——FDA2011年5月23日批准INCIVEK(TELAPREVIR)TABLET ORAL治疗慢性丙型肝炎 美国食品与药物管理局（FDA）发布公告，批准Incivek（活性成分：telaprevir）与聚乙二醇干扰素α和利巴韦林联合使用，用于治疗未经干扰素为基础的抗感染药物治疗的患者、或对此类治疗反应不佳的患者。 此前，FDA已批准了另一个治疗慢性丙型肝炎的新药Victrelis（活性成分：boceprevir）。 目前对慢性丙型肝炎病毒感染患者的标准治疗是使用48周的聚乙二醇干扰素α和利巴韦林。不到50%的患者对这种疗法产生应答。3项3期临床试验评估了Incivek的安全性和有效性。有大约2250例成人患者被纳入研究，他们之前有的未经治疗，有的接受过治疗。所有研究中，患者同时接受了标准治疗药物。在以前未经治疗的患者中，与单独的标准治疗相比，接受Incivek治疗的患者中有79%呈现持续性病毒学应答（即停止治疗后24周，血液中不再检出病毒感染）。所有研究、所有患者分组中，Incivek治疗组产生持续性病毒学应答的患者比标准治疗组高出20%—45%。 研究表明，对于大多数患者，Incivek的治疗时间可从48周缩短至24周。60%以前未经治疗的患者取得了早期应答，并接受了仅24周的治疗（相比于标准治疗的48周）。这些患者有90%达到了持续性病毒学应答。当患者结束治疗后达到持续性病毒学应答，则表明丙型肝炎病毒感染已被治愈。持续性病毒学应答可减少肝硬化和肝病并发症、降低肝癌（肝细胞癌）率、降低死亡率。 Incivek每日服用3次，于进餐时服用。前12周，Incivek应与聚乙二醇干扰素α和利巴韦林联合应用。大部分对Incivek联合方案有良好早期应答的患者可采用24周疗程，而不是采用标准治疗时建议的48周。 接受Incivek联合聚乙二醇干扰素α和利巴韦林治疗的患者最常见的副作用包括皮疹、红细胞计数降低（贫血）、恶心、疲劳、头痛、腹泻、瘙痒以及肛门或直肠刺激和疼痛。皮疹可能很严重，可能需要停用Incivek或所有治疗方案中的3种药物。   Incivek(Telaprevir Film-Coated Tablets) WARNING: SERIOUS SKIN REACTIONS Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with telaprevir combination treatment [see Warnings and Precautions]. Fatal cases have been reported in patients with progressive rash and systemic symptoms who continued to receive telaprevir combination treatment after a serious skin reaction was identified. For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, telaprevir, peginterferon alfa, and ribavirin must be discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients should be promptly referred for urgent medical care. 1. DESCRIPTION  Telaprevir is an inhibitor of the HCV NS3/4A protease. The IUPAC name for telaprevir is (1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide. Telaprevir has the following structural formula: Molecular formula: C36H53N7O6 - Molecular weight: 679.85 Telaprevir drug substance is a white to off-white powder with a solubility in water of 0.0047 mg/mL. Telaprevir interconverts to an R-diastereomer, VRT-127394, which is the major metabolite in plasma and is approximately 30-fold less potent than telaprevir. Telaprevir is available as a purple, capsule-shaped, film-coated tablet for oral administration containing 375 mg of telaprevir. Each tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, D&C Red No. 40, dibasic calcium phosphate (anhydrous), FD&C Blue No. 2, hypromellose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium stearyl fumarate, talc, and titanium dioxide. 2. INDICATIONS AND USAGE  2.1 Chronic Hepatitis C Telaprevir, in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment-naive or who have previously been treated with interferon-based treatment, including prior null responders, partial responders, and relapsers. The following points should be considered when initiating treatment with telaprevir: • Telaprevir must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin [see Warnings and Precautions]. • A high proportion of previous null responders (particularly those with cirrhosis) did not achieve a Sustained Virologic Response (SVR) and had telaprevir resistance-associated substitutions emerge on treatment with telaprevir combination treatment [see Microbiology]. • Telaprevir efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes telaprevir or other HCV NS3/4A protease inhibitors [see Microbiology]. 3. DOSAGE AND ADMINISTRATION  3.1 Telaprevir/Peginterferon Alfa/Ribavirin Combination Treatment The recommended dose of telaprevir tablets is 750 mg (two 375-mg tablets) taken orally 3 times a day (7-9 hours apart) with food (not low fat). For specific dosage instructions for peginterferon alfa and ribavirin, refer to their respective prescribing information. Duration of Treatment The recommended duration of treatment with telaprevir is 12 weeks in combination with peginterferon alfa and ribavirin. HCV-RNA levels should be monitored at weeks 4 and 12 to determine combination treatment duration and assess for treatment futility (Tables 1 and 2). Table 1: Recommended Treatment Duration (See also Table 2 for Treatment Futility Rules) a In clinical trials, HCV-RNA in plasma was measured using a COBAS® TaqMan® assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 10 IU/mL. See Laboratory Tests for a description of HCV-RNA assay recommendations. For the purpose of assessing response-guided therapy eligibility at weeks 4 and 12 (see Table 1), an "undetectable" HCV-RNA result is required; a confirmed "detectable but below limit of quantification" HCV-RNA result should not be considered equivalent to an "undetectable" HCV-RNA result [see Laboratory Tests]. Treatment-naïve patients with cirrhosis who have undetectable HCV-RNA at weeks 4 and 12 of telaprevir combination treatment may benefit from an additional 36 weeks of peginterferon alfa and ribavirin (48 weeks total). 3.2 Dose Reduction To prevent treatment failure, the dose of telaprevir must not be reduced or interrupted. Refer to the respective prescribing information for dose modification of peginterferon alfa and ribavirin [see Warnings and Precautions]. 3.3 Discontinuation of Dosing Patients with inadequate viral response are unlikely to achieve SVR, and may develop treatment-emergent resistance substitutions [see Microbiology]. Discontinuation of therapy is recommended in all patients with (1) HCV-RNA levels of greater than or equal to 1000 IU/mL at Treatment Week 4 or 12; or (2) confirmed detectable HCV-RNA levels at Treatment Week 24 (see Table 2). Table 2: Treatment Futility Rules: All Patients If peginterferon alfa or ribavirin is discontinued for any reason, telaprevir must also be discontinued. 4. CONTRAINDICATIONS  Contraindications to peginterferon alfa and ribavirin also apply to telaprevir combination treatment. Telaprevir combination treatment is contraindicated in: • women who are or may become pregnant. Ribavirin may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug treatment, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions, Use in Specific Populations]. • men whose female partners are pregnant. Telaprevir is a strong inhibitor of CYP3A. Telaprevir is contraindicated when combined with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Telaprevir is contraindicated when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of telaprevir. Contraindicated drugs are listed below in Table 3 [also see Drug Interactions, Table 5]. Table 3: Drugs that are Contraindicated with Telaprevir a See Drug Interactions, Table 5 for co-administration of sildenafil and tadalafil when dosed for erectile dysfunction. b See Drug Interactions, Table 5 for parenterally administered midazolam. 5. MECHANISM OF ACTION  Telaprevir is a direct-acting antiviral agent (DAA) against the hepatitis C virus. Microbiology Mechanism of Action Telaprevir is an inhibitor of the HCV NS3/4A serine protease, necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins and essential for viral replication. In a biochemical assay, telaprevir inhibited the proteolytic activity of the recombinant HCV NS3 protease domain with an IC50 value of 10 nM. Antiviral Activity in Cell Culture In an HCV subtype 1b replicon assay, the telaprevir EC50 value against wild-type HCV was 354 nM in a 2-day cell culture assay, and in a subtype 1a infectious virus assay, the EC50 value was 280 nM in a 5-day cell culture assay. In biochemical enzymatic assays, the median IC50 values of telaprevir against genotype 2, 3a, and 4a were 16 nM (range 6-32 nM; n=5), 40 nM (range 39-88 nM; n=5), and 130 nM (n=1), respectively, compared to a median IC50 value of 20 nM (range 16-23; n=2) for genotype 1a and 20 nM for genotype 1b (range 13-33; n=4). The presence of 40% human serum reduced the anti-HCV activity of telaprevir by approximately 10-fold. Evaluation of telaprevir in combination with interferon alfa or ribavirin showed no evidence of antagonism in reducing HCV-RNA levels in HCV replicon cells. Resistance In Cell Culture HCV genotype 1b replicons with reduced susceptibility to telaprevir have been selected in cell culture and characterized for telaprevir genotypic and phenotypic resistance. Additionally, resistance to telaprevir was evaluated in both biochemical and HCV genotype 1b replicon assays using site-directed mutants and recombinant NS3/4A from telaprevir Phase 2 clinical trials isolates. Variants V36A/M, T54A/S, R155K/T, A156S, R155T+D168N, and V36A+T54A conferred 3- to 25-fold reduced susceptibility to telaprevir; and A156V/T variants and the V36M/A+R155K/T and T54S/A+A156S/T double variants conferred greater than 62-fold reduced susceptibility to telaprevir. No amino acid substitutions were observed at the proteolytic cleavage sites. Cross-Resistance Treatment-emergent NS3 amino acid substitutions detected in telaprevir-treated subjects who did not achieve SVR in the clinical trials (substitutions at positions V36, T54, R155, A156 or D168) have been demonstrated to reduce the anti-HCV activity of boceprevir and other HCV NS3/4A protease inhibitors. The impact of prior telaprevir exposure or treatment failure on the efficacy of boceprevir or other HCV NS3/4A protease inhibitors has not been studied. Telaprevir efficacy has not been established for patients with a history of exposure to NS3/4A protease inhibitors. Cross-resistance is not expected between telaprevir and interferons, or telaprevir and ribavirin. HCV replicons expressing telaprevir-associated resistance substitutions remained fully sensitive to interferon-alfa and ribavirin, as well as other direct-acting antivirals with different mechanisms of action, such as NS5B polymerase inhibitors. 6. USE IN SPECIFIC POPULATIONS  6.1 Usage in Pregnancy Because telaprevir must be used in combination with ribavirin and peginterferon alfa, the contraindications and warnings applicable to those drugs are applicable to combination treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Telaprevir/Peginterferon Alfa/Ribavirin Combination Treatment Pregnancy Category X: Animal studies have shown that ribavirin causes birth defects and/or fetal deaths while peginterferon alfa is abortifacient [see Contraindications and Warnings and Precautions]. See the prescribing information for ribavirin. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant [see Contraindications, Warnings and Precautions and ribavirin prescribing information]. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans (see peginterferon alfa prescribing information). Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using effective contraception (two reliable forms) during treatment with ribavirin and for 6 months after treatment. Systemic hormonal contraceptives may not be as effective in women while taking telaprevir. Therefore, two alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with telaprevir and concomitant ribavirin [see Warnings and Precautions]. A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Health care providers and patients are encouraged to report such cases by calling 1-800-593-2214. Telaprevir Tablets Pregnancy Category B: Telaprevir treatment alone in mice and rats did not result in harm to the fetus. The highest doses tested produced exposures equal to 1.84- and 0.60-fold the exposures in humans at the recommended clinical dose, respectively. Telaprevir treatment alone had effects on fertility parameters in rats. The no observed adverse effect level (NOAEL) for testicular toxicity was established at exposures 0.17-fold the human exposures at the recommended clinical dose. Potential effects on sperm (e.g., decreased % motile sperm and increased non-motile sperm count) were observed in a rat fertility study at exposures 0.30-fold the human exposures at the recommended clinical dose. Additional effects on fertility include minor increases in percent preimplantation loss, in percent of dams with nonviable embryos and percent of nonviable conceptuses per litter. These effects are likely associated with testicular toxicity in male but contributions of the female cannot be ruled out. There are, however, no adequate and well-controlled studies in pregnant women. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients - both during treatment and for 6 months after the completion of all treatment. Telaprevir combination treatment should not be started unless a female patient has a negative pregnancy test immediately prior to initiation of treatment. Pregnancy testing should occur monthly during telaprevir combination treatment and for 6 months after all treatment has ended [see Contraindications]. Pregnancy testing in non-pregnant female partners is recommended before telaprevir combination therapy, every month during telaprevir combination therapy, and for 6 months after ribavirin therapy has ended. Hormonal contraceptives may be continued but may not be reliable during telaprevir dosing and for up to two weeks following cessation of telaprevir [see Drug Interactions]. During this time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception. Examples may include barrier methods or IUDs [see also Warnings and Precautions]. Refer also to the prescribing information for ribavirin. Two weeks after completion of telaprevir treatment, hormonal contraceptives are again appropriate as one of the 2 required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives. Refer also to the prescribing information for ribavirin. 6.2 Nursing Mothers It is not known whether telaprevir is excreted in human breast milk. When administered to lactating rats, levels of telaprevir were higher in milk compared to those observed in plasma. Rat offspring exposed to telaprevir in utero showed no effects on body weight at birth. However, when fed via milk from telaprevir-treated dams, body weight gain of pups was lower than pups fed milk from control dams. After weaning, rat pup body weight gain was similar in offspring from telaprevir-treated and control dams. Because of the potential for adverse reactions in nursing infants, nursing must be discontinued prior to initiation of treatment. See also the prescribing information for ribavirin. 6.3 Pediatric Use The safety, efficacy and pharmacokinetic profile of telaprevir in pediatric patients have not been established. 6.4 Geriatric Use Clinical studies of telaprevir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of telaprevir in geriatric patients reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy. 6.5 Hepatic Impairment Telaprevir is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) because no pharmacokinetic or safety data are available regarding the use of telaprevir in HCV-infected patients with moderate or severe hepatic impairment, and appropriate doses have not been established [see Warnings and Precautions]. No dose adjustment of telaprevir is necessary for patients with mild hepatic impairment (Child-Pugh A, score 5-6). Refer also to the prescribing information for peginterferon alfa and ribavirin which must be co-administered with telaprevir. 6.6 Renal Impairment No dose adjustment is necessary for telaprevir in HCV-infected patients with mild, moderate or severe renal impairment. Telaprevir has not been studied in HCV-infected patients with CrCl less than or equal to 50 mL/min. The pharmacokinetics of telaprevir were assessed after administration of a single dose of 750 mg to HCV-negative subjects with severe renal impairment (CrCl less than 30 mL/min). Telaprevir has not been studied in patients with end-stage renal disease (ESRD) or on hemodialysis. Refer also to the prescribing information for peginterferon alfa and ribavirin which must be co-administered with telaprevir. 6.7 Co-infection The safety and efficacy of telaprevir have not been established in patients co-infected with HCV/HIV or HCV/HBV [see Drug Interactions]. 6.8 Solid Organ Transplantation The safety and efficacy of telaprevir have not been established in solid organ transplant patients [see Drug Interactions]. 7. WARNINGS AND PRECAUTIONS  7.1 Serious Skin Reactions/Rash Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with telaprevir combination treatment. Fatal cases have been reported in patients with progressive rash and systemic symptoms who continued to receive telaprevir combination treatment after a serious skin reaction was identified. For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, telaprevir, peginterferon alfa, and ribavirin must be discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients should be promptly referred for urgent medical care. In clinical trials, serious skin reactions, including DRESS and SJS were reported in less than 1% of subjects who received telaprevir combination treatment compared to none who received peginterferon alfa and ribavirin alone. These serious skin reactions required hospitalization, and all subjects recovered. The presenting signs of DRESS may include rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips). TEN and Erythema Multiforme (EM) have been observed in post-marketing experience [see also Boxed Warning and Adverse Reactions]. Rash events (all grades) developed in 56% of subjects who received telaprevir combination treatment [see Adverse Reactions] and in 34% of subjects who received peginterferon alfa and ribavirin. Rash most frequently began during the first 4 weeks, but could occur at any time during telaprevir combination treatment. Rash events led to discontinuation of telaprevir alone in 6% of subjects and discontinuation of telaprevir combination treatment in 1% of subjects. Severe rash (e.g., a generalized rash or rash with vesicles or bullae or ulcerations other than SJS) was reported in 4% of subjects who received telaprevir combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a prominent eczematous component. Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe, telaprevir should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of telaprevir discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered [see also Boxed Warning]. Patients should be monitored until the rash has resolved. Telaprevir must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended [see Drug Interactions]. 7.2 Anemia Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of telaprevir to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. A decrease in hemoglobin levels occurred during the first 4 weeks of treatment, with lowest values reached at the end of telaprevir dosing. Hemoglobin values gradually returned to levels observed with peginterferon alfa and ribavirin after telaprevir dosing was completed. Hemoglobin values less than or equal to 10 g per dL were observed in 36% of subjects who received telaprevir combination treatment compared to 17% of subjects who received peginterferon alfa and ribavirin. In clinical trials, the median time to onset of hemoglobin less than or equal to 10 g per dL was faster among subjects treated with telaprevir combination treatment compared to those who received peginterferon alfa and ribavirin: 56 days (range 8-365 days) versus 63 days (range 13-341 days), respectively. Hemoglobin values less than 8.5 g per dL were observed in 14% of subjects who received telaprevir combination treatment compared to 5% of subjects receiving peginterferon alfa and ribavirin. In subjects receiving telaprevir combination treatment, 32% underwent a ribavirin dose modification (reduction, interruption or discontinuation) due to anemia, 6% received a blood transfusion, 4% discontinued telaprevir, and 1% discontinued telaprevir combination treatment. In subjects treated with peginterferon alfa and ribavirin alone, 12% underwent ribavirin dose modification due to anemia, 1% received a blood transfusion, and fewer than 1% discontinued treatment. Anemia requiring ribavirin dose reduction, blood transfusion, and/or erythropoiesis stimulating agent (ESA) has been reported to occur as soon as 10 days following initiation of telaprevir combination treatment. Hemoglobin should be monitored prior to and at least at weeks 2, 4, 8 and 12 during telaprevir combination treatment and as clinically appropriate. Earlier and more frequent monitoring for some patients should be considered. For the management of anemia, ribavirin dose reductions should be used (refer to the prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose reductions are inadequate, discontinuation of telaprevir should be considered. If ribavirin is permanently discontinued for the management of anemia, telaprevir must also be permanently discontinued. Ribavirin may be restarted per the dosing modification guidelines for ribavirin. The dose of telaprevir must not be reduced and telaprevir must not be restarted if discontinued. 7.3 Pregnancy: Use with Ribavirin and Peginterferon Alfa 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. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Because telaprevir must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those drugs are applicable to combination therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use 2 effective contraceptive methods during treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests during treatment and during the 6-month period after stopping treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients as significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin [see Contraindications, Use in Specific Populations]. Refer also to the prescribing information for ribavirin. Female Patients Hormonal contraceptives may be continued but may not be reliable during telaprevir dosing and for up to two weeks following cessation of telaprevir [see Drug Interactions]. During this time, female patients of childbearing potential should use two effective non-hormonal methods of contraception. Examples may include barrier methods or intrauterine devices (IUDs) [see also Use in Specific Populations: Pregnancy]. Two weeks after completion of telaprevir treatment, hormonal contraceptives are again appropriate as one of the two required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives. 7.4 Drug Interactions See Table 3 for a listing of drugs that are contraindicated for use with telaprevir due to potentially life-threatening adverse events or potential loss of therapeutic effect to telaprevir [see Contraindications]. Refer to Table 5 for established and other potentially significant drug-drug interactions [see Drug Interactions]. 7.5 Laboratory Tests HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated. Use of a sensitive real-time RT-PCR assay for monitoring HCV RNA levels during treatment is recommended. The assay should have a lower limit of HCV RNA quantification equal to or less than 25 IU per mL and a limit of HCV RNA detection of approximately 10-15 IU per mL. For the purpose of assessing response-guided therapy eligibility, an “undetectable” HCV RNA (Target Not Detected) result is required; a confirmed “detectable but below limit of quantification” HCV RNA result should not be considered equivalent to an “undetectable” HCV RNA result (reported as "Target Not Detected" or "HCV RNA Not Detected"). Hematology evaluations (including hemoglobin, white cell differential, and platelet count) are recommended prior to and at weeks 2, 4, 8 and 12 and as clinically appropriate. Chemistry evaluations (including electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, and TSH) are recommended as frequently as hematology evaluations or as clinically appropriate [see Adverse Reactions]. Refer to the prescribing information for peginterferon alfa and ribavirin, including pregnancy testing requirements. 7.6 General Telaprevir must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. Therefore, the prescribing information for peginterferon alfa and ribavirin must be consulted before starting treatment with telaprevir. There are no clinical data on re-treating patients who have failed an HCV NS3/4A protease inhibitor-based treatment, nor are there data on repeated courses of telaprevir [see Microbiology]. 7.7 Hepatic Impairment Telaprevir is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) or patients with decompensated liver disease. Refer to prescribing information for peginterferon alfa and ribavirin which must be co-administered with telaprevir [see Use in Specific Populations: Hepatic Impairment]. 8. ADVERSE REACTIONS  The following adverse reactions are discussed in greater detail in other sections of the label: • Pregnancy: Use with Ribavirin and Peginterferon alfa [see Contraindications, Warnings and Precautions, Use in Specific Populations] • Serious Skin Reactions/Rash [see Warnings and Precautions] • Anemia [see Warnings and Precautions] Telaprevir must be administered with peginterferon alfa and ribavirin. Refer to their respective prescribing information for their associated adverse reactions. 8.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety assessment is based on data from pooled adequate and well-controlled clinical trials including 1797 subjects who received telaprevir combination treatment and 493 who received peginterferon alfa and ribavirin. Serious adverse drug reactions occurred in 3% of subjects who received telaprevir combination treatment compared to none of the subjects treated with peginterferon alfa and ribavirin. The most frequent serious adverse events in subjects treated with telaprevir combination treatment were skin disorders (rash and/or pruritus) and anemia [see Warnings and Precautions]. Fourteen percent of subjects discontinued telaprevir due to adverse drug reactions. Rash, anemia, fatigue, pruritus, nausea, and vomiting were the most frequent adverse drug reactions leading to discontinuation of telaprevir. Telaprevir was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactions that occurred in telaprevir-treated subjects with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone (Table 4). Table 4: Clinical Adverse Drug Reactions Reported with at Least 5% Higher Frequency Among Subjects Receiving Telaprevir * Rash and anemia based on SSC (Special Search Category) grouped terms. Description of Selected Adverse Drug Reactions Rash In controlled clinical trials, rash events (all grades) were reported in 56% of subjects who received telaprevir combination treatment and in 34% of subjects who received peginterferon alfa and ribavirin. Rash most frequently began during the first 4 weeks, but could occur at any time during telaprevir combination treatment. Improvement of rash occurs after telaprevir dosing completion or discontinuation; however, rashes may take weeks for complete resolution. Rash events led to discontinuation of telaprevir alone in 6% of subjects and discontinuation of telaprevir combination treatment in 1% of subjects. For serious skin reactions and severe rash, see Warnings and Precautions. Anemia In controlled clinical trials, the overall incidence and severity of anemia increased with telaprevir combination treatment compared to peginterferon alfa and ribavirin alone. The incidence of anemia adverse events was 36% with telaprevir combination treatment compared to 17% with peginterferon alfa and ribavirin alone. A decrease in hemoglobin levels occurred during the first 4 weeks of treatment, with lowest values reached at the end of telaprevir dosing. Hemoglobin values gradually returned to levels observed with peginterferon alfa and ribavirin after telaprevir dosing was completed [see Warnings and Precautions]. Anorectal Signs and Symptoms In the controlled clinical trials, 29% of subjects treated with telaprevir combination treatment experienced anorectal adverse events, compared to 7% of those treated with peginterferon alfa and ribavirin alone. The majority of these events (e.g., hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate in severity; less than 1% led to treatment discontinuation and all resolved during or after completion of telaprevir dosing. Laboratory abnormalities White Blood Cells: Treatment with peginterferon alfa is associated with decreases in mean values for total white blood cell, absolute neutrophil, and absolute lymphocyte count. More telaprevir-treated subjects had decreases in lymphocyte counts to 499/mm3 or less (15% compared to 5%). Decreases in total white cell counts to 1,499/mm3 or less were comparable (8% compared to 5%). The incidence of decreases in absolute neutrophil counts to 749/mm3 or less was 15% in subjects treated with peginterferon alfa and ribavirin alone compared to 12% among those treated with telaprevir combination treatment. Platelets: Treatment with peginterferon alfa is associated with decreases in mean platelet counts. More patients treated with telaprevir combination treatment had decreases in mean platelet values of all grades: 47% compared to 36% treated with peginterferon alfa and ribavirin alone. Three percent of telaprevir combination treatment subjects had decreases to 49,999/mm3 or less compared to 1% of those treated with peginterferon alfa and ribavirin-treated alone. Bilirubin: Forty one percent of telaprevir-treated subjects compared to 28% of peginterferon alfa and ribavirin-treated subjects had all grade elevations in bilirubin levels; 4% and 2% of subjects, respectively, had greater than or equal to 2.6 x ULN elevations. Bilirubin levels increased most steeply during the first 1 to 2 weeks of telaprevir dosing, stabilized and between Weeks 12 and 16 were at baseline levels. Uric Acid: During the telaprevir combination treatment period, 73% of subjects had elevated uric acid levels compared to 29% for those treated with peginterferon alfa and ribavirin alone. Shifts to greater than or equal to 12.1 mg/dL from baseline in uric acid levels were also more frequent among subjects treated with telaprevir (7%) compared to peginterferon alfa and ribavirin (1%). Less than 1% of subjects had clinical events of gout/gouty arthritis; none were serious and none resulted in treatment discontinuation. 9. OVERDOSAGE  The highest documented dose administered is 1875 mg every 8 hours for 4 days in healthy subjects with telaprevir alone. In that study, the following common adverse events were reported more frequently with the 1875 mg q8h regimen compared to the 750 mg q8h regimen: nausea, headache, diarrhea, decreased appetite, dysgeusia, and vomiting. No specific antidote is available for overdose with telaprevir. Treatment of overdose with telaprevir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. In the event of an overdose, it is reasonable to employ the standard supportive measures, such as, removing unabsorbed material from the gastrointestinal tract, employing clinical monitoring (including obtaining an electrocardiogram), and instituting supportive therapy if required. It is not known whether telaprevir is dialyzable by peritoneal or hemodialysis. 10. DRUG INTERACTIONS  10.1 Potential for Telaprevir to Affect Other Drugs Telaprevir is an inhibitor of CYP3A. Co-administration of telaprevir with drugs that are primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions (see Table 5). Telaprevir is also an inhibitor of P-gp. Co-administration of telaprevir with drugs that are substrates for P-gp transport may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions (see Table 5). If dose adjustments of concomitant medications are made during telaprevir treatment, they should be re-adjusted after administration of telaprevir is completed. 10.2 Potential for Other Drugs to Affect Telaprevir Telaprevir is a substrate of CYP3A and P-gp; therefore, drugs that induce CYP3A and/or P-gp may decrease telaprevir plasma concentrations and reduce the therapeutic effect of telaprevir. Co-administration of telaprevir with drugs that inhibit CYP3A and/or P-gp may increase telaprevir plasma concentrations. 10.3 Established and Other Potentially Significant Drug Interactions Table 5 provides effect of concentration of telaprevir or concomitant drug with telaprevir. These recommendations are based on either drug interaction studies (indicated with *) or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction *These interactions have been studied. The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK. In addition to the drugs included in Table 5, the interaction between telaprevir and the following drug was evaluated in clinical trials and no dose adjustment is needed for either drug: esomeprazole, raltegravir, or buprenorphine. 11. PHARMACOKINETICS   The pharmacokinetic properties of telaprevir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following multiple doses of telaprevir (750 mg every 8 hours) in combination with peginterferon alfa and ribavirin in treatment-naïve subjects with genotype 1 chronic hepatitis C, mean (SD) Cmax was 3510 (1280) ng/mL, Cmin was 2030 (930) ng/mL, and AUC8h was 22,300 (8650) ng•hr/mL. Absorption and Bioavailabilty Telaprevir is orally available, most likely absorbed in the small intestine, with no evidence for absorption in the colon. Maximum plasma concentrations after a single dose of telaprevir are generally achieved after 4 to 5 hours. In vitro studies performed with human Caco-2 cells indicated that telaprevir is a substrate of P-glycoprotein (P-gp). Exposure to telaprevir is higher during co-administration of peginterferon alfa and ribavirin than after administration of telaprevir alone. Effects of Food on Oral Absorption The systemic exposure (AUC) to telaprevir was increased by 237% when telaprevir was administered with a standard fat meal (containing 533 kcal and 21 g fat) compared to when telaprevir was administered under fasting conditions. In addition, the type of meal significantly affects exposure to telaprevir. Relative to fasting, when telaprevir was administered with a low-fat meal (249 kcal, 3.6 g fat) and a high-fat meal (928 kcal, 56 g fat), the systemic exposure (AUC) to telaprevir was increased by approximately 117% and 330%, respectively. Doses of telaprevir were administered within 30 minutes of completing a meal or snack containing approximately 20 grams of fat in the Phase 3 trials. Therefore, telaprevir should always be taken with food (not low fat). Distribution In vitro, within a concentration range of 0.1 μM (68 ng/mL) to 20 μM (13600 ng/mL), telaprevir is approximately 59% to 76% bound to plasma proteins. Telaprevir binds primarily to alpha 1-acid glycoprotein and albumin and the binding is concentration dependent, decreasing with increasing concentrations of telaprevir. After oral administration, the typical apparent volume of distribution (Vd/F) was estimated to be 252 L, with an inter-individual variability of 72%. Metabolism Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in feces, plasma, and urine. After repeated-oral administration, the R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the α-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir. In vitro studies using recombinant human cytochrome P450 (CYP) isoforms indicated that CYP3A4 was the major CYP isoform responsible for telaprevir metabolism. However, non-CYP mediated metabolism likely plays a role after multiple dosing of telaprevir. Elimination Following administration of a single oral dose of 750 mg 14C-telaprevir in healthy subjects, 90% of total radioactivity was recovered in feces, urine and expired air within 96 hours post-dose. The median recovery of the administered radioactive dose was approximately 82% in the feces, 9% in exhaled air and 1% in urine. The contribution of unchanged 14C-telaprevir and the R-diastereomer of telaprevir towards total radioactivity recovered in feces was 31.9% and 18.8%, respectively. After oral administration, the apparent total clearance (Cl/F) was estimated to be 32.4 L/h with an inter-individual variability of 27.2%. The mean elimination half-life after single-dose oral administration of telaprevir 750 mg typically ranged from about 4.0 to 4.7 hours. At steady state, the effective half-life is about 9 to 11 hours. Specific Populations Hepatic Impairment Steady-state exposure to telaprevir was reduced by 46% in HCV-negative subjects with moderate hepatic impairment (Child-Pugh Class B) compared to healthy subjects. The appropriate dose of telaprevir in HCV-infected subjects with moderate or severe hepatic impairment has not been determined and therefore telaprevir is not recommended in these populations. Steady-state exposure to telaprevir was reduced by 15% in HCV-negative subjects with mild hepatic impairment (Child-Pugh Class A) compared to healthy subjects. Dose modification of telaprevir is not required when administered to subjects with mild hepatic impairment. In previously treated subjects who had compensated liver disease and were treated with telaprevir in combination with peginterferon alfa and ribavirin, subjects with cirrhosis had similar PK parameters compared to those without cirrhosis. Renal Impairment After administration of a single dose of 750 mg to HCV-negative subjects with severe renal impairment (CrCl less than 30 mL/min), the LS means of telaprevir Cmax and AUCinf were increased by 3% and 21%, respectively, compared to healthy subjects. Gender The effect of subject gender on telaprevir pharmacokinetics was evaluated using population pharmacokinetics of data from clinical trials of telaprevir. No dose adjustments are deemed necessary based on gender. Race Population pharmacokinetic analysis of telaprevir in HCV-infected subjects indicated that race had no apparent effect on the exposure to telaprevir. Geriatric Use Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19-70 years) investigated (35 subjects 65 years of age and older), subject age did not have a clinically relevant effect on the exposure to telaprevir. Pediatric Use The pharmacokinetics of telaprevir in pediatric patients have not been evaluated. 12. HOW SUPPLIED/STORAGE AND HANDLING  1) How Available: a) Brand name: INCIVEK, by Vertex Pharmaceuticals. b) Generic drugs: None. 2) How Supplied: INCIVEK® (telaprevir) is supplied as purple film-coated capsule-shaped tablets containing 375 mg of telaprevir. Each tablet is debossed with the characters “V 375” on one side and is packaged as follows: 28-day packer contains 4 weekly cartons of 7 blister strips each (6 tablets per blister strip) NDC 51167-100-01 3) Storage and Handling: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Once the bottle is opened use within 28 days. Keep bottle tightly closed