Pegasys

Pegasys

peginterferon alfa-2a

Manufacturer:

Roche

Marketer:

DKSH
Full Prescribing Info
Contents
Peginterferon alfa-2a.
Description
Active ingredient: peginterferon alfa-2a.
Pegasys is supplied as a sterile, ready-to-use liquid for subcutaneous injection as prefilled syringes: 180 mcg Pegasys prefilled syringe: each single use syringe contains 0.5 mL with 180 mcg peginterferon alfa-2a.
135 mcg Pegasys prefilled syringe: each single use syringe contains 0.5 mL with 135 mcg peginterferon alfa-2a.
Excipients/Inactive Ingredients: Sodium chloride, polysorbate 80, benzyl alcohol, sodium acetate, acetic acid, water for injection.
Action
Pharmacotherapeutic Group: Immunostimulants/Interferons. ATC Code: L03A B11.
Pharmacology: Pharmacodynamics: General: The conjugation of PEG reagent (bis-monomethoxypolyethylene glycol) to interferon alfa-2a forms a pegylated interferon alfa-2a (Pegasys). Interferon alfa-2a is produced biosynthetically using recombinant DNA technology, and is the product of a cloned human leukocyte interferon gene inserted into and expressed in E. coli. The structure of the PEG moiety directly affects the clinical pharmacology of Pegasys. Specifically, the size and branching of the 40 kDa PEG moiety define the absorption, distribution and elimination characteristics of Pegasys.
Mechanism of Action: Pegasys possesses the in-vitro antiviral and antiproliferative activities of interferon alfa-2a. Interferons bind to specific receptors on the cell surface initiating a complex intracellular signaling pathway and rapid activation of gene transcription. Interferon-stimulated genes modulate many biological effects including the inhibition of viral replication in infected cells, inhibition of cell proliferation and immunomodulation.
HCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who have received Pegasys. The first phase of decline occurs within 24 to 36 hours after the first dose of Pegasys and the second phase of decline occurs over the next 4 to 16 weeks in patients who achieve a sustained response. Pegasys 180 mcg per week enhances the virion clearance and improves the virological end of treatment responses compared to treatment with standard alpha interferons. Ribavirin had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of pegylated interferon alfa-2a and ribavirin or interferon alfa.
Pegasys stimulates the production of effector proteins such as serum neopterin and 2',5'-oligoadenylate synthetase in a dose-dependent manner. The stimulation of 2',5'-oligoadenylate synthetase is maximal after single doses of 135 to 180mcg Pegasys and stays maximal throughout the one-week dosing interval. The magnitude and duration of Pegasys induced 2',5'-oligoadenylate synthetase activity were reduced in subjects older than 62 years and in subjects with significant renal impairment (creatinine clearances of 20 to 40 ml/min). The clinical relevance of these findings with pharmacodynamic markers of Pegasys is not known.
Efficacy/Clinical Studies: Hepatitis B: Clinical studies have demonstrated that Pegasys monotherapy is effective in the treatment of patients with chronic hepatitis B, both in patients who are HBeAg-positive and in patients who are HBeAg-negative/anti-HBe-positive.
Confirmatory clinical trials: All clinical trials recruited patients with chronic hepatitis B who had active viral replication measured by HBV DNA, elevated levels of ALT and a liver biopsy consistent with chronic hepatitis. Study WV16240 recruited patients who were positive for HBeAg, while study WV16241 recruited patients who were negative for HBeAg and positive for anti-HBe. In both studies the treatment duration was 48 weeks, with 24 weeks of treatment-free follow-up. Both studies compared Pegasys plus placebo vs Pegasys plus lamivudine vs lamivudine alone. No HBV-HIV co-infected patients were included in these clinical trials.
Response rates at the end of follow-up for the two studies are presented in Table 1. HBV DNA was measured by the COBAS AMPLICOR HBV MONITOR Assay (limit of detection 200 copies/ml). (See Table 1.)

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Histological response was similar across the three treatment groups in each study; however, patients showing a sustained response 24 weeks after the end of treatment were significantly more likely to also show histological improvement.
All patients who completed the phase III studies were eligible for entry into a long-term follow-up study (WV16866). Among patients from study WV16240, who received Pegasys monotherapy and entered the long-term follow-up study, the rate of sustained HBeAg seroconversion 12 months after the end of therapy was 48% (73/153). In patients receiving Pegasys monotherapy in study WV16241, the rate of HBV DNA response and ALT normalization 12 months after end of treatment were 42% (41/97) and 59% (58/99), respectively.
Chronic Hepatitis C: Clinical studies have demonstrated that Pegasys alone or in combination with ribavirin is effective in the treatment of patients with chronic hepatitis C, including cirrhotic patients with compensated liver disease.
Clinical Trial Results: Predictability of response: Patients demonstrating an early virological response by week 12 (86% of total patients treated) have an increased probability of achieving a sustained virological response with a full course of therapy. An early virological response is defined as unquantifiable levels of HCV RNA or at least a 99% reduction (2 log drop) in viral titre from baseline by week 12 of therapy. In clinical trials, 66% of patients experiencing an early virological response went on to achieve a sustained virological response.
Pegasys monotherapy: In three randomised studies, altogether 701 adult, interferon-naive patients with a diagnosis of chronic hepatitis C were treated at the recommended monotherapy dose of 180 micrograms Pegasys. An additional study specifically recruited patients with a histological diagnosis of cirrhosis or transition to cirrhosis and 87 patients were treated with Pegasys 180 micrograms per week. About 80% of the patients in this study had compensated cirrhosis (i.e., Child-Pugh A). In all studies, patients were treated for 48 weeks followed by an observation period of 24 weeks.
The virological responses for Pegasys and interferon alfa-2a are summarised in Table 2. Superior efficacy of Pegasys compared to interferon alfa-2a was demonstrated also in terms of histological response, including patients without sustained viral response and patients with cirrhosis.
Confirmatory clinical trials in treatment-naive patients: All clinical trials recruited interferon-naive patients with chronic hepatitis C confirmed by detectable levels of serum HCV RNA, elevated levels of ALT (with the exception of study NR16071) and a liver biopsy consistent with chronic hepatitis. Study NV15495 specifically recruited patients with a histological diagnosis of cirrhosis (about 80%) or transition to cirrhosis (about 20%). Only HIV-HCV co-infected patients were included in the study NR15961 (see Table 4). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/μl. Clinical trials in non-responders and in relapsers are in progress.
For HCV monoinfected patients and HIV-HCV co-infected patients , for treatment regimens, duration of therapy and study outcome see Tables 2, 3, 4 and Table 10, respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICOR HCV Test, version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained response as one negative sample approximately 6 months after end of therapy. (See Table 2.)

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The virological responses of patients treated with Pegasys monotherapy and with Pegasys and ribavirin combination therapy in relation to genotype and viral load are summarised in Tables 3 and 4 for HCV monoinfected patients and HIV-HCV co-infected patients, respectively. The results of study NV15942 provide the rationale for recommending treatment regimens based on genotype (see Table 13).
The difference between treatment regimens was in general not influenced by viral load or presence/absence of cirrhosis; therefore treatment recommendations for genotype 1,2 or 3 are independent of these baseline characteristics. (See Table 3.)

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The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients was examined based on a sustained rapid virological response observed in patients with rapid virological response at week 4 in studies NV15942 and ML17131 (see Table 4).

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Although limited, data indicated that shortening treatment to 24 weeks might be associated with a higher risk of relapse (see Table 5).

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The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on a sustained virological response observed in patients with rapid virological response by week 4 in study NV17317 (see Table 6).
In study NV17317 in patients infected with viral genotype 2 or 3, all patients received Pegasys 180 μg sc qw and a ribavirin dose of 800 mg and were randomized to treatment for either 16 or 24 weeks. Overall treatment for 16 weeks resulted in lower sustained viral response (65%) than treatment for 24 weeks (76%) (p < 0.0001).
The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline (see Table 6).

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The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse (see Table 7).

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Superior efficacy of Pegasys compared to interferon alfa-2a was demonstrated also in terms of histological response, including patients with cirrhosis and/or HIV-HCV co-infection.
Chronic hepatitis C prior treatment non-responder patients: In study MV17150, patients who were non-responders to previous therapy with pegylated interferon alfa-2b plus ribavirin were randomized to four different treatments: Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 60 weeks; Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 36 weeks; Pegasys 180 mcg/week for 72 weeks; Pegasys 180 mcg/week for 48 weeks.
All patients received ribavirin (1000 or 1200 mg/day) in combination with Pegasys. All treatment arms had 24 week treatment-free follow-up.
Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 8. (See Table 8.)

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In the HALT-C study, patients with chronic hepatitis C and advanced fibrosis or cirrhosis who were non-responders to previous treatment with interferon alfa or pegylated interferon alfa monotherapy or in combination therapy with ribavirin were treated with Pegasys 180 mcg/week and ribavirin 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on Pegasys plus ribavirin combination therapy for a total of 48 weeks and were then followed for 24 weeks after the end of treatment. The probability for sustained virological response varied depending upon the previous treatment regimen (see Table 9).

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Superior efficacy of Pegasys compared to interferon alfa-2a was demonstrated also in terms of histological response, including patients with cirrhosis and/or HIV-HCV co-infection.
HIV-HCV co-infected patients: (See Table 10.)

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HCV patients with normal ALT: In study NR16071, HCV patients with normal ALT values were randomized to receive peginterferon alfa-2a 180 micrograms/week with a Copegus dose of 800 milligrams/day for either 24 or 48 weeks regardless of HCV genotype, followed by a 24 week treatment free follow-up period or an untreated control group for 72 weeks. (see Table 3 and Table 11 for the SVRs reported in the treatment arms of this study as compared to corresponding treatment arms from study NV15942). (See Table 11.)

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There were no actual studies conducted in patients with normal ALT values using Copegus dose of 1000 or 1200 milligrams/day.
Pharmacokinetics: The pharmacokinetics of Pegasys were studied in healthy volunteers and hepatitis C virus infected patients (see Table 12). The results for patients with chronic hepatitis B were similar to those for patients with chronic hepatitis C.
Absorption:
The absorption of Pegasys is sustained with peak serum concentrations reached 72 to 96 hours after dosing. Serum concentrations are measurable within 3 to 6 hours of a single subcutaneous injection of Pegasys 180mcg. Within 24 hours, about 80% of the peak serum concentration is reached. The absolute bioavailability of Pegasys is 84% and is similar to that seen with interferon alfa-2a.
Distribution: The volume of distribution at steady-state (Vss) is 6 to 14 liters after intravenous dosing. Based on studies in rats, the drug is distributed to the liver, kidney, and bone marrow as well as being highly concentrated in the blood.
Metabolism: Metabolism is the main clearance mechanism for Pegasys. The metabolic profile of Pegasys is not fully characterized. In humans the systemic clearance of Pegasys is about 100 ml/h, which is 100-fold lower than that of the native interferon alfa-2a. Studies in rats indicate the metabolic products of Pegasys are excreted in the urine and to a lesser degree in the bile. The kidneys eliminate less than 10% of a dose as the intact peginterferon alfa-2a. While the PEG moiety remains attached to the interferon alfa-2a, both the PEG and the interferon alfa-2a are metabolized.
Elimination: After intravenous administration, the terminal half-life of Pegasys is approximately 60 hours compared with values of 3 to 4 hours for standard interferon. The terminal half-life after subcutaneous administration is longer [about 80 hours, range 50 to 130 hours]. The terminal half-life determined after subcutaneous administration may not only reflect the elimination phase of the compound, but may also reflect the sustained absorption of Pegasys.
Dose-proportional increases in AUC and Cmax are seen in healthy subjects and patients with chronic hepatitis C after once-weekly doses of Pegasys. The pharmacokinetic parameters of Pegasys are given in Table 18 for healthy subjects receiving a single subcutaneous injection of 180 mcg of Pegasys and for patients with chronic hepatitis C receiving 48 weeks of 180 mcg of Pegasys once-weekly. (See Table 12.)

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In patients with chronic hepatitis C, steady state serum concentrations increase 2 to 3-fold compared with single-dose values and reach steady state within 5 to 8 weeks of once-weekly dosing. Once steady state has been achieved there is no accumulation of peginterferon alfa- 2a. The peak to trough ratio after 48 weeks of treatment is about 1.5 to 2.0. Peginterferon alfa-2a serum concentrations are sustained throughout 1 full week (168 hours). (See figure.)

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Pharmacokinetics and Pharmacodynamics in Special Populations: Patients with renal impairment: A clinical trial evaluated 50 CHC patients with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment, or with end stage renal disease (ESRD) requiring chronic hemodialysis (HD). Patients with moderate renal impairment receiving Pegasys 180 mcg once weekly exhibited similar peginterferon alfa-2a plasma exposures compared to patients with normal renal function.
Patients with severe renal impairment receiving Pegasys 180 mcg once weekly showed a 60% higher peginterferon alfa-2a exposure than patients with normal renal function, therefore a reduced dose of Pegasys 135 mcg once weekly is recommended in patients with severe renal impairment. In 18 patients with ESRD requiring chronic HD, administration of Pegasys 135 mcg once weekly resulted in 34% lower peginterferon alfa-2a exposure than in patients with normal renal function. Despite the lower plasma peginterferon alfa-2a exposure, patients with ESRD experienced the highest frequency of serious adverse events among the other groups in the study, likely owing to the severity and complexity of comorbidities in this patient population.
Gender: The pharmacokinetics of Pegasys were comparable between male and female healthy subjects.
Elderly: The AUC was modestly increased in subjects older than 62 years taking 180mcg Pegasys, but peak concentrations were similar in those older and younger than 62 years. Based on drug exposure, pharmacodynamic response, and tolerability, a lower starting dose of Pegasys is not needed in the geriatric patient (see Use in the Elderly under Precautions).
Non-cirrhotic and cirrhotic patients: The pharmacokinetics of Pegasys were similar between healthy subjects and patients with chronic hepatitis B or chronic hepatitis C. Comparable exposure and pharmacokinetic profiles were seen in patients with cirrhosis with compensated liver disease and patients without cirrhosis.
Site of Administration: Subcutaneous administration of Pegasys should be limited to the abdomen and thigh. Exposure to Pegasys was decreased in studies following administration of Pegasys in the arm compared to administration in the abdomen and thigh.
Toxicology: Preclinical Safety: The preclinical toxicity studies conducted with Pegasys were limited due to species specificity of interferons. Acute and chronic toxicity studies have been carried out in cynomolgus monkeys, and the findings observed in peginterferon alfa-2a dosed animals were similar in nature to those produced by interferon alfa-2a.
Reproductive toxicity studies have not been performed with Pegasys. As with other alpha interferons, prolongation of the menstrual cycle was observed following administration of peginterferon alfa-2a to female monkeys. Treatment with interferon alfa-2a resulted in a statistically significant increase in abortifacient activity in rhesus monkeys. Although no teratogenic effects were seen in the offspring delivered at term, adverse effects in humans cannot be excluded.
Pegasys plus ribavirin: When used in combination with ribavirin, Pegasys did not cause any effects in monkeys not previously seen with either active substance alone. The major treatment-related change was reversible mild to moderate anemia, the severity of which was greater than that produced by either active substance alone.
Carcinogenicity: Pegasys has not been tested for its carcinogenic potential.
Mutagenicity: Pegasys was neither mutagenic nor clastogenic when tested in the Ames bacterial mutagenicity assay and in the in vitro chromosomal aberration assay in human lymphocytes, either in the presence or absence of metabolic activation.
Impairment of Fertility: Reproductive toxicity studies have not been performed with Pegasys. As with other alpha interferons, prolongation of the menstrual cycle was observed following administration of peginterferon alfa-2a to female monkeys.
Teratogenicity: Treatment with interferon alfa-2a resulted in a statistically significant increase in abortifacient activity in rhesus monkeys. Although no teratogenic effects were seen in the offspring delivered at term, adverse effects in humans cannot be excluded.
Indications/Uses
Pegasys is indicated in combination with other medicinal products, for the treatment of chronic hepatitis C (CHC) in patients with compensated liver disease. This includes patients with compensated cirrhosis and patients with HIV disease that is clinically stable (e.g. antiretroviral therapy not required or receiving stable antiretroviral therapy).
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.
Chronic Hepatitis B (CHB): Pegasys is indicated for the treatment of both HBeAg-positive and HBeAg-negative chronic hepatitis B in adult patients with compensated liver disease and evidence of viral replication and liver inflammation.
Dosage/Direction for Use
Substitution by any other biological medicinal product requires the consent of the prescribing physician.
Treatment should be initiated only by a physician experienced in the treatment of patients with hepatitis B or C.
Standard Dosage: Chronic Hepatitis B: The recommended dosage of Pegasys for both HBeAg-positive and HBeAg-negative chronic hepatitis B is 180 mcg once weekly by subcutaneous administration in the abdomen or thigh. The recommended duration of therapy is 48 weeks.
Chronic Hepatitis C - treatment-naive patients: The recommended dosage for Pegasys, alone or in combination with oral ribavirin, is 180 mcg once-weekly by subcutaneous administration in the abdomen or thigh. Ribavirin should be administered with food. The recommended duration of Pegasys monotherapy is 48 weeks. The duration of combination therapy and the daily dose of ribavirin given in combination with Pegasys should be individualized based on the patient's viral genotype (see Table 13). The use of Pegasys monotherapy in patients with normal ALT levels at baseline have not been studied in any clinical trials. (See Table 13.)

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In general, patients infected with genotype 4 are considered hard to treat and limited study data (N=49) are compatible with a posology as for genotype 1. When deciding on the duration of therapy, the presence of additional risk factors should also be considered. For patients infected with genotype 5 or 6, this posology should also be considered.
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 duration of therapy is up to 72 weeks in genotype 1 or 4 patients and 48 weeks in genotype 2 or 3 patients.
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 or a duration of therapy less than 48 weeks has not been studied.
Duration of therapy when Pegasys is used in combination with other medicinal products: Predictability of response - Naive 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 14). (See Table 14.)

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Patients treated with Pegasys who failed to achieve an early virological response were highly unlikely (<5%) to achieve a sustained virological response with continued therapy. In clinical studies, 97 of 102 difficult to treat patients (genotype 1) who received Pegasys and ribavirin combination therapy for 48 weeks and who failed to achieve an early virological response also failed to achieve a sustained virological response 24 weeks after therapy. This indicates a 95% negative predictability by week 12. Consideration should be given to discontinuing anti-viral therapy in these patients, especially if in a non-cirrhotic stage of disease.
The negative predictive value of week 12 virological response 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, respectively, for genotype 1 and genotype 2/3 HIV-HCV co-infected patients receiving combination therapy.
Prior treatment-experienced patients: In non-responder patients re-treated for 48 (genotype 2 and 3) or 72 weeks (genotype 1 and 4), viral suppression at week 12 (undetectable HCV RNA defined as <50 IU/mL) has 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.
Discontinuation of treatment: Discontinuation of treatment is recommended if at least a 2 log10 reduction from baseline or undetectable HCV RNA has not been demonstrated by 12 weeks of therapy (see text on Predictability of response as previously mentioned). Additionally, if patients have not achieved undetectable HCV RNA by week 24, therapy should be discontinued.
Special Dosage Instructions: Dose modification: General: When dose modification is required for moderate to severe adverse reactions (clinical and/or laboratory), initial dose reduction to 135 mcg is generally adequate. However, in some cases, dose reduction to 90 mcg or 45 mcg is necessary. Dose increases to or toward the original dose may be considered when the adverse reaction abates (see Precautions and Adverse Reactions).
Hematological: Dose reduction is recommended if the absolute neutrophil count (ANC) is less than 750 cells/mm3. For patients with ANC values below 500 cells/mm3, treatment should be suspended until ANC values return to more than 1000 cells/mm3. Therapy should initially be reinstituted at 90 mcg Pegasys and the neutrophil count monitored.
Dose reduction to 90 mcg is recommended if the platelet count is less than 50,000 cells/mm3. Cessation of therapy is recommended if platelet count decreases to levels below 25,000 cells/mm3.
Renal impairment: No dose adjustment is required for adult patients with mild or moderate renal impairment A reduced dose of 135 mcg once weekly Pegasys is recommended in adult patients with severe renal impairment. In adult patients with end stage renal disease, a starting dose of Pegasys 135 mcg once weekly should be used (see Pharmacology: Pharmacokinetics: Pharmacokinetics and Pharmacodynamics in Special Populations under Actions).
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.
No data is available for pediatric patients with renal impairment.
Liver function: Fluctuations in abnormalities of liver function tests are common in patients with chronic hepatitis. However, as with other alpha interferons, increases in ALT levels above baseline have been observed in patients treated with Pegasys, including patients with a virological response.
For HCV patients, the dose should be reduced initially to 135 mcg in the presence of progressive or persistent ALT increases above baseline values. 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 (see Precautions).
For HBV 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 ≥ 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 Precautions).
Dose modification for Copegus when administered in combination therapy: For management of treatment-emergent anemia, the dose of Copegus should be reduced to 600 mg per day (200 mg in the morning and 400 mg in the evening) if either of the following apply: A patient without significant cardiovascular disease experiences a fall in hemoglobin levels to <10 g/dl and ≥8.5 g/dl or; A patient with stable cardiovascular disease experiences a fall in hemoglobin levels by ≥2 g/dl during any 4 weeks of treatment.
Ribavirin should be discontinued under the following circumstances: If a patient without significant cardiovascular disease experiences a confirmed decrease in hemoglobin levels to <8.5 g/dl.
If a patient with stable cardiovascular disease maintains a hemoglobin value <12 g/dl despite 4 weeks on a reduced dose.
Once the patient's ribavirin dose has been withheld due to a laboratory abnormality or clinical manifestation an attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily depending upon the physician's judgment. However, it is not recommended that ribavirin be increased to the original dose (1000 mg or 1200 mg). (See Table 15.)

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In case of intolerance to ribavirin, Pegasys monotherapy may be continued.
Overdosage
Overdoses with Pegasys involving at least two injections on consecutive days (instead of weekly interval) up to daily injections for one week (i.e. 1260mcg/week) have been reported. None of these patients experienced unusual, serious or treatment-limiting events. Weekly doses of up to 540 mcg and 630 mcg have been administered in renal cell carcinoma and chronic myelogenous leukemia clinical trials, respectively. Dose-limiting toxicities were fatigue, elevated liver enzymes, neutropenia and thrombocytopenia consistent with interferon therapy. No cases of overdose of ribavirin have been reported in clinical trials.
Contraindications
Pegasys is contraindicated in: patients with known hypersensitivity to alpha interferons, to E. coli-derived products, to polyethyleneglycol or to any component of the product.
Patients with autoimmune hepatitis.
Patients with severe hepatic dysfunction or decompensated cirrhosis.
Neonates and infants up to 3 years of age.
A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months (see Precautions).
Initiation of Pegasys is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6 except if only due to indirect hyperbilirubinemia caused by drugs such as atazanavir and indinavir.
Pre-existing severe psychiatric condition or a history of severe psychiatric disorders, mainly depression.
Due to the use of ribavirin, pregnant or breast feeding women must not be exposed to Pegasys/ribavirin combination therapy (see Use in Pregnancy & Lactation).
Special Precautions
In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Treatment with Pegasys monotherapy or Pegasys/ribavirin combination therapy should be initiated only by a physician experienced in the treatment of patients with hepatitis C and may lead to moderate to severe adverse experiences requiring dose reduction, temporary dose cessation or discontinuation of further therapy.
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.
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.
Pegasys or Pegasys/ribavirin treatments were associated with decreases in both total white blood cell (WBC) count and ANC, usually starting within the first 2 weeks of treatment (see Laboratory Abnormalities under Adverse Reactions). In clinical studies, progressive decreases thereafter were infrequent. Dose reduction is recommended when ANC decreases to levels below 750 cells/mm3 (see Dosage & Administration). For patients with ANC values below 500 cells/mm3, treatment should be suspended until ANC values return to more than 1000 cells/mm3. In clinical trials with Pegasys or Pegasys/ribavirin, the decrease in ANC was reversible upon dose reduction or cessation of therapy.
Pegasys or Pegasys/ribavirin treatments were associated with decreases in platelet count, which returned to pretreatment (baseline) levels during the posttreatment observation period (see Adverse Reactions). Dose reduction is recommended when platelet count decreases to levels below 50,000 cells/mm3 and cessation of therapy is recommended when platelet count decreases to levels below 25,000 cells/mm3 (see Dosage & Administration).
Anemia: Anemia (hemoglobin ≤10 g/dL) was observed in 13% of patients in clinical trials treated with Pegasys/ribavirin 1000 mg or 1200 mg for 48 weeks and in 3% with Pegasys/ribavirin 800 mg for 24 weeks (see Laboratory Abnormalities under Adverse Reactions). The maximum drop in hemoglobin occurred within 4 weeks of initiation of ribavirin therapy. Complete blood counts should be obtained pretreatment, at weeks 2 and 4 of therapy and periodically thereafter. If there is any deterioration of cardiovascular status, ribavirin therapy should be suspended or discontinued (see Dosage & Administration). Please refer also to the approved Copegus (ribavirin) prescribing information.
The use of Pegasys and Copegus 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 retreatment. The risk of developing anaemia is higher in the female population. Pancytopenia (marked decreases in red blood cells, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of ribavirin and 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 Interactions).
Infections: While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever must be ruled out, particularly 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.
Neuropsychiatric: Severe psychiatric adverse reactions may manifest in patients receiving therapy with interferons, including Pegasys or Pegasys/ribavirin. Depression, suicidal ideation, and suicide may occur in patients with and without previous psychiatric illness. Other CNS effects including aggressive behaviour, confusion and alterations of mental status have been observed with interferon or Pegasys. Pegasys monotherapy and Pegasys/ribavirin combination therapy should be used with caution in patients who report a history of depression, and physicians should monitor all patients for evidence of depression. Physicians should inform patients of the possible development of depression prior to initiation of Pegasys or Pegasys/ribavirin therapies, and patients should report any sign or symptom of depression immediately. In severe cases therapy should be stopped and psychiatric intervention sought (see Adverse Reactions).
Cardiovascular: Because cardiac disease may be worsened by ribavirin-induced anemia, HCV patients with a history of significant or unstable cardiac disease should not use Copegus (ribavirin). Cardiovascular events such as hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial infarction have been associated with alpha interferon therapies, including Pegasys and Pegasys/ribavirin. It is recommended that patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to initiation of 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 Special Dosage Instructions under Dosage & Administration and refer also to the approved ribavirin prescribing information).
Hepatic function: HCV: In patients who develop evidence of hepatic decompensation during treatment, Pegasys or Pegasys/ribavirin should be discontinued. As with other alpha interferons, increases in ALT levels above baseline have been observed in patients treated either with Pegasys or with Pegasys/ribavirin, including patients with a virological response. When the increase in ALT levels is progressive despite dose reduction or is accompanied by increased direct bilirubin, therapy should be discontinued (see Dosage & Administration).
HBV: Unlike HCV, disease exacerbations during therapy are not uncommon and are characterized 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.
Bone marrow suppression: Alfa-interferons suppress bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts (CBC) be obtained pretreatment and monitored routinely during therapy. Pegasys monotherapy or Pegasys/ribavirin combination therapy should be used with caution in patients with baseline neutrophil counts <1500 cells/mm3, with baseline platelet count <90,000 cells/mm3 or baseline hemoglobin <12 g/dl (see Dosage & Administration). As with other interferons, caution should be exercised when administering Pegasys or Pegasys/ribavirin in combination with other potentially myelosuppressive agent.
Endocrine: As with other interferons, Pegasys or Pegasys/ribavirin may cause or aggravate hypothyroidism and hyperthyroidism. Discontinuation of therapy should be considered in patients whose thyroid abnormalities cannot be adequately treated. Hyperglycemia, hypoglycemia and diabetes mellitus have been observed in patients treated with alpha interferons. 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 therapies.
Autoimmune: Exacerbation of autoimmune disease has been reported in patients receiving alpha interferon therapy; Pegasys or Pegasys/ribavirin should be used with caution in patients with autoimmune disorders.
Use of alpha interferons has been associated with exacerbation or provocation of psoriasis and sarcoidosis. Pegasys alone or in combination with ribavirin must be used with caution in patients with psoriasis, and in case of appearance or worsening of psoriatic lesions, discontinuation of therapy should be considered.
Hypersensitivity: Serious, acute hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during alpha interferon therapy. If such a reaction develops during treatment either with Pegasys or with Pegasys/ribavirin, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.
Pulmonary: As with other alpha interferons, pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonia, and pneumonitis, including fatality, have been reported during therapy with Pegasys alone or in combination with ribavirin. If there is evidence of persistent or unexplained pulmonary infiltrates or pulmonary function impairment, treatment should be discontinued.
Ophthalmologic: As with other interferons, retinopathy including retinal hemorrhages, cotton wool spots, papilledema, optic neuropathy and retinal artery or vein obstruction, which may result in loss of vision, have been reported after treatment with peginterferon alfa-2a. All patients should have a baseline eye examination. Any patient complaining of decreased or loss of vision must have an eye examination. Because these ocular events may occur in conjunction with other disease states, a visual exam prior to initiation of Pegasys monotherapy or Pegasys/ribavirin combination therapy is recommended in patients with diabetes mellitus or hypertension. Pegasys or Pegasys/ribavirin should be discontinued in patients who develop new or worsening ophthalmologic disorders.
HIV-HCV Coinfection: 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 Copegus Tablet package insert).
Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with alpha interferous, including Pegasys, with or without ribavirin. 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 Interactions).
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. The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Pegasys should be discontinued immediately in patients with hepatic decompensation.
Transplantation: The safety and efficacy of Pegasys and Copegus treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on Pegasys, alone or in combination with Copegus.
Colitis: Fatal and non-fatal ulcerative or hemorrhagic/ischemic colitis have been observed within 12 weeks of starting alfa interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations. Pegasys treatment should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1 to 3 weeks of discontinuation of alfa interferon.
Pancreatitis: Fatal and non-fatal pancreatitis have occurred during alpha interferon and ribavirin treatment. Pegasys and ribavirin should be suspended if symptoms or signs suggestive of pancreatitis are observed. Pegasys and ribavirin should be discontinued in patients diagnosed with pancreatitis.
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.
Laboratory Tests:
Before beginning Pegasys monotherapy or Pegasys/ribavirin combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional laboratory testing should be performed periodically during therapy.
The entrance criteria used for the clinical studies of Pegasys alone or in combination with ribavirin may be considered as a guideline to acceptable baseline values for initiation of treatment: Platelet count ≥90,000/mm3, Absolute neutrophil count (ANC) ≥1500 cells/mm3, TSH and T4 within normal limits or adequately controlled thyroid function.
HIV-HCV co-infection: CD4+ ≥ 200/μl or CD4+ ≥ 100/μl - < 200/μl and HIV-1 RNA < 5000 copies/mL using Amplicor HIV-1 Monitor Test, v 1.5
Renal Impairment: No dose adjustment is required for patients with mild or moderate renal impairment. A reduced dose of 135 mcg once weekly Pegasys is recommended in patients with severe renal impairment. In patients with severe renal impairment, a starting dose of Pegasys 135 mcg once weekly should be used (see Pharmacology: Pharmacokinetics: Pharmacokinetics and Pharmacodynamics in Special Populations under Actions). 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 (see Special Dosage Instruction under Dosage & Administration). Pegasys should be used with caution in patients with creatinine clearance < 50ml/min. Please refer to the approved ribavirin prescribing information for information regarding the use of ribavirin in patients with renal impairment.
Hepatic Impairment: In patients with compensated cirrhosis (e.g. Child Pugh A), Pegasys has been shown to be effective and safe. Pegasys has not been studied in patients with decompensated cirrhosis (e.g. Child Pugh B/C or esophageal varices) (see Contraindications).
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. (See Table 16.)

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Effects on Ability to Drive and Use Machines: Patients who develop dizziness, confusion, somnolence or fatigue should be cautioned to avoid driving or operating machinery.
Use in Children: Safety and effectiveness have not been established in patients below the age of 18. In addition, Pegasys injectable solutions contain benzyl alcohol. There have been rare reports of death in neonates and infants associated with excessive exposure to benzyl alcohol. The amount of benzyl alcohol at which toxicity or adverse effects may occur in neonates or infants is not known. Therefore, Pegasys should not be used in neonates or infants (see Contraindications).
Use in the Elderly: No special dosage modification of Pegasys is required for geriatric patients based upon pharmacokinetic, pharmacodynamic, tolerability, and safety data from clinical trials.
Use In Pregnancy & Lactation
Pregnancy: Pegasys should not be used in pregnant women. Pegasys has not been studied for its effect on fertility. As with other alpha interferons, prolongation of the menstrual cycle accompanied by both a decrease and a delay in the peak of 17β-estradiol and progesterone levels have been observed following administration of peginterferon alfa-2a to female monkeys. A return to normal menstrual rhythm followed discontinuation of treatment.
Pegasys has not been studied for its effect on male fertility. However, treatment with interferon alfa-2a did not affect fertility of male rhesus monkeys treated for 5 months at doses up to 25 x 106 IU/kg/day.
Pegasys has not been studied for its teratogenic effect. Treatment with interferon alfa-2a resulted in a statistically significant increase in abortifacient activity in rhesus monkeys. No teratogenic effects were seen in the offspring delivered at term. However, as with other alpha interferons, women of childbearing potential receiving Pegasys therapy should be advised to use effective contraception during therapy.
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 and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking ribavirin. Ribavirin therapy must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Any birth control method can fail. Therefore, it is critically important that women of childbearing potential and their partners must use 2 forms of effective contraception simultaneously, during treatment and for 6 months after treatment has been concluded.
Patients on treatment with Pegasys should take effective contraceptive measures.
Nursing Mothers: It is not known whether Pegasys or ribavirin are excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from Pegasys or ribavirin, a decision should be made either to discontinue nursing or treatment, based on the importance of the therapy to the mother.
Adverse Reactions
Experience from clinical trials: The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a. 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, although the frequency of reported adverse reactions was notably less in CHB (see Table 18). Eighty eight (88%) percent of Pegasys-treated patients experienced adverse reactions, as compared to 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. Five percent of patients withdrew from Pegasys treatment due to adverse events or laboratory abnormalities, while less than 1% withdrew from lamivudine treatment for safety reasons. The withdrawal rates for patients with cirrhosis were similar to those of the overall population in each treatment group. The addition of lamivudine had no effect on the safety profile of Pegasys.
Chronic Hepatitis C: In clinical trials, the incidence of withdrawal from treatment for all patients due to adverse events and laboratory abnormalities was 9% for Pegasys monotherapy and 13% for Pegasys in combination with Copegus (ribavirin) 1000/1200 mg given for 48 weeks. Respectively, only 1% or 3% of patients required discontinuation of either Pegasys or Pegasys/ribavirin for laboratory abnormalities. The withdrawal rates for patients with cirrhosis were similar to those of the overall population. In comparison to 48 weeks of treatment with Pegasys and Copegus 1000/1200 mg, reducing treatment exposure to 24 weeks and daily dose of Copegus to 800 mg resulted in a reduction in serious adverse events (11% vs 3%), premature withdrawals for safety reasons (13% vs 5%) and the need for Copegus dose modification (39% vs 19%).
Chronic Hepatitis C prior non-responder patients: In a clinical trial which included 72 and 48 weeks treatments of prior pegylated interferon alfa-2b/ribavirin non-responder patients, the frequency of withdrawal from Pegasys treatment was 12% and Copegus treatment was 13% due to adverse events or laboratory abnormalities, for patients in the 72-week arms. In comparison, in 48 week treatment arms, 6% withdrew from Pegasys and 7% withdrew from Copegus treatment. Similarly for patients with cirrhosis, withdrawal rates from Pegasys and Copegus treatment were higher in the 72-week treatment arms, (13% and 15%) compared to the 48-week arms which were (6% and 6%). Patients who withdrew from previous therapy due to hematological toxicity were excluded from enrolling in this trial.
In another clinical trial, patients with advanced fibrosis or cirrhosis (Ishak score of 3 to 6) who had not responded to previous treatment were enrolled with baseline platelet counts as low as 50,000/mm3 and treated for 48 weeks. Due to a high prevalence of the advanced cirrhosis/fibrosis state and the low baseline platelet counts among patients in this study, the frequency of haematologic lab abnormalities in the first 20 weeks of the trial were as follows: hemoglobin <10 g/dL, 26.3%;, ANC <750/mm3, 30%;, and platelet <50,000/mm3, 13%.
HIV-HCV Co-infection: In HIV-HCV co-infected patients, the clinical adverse events reported on Pegasys, alone or in combination with Copegus, were similar to that observed in HCV mono-infected patients. Limited safety data (N= 51) is available in co-infected patients with CD4+ cell counts <200/μl. In study NR15961, the incidence of withdrawal from treatment for clinical adverse events, laboratory abnormalities or AIDS-defining events was 16% for Pegasys monotherapy, and 15% for Pegasys in combination with Copegus 800 mg, given for 48 weeks. Respectively, 4% or 3% of patients required discontinuation of Pegasys or Pegasys/Copegus for laboratory abnormalities. In combination therapy, Pegasys dose modification occurred in 39%, and Copegus dose modification occurred in 37%, of the co-infected patients. Serious adverse events were reported in 21% and 17% of those receiving Pegasys monotherapy or in combination with Copegus, respectively.
Pegasys containing treatment was associated with an on-treatment reduction in absolute CD4+ cell count without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. Pegasys containing treatment had no apparent negative impact on the control of HIV viremia during therapy or follow-up.
Table 17 summarises the safety overview of different treatment regimens of Pegasys in combination with ribavirin for HCV and HIV-HCV patients. (See Table 17.)

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Table 18 shows those adverse reactions occurring in ≥ 10% of patients who have received Pegasys, Pegasys plus ribavirin or interferon alfa-2b plus ribavirin in different indications. (See Tables 18 and 19.)

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Adverse reactions reported in ≥1% but <10% on Pegasys/Copegus combination or Pegasys monotherapy in HBV, HCV and HIV-HCV patients were: Infections and Infestations: Herpes simplex, URI infection, bronchitis, oral candidiasis.
Blood and the lymphatic system disorders: Lymphadenopathy, anemia, thrombocytopenia.
Endocrine disorders: Hypothyroidism, hyperthyroidism.
Neuropsychiatric disorders: Memory impairment, taste disturbance, paraesthesia, hypoesthesia, tremor, weakness, emotional disorders, mood alteration, nervousness, aggression, libido decreased, migraine, somnolence, hyperesthesia, nightmares, syncope.
Eye disorders: Vision blurred, xerophthalmia, eye inflammation, eye pain.
Ear and labyrinth disorders: Vertigo, earache.
Cardiac disorders: Palpitations, edema peripheral, tachycardia.
Vascular disorders: Flushing.
Respiratory, thoracic and mediastinal disorders: Sore throat, rhinitis, nasopharyngitis, sinus congestion, dyspnea exertional, epistaxis.
Gastrointestinal disorders: Vomiting, dyspepsia, flatulence, dry mouth, mouth ulceration, gingival bleeding, stomatitis, dysphagia, glossitis.
Skin and subcutaneous tissue disorders: Skin disorder, rash, eczema, psoriasis, urticaria, photosensitivity reaction, sweating increased, night sweats.
Musculoskeletal, connective tissue and bone disorders: Bone pain, back pain, neck pain, muscle cramps, muscle weakness, musculoskeletal pain, arthritis.
Reproductive system and breast disorders: Impotence.
General disorders and administration site conditions: Influenza-like illness, malaise, lethargy, hot flushes, chest pain, thirst.
Other adverse reactions reported in ≥ 1% to ≤ 2% of HIV-HCV patients receiving Pegasys/Copegus combination included: hyperlactacidemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia.
As with other alpha interferon therapies, uncommon to rare cases of the following serious adverse events have been reported in patients receiving Pegasys/ribavirin combination or Pegasys monotherapy during clinical trials: lower respiratory tract infection, skin infection, otitis externa, endocarditis, suicide, substance overdose, hepatic dysfunction, fatty liver, cholangitis, malignant hepatic neoplasm, peptic ulcer, gastrointestinal bleeding, pancreatitis, arrhythmia, atrial fibrillation, pericarditis, autoimmune phenomena (e.g., ITP, thyroiditis, psoriasis, rheumatoid arthritis, SLE), myositis, peripheral neuropathy, sarcoidosis, interstitial pneumonitis with fatal outcome, pulmonary embolism, corneal ulcer, coma, cerebral hemorrhage, TTP, psychotic disorder, and hallucination.
Based on cumulative data set, rarely, alpha interferon including Pegasys, used alone or in combination with Copegus, may be associated with pancytopenia, and very rarely, aplastic anemia has been reported. For HIV-HCV patients receiving Pegasys and ribavirin combination therapy other undesirable effects have been reported in ≥ 1% to ≤ 2% of patients: hyperlactacidemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia.
Laboratory Abnormalities:
For combination therapy in HCV patients, please refer also to the approved ribavirin prescribing information for the effects of ribavirin on laboratory parameters.
Hematology: As with other interferons, treatment with either Pegasys or Pegasys/ribavirin was associated with decreases in hematological values, which generally improved with dosage modification and returned to pretreatment levels within 4 to 8 weeks upon cessation of therapy (see Dosage & Administration and Precautions). Although hematological toxicities of neutropenia, thrombocytopenia and anemia 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.
Hemoglobin and hematocrit: Although treatment with Pegasys monotherapy was associated with small gradual decreases in hemoglobin and hematocrit, less than 1% of all patients, including those with cirrhosis, required dose modification for anemia. Approximately 10% of patients on 48 weeks Pegasys/ribavirin 1000/1200 mg combination therapy required dose modification for anemia. Anemia (hemoglobin < 10g/dL) was reported in 7% and 14% of HIV-HCV co-infected patients treated with Pegasys monotherapy or in combination with Copegus, respectively.
White blood cells: Pegasys treatment was associated with decreases in values for both total WBC count and ANC. Approximately 4% of HBV or HCV patients receiving Pegasys and 5% of HCV patients receiving Pegasys/ribavirin had transient decreases in ANC to levels below 500 cells/mm3 at some time during therapy. In HIV-HCV co-infected patients, 13% and 11% of those receiving Pegasys monotherapy and combination therapy, respectively, had decreases in ANC levels below 500 cells/mm3.
Platelet count: Pegasys treatment was associated with decreases in values for platelet counts. In clinical trials, approximately 5% of patients had decreases in platelet counts to levels below 50,000/mm3, mostly in patients with cirrhosis and who entered the study with baseline platelet counts as low as 75,000/mm3. In clinical trials for hepatitis B, 14% of patients had decreases in platelet counts to below 50,000/mm3, mostly in patients who entered the study with low baseline platelet counts. In HIV-HCV patients, 10% and 8% of those receiving Pegasys monotherapy and combination therapy, respectively, had decreases in platelets below 50,000/mm3.
Thyroid function: Pegasys treatment was associated with clinically significant abnormalities in thyroid laboratory values requiring clinical intervention (see Precautions). The frequencies observed with Pegasys were similar to those observed with other interferons.
Triglycerides: Triglyceride levels are found to be elevated in patients receiving alpha interferon therapy, including Pegasys.
Anti-interferon Antibodies: Three percent of HCV patients (25/835) receiving Pegasys with or without Copegus (ribavirin) developed low-titer neutralizing anti-interferon antibodies. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed.
Laboratory values for HIV-HCV co-infected patients: Although hematological toxicities of neutropenia, thrombocytopenia and anemia 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. Anemia (hemoglobin < 10g/dL) was reported in 7% and 14% of patients treated with Pegasys monotherapy or in combination therapy, respectively.
Post Marketing: During the post-marketing period, erythema multiforme, Stevens Johnson Syndrome, toxic epidermal necrolysis, pure red cell aplasia (PRCA) and homicidal ideation have been reported very rarely with combination therapy of Pegasys and ribavirin.
Dehydration has been reported rarely with combination therapy of Pegasys and ribavirin.
As with other alpha interferons, serous retinal detachment has been reported with Pegasys and Copegus combination therapy.
As with other alpha interferons, liver and renal graft rejections have been reported on Pegasys, alone or in combination with Copegus.
Adverse reactions reported in a post-marketing setting are: tongue pigmentation.
Facial palsy has been reported with Pegasys.
Respiratory, thoracic and mediastinal disorders: Pulmonary arterial hypertension (Frequency unknown).
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, notably in patients with risk factors for PAH (such as portal hypertension, HIV infection, cirrhosis).
Events were reported at various time points typically several months after starting treatment with interferon alfa.
Drug Interactions
No pharmacokinetic interactions between Pegasys and Copegus (ribavirin) have been observed in HCV clinical trials in which Pegasys was used in combination with ribavirin. Similarly, lamivudine had no effect on Pegasys pharmacokinetics in HBV clinical trials in which Pegasys was used in combination with lamivudine.
Treatment with Pegasys 180 mcg once weekly for 4 weeks had no effect on the pharmacokinetics profiles of tolbutamide (CYP 2C9), mephenytoin (CYP 2C19), debrisoquine (CYP 2D6), and dapsone (CYP 3A4) in healthy male subjects. Pegasys is a modest inhibitor of cytochrome P450 1A2 as a 25% increase in theophylline's AUC was observed in the same study. Comparable effects on theophylline's pharmacokinetics have been seen after treatment with standard alpha interferons. Alpha interferons have been shown to affect the oxidative metabolism of some drugs by reducing the activity of hepatic microsomal cytochrome P450 enzymes. Theophylline serum concentrations should be monitored and appropriate dose adjustments of theophylline made for patients taking theophylline and Pegasys or Pegasys/ribavirin therapy concomitantly.
In a pharmacokinetic study of 24 HCV patients concomitantly receiving methadone maintenance therapy (median dose 95mg; range 30mg to 150mg), treatment with PEGASYS 180μg 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.
No 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, zidovudine, or stavudine). Plasma exposure of ribavirin did not appear to be affected by concomitant administration of NRTIs.
Co-administration of ribavirin and didanosine is not recommended. Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure, as well as, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/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 2 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.
A non-Roche clinical trial investigating the combination of telbivudine 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that the combination is associated with an increased risk for developing peripheral neuropathy. The mechanism behind these events is not known. Such an increased risk can not be excluded for other interferons (pegylated or standard). Moreover, the benefit of the combination of telbivudine with interferon alfa (pegylated or standard) is not currently established.
Azathioprine: 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 azathioprine 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 Precautions).
Caution For Usage
Instructions for Use, Handling and Disposal: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.
Disposal of syringes/sharps: The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps: Needles and syringes should never be reused.
Place all used needles and syringes into a sharps container (puncture-proof disposable container).
Keep this container out of the reach of children.
Placing used sharps containers in the household waste should be avoided.
Dispose of the full container according to local requirements or as instructed by your healthcare provider.
For home use, a puncture resistant container for the disposal of used syringes and needles should be supplied to the patients. Patients should be thoroughly instructed in the importance of proper disposal and caution against any reuse of any needles and syringes. The full container should be disposed of according to the directions provided by the physician.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems" if available in your location.
Incompatibilities: It is inappropriate to mix Pegasys with other products.
Storage
Store in the refrigerator at 2 - 8°C. Do not freeze or shake. Store in the original package in order to protect from light.
MIMS Class
ATC Classification
L03AB11 - peginterferon alfa-2a ; Belongs to the class of interferons. Used as immunostimulants.
Presentation/Packing
Inj (pre-filled syringe, sterile, ready-to-use liquid for SC inj) 135 mcg/0.5 mL x 1's, 4's. 180 mcg/0.5 mL x 1's, 4's.
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