Summary of medicine characteristics - PegIntron
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
2. QUALITATIVE AND QUANTITATIVE COMPOSITIONPegIntron 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 inje ction s
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 hen 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.
eutic class (see section 5.1).
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 sa *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 ef ffsct^
Each vial contains 40mg of sucrose per 0.5 ml.
For the full list
ients, see section 6.1.
3.
Powder and solvent for solution for injection.
White powder.
Clear and colourless solvent.
4. CLINICAL PARTICULARS4.1 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 infe adult patients who are previously untreated including patients with clinically stable HIV co-in and in adult patients who have failed previous treatment with interferon alpha (pegylated nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy (s
r
Interferon monotherapy, including PegIntron, is indicated mainly in case of intol 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).
r oral solution when PegIntron is to be used in
Please refer to the ribavirin SmPC for ca combination with ribavirin.
4.2 Posology and method of administrationTreatment should be initiate patients with hepatitis C
| Body weighty (kg)A | (¿PegIntron strength ( p g/0.5 ml) | Amount of PegIntron to administer ( p g) | Volume of PegIntron to administer (ml) |
| <3035 | 50* | 15 | 0.15 |
| OÏ36–45 | 50 | 20 | 0.20 |
| JC/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.
Special populations
Rena l 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 comb with ribavirin (see ribavirin SmPC). When administered in combination therapy, patients with renal function should be more carefully monitored with respect to the developmen
Hepatic impairment
epatic
The safety and efficacy of PegIntron therapy has not been evaluated in patients with se 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
4.3 ContraindicationsHypersensitivity to th
section 6.1; A history of in the previo Severe, deb
substance or to any interferon or to any of the excipients listed in
Autoim
Seve Pre-e
re-existing cardiac disease, including unstable or uncontrolled cardiac disease onths (see section 4.4);
medical conditions;
atitis or a history of autoimmune disease;
ic dysfunction or decompensated cirrhosis of the liver;
g thyroid disease unless it can be controlled with conventional treatment;
pilepsy and/or compromised central nervous system (CNS) function;
¡CV/HIV patients with cirrhosis and a Child-Pugh score > 6.
ombination of PegIntron with telbivudine.
ediatric 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
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 discontinu 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 exis of severe psychiatric conditions, this should only be initiated after having ensured ap individualised diagnostic and therapeutic management of the psychiatric condition.
story
– 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 re compared to adult patients (2.4 % vs 1 %) during treatment and during the treatment. As in adult patients, children and adolescents experience (e.g. depression, emotional lability, and somnolence).
Patients with substance use/abuse
HCV infected patients having a co-occurring substance u increased risk of developing psychiatric disorders or when treated with alpha interferon. If treatment wi
ed more frequently nth follow-up after ychiatric adverse events
e disorder (alcohol, cannabis, etc) are at an rbation of already existing psychiatric disorders interferon is judged necessary in these patients,
the presence of psychiatric co-morbidities and thotential for other substance use should be carefully assessed and adequately managed before initiatinerapy. 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 -emergence or development of psychiatric disorders and
substance use is recommended.
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).
benefit/risk assessment in children
ed benefit of treatment should be carefully weighed against the safety findings observed for 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) ha been observed rarely during interferon alfa-2b therapy. If such a reaction develops during treatment w 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, myal 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 therapy, other causes of persistent pyre
syndrome reported commonly during interferon be ruled out.
Hydration
Adequate hydration must be maintained in patients undergoing PegIntron therapy since hypotension related to fluid depletion has ben seen in some patients treated with alpha interferons. Fluid replacement may be necess
Pulmonary changi
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
Ophthaimoiogic disorders, inciuding retinai haemorrhages, retinai exudates, serous retinai detachment, and retinai artery or vein occiusion have been reported in rare instances after treatment with aipha interferons (see section 4.8). Aii patients shouid have a baseiine eye examination. Any patient compiaining of ocuiar symptoms, inciuding ioss of visuai acuity or visuai fieid must have a prompt and compiete eye examination. Periodic visuai examinations are recommended during PegIntron therapy, particuiariy in patients with disorders that may be associated with retinopathy, such as diabetes meiiitus or hypertension. Discontinuation of PegIntron shouid be considered in patients who deveiop new or worsening ophthaimoiogicai disorders.
Thyroid changes
Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have develope thyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21 % of chil treated with PegIntron/ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another approximately 2 % had a transient decrease below the low Prior to initiation of PegIntron therapy, TSH levels must be evaluated and any thyroi detected at that time must be treated with conventional therapy. Determine TSH leve
limit of normal. abnormality
s if, during the nction. In the
course of therapy, a patient develops symptoms consistent with possible thyroi presence of thyroid dysfunction, PegIntron treatment may be continued if TSH
evels can be
maintained in the normai range by medicine. Chiidren and adoiescents shouid be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH).
Metabolic disturbances Z\X
severe, have been observed.
Hypertriglyceridemia and aggravation of hypertriglyceridemia, someti 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 ribavi
Hepatic decompensation in HCV/ Co-infected patients with advanc decompensation and death. A ribavirin may increase the ri
-infected patients with advanced cirrhosis
may be associated with
cirrhosis receiving HAART may be at increased risk of hepatic reatment with aifa interferons aione or in combination with is patient subset. Other baseiine factors in co-infected patients that
elevated bilirubin Co-infected patie monitored, assess decompensation s treatment reassess
r risk of hepatic decompensation inciude treatment with didanosine and centration.
eiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely g their Child-Pugh score during treatment. Patients progressing to hepatic ould have their anti-hepatitis treatment immediately discontinued and the ARV gical abnormalities in HCV/HIV co-infected patients
Ha
co-infected patients receiving peginterferon aifa-2b/ribavirin treatment and HAART may 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 ceiis/^i. 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 coinfected 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 patients co-infected with hepatitis B and C must then be monitored and managed according to cu clinical guidelines.
Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reporte receiving PegIntron and ribavirin combination therapy. In addition, dry mouth coul effect on teeth and mucous membranes of the mouth during long-term treatment wi of PegIntron and ribavirin. Patients should brush their teeth thoroughly twice dai
a damaging combination have regular
ction occurs, they
dental examinations. In addition some patients may experience vomiting. If t 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 sarcoiis 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 th
e:
- • • •
Laborat clin
Platelets Neutrophil TSH level
> 100,000/mm3
> 1,500/mm3
must be within normal limits
ons are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as te. HCV-RNA should be measured periodically during treatment (see section 4.2).
maintenance monotherapy
been demonstrated in a clinical study that peginterferon alfa-2b at low-dose (0.5 ^g/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 thes events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SmPC). Moreover, the safety efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B been demonstrated. Therefore, the combination of PegIntron with telbivudine is contraindicated ( 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 depresn. Especially in patients on a high dose of methadone, the risk for QTc prolongation should bred.
The potential interaction of peginterferon alfa-2b (PegIntron) on substrates of metabolic enzymes was
evaluated in 3 multiple-dose clinical pharmacology
multiple-dose regimens of peginterferon alfa-2b (1.5 mcg/week) or healthy subjects (1 mcg/week
es. In these studies, the effects of
on) were investigated in Hepatitis C subjects
pharmacokinetic interaction was not obse tolbutamide, midazolam or dapsone; ther alfa-2b (PegIntron) is administered wit
N-acetyltransferase. Concomitant desipramine modestly increased t
r 3 mcg/week) (Table 4 ). A clinically significant
between peginterferon alfa-2b (PegIntron) and
, no dosing adjustment is necessary when peginterferon cines metabolized by CYP2C9, CYP3A4 and
inistration of peginterferon alfa-2b (PegIntron) with caffeine or osure of caffeine and desipramine. When patients are administered PegIntron with medations 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
| Co-administered MedjC^e^> | Dose of peginterferon alfa-2b | Study Population | Geometric Mean Ratio (Ratio with/without peginterferon alfa-2b) | |
| AUC (90% CI) | C vmax (90% CI) | |||
| ACYP1A2 substrate) | 1.5 mcg/kg/week (4 weeks) | Chronic Hepatitis C Subjects (N=22) | 1.39 (1.27, 1.51) | 1.02 (0.95, 1.09) |
| 1 mcg/kg/week (4 weeks) | Healthy Subjects (N=24) | 1.18 (1.07, 1.31) | 1.12 (1.05, 1.19) | |
| 3 mcg/kg/week (2 weeks) | Healthy Subjects (N=13) | 1.36 (1.25, 1.49) | 1.16 (1.10, 1.24) | |
| Tolbutamide (CYP2C9 substrate) | 1.5 mcg/kg/week (4 weeks) | Chronic Hepatitis C Subjects (N=22) | 1.1# (0.94, 1.28) | NA |
| 1 mcg/kg/week (4 weeks) | Healthy Subjects (N=24) | 0.90# (0.81, 1.00) | NA | |
| 3 mcg/kg/week (2 weeks) | Healthy Subjects (N=13) | 0.95 (0.89, 1.01) | 0.99 (0.92, 1.07) | |
administered with care
when co-administered with the
medi
Table 5 Precautions for co-administration (PegIntron
| Medicines | Signs, Symptoms, and Treatments | Mechanism and Risk Factors |
| Theophylline | Co-administration of theophyi^^^ with the product (PegIntron) may increase the blood concentrations of theophylline. Careful co-administration of theophylline with the product (PegIntron) is recommended. Package inserts of theophylline should be referred to when co-administering with the prodUCnPegIntron) | Metabolism of theophylline is suppressed by inhibitory action of the product (PegIntron) on CYP1A2. |
| Thioridazine Ci | Ao-Odministration of thioridazine with the product (PegIntron) may increase the blood concentrations of thioridazine. Careful 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) | Metabolism of thioridazine is suppressed by inhibitory action of the product (PegIntron) on CYP2D6. |
| .Theophylline, Antipyrine, F Warfarin | Elevation of blood concentrations of these medicines has been reported when administered in combination with other interferon preparations and therefore care should be taken. | Metabolism of other medicines in the liver may be suppressed. |
| Co-administered Medicine | Dose of peginterferon alfa-2b | Study Population | Geometric Mean Ratio (Ratio with/without peginterferon alfa-2b) | |
| AUC (90% CI) | C vmax (90% CI) | |||
| Dextromethorphan hydrobromide (CYP2D6 and CYP3A substrate) | 1.5 mcg/kg/week (4 weeks) | Chronic Hepatitis C Subjects (N=22) | 0.96## (0.73, 1.26) | NA |
| 1 mcg/kg/week (4 weeks) | Healthy Subjects (N=24) | 2.03# (1.55, 2.67) | NA | |
| Desipramine (CYP2D6 substrate) | 3 mcg/kg/week (2 weeks) | Healthy Subjects (N=13) | 1.30 (1.18, 1.43) | 1.08 (1.00, 1.16) ß |
| Midazolam (CYP3A4 substrate) | 1.5 mcg/kg/week (4 weeks) | Chronic Hepatitis C Subjects (N=24) | 1.07 (0.91, 1.25) | 1.12 ♦ (0.94/33P |
| 1 mcg/kg/week (4 weeks) | Healthy Subjects (N=24) | 1.07 (0.99, 1.16) | 1.33JC* (,1Í5Y53) | |
| 3 mcg/kg/week (2 weeks) | Healthy Subjects (N=13) | 1.18 (1.06, 1.32)?\ | PV 11.07, 1.43) | |
| Dapsone (N-acetyltransferase substrate) | 1.5 mcg/kg/week (4 weeks) | Chronic Hepatitis C Subjects (n=24) | 1.05 vy (1.02, | 1.03 (1.00, 1.06) |
# Calculated from urine data collected over an interval of 48-hours
## Calculated from urine data collected over an interval of 24-hours
| Medicines | Signs, Symptoms, and Treatment | Mechanism and Risk Factors |
| Zidovudine | When administered in combination with other interferon preparations, suppressive effect on bone marrow function may be strengthened and aggravation of blood cell reduction such as white blood cells decreased may occur. | Mechanism of action is unknown, but it is considered that both medicines have bone marrow depressive effects. |
| Immuno-suppressive therapy | When administered in combination with other interferon preparations, effect of immunosuppressive therapy may be weakened in transplant (kidney, bone marrow, etc.) patients. | It is considered that graft rejection reactions may be induced. |
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 nucleo
acidosis. Pharmacologically, ribavirin increases phosphorylated vitro. This activity could potentiate the risk of lactic acidosis i (e.g. didanosine or abacavir). Co-administration of ribavirin Reports of mitochondrial toxicity, in particular lactic aci have been reported (see ribavirin SmPC).
pancreatitis, of which some fatal,
as resulted in lactic ites of purine nucleosides in purine nucleoside analogs sine is not recommended.
Exacerbation of anaemia due to ribavirin has been red 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 recommen Consideration should be given to replaci (ART) regimen if this is already establi known history of zidovudine-indu
4.6 Fertility, pregnancy and lactation
4.6 Fertility, pregnancy and lactationdue to an increased risk of anaemia (see section 4.4). udine in a combination anti-retroviral treatment
is would be particularly important in patients with a
Women of childbearing^otenrial/contraception in males and females
PegIntron is recomed for use in fertile women only when they are using effective contraception during the treatm
Combination therapy with ribavirin
Extreme must be taken to avoid pregnancy in female patients or in partners of male patients taking
in combination with ribavirin. Females of childbearing potential must use an effective ive during treatment and for 4 months after treatment has been concluded. Male patients or their artners must use an effective contraceptive during treatment and for 7 months after treatment has concluded (see ribavirin SmPC).
Pe co
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
ned to
Patients who develop fatigue, somnolence or confusion during treatment with PegIntro avoid driving or operating machines.
4.8 Undesirable effects
4.8 Undesirable effectsAdults
Tritherapy
Refer to the SmPC for boceprevir.
Bitherapy and monotherapy
Summary of the safety profile <
The most common treatment-related adverse reactions r
combination with ribavirin in adults, seen in more t headache, and injection site reaction. Additional ad subjects included nausea, chills, insomnia, anaemia
during clinical trials with PegIntron in
anorexia, weight decreased, depression, ras reactions were mostly mild to moderate i modification of doses or discontinuatio
nd
weight decreased, irritability and PegIntron monotherapy compare
earnsehalf of the study subjects, were fatigue, reactions reported in more than 25 % of pyrexia, myalgia, asthenia, pain, alopecia, tability. The most frequently reported adverse
ity and were manageable without the need for erapy. Fatigue, alopecia, pruritus, nausea, anorexia, occur at a notably lower rate in patients treated with
ose treated with combination therapy (see Table 6 ).
Tabulated summary of aclvrefictions
The following treatment-re 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^Q^mon (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/B0,000ro < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the availa
equency grouping, undesirable effects are presented in order of decreasing seriousness.
Wi
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, syetemcfc lupus erythematosus |
| Endocrine disorders _ C J | |
| Common: | Hypothyroidism, hyperthyroidism k^<X |
| Metabolism and nutrition disorders V* | |
| Very common: | Anorexia |
| Common: | Hypocalcemia, hyperuricemia, dehydration, increasedOppetite |
| Uncommon: | Diabetes mellitus, hypertriglyceridaemia |
| Rare: | Diabetic ketoacidosis |
| Psychiatric disorders X | |
| Very common: | Depression, anxiety , emotiona^ablliTy , concentration impaired, insomnia |
| Common: | Aggression, agitation, angeriMuood altered, abnormal behaviour, nervousness, sleep disorder.Zbido decreased, apathy, abnormal dreams, crying |
| Uncommon: | Suicide, siiicide^ttempt, suicidal ideation, psychosis, hallucination, panic attack x |
| Rare: | Bipolaridi^ordersr |
| Not known: | Homicida^ideStion, 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 ^ara*‚^‘ | Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy |
| Not^nown: | Facial palsy, mononeuropathies |
| . Eyeldisorders | |
| wommon: | 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 conge stions sinus congestion, nasal congestion, rhinorrhea, increased upper aiway secretion, pharyngolaryngeal pain |
| Very rare: | Interstitial lung disease "" |
| Not known: | Pulmonary fibrosis, pulmonary arterial hypertension# v |
| Gastrointestinal disorders | |
| Very common: | Vomiting , nausea, abdominal pain, diarrhoea,Jry moUth |
| Common: | Dyspepsia, gastroesophageal reflux disease-^tomatitis, mouth ulceration, glossodynia, gingival bleeding, constipationfatiilence, haemorrhoids, cheilitis, abdominal distension, gingivitfs^Sj^ssitis, tooth disorder |
| Uncommon: | Pancreatitis, oral pain |
| Rare: | Colitis ischaemic |
| Very rare: | Colitis ulcerative |
| Not known | Tongue pigmentation^\^^ |
| Hepatobiliary disorders k a | |
| Common: | Hyperbilirubinemia, hepatomegaly |
| Skin and subcutaneous tissue disorders J | |
| Very common: | Alopecia,®ruriius , dry skin , rash |
| Common: | Psoriasis,\hotosensitivity 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 |
| Musculoskeletofandconnective tissue disorders | |
| Very commons | Myalgia, arthralgia, musculoskeletal pain |
| Commons | Arthritis, back pain, muscle spasms, pain in extremity |
| Uncommon^ | Bone pain, muscle weakness |
| RareZz | Rhabdomyolysis, myositis, rheumatoid arthritis |
| RenaTand urinary disorc | ers |
| ^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 |
- ‚T‘1 1 J' -l/IZ-W' 1’ <• << <1 •<1T'XT< <1
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 i combination with ribavirin reported life-threatening psychiatric events during treatment. These 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 agent ). Cardiomyopathy,
that may be reversible upon discontinuation of interferon alpha, harely in patients without prior evidence of cardiac disease.
interferon alfa products,
, HIV-infection, cirrhosis). after starting treatment with
Cases of pulmonary arterial hypertension (PAH) have been report notably in patients with risk factors for PAH (such as portal hy Events were reported at various time points typically sever interferon alfa.
Ophthalmological disorders that have been reporte (including macular oedema), retinal haemorrha loss of visual acuity or visual field, optic neuriti
y with alpha interferons include retinopathies inal artery or vein occlusion, retinal exudates, 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 pati
Summary of the safety
For HCV/HIV co-infetients 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 lymp
hep
cytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased ain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic ), lipase increased (6 %) and pain in limb (6 %).
ption of selected adverse reactions
tQchondrial toxicity
itochondrial 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
(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/^1 (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 pr 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) treith 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 reactio adolescents was similar to that observed in adults, although there is a pae regarding growth inhibition. During combination therapy for up to 4 growth inhibition was observed that resulted in reduced height in loss and growth inhibition were very common during the treatment
ile in children and
-specific concern
ith PegIntron and ribavirin, ients (see section 4.4). Weight end of treatment, mean
decrease from baseline in weight and height percentile were of rcentiles 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 (growt enrolled in the 5 year long-term follow-u treated for 24 weeks than those treated up among subjects treated for 24 o
y < 3rd percentile). Ninety-four of 107 subjects
e effects on growth were less in those subjects weeks. From pre-treatment to end of long-term follow-ks, 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 4 s had a > 15 percentile height-for-age decrease from pre-treatment
to the end of the 5 year long- ollow-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 aase from pre-treatment baseline of > 30 height-for-age percentiles to the end of the 5 year lon ollow-up. For weight, pre-treatment to end of long-term follow-up, weight-
for-age percentilreased 1.3 and 5.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. FoI, 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
ent phase in comparison to a normative population did not fully recover at the end of long-term -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.
Tabu lated 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 J |
| Uncommon: | Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis,ftrinary tract infection, gastroenteritis |
| Blood and lymphatic system disorders | |
| Very common: | Anaemia, leucopenia, neutropenia |
| Common: | Thrombocytopenia, lymphadenopathy |
| Endocrine disorders | ■ A |
| Common: | Hypothyroidism |
| Metabolism and nutrition disorders | |
| Very common: | Anorexia, decreased appetite |
| Psychiatric disorders | |
| Common: | Suicidal ideation§, suicide^ttcmpt§, depression, aggression, affect lability, anger, agitation, anxiety^ood altered, restlessness, nervousness, insomnia |
| Uncommon: | Abnormal behaviour, "depressed mood, emotional disorder, fear, nightmare |
| Nervous system disorders | |
| Very common: | Headache, dizziness |
| Common: | Dysgeusia,teyncope, disturbance in attention, somnolence, poor quality sleep |
| Uncommon: | Neuralg ia, lethargy, paraesthesia, hypoaesthesia, psychomotor ■hyperactivity, tremor |
| Eye disorders . A | |
| Common: | >ye pain |
| Uncommon: | Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia |
| Ear and labyrinth disorders | |
| Commons v | Vertigo |
| Cardiacdisorders | |
| Common | Palpitations, tachycardia |
| VascUrar 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 aÇ |
| Common: | Musculoskeletal pain, pain in extremity, back pain |
| Uncommon: | Muscle contracture, muscle twitching „JY |
| Renal and urinary disorders | |
| Uncommon: | Proteinuria X |
| Reproductive system and breast disorders | |
| Uncommon: | Female: Dysmenorrhoea
|
| General disorders and administration site conditions £ | |
| Very common: | Injection site erythema, fatigue, pyrexia, rigojs/lnfluenza-like illness, asthenia, pain, malaise, irritability |
| Common: | Injection site reaction, injection site^rUritUsSinjection site rash injection site dryness, injection site pain, feejngoora |
| Uncommon: | Chest pain, chest discomforttfaciaiYain |
| Investigations | |
| Very common: | Growth rate decrease (heightSnd/or weight decrease for age) |
| Common: | Blood thyroid stimulainghormone increased, thyroglobulin increased |
| Uncommon: | Anti-thyroid antibody positive |
| Injury and poisoning [ | |
| Uncommon: | Contusion |
§class effect of interferon-alfa containing jproducts^ 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.
RepOrtlngof suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows lontinued 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
4.9 Overdose
4.9 OverdoseDoses up to 10.5 times the intended dose have been reported. The maximum daily dose reported is 1,200 pg 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 PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB10.
eron
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 fr 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 inhi antiviral mode of action of recombinant i metabolism. This action inhibits v unable to leave the cell.
l replication in vitro and in vivo. Although the exact eron alfa-2b is unknown, it appears to alter the host cell cation or if replication occurs, the progeny virions are
Pharmacodynamic effects
PegIntron pharmacodynam changes in oral temperatur
oligoadenylate s PegIntron showe between 0.25 an manner.
were assessed in a rising single-dose trial in healthy subjects by examining oncentrations of effector proteins such as serum neopterin and 2’5’-5’-OAS), as well as white cell and neutrophil counts. Subjects treated with
mild dose-related elevations in body temperature. Following single doses of PegIntron 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-related il and white cell count reductions at the end of week 4 correlated with the dose of
efficacy and safety – Adults
py with PegIntron, ribavirin and boceprevir efer 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 signi more effective than the combination of interferon alfa-2b and ribavirin (Table 8 ), particularl patients infected with Genotype 1 (Table 9 ). Sustained response was assessed by the respons months after the cessation of treatment.
HCV genotype and baseline virus load are prognostic factors which are known to aesponse 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 rec 10.6 mg/kg ribavirin
(Table 9 ), while response rates in patients that received > 13.2 mirin were even higher.
Table 8 Sustained
| PegIntron monotherapy' | PegIntron + ribavirin | ||||||
| Treatment regimen Number of patients | P 1.5 304 | P 1.0 297 | P0.^ rv | I ’ 303 | P 1.5/R 511 | P 0.5/R 514 | I/R 505 |
| Response at end of treatment Sustained response | 49% 23 % | 41 V ¿5 %^ | >33/0 i8% | 24% 12% | 65% 54 % | 56% 47% | 54% 47 % |
P1.0
P 0.5
I
P 1.5/R
P 0.5/R I/R
Interferon alfa-2b 3 MIU PegIntron (1.5 microgr PegIntron (1.5 to 0.5 mi Interferon alfa-2b p < 0.001 P 1.5 vs
PegIntron 1.5 micrograms/kg
PegIntron 1.0 microgram/kg
PegIntron 0.5 microgram/kg
p = 0.0143
I/R
ribavirin (800 mg)
/kg) + ribavirin (1,000/1,200 mg) + ribavirin (1,000/1,200 mg)
nse rates with PegIntron + ribavirin (by ribavirin dose, genotype
Table 9
Sust and
| HCV Genotyp?^ | Ribavirin dose (mg/kg) | P 1.5/R | P 0.5/R | I/R |
| 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 lU/ml | < 10.6 | 74% | 25 % | 33 % |
| > 10.6 | 71 % | 52% | 45 % | |
| Genotype 1 | All | 30% | 27% | 29% |
| > 600,000 lU/ml | < 10.6 | 27% | 25 % | 17% |
| > 10.6 | 37 % | 27% | 29% |
| HCV Genotype | Ribavirin dose (mg/kg) | P 1.5/R | P 0.5/R | I/R |
| Genotype 2/3 | 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)
and relapse by
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 (based on body weight, only three patients weighing > 105 kg, received the 1,400 mg d (Table 10 ). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).
The 6 month treatment duration i pivotal combination trial; for di
In a non-comparative trial, PegIntron, 1.5 microgra
ribavirin. The overa percent of subje
therapy. In thi sustained resp prospect
al was better tolerated than one year of treatment in the inuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %.
patients with genotype 1 and low viral load (< 600,000 IU/ml) received subcutaneously, once weekly, in combination with weight adjusted
ustained response rate after a 24-week treatment duration was 50 %. Forty-one 35) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of oup, there was a 92 % (89/97) sustained virological response rate. The high
nse rate in this subgroup of patients was identified in an interim analysis (n=49) and onfirmed (n=48).
cal 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 ^g/kg and 1 ^g/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 gg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naive 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 ).
HCV
and viral load
Table 10 Virologic response at end of treatment, Sustained Virologic R
| PegIntron 1.5 gg/kg once weekly plus Ribavirin 800–1,400 mg/day | |||
| End of treatment response | Sustained VirologcRsponse | Relapse | |
| All subjects | 94% (211/224) | 81 %(j82/224) | 12 % (27/224) |
| HCV 2 < 600,000 lU/ml > 600,000 lU/ml | 100 % (42/42) 100 % (20/20) 100 % (22/22) | 93"%J3942) . fSp/o (19/20) ^C*91 % (20/22) | 7 % (3/42) 5 % (1/20) 9 % (2/22) |
| HCV 3 < 600,000 lU/ml > 600,000 lU/ml | 93 % (169/182) 93 % (92/99) z 93 % (77/83) X | %9% (143/182) A} 86 % (85/99) X 70 % (58/83) | 14 % (24/166) 8 % (7/91) 23 % (17/75) |
* Any subject with an undetectable HCV-RNA level week 24 visit was considered a sustained responder. window was considered to be a non-responder at wee
he follow-up week 12 visit and missing data at the follow-up subject with missing data in and after the follow-up week 12
4 of follow-up.
Table 11 Virologic response at treatment week 12, end of treatment response, relapse rate
(SVR)
and Sustained
| Treatment group | % (number) of patients | ||
| PegIntron 1.5 ^g/kg + ribavirin | PegIntron 1 ^g/kg + ribavirin | peginterferon alfa-2a 180 ^g + ribavirin | |
| Undetectable HCV-RNA at treatment week 12 | 40 (407/1,019) | 36 (366/1,016) | 45 (466/1,035) |
| End of treatment response | 53 (542/1,019) | 49 (500/1,016) | 64 (667/1,035) |
| Relapse | 24 (123/523) | 20 (95/475) | 32 (193/612) Q |
| SVR | 40 (406/1,019) | 38 (386/1,016) | 41 (423/1,035)^ |
| SVR in patients with undetectable HCV-RNA at treatment week 12 | 81 (328/407) | 83 (303/366) | 74 (3447466) |
(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 re a criterion for discontinuation of treatment.
aseline) was
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 |jg/kg)/ribavirin combination therapy resulted in a hjg|he£slstained virologic response rate compared to PegIntron 1 ^g/kg dose. At the PegIntron 1.5 ^g/kgpus 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—Na^epatients: 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 vir decrease or undetectable levels of HCV-RNA. These
time points (treatment week 4 and treatmeek 12) have been shown to be predictive for sustained response (Table 12 ).
Table 12 Predictive value
eatment Virologic Response while on PegIntron
rib
1.5
| Negative | Positive | |||||
| ^No response at treatment week | No sustained response | Negative predictive value | Response at treatment week | Sustained response | Positive predictive value | |
| Genotypes* " | ||||||
| By Week4 *** /n^y50) | ||||||
| A^CV-RNA negative | 834 | 539 | 65 % (539/834) | 116 | 107 | 92 % (107/116) |
| HCV-RNA negative or > 1 log decrease in viral load | 220 | 210 | 95 % (210/220) | 730 | 392 | 54 % (392/730) |
| By week 12 (n=915 ) | ||||||
| HCV-RNA negative | 508 | 433 | 85 % (433/508) | 407 | 328 | 81 % (328/407) |
Positive
| No response at treatment week | No sustained response | Negative predictive value | Response at treatment week | Sustained response | Positive predictive value | |
| HCV-RNA negative or > 2 log decrease in viral load | 206 | 205 | N/A " | 709 | 402 | 57% (402/709) |
| Genotype 2, 3 | ||||||
| By week 12 (n= 215) | ||||||
| HCV-RNA negative or > 2 log decrease in viral load | 2 | 1 | 50 % (1/2) | 213 | 177 | ✓^3% X177/213) |
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.
t These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2lo rease from baseline, patients to
stop therapy. If week 12 HCV-RNA is positive and decreased > 2logi0 from baseli 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-infecith 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 wereFandoniized to receive either PegIntron (1.5 ^g/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^vere randomized to receive either PegIntron (100 or 150 ^g/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 1 1 | Study 2 2 | |||||
| PegIntron (1.5 Lg/kg/ week) + ribavirin (800 mg) | Interferon alfa-2b (3 MIU TIW) + ribavirin (800 mg) | P valuea | PegIntron (100 or 150c Ltg/week) + ribavirin (8001,200 mg)d | Interferon alfa-2b (3 MIU TIW) + ribavirin (8001,200 mg)d | P valueb | |
| All | 27 % (56/205) | 20 % (41/205) | 0.047 | 44 % (23/52) | 21 % (9/43) | 0.017 |
| Genotype 1, 4 | 17% (21/125) | 6 % (8/129) | 0.006 | 38 % (12/32) | 7 % (2/27) | 0.00^ |
| Genotype 2, 3 | 44 % (35/80) | 43 % (33/76) | 0.88 | 53 % (10/19) | 47 % (7/15) | |
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 Ltg/week PegIntron and subjects > 75 kg received 150 Ltg/week PegI
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.
1 Carrat 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 an available for 210 of the 412 subjects (51 %). Both the Metavir sco subjects treated with PegIntron in combination with ribavirin.
nt in Study 1 and were Ishak grade decreased among ne was significant among
responders (-0.3 for Metavir and –1.2 for Ishak) and stable r Metavir and –0.2 for Ishak) among
non-responders. In terms of activity, about one-third of susd 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 Genotype 3.
PegIntron/ribavirin retreatment of prior tr
es
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 subcutaneousle weekly, in combination with weight adjusted ribavirin. Failure to prior therapy was definrelapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of trea
Patients who were HCV were followed for HCV-RNA after undetectable HC
egative at treatment week 12 continued treatment for 48 weeks and ost-treatment. Response week 12 was defined as undetectable treatment. Sustained Virologic Response (SVR) is defined as
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 | ||||||
| interferon alpha/ribavirin | peginterferon alpha/ribavirin | Overall population | ||||
| Response week 12 % (n/N) | SVR % (n/N) 99% CI | Response week 12 % (n/N) | SVR % (n/N) 99% CI | SVR % (n/N) 99 % CI | ||
| Overall | 38.6 (549/1,423) | 59.4 (326/549) 54.0,64.8 | 31.5 (272/863) | 50.4 (137/272) 42.6, 58.2 | 21.7 (497/2,293) 19.5, 23.9 Ç | |
| Prior response | ||||||
| Relapse | 67.7 (203/300) | 59.6 (121/203) 50.7, 68.5 | 58.1 (200/344) | 52.5 (105/200) 43.4, 61.6 | 37.7 (243Æ^) 32.W26^ | |
| Genotype 1/4 | 59.7 (129/216) | 51.2 (66/129) 39.8, 62.5 | 48.6 (122/251) | 44.3 (54/122)} 32.7, 55.8 | ^8.6(134/468) J3.3, 34.0 | |
| Genotype 2/3 | 88.9 (72/81) | 73.6 (53/72) (60.2, 87.0) | 83.7 (77/92) | 64.9 (50/77)} 50.9, 78XU | /61.3 (106/173) 51.7, 70.8 | |
| NR | 28.6 (258/903) | 57.0 (147/258) 49.0, 64.9 | 12.4 (59/476) | 44J (26/59) ^7160.7 | 13.6 (188/1,385) 11.2, 15.9 | |
| Genotype 1/4 | 23.0 (182/790) | 51.6 (94/182) 42.1, 61.2 | 9.9 (44/446A | ¡386 (17/44) ^9.7, 57.5 | 9.9 (123/1,242) 7.7, 12.1 | |
| Genotype 2/3 | 67.9 (74/109) | 70.3 (52/74) 56.6, 84.0 | 536^^28) | 60.0 (9/15) 27.4, 92.6 | 46.0 (63/137) 35.0, 57.0 | |
| Genotype | ||||||
| 1 | 30.2 (343/1,135) | 51.3 C (176/343)/^ 44.4,£8.3X | 23.0 -(162/704) | 42.6 (69/162) 32.6, 52.6 | 14.6 (270/1,846) 12.5, 16.7 | |
| 2/3 | 77.1 (185/240) X | 73-FX^ (135J5) ^>4p1.4 | 75.6 (96/127) | 63.5 (61/96) 50.9, 76.2 | 55.3 (203/367) 48.6, 62.0 | |
| 4 | 42.5 (17/40) Z | 70166 (12/17) 422.1, 99.1 | 44.4 (12/27) | 50.0 (6/12) 12.8, 87.2 | 28.4 (19/67) 14.2, 42.5 | |
| METAVIR Fibrosis score | ||||||
| F2 | ^6.0^^3/420) | 66.8 (129/193) 58.1, 75.6 | 33.6 (78/232) | 57.7 (45/78) 43.3, 72.1 | 29.2 (191/653) 24.7, 33.8 | |
| F3 , | 388.0 (163/429) | 62.6 (102/163) 52.8, 72.3 | 32.4 (78/241) | 51.3 (40/78) 36.7, 65.9 | 21.9 (147/672) 17.8, 26.0 | |
| 33.6 (192/572) | 49.5 (95/192) 40.2, 58.8 | 29.7 (116/390) | 44.8 (52/116) 32.9, 56.7 | 16.5 (159/966) 13.4, 19.5 | ||
| aseline Viral 5ad | ||||||
| ÓHV1, (>600,000 lU/ml) | 32.4 (280/864) | 56.1 (157/280) 48.4, 63.7 | 26.5 (152/573) | 41.4 (63/152) 31.2, 51.7 | 16.6 (239/1,441) 14.1, 19.1 | |
| LVL (<600,000 lU/ml) | 48.3 (269/557) | 62.8 (169/269) 55.2, 70.4 | 41.0 (118/288) | 61.0 (72/118) 49.5, 72.6 | 30.2 (256/848) 26.1, 34.2 | |
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 SV 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 wi
ntron
(with or without ribavirin). The purpose of the study was to evaluate the durability o virologic response (SVR) and assess the impact of continued viral negativity on clin 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 ic infection and clinical
“cure” from chronic HCV. However, this does not preclude the occur of hepatic events in
patients with cirrhosis (including hepatocarcinoma).
utcomes.
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 d with ribavirin 15 mg/kg per day plus
PegIntron 60 pg/m2 once weekly for 24 or 48 weed 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 % < 12 years of age. The population enrolled hepatitis C. Due to the lack of data in child
for undesirable effects, the benefi carefully considered in this popul summarized in Table 15.
Caucasian, 67 % with HCV Genotype 1 and 63 % ainly consisted of children with mild to moderate en with severe progression of the disease, and the potential e combination of PegIntron with ribavirin needs to be
see sections 4.1, 4.4 and 4.8). The study results are
ical response rates (na,b (%)) in previously untreated children and
Table 15 Sustained
| adolescents^ | [genotype and treatment duration – All subjects n = 107 | |
| 24 weeks | 48 weeks | |
| All Genotapgsf^ | 26/27 (96 %) | 44/80 (55 %) |
| Genott'peL | – | 38/72 (53 %) |
| Genotypes | 14/15 (93 %) | – |
| senotype 3c | 12/12 (100%) | 2/3 (67 %) |
| Penotype 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 lU/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 h post-dose, and are sustained for up to 48–72 hours post-dose.
of
PegIntron Cmaxand AUC measurements increase in a dose-related manner. Mean appar distribution is 0.99 l/kg.
is, however, only a
Upon multiple dosing, there is an accumulation of immunoreactive interferons. modest increase in biologic activity as measured by a bioassay.
Mean (SD) PegIntron elimination half-life is approximately 40 hours (1 clearance of 22.0 ml/hr/kg. The mechanisms involved in clearance o fully elucidated. However, renal elimination may account for a mino PegIntron apparent clearance.
not yet been proximately 30 %) of
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.tients with creatinine clearance < 50 ml/minute must not be treated with PegIntron in comn with ribavirin (bitherapy or tritherapy) (see section 4.3).
Because of patients wi sec
inter-subject variability in interferon pharmacokinetics, it is recommended that ere renal impairment be closely monitored during treatment with PegIntron (see
impairment
harmacokinetics of PegIntron have not been evaluated in patients with severe hepatic ysfunction.
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 p.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 jag/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 partner after sexual intercourse with a treated patient has been estimated and remains extremel limited compared to therapeutic plasma concentration of ribavirin.
5.3 Preclinical safety data
5.3 Preclinical safety dataPegIntron
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. Inte abortifacient in primates. PegIntron is likely to also cause this determined. It is not known whether the components of thi experimental animal or human milk (see section 4.6 for rele PegIntron showed no genotoxic potential.
–2b has been shown to be an cts on fertility have not been inal product are excreted into uman data on pregnancy and lactation).
The relative non-toxicity of monomethoxy PegIntron by metabolism in vivo has been studies in rodents and monkeys, stan mutagenicity assays.
hylene glycol (mPEG), which is liberated from trated in preclinical acute and subchronic toxicity foetal development studies and in in vitro
PegIntron plus ribavirin _VP
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 benducted 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).
RMACEUTICAL PARTICULARS
.1 List of excipients
.1 List of excipientsPowder
Disodium phosphate, anhydrous
Sodium dihydrogen phosphate dihydrate
Sucrose
Polysorbate 80
Solvent
Water for injections
6.2 Incompatibilities
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.
6.3 Shelf life
Before reconstitution 3 years.
After reconstitution
Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C – 8°C. From a microbiological point of view, the product is to be used immediately. If not used use storage times and conditions prior to use are the responsibility of the user and woul longer than 24 hours at 2°C – 8°C.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
, innot be
For storage conditions of the reconstituted medicinal product,
6.5 Nature 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 a2 ml ampoule (Type I flint glass).
PegIntron is supplied as:
1 vial of powder for solution for injec
1 vial of powder for solution for inj syringe, 2 injection needles and 1
4 vials of powder for solutio
4 vials of powder for solutio
and 1 ampoule of solvent for parenteral use;
, 1 ampoule of solvent for parenteral use, 1 injection ng swab;
syringes, 8 injecti 6 vials of powder 12 vials of powde syringes, 24 injec
injection and4 ampoules of solvent for parenteral use;
for injection, 4 ampoules of solvent for parenteral use, 4 injection
nd4 cleansing swabs;
for injection and6 ampoules of solvent for parenteral use.
n for injection, 12 ampoules of solvent for parenteral use, 12 injection
eedles and 12 cleansing swabs.
Not all pac
e marketed.
6.6 Special precautions for disposal and other handlingPe
6.6 Special precautions for disposal and other handlingPe0 micrograms powder and solvent for solution for injection ial is to be reconstituted with 0.7 ml of water for injections for administration of up to 0.5 ml of ion. 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 of80 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 ens delivery of the labelled dose in 0.5 ml of PegIntron, solution for injection. The reconstituted so 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
ituted solution has a
delivery of the labelled dose in 0.5 ml of PegIntron, solution concentration of 150 micrograms/0.5 ml.
injections is injected into the. The appropriate dose can then et of instructions is provided in
Using a sterilised injection syringe and injection needle, 0.7 ml of w vial of PegIntron. Dissolution of powder is completed by agitating it be withdrawn with a sterilised injection syringe and injected. A com the Annex to the Package Leaflet.
As for all parenteral medicinal products, the reconstituted solution isto 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 AUTHORISA
8. MA
Merck Sharp & Dohme B.V. Waarderweg 39 2031 BN Haarlem The Netherlands
PegIntroi
EU
EU
1/001
1/002
131/003 /00/131/004
EU/1/00/131/005
EU/1/00/131/026
rograms powder and solvent for solution for injection
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
THE AUTHORISATION
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/RENEW
9. DATE OF FIRST AUTHORISATION/RENEWDate of first authorisation: 25 May 2000
Date of latest renewal: 25 May 2010
10. DATE OF REVISION OF TH
Detailed information on this med
product is available on the web-site of the European Medicines
Agency