Drug Class Description

Generic Name

Drug Description

Presentation

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.

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.

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.

Adult Dosage

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

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 is 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) ( 800,000 IU/mL) at baseline or

- 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. In these patients, tolerability to combination therapy and additional prognostic factors such as degree of fibrosis should be taken into account when deciding on treatment duration. Shortening the treatment duration in patients with genotype 1 and high viral load (HVL) (>800, 000 IU/ml) at baseline who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24 should be considered with even more caution since the limited data available suggest that this may significantly negatively impact the sustained virologic response.

Patients infected with HCV genotype 2 or 3 who have detectable HCV RNA at week 4, regardless of pre-treatment viral load should receive 24 weeks of therapy. Treatment for only 16 weeks may be considered in selected patients infected with genotype 2 or 3 with LVL ( 800,000 IU/mL) at baseline who become HCV negative by week 4 of treatment and remains HCV negative by week 16. Overall 16 weeks of treatment may be associated with a lower chance of response and is associated with a higher risk of relapse than a 24 week treatment duration. In these patients, tolerability to combination therapy and the presence of additional clinical or prognostic factors such as degree of fibrosis should be taken into account when considering deviations from standard 24 weeks treatment duration. Shortening the treatment duration in patients infected with genotype 2 or 3 with HVL (> 800,000 IU/mL) at baseline who become HCV negative by week 4 should be considered with more caution as this may significantly negatively impact the sustained virological response (see Table 1).

Available data for patients infected with genotype 5 or 6 are limited; therefore combination treatment with 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 75 kg = 1200 mg	24 weeks or 48 weeks
Genotype 1 HVL with RVR*	180 micrograms	<75 kg = 1000 mg 75 kg = 1200 mg	48 weeks
Genotype 4 with RVR*	180 micrograms	<75 kg = 1000 mg 75 kg = 1200 mg	24 weeks or 48 weeks
Genotype 1 or 4 without RVR*	180 micrograms	<75 kg = 1000 mg 75 kg = 1200 mg	48 weeks
Genotype 2 or 3 without RVR**	180 micrograms	800 mg	24 weeks
Genotype 2 or 3 LVL with RVR**	180 micrograms	800 mg	16 weeks 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= 800,000 IU/mL; HVL= > 800,000 IU/mL

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 75 kg, 1000 mg daily and 1200 mg daily of ribavirin,respectively, should be administered.

Patients who have detectable virus at week 12 should stop therapy. The recommended total duration of therapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment with PEG-IFN and ribavirin are considered for treatment, the recommended total duration of therapy is 72 weeks.

HIV-HCV co-infection

The recommended dosage for Pegasys, alone or in combination with 800 milligrams of ribavirin, is 180 micrograms once weekly subcutaneously for 48 weeks, regardless of genotype. The safety and efficacy of combination therapy with ribavirin doses greater than 800 milligrams daily is currently being studied. A duration of therapy less than 48 weeks has not been adquately studied.

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

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.

Haematological (see also Table 3)

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 8.5 g/dl, or (2) a patient with stable cardiovascular disease experiences a fall in haemoglobin by 2 g/dl during any 4 weeks of treatment. A return to original dosing is not recommended. Ribavirin should be discontinued if either of the following apply: (1) A patient without significant cardiovascular disease experiences a fall in haemoglobin confirmed to < 8.5 g/dl; (2) A patient with stable cardiovascular disease maintains a haemoglobin value < 12 g/dl despite 4 weeks on a reduced dose. If the abnormality is reversed, ribavirin may be restarted at 600 milligrams daily, and further increased to 800 milligrams daily at the discretion of the treating physician. A return to original dosing is not recommended.

Table 3: Dose Adjustment for Adverse 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	< 8.5 g/dl
Haemoglobin stable cardiac disease	decrease 2 g/dl during any 4 weeks	< 12 g/dl despite 4 weeks at reduced dose

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

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 ( 10x ULN, or 2x BL for patients with a BL ALT 10x ULN) which resolved without dose-modification were observed in 8 of 451 patients treated with combination therapy. If ALT increase is progressive or persistent, the dose should be reduced initially to 135 micrograms. When increase in ALT levels is progressive despite dose reduction, or is accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be discontinued.

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.

Special populations

Elderly

Adjustments in the recommended dosage of 180 micrograms once weekly are not necessary when instituting Pegasys therapy in elderly patients.

Children and adolescents

Only limited safety and efficacy data are available in children and adolescents (6-18 years). Pegasys is contraindicated in neonates and young children up to 3 years old because of the excipient benzyl alcohol.

Patients with renal impairment

In patients with end stage renal disease, a starting dose of 135 micrograms should be used. 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).

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

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

Child Dosage

Elderly Dosage

Contra Indications

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

• A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months

• Initiation of Pegasys is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score 6

Special Precautions

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 90,000/mm³

- Absolute neutrophil counts 1500/mm³

- 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. Progressive decreases after 8 weeks of therapy were infrequent. The decrease in ANC was reversible upon dose reduction or cessation of therapy, 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. In some cases, dose modification may be necessary.

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. 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.

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 haematological 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. As with other interferons, hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed with Pegasys. 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.

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.

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.

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) 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 treatment have not been established in patients with liver transplantation.

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.

Co-infected patients should be closely monitored, assessing their Child-Pugh score during treatment, and should be immediately discontinued if they progress to a Child-Pugh score of 7 or greater.

In patients co-infected with HIV-HCV, limited efficacy and safety data (N = 51) 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.

Interactions

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.

Results from pharmacokinetic substudies of pivotal phase III trials demonstrated no pharmacokinetic interaction of lamivudine on Pegasys in HBV patients or between Pegasys and ribavirin in HCV 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.

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 substudy 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. 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.

Adverse Reactions

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.

Chronic hepatitis B

In clinical trials of 48 week treatment and 24 weeks follow-up, the safety profile for Pegasys in chronic hepatitis B was similar to that seen in chronic hepatitis C . With the exception of pyrexia the frequency of the majority of the reported adverse reactions was notably less in CHB patients treated with Pegasys monotherapy compared with HCV patients treated with Pegasys monotherapy (see Table 4). Adverse events were experienced by 88% of Pegasys-treated patients as compared with 53% of patients in the lamivudine comparator group, while 6% of the Pegasys-treated and 4% of the lamivudine-treated patients experienced serious adverse events during the studies. Adverse events or laboratory abnormalities led to 5% of patients withdrawing from Pegasys treatment, while less than 1% of patients withdrew from lamivudine treatment for these reasons. The percentage of patients with cirrhosis who withdrew from treatment was similar to that of the overall population in each treatment group.

Chronic hepatitis C in prior non-responder patients

Overall, the safety profile for Pegasys in combination with ribavirin in prior non-responder patients was similar to that in naïve patients. In a clinical trial of non-responder patients to prior pegylated interferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, the frequency of withdrawal for adverse events or laboratory abnormalities from Pegasys treatment and ribavirin treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13% ,respectively, in the 72 week arms. Similarly for patients with cirrhosis or transition to cirrhosis, the frequencies of withdrawal from Pegasys treatment and ribavirin treatment were higher in the 72-week treatment arms (13% and 15%) than in the 48-week arms (6% and 6%). Patients who withdrew from previous therapy with pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded from enrolling in this trial.

In another clinical trial, non-responder patients with advanced fibrosis or cirrhosis (Ishak score of 3 to 6) and baseline platelet counts as low as 50,000/mm³ were treated for 48 weeks. Haematologic laboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% of patients experienced a haemoglobin level of <10 g/dL), neutropenia (30% experienced an ANC <750/mm³), and thrombocytopenia (13% experienced a platelet count <50,000/ mm³).

Chronic hepatitis C and HIV co-infection

In HIV-HCV co-infected patients, the clinical adverse event profiles reported for Pegasys, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients For HIV-HCV patients receiving Pegasys and ribavirin combination therapy other undesirable effects have been reported in 1% to 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Pegasys treatment 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 Pegasys had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N= 51) are available in co-infected patients with CD4+ cell counts <200/µl.

Table 4 summarises the undesirable effects reported with Pegasys monotherapy in CHB or CHC patients and with Pegasys in combination with ribavirin in CHC patients.

Table 4: Undesirable Effects Reported with Pegasys Monotherapy for HBV or HCV or In Combination with Ribavirin for HCV Patients

*These adverse reactions were common (1/100 to < 1 /10) in CHB patients treated with Pegasys monotherapy

Post marketing adverse events

Nervous System Disorders:

Cerebral ischaemia: frequency unknown.

Eye Disorders:

Serous retinal detachment: frequency unknown.

As with other alpha interferons, serous retinal detachment has been reported with Pegasys.

Musculoskeletal connective tissue and bone disorders:

Rhabdomyolysis: frequency unknown.

Laboratory values

Pegasys treatment was associated with abnormal laboratory values: ALT increase, bilirubin increase, electrolyte disturbance (hypokalaemia, hypocalcaemia, hypophosphataemia), hyperglycaemia, hypoglycaemia and elevated triglycerides. With both Pegasys monotherapy, and also the combined treatment with ribavirin, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of the treatment.

Treatment with Pegasys was associated with decreases in haematological values (leucopenia, neutropenia, lymphopenia, thrombocytopenia and haemoglobin), which generally improved with dose modification, and returned to pre-treatment levels within 48 weeks upon cessation of therapy.

Moderate (ANC: 0.749 0.5 x 10⁹/l) and severe (ANC: < 0.5 x 10⁹/l) neutropenia was observed respectively in 24% (216/887) and 5% (41/887) of patients receiving Pegasys 180 micrograms and ribavirin 1000/1200 milligrams for 48 weeks.

Anti-interferon antibodies

1-5% of patients treated with Pegasys developed neutralising anti-interferon antibodies. As with other interferons, a higher incidence of neutralising antibodies was seen in chronic hepatitis B. However in neither disease was this correlated with lack of therapeutic response.

Thyroid function

Pegasys treatment was associated with clinically significant abnormalities in thyroid laboratory values requiring clinical intervention. The frequencies observed (4.9%) in patients receiving Pegasys/ribavirin (NV15801) are similar to those observed with other interferons.

Laboratory values for HIV-HCV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC levels below 500 cells/mm³ was observed in 13% and 11% of patients receiving Pegasys monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm³ was observed in 10% and 8% of patients receiving Pegasys monotherapy and combination therapy, respectively. Anaemia (haemoglobin < 10g/dL) was reported in 7% and 14% of patients treated with Pegasys monotherapy or in combination therapy, respectively.

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