1. Name Of The Medicinal Product
Pegasys 135 micrograms solution for injection in pre-filled pen
Pegasys 180 micrograms solution for injection in pre-filled pen
2. Qualitative And Quantitative Composition
One pre-filled pen contains
peginterferon alfa-2a*.....................................................................135 micrograms
Each pen of 0.5 ml solution contains 135 micrograms peginterferon alfa-2a*. The strength indicates the quantity of the interferon alfa-2a moiety of peginterferon alfa-2a without consideration of the pegylation.
One pre-filled pen contains
peginterferon alfa-2a*.....................................................................180 micrograms
Each pen of 0.5 ml solution contains 180 micrograms peginterferon alfa-2a*. The strength indicates the quantity of the interferon alfa-2a moiety of peginterferon alfa-2a without consideration of the pegylation.
*The active substance, peginterferon alfa-2a, is a covalent conjugate of the protein interferon alfa-2a produced by recombinant DNA technology in Escherichia coli with bis-[monomethoxy polyethylene glycol].
The potency of this product should not be compared to the one of another pegylated or non-pegylated protein of the same therapeutic class. For more information, see section 5.1.
For a full list of excipients, see section 6.1.
Excipient:
Benzyl alcohol (10 mg/ 1 ml)
3. Pharmaceutical Form
Solution for injection (injection) in pre-filled pen.
The solution is clear and colourless to light yellow.
4. Clinical Particulars
4.1 Therapeutic Indications
Chronic hepatitis B:
Pegasys is indicated for the treatment of HBeAg-positive or HBeAg-negative-chronic hepatitis B in adult patients with compensated liver disease and evidence of viral replication, increased ALT and histologically verified liver inflammation and/or fibrosis (see sections 4.4 and 5.1).
Chronic hepatitis C:
Pegasys is indicated for the treatment of chronic hepatitis C in adult patients who are positive for serum HCV-RNA, including patients with compensated cirrhosis and/or co-infected with clinically stable HIV (see section 4.4).
The optimal way to use Pegasys in patients with chronic hepatitis C is in combination with ribavirin. The combination of Pegasys and ribavirin is indicated in naive patients and patients who have failed previous treatment with interferon alpha (pegylated or non-pegylated) alone or in combination therapy with ribavirin.
Monotherapy is indicated mainly in case of intolerance or contraindication to ribavirin.
4.2 Posology And Method Of Administration
Treatment should be initiated only by a physician experienced in the treatment of patients with hepatitis B or C.
Please refer also to the ribavirin Summary of Product Characteristics (SPC) when Pegasys is to be used in combination with ribavirin.
Dose to be administered and duration of treatment
Chronic hepatitis B:
The recommended dosage and duration of Pegasys for both HBeAg-positive and HBeAg-negative chronic hepatitis B is 180 micrograms once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh.
Chronic hepatitis C – treatment-naïve patients:
The recommended dose for Pegasys is 180 micrograms once weekly by subcutaneous administration in the abdomen or thigh given in combination with oral ribavirin or as monotherapy.
The dose of ribavirin to be used in combination with Pegasys s given in Table 1.
The ribavirin dose should be administered with food.
Duration of treatment
The duration of combination therapy with ribavirin for chronic hepatitis C depends on viral genotype. Patients infected with HCV genotype 1 who have detectable HCV RNA at week 4 regardless of pre-treatment viral load should receive 48 weeks of therapy.
Treatment for 24 weeks may be considered in patients infected with
- genotype 1 with low viral load (LVL) (
- genotype 4
who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24. However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration (see section 5.1). In these patients, tolerability to combination therapy and additional prognostic factors such as degree of fibrosis should be taken into account when deciding on treatment duration. Shortening the treatment duration in patients with genotype 1 and high viral load (HVL) (>800, 000 IU/ml) at baseline who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24 should be considered with even more caution since the limited data available suggest that this may significantly negatively impact the sustained virologic response.
Patients infected with HCV genotype 2 or 3 who have detectable HCV RNA at week 4, regardless of pre-treatment viral load should receive 24 weeks of therapy. Treatment for only 16 weeks may be considered in selected patients infected with genotype 2 or 3 with LVL (
Available data for patients infected with genotype 5 or 6 are limited; therefore combination treatment with 1000/1200 mg of ribavirin for 48 weeks is recommended.
Table 1: Dosing Recommendations for Combination therapy for HCV Patients
Genotype
|
Pegasys Dose
|
Ribavirin Dose
|
Duration
|
Genotype 1 LVL with RVR*
|
180 micrograms
|
<75 kg = 1000 mg
|
24 weeks or
48 weeks
|
Genotype 1 HVL with RVR*
|
180 micrograms
|
<75 kg = 1000 mg
|
48 weeks
|
Genotype 4 with RVR*
|
180 micrograms
|
<75 kg = 1000 mg
|
24 weeks or
48 weeks
|
Genotype 1 or 4 without RVR*
|
180 micrograms
|
<75 kg = 1000 mg
|
48 weeks
|
Genotype 2 or 3 without RVR**
|
180 micrograms
|
800 mg
|
24 weeks
|
Genotype 2 or 3 LVL with RVR**
|
180 micrograms
|
800 mg(a)
|
16 weeks(a) or 24 weeks
|
Genotype 2 or 3 HVL with RVR**
|
180 micrograms
|
800 mg
|
24 weeks
|
*RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24;
**RVR = rapid viral response (HCV RNA negative) by week 4
LVL=
(a) It is presently not clear whether a higher dose of ribavirin (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.
The ultimate clinical impact of a shortened initial treatment of 16 weeks instead of 24 weeks is unknown, taking into account the need for retreating non-responding and relapsing patients.
The recommended duration of Pegasys monotherapy is 48 weeks.
Chronic hepatitis C – treatment-experienced patients:
The recommended dose of Pegasys in combination with ribavirin is 180 mcg once weekly by subcutaneous administration. For patients <75 kg and
Patients who have detectable virus at week 12 should stop therapy. The recommended total duration of therapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment with PEG-IFN and ribavirin are considered for treatment, the recommended total duration of therapy is 72 weeks (see section 5.1).
HIV-HCV co-infection
The recommended dosage for Pegasys, alone or in combination with ribavirin, is 180 micrograms once weekly subcutaneously for 48 weeks. For patients infected with HCV genotype 1 <75 kg and
Predictability of response and non-response – treatment-naïve patients
Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of HCV RNA has been shown to be predictive for sustained response (see Tables 2 and 6).
Table 2: Predictive Value of Week 12 Virological Response at the Recommended Dosing Regimen while on Pegasys Combination Therapy
Genotype
|
Negative
|
Positive
|
|
|
|
|
|
No response by
week 12
|
No sustained response
|
Predictive Value
|
Response by week 12
|
Sustained response
|
Predictive Value
|
Genotype 1
(N= 569)
|
102
|
97
|
95%
(97/102)
|
467
|
271
|
58%
(271/467)
|
Genotype 2 and 3
(N=96)
|
3
|
3
|
100%
(3/3)
|
93
|
81
|
87%
(81/93)
|
The negative predictive value for sustained response in patients treated with Pegasys in monotherapy was 98%.
A similar negative predictive value has been observed in HIV-HCV co-infected patients treated with Pegasys monotherapy or in combination with ribavirin (100% (130/130) or 98% (83/85), respectively). Positive predictive values of 45% (50/110) and 70% (59/84) were observed for genotype 1 and genotype 2/3 HIV-HCV co-infected patients receiving combination therapy.
Predictability of response and non-response – treatment-experienced patients
In non-responder patients re-treated for 48 or 72 weeks, viral suppression at week 12 (undetectable HCV RNA defined as <50 IU/mL) has been shown to be predictive for sustained virological response. The probabilities of not achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was not achieved at week 12 were 96% (363 of 380) and 96% (324 of 339), respectively. The probabilities of achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was achieved at week 12 were 35% (20 of 57) and 57% (57 of 100), respectively.
Dose adjustment for adverse reactions
General
Where dose adjustment is required for moderate to severe adverse reactions (clinical and/or laboratory) initial dose reduction to 135 micrograms is generally adequate. However, in some cases, dose reduction to 90 micrograms or 45 micrograms is necessary. Dose increases to or towards the original dose may be considered when the adverse reaction abates (see section 4.4 for use and section 4.8).
Haematological (see also Table3)
Dose reduction is recommended if the neutrophil count is < 750/mm3. For patients with Absolute Neutrophil Count (ANC) < 500/mm3 treatment should be suspended until ANC values return to > 1000/mm3. Therapy should initially be re-instituted at 90 micrograms Pegasys and the neutrophil count monitored.
Dose reduction to 90 micrograms is recommended if the platelet count is < 50,000/mm3. Cessation of therapy is recommended when platelet count decreases to levels < 25,000/mm3.
Specific recommendations for management of treatment-emergent anaemia are as follows: ribavirin should be reduced to 600 milligrams/day (200 milligrams in the morning and 400 milligrams in the evening) if either of the following apply: (1) a patient without significant cardiovascular disease experiences a fall in haemoglobin to < 10 g/dl and
Table 3: Dose Adjustment for Adverse Reaction (For further guidance see also text above)
|
|
|
|
|
|
|
Reduce ribavirin to 600 mg
|
Withhold ribavirin
|
Reduce Pegasys to 135/90/45 micrograms
|
Withhold Pegasys
|
Discontinue Combination
|
Absolute Neutrophil Count
|
|
|
< 750/mm3
|
< 500/mm3
|
|
Platelet Count
|
|
|
< 50,000/mm3
> 25,000/mm3
|
|
< 25,000/mm3
|
Haemoglobin
- no cardiac disease
|
< 10 g/dl, and
|
< 8.5 g/dl
|
|
|
|
Haemoglobin
- stable cardiac disease
|
decrease
|
< 12 g/dl despite 4 weeks at reduced dose
|
|
|
|
In case of intolerance to ribavirin, Pegasys monotherapy should be continued.
Liver function
Fluctuations in abnormalities of liver function tests are common in patients with chronic hepatitis C. As with other alpha interferons, increases in ALT levels above baseline (BL) have been observed in patients treated with Pegasys, including patients with a virological response.
In chronic hepatitis C clinical trials, isolated increases in ALT (
For chronic hepatitis B patients, transient flares of ALT levels sometimes exceeding 10 times the upper limit of normal are not uncommon, and may reflect immune clearance. Treatment should normally not be initiated if ALT is >10 times the upper limit of normal. Consideration should be given to continuing treatment with more frequent monitoring of liver function during ALT flares. If the Pegasys dose is reduced or withheld, therapy can be restored once the flare is subsiding (see section 4.4).
Special populations
Elderly
Adjustments in the recommended dosage of 180 micrograms once weekly are not necessary when instituting Pegasys therapy in elderly patients (see section 5.2).
Children and adolescents
Only limited safety and efficacy data are available in children and adolescents (6-18 years) (see section 5.1). Pegasys is contraindicated in neonates and young children up to 3 years old because of the excipient benzyl alcohol (see sections 4.3 and 4.4).
Patients with renal impairment
In patients with end stage renal disease, a starting dose of 135 micrograms should be used (see section 5.2). Regardless of the starting dose or degree of renal impairment, patients should be monitored and appropriate dose reductions of Pegasys during the course of therapy should be made in the event of adverse reactions.
Patients with hepatic impairment
In patients with compensated cirrhosis (eg, Child-Pugh A), Pegasys has been shown to be effective and safe. Pegasys has not been evaluated in patients with decompensated cirrhosis (eg, Child-Pugh B or C or bleeding oesophageal varices) (see section 4.3).
The Child-Pugh classification divides patients into groups A, B, and C, or "Mild", "Moderate" and "Severe" corresponding to scores of 5-6, 7-9 and 10-15, respectively.
Modified Assessment
Assessment
|
Degree of abnormality
|
Score
|
Encephalopathy
|
None
Grade 1-2
Grade 3-4*
|
1
2
3
|
Ascites
|
Absent
Slight
Moderate
|
1
2
3
|
S-Bilirubin (mg/dl)
SI unit = μmol/l)
|
<2
2.0-3
>3
<34
34-51
>51
|
1
2
3
1
2
3
|
S-Albumin (g/dl)
|
>3.5
3.5-2.8
<2.8
|
1
2
3
|
INR
|
<1.7
1.7-2.3
>2.3
|
1
2
3
|
*Grading according to Trey, Burns and Saunders (1966)
4.3 Contraindications
• Hypersensitivity to the active substance, to alpha interferons, or to any of the excipients
• Autoimmune hepatitis
• Severe hepatic dysfunction or decompensated cirrhosis of the liver
• Neonates and young children up to 3 years old, because of the excipient benzyl alcohol (see section 4.4 for benzyl alcohol)
• A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months (see section 4.4)
• Initiation of Pegasys is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score
• Combination of Pegasys with telbivudine (see section 4.5).
For contraindications to ribavirin, please refer also to the ribavirin Summary of Product Characteristics (SPC) when Pegasys is to be used in combination with ribavirin.
4.4 Special Warnings And Precautions For Use
Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Pegasys 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 ideation is identified, it is recommended that treatment with Pegasys be discontinued, and the patient followed, with psychiatric intervention as appropriate.
Patients with existence of, or history of severe psychiatric conditions: If treatment with Pegasys is judged necessary in patients with existence or history of severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition.
|
Please refer also to the ribavirin Summary of Product Characteristics (SPC) when Pegasys is to be used in combination with ribavirin.
All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (ie, patients with genotype 2 or 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.
In patients with normal ALT, progression of fibrosis occurs on average at a slower rate than in patients with elevated ALT. This should be considered in conjunction with other factors, such as HCV genotype, age, extrahepatic manifestations, risk of transmission, etc. which influence the decision to treat or not.
Excipient: Benzyl alcohol. Pegasys is contraindicated in infants or young children up to 3 years old because of the excipient benzyl alcohol.
Laboratory tests prior to and during therapy
Prior to beginning Pegasys therapy, standard haematological and biochemical laboratory tests are recommended for all patients.
The following may be considered as baseline values for initiation of treatment:
- Platelet count 3
- Absolute neutrophil counts 3
- Adequately controlled thyroid function (TSH and T4)
Haematological tests should be repeated after 2 and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy.
In clinical trials, Pegasys treatment was associated with decreases in both total white blood cell (WBC) count and absolute neutrophil count (ANC), usually starting within the first 2 weeks of treatment (see section 4.8). Progressive decreases after 8 weeks of therapy were infrequent. The decrease in ANC was reversible upon dose reduction or cessation of therapy (see section 4.2), reached normal values by 8 weeks in the majority of patients and returned to baseline in all patients after about 16 weeks.
Pegasys treatment has been associated with decreases in platelet count, which returned to pre-treatment levels during the post-treatment observation period (see section 4.8). In some cases, dose modification may be necessary (see section 4.2).
The occurrence of anaemia (haemoglobin <10 g/dl) has been observed in up to 15% of chronic hepatitis C patients in clinical trials on the combined treatment of Pegasys with ribavirin. The frequency depends on the treatment duration and the dose of ribavirin (see section 4.8,). The risk of developing anaemia is higher in the female population.
As with other interferons, caution should be exercised when administering Pegasys in combination with other potentially myelosuppressive agents.
Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see section 4.5).
The use of Pegasys and ribavirin combination therapy in chronic hepatitis C patients who failed prior treatment has not been adequately studied in patients who discontinued prior therapy for hematological adverse events. Physicians considering treatment in these patients should carefully weigh the risks versus the benefits of re-treatment.
Endocrine system
Thyroid function abnormalities or worsening of pre-existing thyroid disorders have been reported with the use of alpha interferons, including Pegasys. Prior to initiation of Pegasys therapy, TSH and T4 levels should be evaluated. Pegasys treatment may be initiated or continued if TSH levels can be maintained in the normal range by medication. TSH levels should be determined during the course of therapy if a patient develops clinical symptoms consistent with possible thyroid dysfunction (see section 4.8). As with other interferons, hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed with Pegasys (see section 4.8). Patients with these conditions who cannot be effectively controlled by medication should not begin Pegasys monotherapy nor Pegasys/ribavirin combination therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should discontinue Pegasys or Pegasys/ribavirin therapy.
Cardiovascular system
Hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial infarction have been associated with alpha interferon therapies, including Pegasys. It is recommended that patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to initiation of Pegasys therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. In patients with cardiovascular disease, anaemia may necessitate dose reduction or discontinuation of ribavirin (see section 4.2).
Liver function
In patients who develop evidence of hepatic decompensation during treatment, Pegasys should be discontinued. As with other alpha interferons, increases in ALT levels above baseline have been observed in patients treated with Pegasys, including patients with a viral response. When the increase in ALT levels is progressive and clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy should be discontinued (see sections 4.2 and 4.8).
In chronic hepatitis B, unlike chronic hepatitis C, disease exacerbations during therapy are not uncommon and are characterised by transient and potentially significant increases in serum ALT. In clinical trials with Pegasys in HBV, marked transaminase flares have been accompanied by mild changes in other measures of hepatic function and without evidence of hepatic decompensation. In approximately half the case of flares exceeding 10 times the upper limit of normal, Pegasys dosing was reduced or withheld until the transaminase elevations subsided, while in the rest therapy was continued unchanged. More frequent monitoring of hepatic function was recommended in all instances.
Hypersensitivity
Serious, acute hypersensitivity reaction (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during alpha interferon therapy. If this occurs, therapy must be discontinued and appropriate medical therapy instituted immediately. Transient rashes do not necessitate interruption of treatment.
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 Endocrine System in sections 4.4 and 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).
Fever/infections
While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) and sepsis have been reported during treatment with alpha interferons including Pegasys. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.
Ocular changes
As with other interferons retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and retinal artery or vein obstruction which may result in loss of vision have been reported in rare instances with Pegasys. All patients should have a baseline eye examination. Any patient complaining of decrease or loss of vision must have a prompt and complete eye examination. Patients with preexisting ophthalmologic disorders (eg, diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during Pegasys therapy. Pegasys treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Pulmonary changes
As with other alpha interferons, pulmonary symptoms, including dyspnoea, pulmonary infiltrates, pneumonia, and pneumonitis have been reported during therapy with Pegasys. In case of persistent or unexplained pulmonary infiltrates or pulmonary function impairment, treatment should be discontinued.
Skin disorder
Use of alpha interferons has been associated with exacerbation or provocation of psoriasis and sarcoidosis. Pegasys must be used with caution in patients with psoriasis, and in cases of onset or worsening of psoriatic lesions, discontinuation of therapy should be considered.
Transplantation
The safety and efficacy of Pegasys and ribavirin treatment have not been established in patients with liver and other transplantations. Liver and renal graft rejections have been reported with Pegasys, alone or in combination with ribavirin.
HIV-HCV coinfection
Please refer to the respective Summary of Product Characteristics 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 Pegasys with or without ribavirin. In study NR15961, patients concurrently treated with stavudine and interferon therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should therefore be exercised when adding Pegasys and ribavirin to HAART therapy (see ribavirin SPC).
Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with ribavirin in combination with interferons, including Pegasys. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelet count, and treatment with didanosine (ddI).
The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).
During treatment, co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinaemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Pegasys should be discontinued immediately in patients with hepatic decompensation.
In patients co-infected with HIV-HCV, limited efficacy and safety data are available in subjects with CD4 counts less than 200 cells/uL. Caution is therefore warranted in the treatment of patients with low CD4 counts.
Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Pegasys and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of Pegasys and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.
Use of peginterferon as long term maintenance monotherapy (unapproved use)
In a randomised, controlled US study (HALT-C) of HCV non-responder patients with varied degrees of fibrosis where 3.5 years of treatment with 90 micrograms/week of Pegasys monotherapy was studied, no significant reductions were observed in the rate of fibrosis progression or related clinical events.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Interaction studies have only been performed in adults.
Administration of Pegasys 180 micrograms once weekly for 4 weeks in healthy male subjects did not show any effect on mephenytoin, dapsone, debrisoquine and tolbutamide pharmacokinetics profiles, suggesting that Pegasys has no effect on in vivo metabolic activity of cytochrome P450 3A4, 2C9, 2C19 and 2D6 isozymes.
In the same study, a 25% increase in the AUC of theophylline (marker of cytochrome P450 1A2 activity) was observed, demonstrating that Pegasys is an inhibitor of cytochrome P450 1A2 activity. Serum concentrations of theophylline should be monitored and appropriate dose adjustments of theophylline made for patients taking theophylline and Pegasys concomitantly. The interaction between theophylline and Pegasys is likely to be maximal after more than 4 weeks of Pegasys therapy.
HCV monoinfected patients and HBV monoinfected patients
In a pharmacokinetic study of 24 HCV patients concomitantly receiving methadone maintenance therapy (median dose 95 mg; range 30 mg to 150 mg), treatment with Pegasys 180 micrograms sc once weekly for 4 weeks was associated with mean methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; nonetheless, patients should be monitored for the signs and symptoms of methadone toxicity. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.
Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine. The use of peginterferon alfa-2a and ribavirin concomitantly with azathioprin should be avoided. In individual cases where the benefit of administering ribavirin concomitantly with azathioprine warrants the potential risk, it is recommended that close hematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these drugs should be stopped (see section 4.4).
Results from pharmacokinetic sub studies of pivotal phase III trials demonstrated no pharmacokinetic interaction of lamivudine on Pegasys in HBV patients or between Pegasys and ribavirin in HCV patients.
A clinical trial investigating the combination of telbivudine 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration for the treatment of HBV, indicates that the combination is associated with an increased risk for developing peripheral neuropathy. The mechanism behind these events is not known; thus, co-treatment with telbivudine and other interferons (pegylated or standard) may also entail an excess risk. Moreover, the benefit of the combination of telbivudine with interferon alfa (pegylated or standard) is not currently established.
Therefore, the combination of Pegasys with telbivudine is contraindicated (see section 4.3).
HIV-HCV co-infected patients
No apparent evidence of drug interaction was observed in 47 HIV-HCV co-infected patients who completed a 12 week pharmacokinetic sub study to examine the effect of ribavirin on the intracellular phosphorylation of some nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine or stavudine). However, due to high variability, the confidence intervals were quite wide. Plasma exposure of ribavirin did not appear to be affected by concomitant administration of nucleoside reverse transcriptase inhibitors (NRTIs).
Co-administration of ribavirin and didanosine is not recommended. Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased in vitro when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactataemia/lactic acidosis have been reported with use of ribavirin.
Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.
4.6 Pregnancy And Lactation
There are no adequate data on the use of peginterferon alfa-2a in pregnant women. Studies in animals with interferon alfa-2a have shown reproductive toxicity (see section 5.3) and the potential risk for humans is unknown. Pegasys is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior to initiation of treatment.
Use with ribavirin
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking Pegasys in combination with ribavirin. Female patients of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded. Please refer to the ribavirin SPC.
4.7 Effects On Ability To Drive And Use Machines
Pegasys has a minor or moderate influence on the ability to drive and use machines. Patients who develop dizziness, confusion, somnolence or fatigue should be cautioned to avoid driving or operating machinery.
4.8 Undesirable Effects
Experience from clinical trials
Chronic hepatitis C
The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a (see Table 4).The most frequently reported adverse reactions with Pegasys 180 micrograms were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy.
