirrhosis, the frequency of Pegasys treatment discontinuation and ribavirin treatment was higher in the treated arms for 72 weeks (13% and 15%) than in patients with cirrhosis. treated arms for 48 weeks (6% and 6%). Patients who discontinued previous treatment with pegylated interferon alfa-2b / ribavirin due to haematological toxicity were excluded from recruitment in this study.

In another clinical study, non-responder patients with severe fibrosis or cirrhosis (Ishak score of 3 to 6) and a baseline platelet count of 50, 000 / mm 3 were treated for 48 weeks. Hematologic abnormalities observed during the first 20 weeks of the study included: anemia (26% of patients had hemoglobin <10 g / dl), neutropenia (30% had an absolute number of neutrophils <750 / mm 3 ) and thrombocytopenia (13% had a platelet count <50 000 / mm 3 ) (see Warnings and Precautions ).

Co-infection with chronic hepatitis C and HIV

In patients co-infected with HIV and HCV, the clinical adverse event profile of Pegasys, alone or in combination with ribavirin, was similar to that seen in patients with HCV mono-infection. . In patients co-infected with HIV and HCV treated with Pegasys in combination with ribavirin, other adverse events were reported in ≥ 1% to ≤ 2% of patients: hyperlactatic / lactic acidosis, influenza, pneumonia, disorders emotional, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Pegasys treatment was associated with decreases in the absolute number of CD4 in the first 4 weeks of treatment, without decreasing the percentage of CD4. This decrease in CD4 count was reversible following a dose reduction or discontinuation of treatment. No negative impact on control of HIV viremia was observed during treatment with Pegasys or during follow-up. Data on safety in coinfected patients with a CD4 count <200 / μl is limited.


Table of adverse effects

Table 9 presents the adverse effects reported with Pegasys used as monotherapy in patients infected with HBV or HCV and with Pegasys in combination with ribavirin in patients with HCV.

Adverse reactions reported in clinical trials are grouped by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100) ), rare (≥ 1/10 000 to <1/1000), very rare (<1 / 10, 000). For spontaneous adverse reactions reported post-marketing, the frequency is indeterminate (can not be estimated on the basis of available data). Within each frequency group, adverse effects are presented in descending order of severity.

Table 9: Adverse reactions reported with Pegasys as monotherapy in patients infected with HBV or HCV or in combination with ribavirin in HCV-infected patients in clinical trials and post-marketing

System / organ

Very common

Frequent

Rare

Rare

Very rare

Not known frequency

Infections and infestations

Bronchitis, upper respiratory infection, oral candidiasis, herpes, fungal, bacterial and viral infections

Pneumonia,

infection

cutaneous

Endocarditis, otitis externa

septicemia

Benign tumors and

malignant

Hepatic neoplasm

Blood and lymphatic system disorders

Thrombocytopenia, anemia,

lymphadenopathy

pancytopenia

Aplastic anemia

Pure red cell aplasia

Affections of

system

immune

Sarcoidosis, thyroiditis

Anaphylaxis, lupus

systemic erythematous, rheumatoid arthritis

purpura

thrombocytopenic

idiopathic,

purpura

thrombocytopenic thrombotic

Rejection of liver and kidney transplant, Vogt-Koyanagi-Harada disease

Endocrine disorders

Hypothyroidism, hyperthyroidism

Diabetes

Diabetic ketoacidosis

Metabolism and nutrition disorders

Anorexia

dehydration

Psychiatric disorders

Depression*,

anxiety,

insomnia*

Aggressiveness, mood alteration, affect disorders, nervousness, decreased libido

ideas

suicidal, hallucinations

Suicide, psychotic disorder

Mania, Bipolar Disorder, Homicide Ideas

Nervous system disorders

Headache, dizziness *, difficulty concentrating

Syncope, migraine,

disorders of the

memory, weakness,

hypoaesthesia,

hyperesthesia,

paresthesia,

tremors,

dysgeusia,

nightmares

drowsiness

Peripheral neuropathy

Coma, convulsions, facial paralysis

Brain ischemia

Eye disorders

Blurred vision, eye pain, eye inflammation, xerophthalmia

Retinal hemorrhage

Optic neuropathy, papilledema, retinal vascular disease, retinopathy, corneal ulcer

Loss of vision

Serous detachment of the retina

Affections of the ear and labyrinth

Dizziness, earache

Loss of hearing

Heart conditions

Tachycardia, edema

peripheral,

palpitations

Infarction

infarction,

insufficiency

cardiac

congestive

cardiomyopathy,

angina, arrhythmia,

fibrillation

ear,

pericarditis,

tachycardia

supraventricular

Vascular disorders

Flushing

Hypertension

Hemorrhage

brain

vasculitis

Peripheral ischemia

Respiratory, thoracic and mediastinal disorders

Dyspnea, cough

Exercise dyspnea, epistaxis, nasopharyngitis, sinus congestion, nasal congestion, rhinitis, angina

Sibilant rattles

Interstitial lung disease (including fatal cases), pulmonary embolism

Gastrointestinal disorders

Diarrhea *, nausea *, abdominal pain *

Vomiting, dyspepsia, dysphagia, oral ulceration, gingivorrhage, glossitis, stomatitis, flatulence, dryness of mouth

Gastrointestinal bleeding

Gastrointestinal ulcer

duodenal,

pancreatitis

Ischemic colitis, tongue pigmentation

Hepatobiliary disorders

Hepatic dysfunction

insufficiency

hepatic,

cholangitis,

steatosis

hepatic

Skin and subcutaneous tissue disorders

Alopecia,

dermatitis,

pruritus,

drought

cutaneous

Psoriasis, urticaria, eczema, rash, hypersudation, skin disorder, photosensitivity reaction, night sweats

Syndrome of

Stevens-Johnson

necrolysis

epidermal

toxic,

angioedema,

erythema

polymorphous

Musculoskeletal and systemic disorders

Myalgia, arthralgia

Low back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps

myositis

rhabdomyolysis

Renal and urinary disorders

Renal failure

Disorders of reproductive organs and breast

Incapacity

General disorders and site abnormalities

administration

Fever,

chills*,

pain*,

asthenia,

tired,

reaction to

point

injection *, irritability *

Chest pain, flu-like syndrome, malaise, lethargy, hot flashes, thirst

investigations

Weightloss

Injury, poisoning and procedural complications

Overdose

* These adverse reactions were common (≥ 1/100, <1/10) in patients with chronic hepatitis B treated with Pegasys monotherapy.


Description of particular adverse effects

Biological constants

Treatment with Pegasys has been accompanied by laboratory abnormalities such as ALT elevation, elevated bilirubin, electrolyte disturbances (hypokalemia, hypocalcemia, hypophosphoremia), hyperglycemia, hypoglycemia, and hypertriglyceridemia (see Warnings and Precautions section). ). When treated with Pegasys alone or in combination with ribavirin, up to 2% of patients experienced elevations of ALT leading to dose modification or discontinuation.

Treatment with Pegasys was accompanied by decreases in hematologic parameters (leukopenia, neutropenia, lymphopenia, thrombocytopenia, and hemoglobin levels), which generally improved after dose adjustment and returned to pre-treatment values ​​within 4 to 8 weeks. after discontinuation of treatment (see sections Posology and method of administration and Warnings and precautions for use ).

Une neutropénie modérée (NAPN : 749 - 5 00 x 10 6 /l) et sévère (NAPN : <500 x 10 6 /l) ont été observées respectivement chez 24 % (216/887) et 5 % (41/887) des patients recevant l'association Pegasys 180 microgrammes et 1000/1200 mg de ribavirine pendant 48 semaines.

Anticorps anti-interféron

1-5 % des patients traités par Pegasys ont développé des anticorps neutralisants anti-interféron. Comme avec d'autres interférons, l'incidence des anticorps neutralisants anti-interféron a été plus élevée chez les patients atteints d'hépatite chronique B. Cependant ce phénomène n'a pas été corrélé avec une absence de réponse thérapeutique dans aucune des deux pathologies.

Fonction thyroïdienne

Le traitement par Pegasys s'est accompagné d'anomalies cliniquement significatives des paramètres de la fonction thyroïdienne nécessitant une prise en charge médicale (voir rubrique Mises en garde et précautions d'emploi ). Les fréquences observées (4, 9 %) chez les patients recevant Pegasys/ribavirine (NV15801) sont similaires à celles observées avec les autres interférons.

Constantes biologiques chez les patients co-infectés par le VIH et le VHC
Bien que les troubles hématologiques (neutropénie, thrombocytopénie et anémie) aient été plus fréquents chez les patients co-infectés par le VIH et le VHC, la majorité d'entre eux a pu être contrôlé par une modification posologique et/ou l'administration de facteurs de croissance. Ces troubles n'ont que rarement imposé un arrêt prématuré du traitement. Parmi les patients recevant Pegasys seul et en association avec la ribavirine, on a observé une diminution du NAPN en-dessous de 500/mm 3 chez respectivement 13 % et 11 %, une diminution des plaquettes en-dessous de 50 000/mm 3 chez respectivement 10 % et 8 % et une anémie (hémoglobine <10 g/dl) chez respectivement 7 % et 14 % des patients.


Pediatric population

Hépatite chronique C

Dans un essai clinique conduit chez 114 patients (âgés de 5 à 17 ans) traités par Pegasys seul ou en association avec la ribavirine (voir rubrique Propriétés pharmacodynamiques ), des modifications de la dose ont été nécessaires chez environ un tiers des patients, le plus souvent en raison d'une neutropénie ou d'une anémie. D'une manière générale, le profil de tolérance observé chez ces patients pédiatriques a été similaire à celui observé chez les adultes. Dans l'étude pédiatrique, les événements indésirables les plus fréquents chez les patients traités jusqu'à 48 semaines par l'association Pegasys et ribavirine ont été les suivants : syndrome pseudo-grippal (91 %), céphalées (64 %), trouble gastro-intestinal (56 %) et réaction au point d'injection (45 %). La liste complète des événements indésirables rapportés dans ce groupe de traitement (n=55) est présentée dans le tableau 10. Sept patients traités pendant 48 semaines par l'association Pegasys et ribavirine ont arrêté le traitement en raison d'un effet indésirable (dépression, évaluation psychiatrique anormale, cécité transitoire, exsudats rétiniens, hyperglycémie, diabète de type 1 et anémie). La plupart des événements indésirables rapportés au cours de l'étude ont été d'intensité légère ou modérée. Des événements indésirables sévères ont été rapportés chez 2 patients du groupe traité par l'association Pegasys et ribavirine (hyperglycémie et cholecystectomie).

Tableau 10: Effets indésirables rapportés parmi les enfants infectés par le VHC et traités par Pegasys plus ribavirine dans l'étude NV17424

Système/organe

Very common

Frequent

Infections and infestations

Mononucléose, pharyngite à streptocoque, grippe, gastroentérite virale, candidose, gastroentérite, abcès dentaire, orgelet, infection des voies urinaires, rhinopharyngite

Blood and lymphatic system disorders

Anemia

Metabolism and nutrition disorders

Diminution de l'appétit

Hyperglycémie, diabète sucré de type 1

Psychiatric disorders

Insomnia

Dépression, anxiété, hallucinations, comportement anormal, agressivité, accès de colère, déficit de l'attention / hyperactivité

Nervous system disorders

headaches

Etourdissements, perturbation de l'attention, migraines

Eye disorders

Cécité transitoire, exsudats rétiniens, trouble visuel, irritation oculaire, douleur oculaire, prurit oculaire

Affections of the ear and labyrinth

Otalgie

Respiratory, thoracic and mediastinal disorders

Dyspnée, épistaxis

Gastrointestinal disorders

Troubles gastro-intestinaux

Douleur abdominale haute, stomatite, nausée, aphte, troubles buccaux

Skin and subcutaneous tissue disorders

Rash, prurit, alopécie

Gonflement du visage, éruption cutanée

Musculoskeletal and systemic disorders

Douleur musculosquelettique

Douleur dorsale, douleur des extrémités

Renal and urinary disorders

Dysurie, incontinence, troubles des voies urinaires

Disorders of reproductive organs and breast

Pertes vaginales

General disorders and administration site conditions

Syndrome pseudo-grippal, réaction au site d'injection, irritabilité, fatigue

Fièvre, hématome au site d'injection, douleur

investigations

Evaluation psychiatrique anormale

Procédures médicales et chirurgicales

Extraction dentaire, cholécystectomie

Caractéristiques socio-environnementales

Problèmes d'éducation

Une inhibition de la croissance a été observée chez les enfants (voir rubrique Mises en garde et précautions d'emploi ). Les enfants traités par l'association Pegasys plus ribavirine ont présenté un retard de croissance staturo-pondérale après 48 semaines de traitement par rapport aux valeurs initiales. Les percentiles de poids et de taille des patients ont diminué au cours du traitement par rapport à la population normale. A la fin du suivi de 2 ans après l'arrêt du traitement, la plupart des patients étaient revenus aux percentiles initiaux des courbes de croissance normales pour le poids et la taille (le percentile moyen du poids était de 64 % initialement et 60 % 2 ans après le traitement ; le percentile moyen de la taille était de 54 % initialement et de 56 % 2 ans après le traitement). A la fin du traitement, 43 % des patients présentaient une diminution d'au moins 15 percentiles du poids et 25 % présentaient une diminution d'au moins 15 percentiles de la taille sur les courbes de croissance normales. Deux ans après l'arrêt du traitement, 16 % des patients présentaient toujours une diminution d'au moins 15 percentiles par rapport à leur courbe de poids initiale et 11 % une diminution d'au moins 15 percentiles par rapport à leur courbe de taille initiale.

Valeurs biologiques

Les baisses de l'hémoglobine, des neutrophiles et des plaquettes peuvent nécessiter une réduction de la dose ou l'arrêt définitif du traitement (voir Tableau 3 et Tableau 7). La plupart des anomalies biologiques observées au cours de l'essai clinique sont revenues aux valeurs initiales peu de temps après l'arrêt du traitement.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Les professionnels de santé déclarent tout effet indésirable suspecté via le système national de déclaration – voir Annexe V .

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