英文药名：PEGASYS（Peginterferon Alfa-2a（Genetical Recombination）） 中文药名：聚乙二醇化干扰素α-2A（遗传学重组） 生产厂家：中外制药 药品介绍 聚乙二醇干扰素-α-2A配方 批准上市日期：2014年1月 商標名 PEGASYS 一般名 ペグインターフェロン アルファ-2a（遺伝子組換え） ［Peginterferon Alfa-2a（Genetical Recombination）］ 品质 1代替干扰素α-2a（重组）的赖氨酸残基的改性蛋白质支链的聚乙二醇分子通过酰胺键共价连接 分子式 干扰素α-2A（遗传基因重组）： C860H1349N227O255S9 支链聚乙二醇： 它包括单甲氧基聚乙二醇为约20,000道尔顿链的绑定逐个通过在α和ε氨基的赖氨酸分子的羰基。 分子量 约60,000 干扰素α-2A（遗传基因重组）： 分子量19,236.87 大约40,000分子量：支聚乙二醇 操作注意事项 1. **打开外包装盒后，**立即使用。 2. **塔底应该被丢弃。 【药理作用】 药理作用： 聚乙二醇干扰素α-2a是聚乙二醇（PEG）与重组干扰素α-2a结合形成的长效干扰 素。干扰素与细胞表面的特异性受体结合，触发细胞内复杂的信号传递途径并迅速 激活基因转录，调节多种生物效应，包括抑制感染细胞内的病毒复制，抑制细胞增 殖，并具有免疫调节作用。 健康人单次皮下注射PEG干扰素α-2a 180μg后3-6小时，血清2, 5-寡腺苷酸合成 酶（2, 5-OAS，抗病毒活性指标）活性迅速升高。PEG干扰素α-2a所引起的2, 5- OAS血清活性可维持1周以上，且比单次皮下注射300万单位和1800万单位干扰素的 活性高。与年轻人比较，62岁以上的老年人单次皮下注射PEG干扰素α-2a 180μg ，所产生的血清2, 5-OAS活性强度和持续时间有所减低。 【适 应 症】 1、慢性乙型肝炎：本品适用于治疗成人慢性乙型肝炎。患者不能处于肝病失代偿期，慢性乙型肝炎必须经过血清标志物（转氨酶升高、HBsAg，HBV DNA）确诊。通常也需获取组织学证据。 2、慢性丙型肝炎：本品适用于治疗之前未接受过治疗的慢性丙型肝炎成年患者。患者必须无肝脏失代偿表现，慢性丙型肝炎须经血清标记物确证（抗HCV抗体和HCV RNA）。通常诊断要经组织学确证。 【用法用量】 1、慢性乙型肝炎用于慢性乙型肝炎患者时本品的推荐剂量为每次180μg，每周1次，共48周，腹部或大腿皮下注射。 2、慢性丙型肝炎本品单药或与利巴韦林联合应用时的推荐剂量为每次180μg，每周1次，腹部或大腿皮下注射。 【不良反应】 最常见不良反应（发生率≥10%）：全身（乏力、发热、寒战、注射局部反应、虚弱、疼痛），胃肠反应（恶心和呕吐、腹泻、腹痛、消化不良），代谢和营养（厌食、体重下降），肌痛、关节痛，神经精神疾病（头痛、失眠、抑郁、头晕、注意力不集中、焦虑），呼吸系统紊乱（呼吸困难、咳嗽），皮肤（脱发、搔痒症、皮炎、皮肤干燥、皮疹），感染和传染病（咽炎）发生率在2～10%之间：血液和淋巴系统异常（淋巴结肿大、贫血和血小板减少），内分泌异常（甲状腺功能减退和甲状腺功能亢进）等。 【注意事项】 抑郁史的患者，有严重或不稳定心脏病的患者，有自身免疫性疾病的患者，牛皮癣患者，与有可能引起骨髓抑制的药物合用时，应慎用本品。中性粒细胞计数小于1500个/mm3和血小板计数小于75,000个/mm3或血红蛋白小于10g/dl（贫血）的患者要慎用本品。在使用本品治疗前，建议所有患者进行血常规检查和生化检查。下列指标是开始治疗前要达到的基础值：1）血小板计数≥90,000个/mm3）中性粒细胞计数（ANC）≥1,500个/mm3）TSH和T4在正常范围内或甲状腺功能可以完全控制出现严重的急性过敏反应，应停药，并立即给予适当的治疗；出现持续的或原因不明的肺浸润或肺功能异常，应停用本品。使用本品时应注意不要驾驶交通工具和操作机械。 【孕妇及哺乳期用药】 妊娠期禁止使用本品。使用本品治疗期间患者应采取有效避孕措施。目前尚不清楚本品及其赋型剂是否经人乳排泌，因此要根据药物治疗对母亲的重要性来决定停止哺乳还是停止治疗。 【禁　　忌】 对活性成分、α-干扰素或本品的任何赋型剂过敏自身免疫性慢性肝炎严重肝功能障碍或失代偿性肝硬化新生儿和3岁以下儿童，因为本产品含有苯甲醇有严重心脏疾病史，包括6个月内有不稳定或未控制的心脏病有严重的精神疾病或严重的精神疾病史，主要是抑郁妊娠和哺乳当本品和利巴韦林联合使用时.  【儿童用药】 不能用于新生儿和婴幼儿。 【老人用药】 老年患者无需调整剂量。 【贮　　藏】 密封、避光、2～8℃保存在原包装中。请勿冷冻。药品应放于小孩接触不到处。 【包装规格】 派罗欣** 长效干扰素皮下注射45μg：1瓶 长效干扰素皮下注射90μg：1瓶 长效干扰素皮下注射，每次180μg：1瓶 制造厂商 中外制药有限公司 完整资料附件：http://www.info.pmda.go.jp/go/pack/6399419A1022_1_19/ PEGASYS (peginterferon alfa-2a) Alpha interferons, including PEGASYS (peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory eva luations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see WARNINGS and ADVERSE REACTIONS). Use with Ribavirin. Ribavirin, including COPEGUS, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen (see COPEGUS Package Insert for additional information and other WARNINGS). PEGASYS, peginterferon alfa-2a, is a covalent conjugate of recombinant alfa-2a interferon (approximate molecular weight [MW] 20,000 daltons) with a single branched bis-monomethoxy polyethylene glycol (PEG) chain (approximate MW 40,000 daltons). The PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine. Peginterferon alfa-2a has an approximate molecular weight of 60,000 daltons. Interferon alfa-2a is produced using recombinant DNA technology in which a cloned human leukocyte interferon gene is inserted into and expressed in Escherichia coli. PEGASYS is supplied as an injectable solution in vials and prefilled syringes. 180 µg/1.0 mL Vial: A vial contains approximately 1.2 mL of solution to deliver 1.0 mL of drug product. Subcutaneous (sc) administration of 1.0 mL delivers 180 µg of drug product (expressed as the amount of interferon alfa-2a), 8.0 mg sodium chloride, 0.05 mg polysorbate 80, 10.0 mg benzyl alcohol, 2.62 mg sodium acetate trihydrate, and 0.05 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0 ± 0.5. 180 µg/0.5 mL Prefilled Syringe: Each syringe contains 0.6 mL of solution to deliver 0.5 mL of drug product. Subcutaneous (sc) administration of 0.5 mL delivers 180 µg of drug product (expressed as the amount of interferon alfa-2a), 4.0 mg sodium chloride, 0.025 mg polysorbate 80, 5.0 mg benzyl alcohol, 1.3085 mg sodium acetate trihydrate, and 0.0231 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0 ± 0.5. Interferons bind to specific receptors on the cell surface initiating intracellular signaling via a complex cascade of protein-protein interactions leading to 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. The clinical relevance of these in vitro activities is not known. PEGASYS stimulates the production of effector proteins such as serum neopterin and 2', 5'-oligoadenylate synthetase. Maximal serum concentrations (C) and AUC increased in a nonlinear dose related manner following administration of 90 to 270 µg of PEGASYS. Maximal serum concentrations (C) occur between 72 to 96 hours post-dose. Week 48 mean trough concentrations (16 ng/mL; range 4 to 28) at 168 hours post-dose are approximately 2-fold higher than week 1 mean trough concentrations (9 ng/mL; range 0 to 15). Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2. The mean systemic clearance in healthy subjects given PEGASYS was 94 mL/h, which is approximately 100-fold lower than that for interferon alfa-2a (ROFERON-A). The mean terminal half-life after sc dosing in patients with chronic hepatitis C was 160 hours (range 84 to 353 hours) compared to 5 hours (range 3.7 to 8.5 hours) for ROFERON-A. PEGASYS administration yielded similar pharmacokinetics in male and female healthy subjects. The AUC was increased from 1295 to 1663 ng∙h/mL in subjects older than 62 years taking 180 µg PEGASYS, but peak concentrations were similar (9 vs. 10 ng/mL) in those older and younger than 62 years. In a population pharmacokinetics study, 14 children 2 to 8 years of age with CHC received PEGASYS based on their body surface area (BSA of the child × 180 µg/1.73m). The clearance of PEGASYS in children was nearly 4-fold lower compared to the clearance reported in adults. Steady-state trough levels in children with the BSA-adjusted dosing were similar to trough levels observed in adults with 180 µg fixed dosing. Time to reach the steady state in children is approximately 12 weeks, whereas in adults, steady state is reached within 5 to 8 weeks. In these children receiving the BSA adjusted dose, the mean exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in adults receiving 180 µg fixed dosing. The safety and effectiveness of PEGASYS in patients below the age of 18 years have not been established (see PRECAUTIONS: Pediatric Use ). In patients with end stage renal disease undergoing hemodialysis, there is a 25% to 45% reduction in PEGASYS clearance (see PRECAUTIONS: Renal Impairment ). The pharmacokinetics of ribavirin following administration of COPEGUS have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of COPEGUS in patients with creatinine clearance <50 mL/min. Therefore, patients with creatinine clearance <50 mL/min should not be treated with COPEGUS (see WARNINGS and DOSAGE AND ADMINISTRATION ). Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (T was doubled) and the AUC and C increased by 42% and 66%, respectively, when COPEGUS was taken with a high-fat meal compared with fasting conditions (see DOSAGE AND ADMINISTRATION ). In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected patients (see PRECAUTIONS: Drug Interactions). In vitro, didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin (see PRECAUTIONS: Drug Interactions ). There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC (see PRECAUTIONS: Drug Interactions ). The pharmacokinetics of concomitant administration of methadone and PEGASYS were eva luated in 24 PEGASYS naive chronic hepatitis C (CHC) patients (15 male, 9 female) who received 180 µg PEGASYS subcutaneously weekly. All patients were on stable methadone maintenance therapy (median dose 95 mg, range 30 mg to 150 mg) prior to receiving PEGASYS. Mean methadone PK parameters were 10% to 15% higher after 4 weeks of PEGASYS treatment as compared to baseline (see PRECAUTIONS: Drug Interactions ). Methadone did not significantly alter the PK of PEGASYS as compared to a PK study of 6 chronic hepatitis C patients not receiving methadone. The safety and effectiveness of PEGASYS for the treatment of hepatitis C virus infection were assessed in three randomized, open-label, active-controlled clinical studies. All patients were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All patients received therapy by sc injection for 48 weeks, and were followed for an additional 24 weeks to assess the durability of response. In studies 1 and 2, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 3 enrolled patients with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%). In Study 1 (n=630), patients received either ROFERON-A (interferon alfa-2a) 3 MIU three times/week (tiw), PEGASYS 135 µg once each week (qw) or PEGASYS 180 µg qw. In Study 2 (n=526), patients received either ROFERON-A 6 MIU tiw for 12 weeks followed by 3 MIU tiw for 36 weeks or PEGASYS 180 µg qw. In Study 3 (n=269), patients received ROFERON-A 3 MIU tiw, PEGASYS 90 µg qw or PEGASYS 180 µg once each week. In all three studies, treatment with PEGASYS 180 µg resulted in significantly more patients who experienced a sustained response (defined as undetectable HCV RNA [<50 IU/mL] using the COBAS AMPLICOR HCV Test, version 2.0 and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A. In Study 1, response to PEGASYS 135 µg was not different from response to 180 µg. In Study 3, response to PEGASYS 90 µg was intermediate between PEGASYS 180 µg and ROFERON-A. Matched pre- and post-treatment liver biopsies were obtained in approximately 70% of patients. Similar modest reductions in inflammation compared to baseline were observed in all treatment groups. Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2log drop in HCV RNA titer from baseline by 12 weeks of PEGASYS 180 µg therapy, 2% (3/156) achieved a sustained virologic response (see DOSAGE AND ADMINISTRATION ). Averaged over Study 1, Study 2, and Study 3, response rates to PEGASYS were 23% among patients with viral genotype 1 and 48% in patients with other viral genotypes. The treatment response rates were similar in men and women. The safety and effectiveness of PEGASYS in combination with COPEGUS for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A). Patients coinfected with HIV were excluded from these studies. In Study 4, patients were randomized to receive either PEGASYS 180 µg sc once weekly (qw) with an oral placebo, PEGASYS 180 µg qw with COPEGUS 1000 mg po (body weight <75 kg) or 1200 mg po (body weight ≥75 kg) or Rebetron (interferon alfa-2b 3 MIU sc tiw plus ribavirin 1000 mg or 1200 mg po). All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (<50 IU/mL) HCV RNA on or after study week 68. PEGASYS in combination with COPEGUS resulted in a higher SVR compared to PEGASYS alone or interferon alfa-2b and ribavirin ( Table 2 ). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate. In Study 5 (see Table 3 ), all patients received PEGASYS 180 µg sc qw and were randomized to treatment for either 24 or 48 weeks and to a COPEGUS dose of either 800 mg or 1000 mg/1200 mg (for body weight <75 kg / ≥75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as >2 × 10 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks. HCV 1 and 4 – Irrespective of baseline viral titer, treatment for 48 weeks with PEGASYS and 1000 mg or 1200 mg of COPEGUS resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg COPEGUS. HCV 2 and 3 – Irrespective of baseline viral titer, treatment for 24 weeks with PEGASYS and 800 mg of COPEGUS resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of COPEGUS (see Table 3 ). The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment. Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies 4 and 5, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians. Paired liver biopsies were performed on approximately 20% of patients in studies 4 and 5. Modest reductions in inflammation compared to baseline were seen in all treatment groups. In studies 4 and 5, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or >2log lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR. In Study 6, patients with CHC/HIV were randomized to receive either PEGASYS 180 µg sc once weekly (qw) plus an oral placebo, PEGASYS 180 µg qw plus COPEGUS 800 mg po daily or ROFERON-A (interferon alfa-2a), 3 MIU sc tiw plus COPEGUS 800 mg po daily. All patients received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded in the PEGASYS treatment arms. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had CD4+ cell count ≥200 cells/µL or CD4+ cell count ≥100 cells/µL but <200 cells/µL and HIV-1 RNA <5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 4 . Treatment response rates are lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA >800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy. Geographic region is not a prognostic factor for response. However, poor prognostic factors occur more frequently in the US population than in the non-US population. Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2log reduction from baseline in HCV RNA titer by 12 weeks of PEGASYS and COPEGUS combination therapy, 2% (2/85) achieved an SVR. In CHC patients with HIV coinfection who received 48 weeks of PEGASYS alone or in combination with COPEGUS treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment. The safety and effectiveness of PEGASYS for the treatment of chronic hepatitis B were assessed in controlled clinical trials in HBeAg positive (Study 7) and HBeAg negative (Study 8) patients with chronic hepatitis B. Patients were randomized to PEGASYS 180 µg sc once weekly (qw), PEGASYS 180 µg sc qw combined with lamivudine 100 mg once daily po or lamivudine 100 mg once daily po. All patients received 48 weeks of their assigned therapy followed by 24 weeks of treatment-free follow-up. Assignment to receipt of PEGASYS or no PEGASYS was not masked. All patients were adults with compensated liver disease, had chronic hepatitis B virus (HBV) infection, and evidence of HBV replication (serum HBV >500,000 copies/mL for Study 7 and >100,000 copies/mL for Study 8) as measured by PCR (COBAS AMPLICOR HBV Assay). All patients had serum alanine aminotransferase (ALT) between 1 and 10 times the upper limit of normal (ULN) and liver biopsy findings compatible with the diagnosis of chronic hepatitis. The results observed in the PEGASYS and lamivudine monotherapy groups are shown in Table 5 . PEGASYS co-administered with lamivudine did not result in any additional sustained response when compared to PEGASYS monotherapy. Conclusions regarding comparative efficacy of PEGASYS and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn. PEGASYS, peginterferon alfa-2a, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that is clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy). PEGASYS is indicated for the treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation. PEGASYS is contraindicated in patients with: PEGASYS is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS combination therapy is additionally contraindicated in: Patients should be monitored for the following serious conditions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn (see BOXED WARNING ). Life-threatening or fatal neuropsychiatric reactions may manifest in patients receiving therapy with PEGASYS and include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose. These reactions may occur in patients with and without previous psychiatric illness. PEGASYS should be used with extreme caution in patients who report a history of depression. Neuropsychiatric adverse events observed with alpha interferon treatment include aggressive behavior, psychoses, hallucinations, bipolar disorders, and mania. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. Patients should be advised to report any sign or symptom of depression or suicidal ideation to their prescribing physicians. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION ). While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with neutropenia. Serious and severe infections (bacterial, viral, fungal), some fatal, 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. PEGASYS suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including PEGASYS. Very rarely alpha interferons may be associated with aplastic anemia. It is advised that complete blood counts (CBC) be obtained pre-treatment and monitored routinely during therapy (see PRECAUTIONS: Laboratory Tests ). PEGASYS and COPEGUS should be used with caution in patients with baseline neutrophil counts <1500 cells/mm, with baseline platelet counts <90,000 cells/mm or baseline hemoglobin <10 g/dL. PEGASYS therapy should be discontinued, at least temporarily, in patients who develop severe decreases in neutrophil and/or platelet counts (see DOSAGE AND ADMINISTRATION: Dose Modifications ). Severe neutropenia and thrombocytopenia occur with a greater incidence in HIV coinfected patients than monoinfected patients and may result in serious infections or bleeding (see ADVERSE REACTIONS ). Pancytopenia (marked decreases in RBCs, 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 pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. PEGASYS, COPEGUS, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine (see PRECAUTIONS: Drug Interactions ). Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction have been observed in patients treated with PEGASYS. PEGASYS should be administered with caution to patients with pre-existing cardiac disease. Because cardiac disease may be worsened by ribavirin-induced anemia, patients with a history of significant or unstable cardiac disease should not use COPEGUS (see WARNINGS: Anemia and COPEGUS Package Insert). Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PEGASYS. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and a causal relationship between interferon alfa-based therapies and these events is difficult to establish. Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study 6, among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs for the associated risk. During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score ≥6) is observed (see CONTRAINDICATIONS ). Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. Chronic hepatitis B patients experienced transient acute exacerbations (flares) of hepatitis B (ALT elevation >10-fold higher than the upper limit of normal) during PEGASYS treatment (12% and 18%) and post-treatment (7% and 12%) in HBeAg negative and HBeAg positive patients, respectively. Marked transaminase flares while on PEGASYS therapy have been accompanied by other liver test abnormalities. Patients experiencing ALT flares should receive more frequent monitoring of liver function. PEGASYS dose reduction should be considered in patients experiencing transaminase flares. If ALT increases are progressive despite reduction of PEGASYS dose or are accompanied by increased bilirubin or evidence of hepatic decompensation, PEGASYS should be immediately discontinued (see ADVERSE REACTIONS: Chronic Hepatitis B and DOSAGE AND ADMINISTRATION: Dose Modifications ). Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been rarely observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with PEGASYS and COPEGUS should be discontinued and appropriate medical therapy immediately instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been rarely reported in patients receiving PEGASYS with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy (see ADVERSE REACTIONS: Postmarketing Experience ). PEGASYS causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with PEGASYS. Patients with these conditions at baseline who cannot be effectively treated by medication should not begin PEGASYS therapy. Patients who develop these conditions during treatment and cannot be controlled with medication may require discontinuation of PEGASYS therapy. Development or exacerbation of autoimmune disorders including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus have been reported in patients receiving alpha interferon. PEGASYS should be used with caution in patients with autoimmune disorders. Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by PEGASYS or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. PEGASYS combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored. Ulcerative and hemorrhagic/ischemic colitis, sometimes fatal, have been observed within 12 weeks of starting alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations of colitis. PEGASYS should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferon. Pancreatitis, sometimes fatal, has occurred during alpha interferon and ribavirin treatment. PEGASYS and COPEGUS should be suspended if symptoms or signs suggestive of pancreatitis are observed. PEGASYS and COPEGUS should be discontinued in patients diagnosed with pancreatitis. Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema and serous retinal detachment are induced or aggravated by treatment with PEGASYS or other alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. PEGASYS treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders. Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking PEGASYS and COPEGUS combination therapy. COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time (see BOXED WARNING, CONTRAINDICATIONS, PRECAUTIONS: Information for Patients, and COPEGUS Package Insert). The primary toxicity of ribavirin is hemolytic anemia. Hemoglobin <10 g/dL was observed in approximately 13% of COPEGUS and PEGASYS treated patients in chronic hepatitis C clinical trials (see PRECAUTIONS: Laboratory Tests ). The anemia associated with COPEGUS occurs within 1 to 2 weeks of initiation of therapy with maximum drop in hemoglobin observed during the first eight weeks. BECAUSE THE INITIAL DROP IN HEMOGLOBIN MAY BE SIGNIFICANT, IT IS ADVISED THAT HEMOGLOBIN OR HEMATOCRIT BE OBTAINED PRE-TREATMENT AND AT WEEK 2 AND WEEK 4 OF THERAPY OR MORE FREQUENTLY IF CLINICALLY INDICATED. Patients should then be followed as clinically appropriate. Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued (see DOSAGE AND ADMINISTRATION: COPEGUS Dosage Modification Guidelines ). Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use COPEGUS (see COPEGUS Package Insert). It is recommended that renal function be eva luated in all patients started on COPEGUS. COPEGUS should not be administered to patients with creatinine clearance <50 mL/min (see CLINICAL PHARMACOLOGY: Special Populations ). Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and pegylated interferon-alfa 2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. The safety and efficacy of PEGASYS alone or in combination with COPEGUS have not been established in: Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding). A 25% to 45% higher exposure to PEGASYS is seen in subjects undergoing hemodialysis. In patients with impaired renal function, signs and symptoms of interferon toxicity should be closely monitored. Doses of PEGASYS should be adjusted accordingly. PEGASYS should be used with caution in patients with creatinine clearance <50 mL/min (see DOSAGE AND ADMINISTRATION: Dose Modifications ). COPEGUS should not be used in patients with creatinine clearance <50 mL/min (see COPEGUS Package Insert). Patients receiving PEGASYS alone or in combination with COPEGUS should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the PEGASYS and, if applicable, COPEGUS (ribavirin) MEDICATION GUIDES. PEGASYS and COPEGUS combination therapy must not be used by women who are pregnant or by men whose female partners are pregnant. COPEGUS therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during COPEGUS therapy and for 6 months post-therapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy (see CONTRAINDICATIONS and WARNINGS ). Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has been stopped; routine monthly pregnancy tests must be performed during this time (see CONTRAINDICATIONS and COPEGUS Package Insert). To monitor maternal and fetal outcomes of pregnant women exposed to COPEGUS, the Ribavirin Pregnancy Registry has been established. Patients should be encouraged to register by calling 1-800-593-2214. Patients should be advised that laboratory eva luations are required before starting therapy and periodically thereafter (see Laboratory Tests ). Patients should be instructed to remain well hydrated, especially during the initial stages of treatment. Patients should be advised to take COPEGUS with food. Patients should be informed that it is not known if therapy with PEGASYS alone or in combination with COPEGUS will prevent transmission of HCV or HBV infection to others or prevent cirrhosis, liver failure or liver cancer that might result from HCV or HBV infection. Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery. If home use is prescribed, a puncture-resistant container for the disposal of used needles and syringes should be supplied to the patients. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of any needles and syringes. The full container should be disposed of according to the directions provided by the physician (see MEDICATION GUIDE ). Before beginning PEGASYS or PEGASYS and COPEGUS combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. 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 testing should be performed periodically during therapy. In the clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy. The entrance criteria used for the clinical studies of PEGASYS may be considered as a guideline to acceptable baseline values for initiation of treatment: PEGASYS treatment was associated with decreases in WBC, ANC, lymphocytes, and platelet counts often starting within the first 2 weeks of treatment (see ADVERSE REACTIONS ). Dose reduction is recommended in patients with hematologic abnormalities (see DOSAGE AND ADMINISTRATION: Dose Modifications ). While fever is commonly caused by PEGASYS therapy, other causes of persistent fever must be ruled out, particularly in patients with neutropenia (see WARNINGS: Infections ). In chronic hepatitis C, transient elevations in ALT (2-fold to 5-fold above baseline) were observed in some patients receiving PEGASYS, and were not associated with deterioration of other liver function tests. When the increase in ALT levels is progressive despite dose reduction or is accompanied by increased bilirubin, PEGASYS therapy should be discontinued (see DOSAGE AND ADMINISTRATION: Dose Modifications ). Unlike hepatitis C, during hepatitis B therapy and follow up, transient elevations in ALT of 5 to 10 × ULN were observed in 25% and 27% and of >10 × ULN were observed in 12% and 18%, of HBeAg negative and HBeAg positive patients, respectively. These ALT elevations have been accompanied by other liver test abnormalities (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations and DOSAGE AND ADMINISTRATION: Dose Modifications ). Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC. Theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and PEGASYS (see CLINICAL PHARMACOLOGY: Drug Interactions ). In a PK study of HCV patients concomitantly receiving methadone, treatment with PEGASYS once weekly for 4 weeks was associated with methadone levels that were 10% to 15% higher than at baseline (see CLINICAL PHARMACOLOGY: Drug Interactions ). The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of methadone toxicity. In Study 6 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs cases of hepatic decompensation (some fatal) were observed (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations ). Patients receiving PEGASYS/COPEGUS and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of PEGASYS, COPEGUS or both should also be considered if worsening toxicities are observed (see WARNINGS, PRECAUTIONS, DOSAGE AND ADMINISTRATION: Dose Modifications ). Co-administration of COPEGUS and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials (see CLINICAL PHARMACOLOGY: Drug Interactions ). In Study 6, patients who were administered zidovudine in combination with PEGASYS/COPEGUS developed severe neutropenia (ANC <500) and severe anemia (hemoglobin <8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or discontinuation of PEGASYS, COPEGUS or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6). In vitro studies have shown ribavirin can