political opinions [10:<8.5 6 3 10 1 Neutrophils ( 10 9 /L)> <0.75 31 18 26 13> <0.5 8 4 7 4 Platelets ( 10 9 /L)> <50 3 1 4 0> <25> <1 0 0 0 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Victrelis in combination with peginterferon alfa and ribavirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: agranulocytosis, pancytopenia , thrombocytopenia [see Warnings and Precautions (5.4) ] Gastrointestinal Disorders: mouth ulceration, stomatitis Infections and Infestations: pneumonia, sepsis Skin and Subcutaneous Tissue Disorders: angioedema, urticaria [see Warnings and Precautions (5.5) ] ; drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, exfoliative rash, exfoliative dermatitis, Stevens-Johnson syndrome, toxic skin eruption, toxicoderma Drug Interactions [See Contraindications (4) , Warnings and Precautions (5.6) , and Clinical Pharmacology (12.3) .] Potential for Victrelis to Affect Other Drugs Boceprevir is a strong inhibitor of CYP3A4/5. Drugs metabolized primarily by CYP3A4/5 may have increased exposure when administered with Victrelis, which could increase or prolong their therapeutic and adverse effects. Boceprevir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 in vitro . In addition, boceprevir does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4/5 in vitro . Boceprevir is a potential inhibitor of p-glycoprotein (P-gp) based on in vitro studies. In a drug interaction trial conducted with digoxin, Victrelis had limited p-glycoprotein inhibitory potential at clinically relevant concentrations. Potential for Other Drugs to Affect Victrelis Boceprevir is primarily metabolized by aldo-ketoreductase (AKR). In drug interaction trials conducted with AKR inhibitors diflunisal and ibuprofen, boceprevir exposure did not increase to a clinically significant extent. Victrelis may be coadministered with AKR inhibitors. Boceprevir is partly metabolized by CYP3A4/5. It is also a substrate for p-glycoprotein. Coadministration of Victrelis with drugs that induce or inhibit CYP3A4/5 could decrease or increase exposure to boceprevir. Established and Other Potential Significant Drug Interactions Table 5 provides recommendations based on established or potentially clinically significant drug interactions. Victrelis is contraindicated with drugs that are potent inducers of CYP3A4/5 and drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events [see Contraindications (4) ] . Table 5 Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Boceprevir or Concomitant Drug Recommendations * These combinations have been studied; see Clinical Pharmacology (12.3) for magnitude of interaction. Antiarrhythmics: amiodarone, bepridil, propafenone, quinidine antiarrhythmics Coadministration with Victrelis has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with Victrelis. digoxin * digoxin Digoxin concentrations increased when administered with Victrelis [see Clinical Pharmacology (12.3) ] . Measure serum digoxin concentrations before initiating Victrelis. Continue monitoring digoxin concentrations; consult the digoxin prescribing information for information on titrating the digoxin dose. Anticoagulant: warfarin or warfarin Concentrations of warfarin may be altered when co-administered with Victrelis. Monitor INR closely. Antidepressants: trazodone, desipramine trazodone desipramine Plasma concentrations of trazodone and desipramine may increase when administered with Victrelis, resulting in adverse events such as dizziness, hypotension and syncope. Use with caution and consider a lower dose of trazodone or desipramine. escitalopram * escitalopram Exposure of escitalopram was slightly decreased when coadministered with Victrelis. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with Victrelis. Antifungals: ketoconazole * , itraconazole, posaconazole, voriconazole boceprevir itraconazole ketoconazole posaconazole voriconazole Plasma concentrations of ketoconazole, itraconazole, voriconazole or posaconazole may be increased with Victrelis. When coadministration is required, doses of ketoconazole and itraconazole should not exceed 200 mg/day. Anti-gout: colchicine colchicine Significant increases in colchicine levels are expected; fatal colchicine toxicity has been reported with other strong CYP3A4 inhibitors. Patients with renal or hepatic impairment should not be given colchicine with Victrelis. Treatment of gout flares (during treatment with Victrelis): 0.6 mg (1 tablet) 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares (during treatment with Victrelis): If the original regimen was 0.6 mg twice a day, reduce dose to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, reduce the dose to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF) (during treatment with Victrelis): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Anti-infective: clarithromycin clarithromycin Concentrations of clarithromycin may be increased with Victrelis; however, no dosage adjustment is necessary for patients with normal renal function. Antimycobacterial: rifabutin boceprevir rifabutin Increases in rifabutin exposure are anticipated, while exposure of boceprevir may be decreased. Doses have not been established for the 2 drugs when used in combination. Concomitant use is not recommended. Calcium Channel Blockers such as: amlodipine, diltiazem, felodipine, nifedipine, nicardipine, nisoldipine, verapamil calcium channel blockers Plasma concentrations of calcium channel blockers may increase when administered with Victrelis. Caution is warranted and clinical monitoring is recommended. Corticosteroid, systemic: dexamethasone boceprevir Coadministration of Victrelis with CYP3A4/5 inducers may decrease plasma concentrations of boceprevir, which may result in loss of therapeutic effect. Therefore, this combination should be avoided if possible and used with caution if necessary. prednisone * prednisone Concentrations of prednisone and its active metabolite, prednisolone, increased when administered with Victrelis [see Clinical Pharmacology (12.3) ] . No dose adjustment of prednisone is necessary when co-administered with Victrelis. Patients receiving prednisone and Victrelis should be monitored appropriately. Corticosteroid, inhaled: budesonide, fluticasone budesonide fluticasone Concomitant use of inhaled budesonide or fluticasone with Victrelis may result in increased plasma concentrations of budesonide or fluticasone, resulting in significantly reduced serum cortisol concentrations. Avoid coadministration if possible, particularly for extended durations. Endothelin Receptor Antagonist: bosentan bosentan Concentrations of bosentan may be increased when coadministered with Victrelis. Use with caution and monitor closely. HIV Integrase Inhibitor: raltegravir * raltegravir No dose adjustment required for Victrelis or raltegravir. HIV Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz * boceprevir Plasma trough concentrations of boceprevir were decreased when Victrelis was coadministered with efavirenz, which may result in loss of therapeutic effect. Avoid combination. etravirine * etravirine Concentrations of etravirine decreased when coadministered with Victrelis. The clinical significance of the reductions in etravirine pharmacokinetic parameters has not been directly assessed. rilpivirine * rilpivirine Concomitant administration of rilpivirine with Victrelis increased the exposure to rilpivirine. No dose adjustment of Victrelis or rilpivirine is recommended. HIV Protease Inhibitors: atazanavir/ritonavir * atazanavir ritonavir Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended. darunavir/ritonavir * darunavir ritonavir boceprevir Concomitant administration of boceprevir and darunavir/ritonavir resulted in reduced steady-state exposures to boceprevir, darunavir and ritonavir. Coadministration of darunavir/ritonavir and boceprevir is not recommended. lopinavir/ritonavir * lopinavir ritonavir boceprevir Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced steady-state exposures to boceprevir, lopinavir and ritonavir. Coadministration of lopinavir/ritonavir and boceprevir is not recommended. ritonavir * boceprevir When boceprevir is administered with ritonavir alone, boceprevir concentrations are decreased. HMG-CoA Reductase Inhibitors: For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4) ]. atorvastatin * atorvastatin Exposure to atorvastatin was increased when administered with Victrelis. Use the lowest effective dose of atorvastatin, but do not exceed a daily dose of 40 mg when coadministered with Victrelis. pravastatin * pravastatin Concomitant administration of pravastatin with Victrelis increased exposure to pravastatin. Treatment with pravastatin can be initiated at the recommended dose when coadministered with Victrelis. Close clinical monitoring is warranted. Immunosuppressants: cyclosporine * cyclosporine Dose adjustments of cyclosporine should be anticipated when administered with Victrelis and should be guided by close monitoring of cyclosporine blood concentrations, and frequent assessments of renal function and cyclosporine-related side effects. tacrolimus * tacrolimus Concomitant administration of Victrelis with tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects. sirolimus * sirolimus Concomitant administration of Victrelis with sirolimus requires significant dose reduction and prolongation of the dosing interval for sirolimus, with close monitoring of sirolimus blood concentrations and frequent assessments of renal function and sirolimus-related side effects. Inhaled beta-agonist: salmeterol salmeterol Concurrent use of inhaled salmeterol and Victrelis is not recommended due to the risk of cardiovascular events associated with salmeterol. Narcotic Analgesic/Opioid Dependence: methadone * R -methadone Plasma concentrations of R -methadone decreased when coadministered with Victrelis [see Clinical Pharmacology (12.3) ] . The observed changes are not considered clinically relevant. No dose adjustment of methadone or Victrelis is recommended. Individual patients may require additional titration of their methadone dosage when Victrelis is started or stopped to ensure clinical effect of methadone. buprenorphine/naloxone * buprenorphine/naloxone Plasma concentrations of buprenorphine and naloxone increased when coadministered with Victrelis [see Clinical Pharmacology (12.3) ] . The observed changes are not considered clinically relevant. No dose adjustment of buprenorphine/naloxone or Victrelis is recommended. Oral hormonal contraceptives: For contraindicated oral contraceptives, [see Contraindications (4) ]. drospirenone/ethinyl estradiol * drospirenone ethinyl estradiol Concentrations of drospirenone increased in the presence of boceprevir. Thus, the use of drospirenone-containing products is contraindicated during treatment with Victrelis due to potential for hyperkalemia [see Contraindications (4) ] . norethindrone/ethinyl estradiol * ethinyl estradiol norethindrone Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Norethindrone C max decreased 17% in the presence of boceprevir [see Clinical Pharmacology (12.3) ] . Coadministration of Victrelis with a combined oral contraceptive containing ethinyl estradiol and at least 1 mg of norethindrone is not likely to alter the effectiveness of this combined oral contraceptive [see Use in Specific Populations (8.1) ]. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. PDE5 inhibitors: For contraindicated PDE5 enzyme inhibitors, [see Contraindications (4) ]. sildenafil, tadalafil, vardenafil sildenafil tadalafil vardenafil Increases in PDE5 inhibitor concentrations are expected, and may result in an increase in adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of REVATIO (sildenafil) or ADCIRCA (tadalafil) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated with Victrelis [see Contraindications (4) ]. Use of PDE5 inhibitors for erectile dysfunction: Use with caution in combination with Victrelis with increased monitoring for PDE5 inhibitor-associated adverse events. Do not exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 24 hours Proton Pump Inhibitor: omeprazole * omeprazole No dose adjustment of omeprazole or Victrelis is recommended. Sedative/hypnotics: For contraindicated sedatives/hypnotics, [see Contraindications (4) ]. alprazolam; IV midazolam midazolam alprazolam Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during coadministration of Victrelis. A lower dose of IV midazolam or alprazolam should be considered. USE IN SPECIFIC POPULATIONS Pregnancy Victrelis must be administered in combination with peginterferon alfa and ribavirin [see Dosage and Administration (2) ]. Pregnancy Category X: Use with Ribavirin and Peginterferon Alfa 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 (4) and Warnings and Precautions (5.1) ] [see prescribing information for ribavirin]. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans [see prescribing information for peginterferon alfa]. 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. One of these reliable forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated [see Contraindications (4) and Warnings and Precautions (5.1) ]. In case of exposure during pregnancy, 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. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214. Pregnancy Category B: Victrelis Victrelis must not be used as a monotherapy [see Indications and Usage (1) ] . There are no adequate and well-controlled studies with Victrelis in pregnant women. No effects on fetal development have been observed in rats and rabbits at boceprevir AUC exposures approximately 11.8- and 2.0-fold higher, respectively, than those in humans at the recommended dose of 800 mg three times daily [see Nonclinical Toxicology (13.1) ] . Nursing Mothers It is not known whether Victrelis is excreted into human breast milk. Levels of boceprevir and/or metabolites in the milk of lactating rats were slightly higher than levels observed in maternal blood. Peak blood concentrations of boceprevir and/or metabolites in nursing pups were less than 1% of those of maternal blood concentrations. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with Victrelis, taking into account the importance of the therapy to the mother. Pediatric Use The safety, efficacy, and pharmacokinetic profile of Victrelis in pediatric patients have not been studied. Geriatric Use Clinical studies of Victrelis did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of Victrelis in geriatric patients due to the greater frequency of decreased hepatic function, concomitant diseases and other drug therapy [see Clinical Pharmacology (12.3) ] . Renal Impairment No dosage adjustment of Victrelis is required for patients with any degree of renal impairment [see Clinical Pharmacology (12.3) ]. Hepatic Impairment No dose adjustment of Victrelis is required for patients with mild, moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) ] . Safety and efficacy of Victrelis have not been studied in patients with decompensated cirrhosis. In published observational studies of patients with compensated cirrhosis treated with first generation HCV protease inhibitors, including boceprevir, in combination with peginterferon alfa and ribavirin, platelet count> < 100,000/mm 3 and serum albumin < 3.5 g/dL were baseline characteristics that were identified as predictors of death or serious complications (severe infection or hepatic decompensation) during therapy. The potential risks and benefits of Victrelis in combination with peginterferon alfa and ribavirin should be carefully considered before initiating therapy in patients with compensated cirrhosis who have platelet count < 100,000/mm 3 and serum albumin <3.5 g/dL at baseline. If therapy is initiated, close monitoring for signs of infections and worsening liver function is warranted. [See the prescribing information for peginterferon alfa for use in patients with hepatic decompensation.] Organ Transplantation The safety and efficacy of Victrelis alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection in liver or other organ transplant recipients have not been studied. For data regarding drug-drug interactions with immunosuppressants, see Drug Interactions (7.3) and Clinical Pharmacology (12.3) . Overdosage Daily doses of 3600 mg have been taken by healthy volunteers for 5 days without untoward symptomatic effects. There is no specific antidote for overdose with Victrelis. Treatment of overdosage with Victrelis should consist of general supportive measures, including monitoring of vital signs, and observation of the patient's clinical status. Victrelis Description Victrelis (boceprevir) is an inhibitor of the hepatitis C virus (HCV) non-structural protein 3 (NS3) serine protease. Boceprevir has the following chemical name: (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide. The molecular formula is C 27 H 45 N 5 O 5 and its molecular weight is 519.7. Boceprevir has the following structural formula: Boceprevir is manufactured as an approximately equal mixture of two diastereomers. Boceprevir is a white to off-white amorphous powder. It is freely soluble in methanol, ethanol and isopropanol and slightly soluble in water. Victrelis 200 mg capsules are available as hard gelatin capsules for oral administration. Each capsule contains 200 mg of boceprevir and the following inactive ingredients: sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, pre-gelatinized starch, and magnesium stearate. The red capsule cap consists of gelatin, titanium dioxide, D&C Yellow #10, FD&C Blue #1, and FD&C Red #40. The yellow capsule body contains gelatin, titanium dioxide, D&C Yellow #10, FD&C Red #40, and FD&C Yellow #6. The capsule is printed with red and yellow ink. The red ink contains shellac and red iron oxide, while the yellow ink consists of shellac, titanium dioxide, povidone and D&C Yellow #10 Aluminum Lake. Victrelis - Clinical Pharmacology Mechanism of Action Victrelis is a direct acting antiviral drug against the hepatitis C virus [see Microbiology (12.4) ]. Pharmacodynamics Evaluation of Effect of Victrelis on QTc Interval The effect of boceprevir 800 mg and 1200 mg on QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 36 healthy subjects. In the study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 1200 mg yields a boceprevir maximum exposure increase of approximately 15% which may not cover exposures due to coadministration with strong CYP3A4 inhibitors or use in patients with severe hepatic impairment. However, at the doses studied in the thorough QT study, no apparent concentration-QT relationship was identified. Thus, there is no expectation of a QTc effect under a higher exposure scenario. Pharmacokinetics Victrelis capsules contain a 1:1 mixture of two diastereomers, SCH534128 and SCH534129. In plasma the diastereomer ratio changes to 2:1, favoring the active diastereomer, SCH534128. Plasma concentrations of boceprevir described below consist of both diastereomers SCH534128 and SCH534129, unless otherwise specified. In healthy subjects who received 800 mg three times daily alone, boceprevir drug exposure was characterized by AUC(т) of 5408 ng hr per mL (n=71), C max of 1723 ng per mL (n=71), and C min of 88 ng per mL (n=71). Pharmacokinetic results were similar between healthy subjects and HCV-infected subjects. Absorption Boceprevir was absorbed following oral administration with a median T max of 2 hours. Steady state AUC, C max , and C min increased in a less-than-dose-proportional manner and individual exposures overlapped substantially at 800 mg and 1200 mg, suggesting diminished absorption at higher doses. Accumulation is minimal (0.8- to 1.5-fold) and pharmacokinetic steady state is achieved after approximately 1 day of three times daily dosing. The absolute bioavailability of boceprevir has not been studied. Effects of Food on Oral Absorption Victrelis should be administered with food. Food enhanced the exposure of boceprevir by up to 65% at the 800 mg three times daily dose, relative to the fasting state. The bioavailability of boceprevir was similar regardless of meal type (e.g., high-fat vs. low-fat) or whether taken 5 minutes prior to eating, during a meal, or immediately following completion of the meal. Therefore, Victrelis may be taken without regard to either meal type or timing of the meal. Distribution Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 772 L at steady state in healthy subjects. Human plasma protein binding is approximately 75% following a single dose of boceprevir 800 mg. Boceprevir is administered as an approximately equal mixture of two diastereomers, SCH534128 and SCH534129, which rapidly interconvert in plasma. The predominant diastereomer, SCH534128, is pharmacologically active and the other diastereomer is inactive. Metabolism Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldo-keto reductase (AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV. After a single 800-mg oral dose of 14 C-boceprevir, the most abundant circulating metabolites were a diastereomeric mixture of ketone-reduced metabolites with a mean exposure approximately 4-fold greater than that of boceprevir. Boceprevir also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5. Drug Interactions Drug interaction studies were performed with boceprevir and drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of boceprevir on AUC, C max and C min are summarized in Table 6 (effects of coadministered drugs on boceprevir) and Table 7 (effects of boceprevir on coadministered drugs). Table 6 Summary of the Effect of Co-administered Drugs on Boceprevir in Healthy Subjects or HCV Positive Genotype-1 Subjects Co-administered Drug Co-administered Drug Dose/Schedule Boceprevir Dose/Schedule Ratio Estimate of Boceprevir Pharmacokinetic Parameters (in Combination vs. Alone) (90% CI of the Ratio Estimate) * Change in mean C max Change in mean AUC Change in mean C min N/A = not available * No effect = 1.00 C 8 hours AUC 0-last Atazanavir/Ritonavir 300 mg/100 mg daily 22 days 800 mg three times daily 6 days 0.93 (0.80-1.08) 0.95 (0.87-1.05) 0.82 (0.68-0.98) Atorvastatin 40 mg single dose 800 mg three times daily 7 days 1.04 (0.89-1.21) 0.95 (0.90-1.01) N/A Buprenorphine/ Naloxone Buprenorphine: 8-24 mg + Naloxone: 2-6 mg daily 6 days 800 mg three times daily 6 days 0.82 (0.71-0.94) 0.88 (0.76-1.02) 0.95 (0.70-1.28) Cyclosporine 100 mg single dose 800 mg single dose 1.08 (0.97-1.20) 1.16 (1.06-1.26) N/A Darunavir/Ritonavir 600 mg/100 mg two times daily 22 days 800 mg three times daily 6 days 0.75 (0.67-0.85) 0.68 (0.65-0.72) 0.65 (0.56-0.76) Diflunisal 250 mg two times daily 7 days 800 mg three times daily 12 days 0.86 (0.56-1.32) 0.96 (0.79-1.17) 1.31 (1.04-1.65) Efavirenz 600 mg daily 16 days 800 mg three times daily 6 days 0.92 (0.78-1.08) 0.81 (0.75-0.89) 0.56 (0.42-0.74) Escitalopram 10 mg single dose 800 mg three times daily 11 days 0.91 (0.81-1.02) 1.02 (0.96-1.08) N/A Etravirine 200 mg two times daily 11-14 days 800 mg three times daily 11-14 days 1.10 (0.94-1.29) 1.10 (0.94-1.28) 0.88 (0.66-1.17) Ibuprofen 600 mg three times daily 6 days 400 mg single oral dose 0.94 (0.67-1.32) 1.04 (0.90-1.20) N/A Ketoconazole 400 mg two times daily 6 days 400 mg single oral dose 1.41 (1.00-1.97) 2.31 (2.00-2.67) N/A Lopinavir/Ritonavir 400 mg/100 mg two times daily 22 days 800 mg three times daily 6 days 0.50 (0.45-0.55) 0.55 (0.49-0.61) 0.43 (0.36-0.53) Methadone 20-150 mg daily 6 days 800 mg three times daily 6 days 0.62 (0.53-0.72) 0.80 (0.69-0.93) 1.03 (0.75-1.42) Omeprazole 40 mg daily 5 days 800 mg three times daily 5 days 0.94 (0.86-1.02) 0.92 (0.87-0.97) 1.17 (0.97-1.42) Peginterferon alfa-2b 1.5 mcg/kg subcutaneous weekly 2 weeks 400 mg three times daily 1 week 0.88 (0.66-1.18) 1.00 * (0.89-1.13) N/A Pravastatin 40 mg single dose 800 mg three times daily 6 days 0.93 (0.83-1.04) 0.94 (0.88-1.01) N/A Raltegravir 400 mg every 12 hours 6 days 800 mg every 8 hours 6 days 0.96 (0.88, 1.05) 0.98 (0.90, 1.08) 0.74 (0.47, 1.16) Rilpivirine 25 mg every 24 hours 11 days 800 mg three times daily 11 days 0.98 (0.89, 1.08) 0.94 (0.88, 1.00) 1.04 (0.93, 1.16) Ritonavir 100 mg daily 12 days 400 mg three times daily 15 days 0.73 (0.57-0.93) 0.81 (0.73-0.91) 1.04 (0.62-1.75) Sirolimus 2 mg single dose 800 mg three times daily 9 days 0.94 (0.82, 1.07) 0.95 (0.89, 1.01) 1.21 (1.00, 1.47) Tacrolimus 0.5 mg single dose 800 mg single dose 0.97 (0.84-1.13) 1.00 * (0.95-1.06) N/A Tenofovir 300 mg daily 7 days 800 mg three times daily 7 days 1.05 (0.98-1.12) 1.08 (1.02-1.14) 1.08 (0.97-1.20) Table 7 Summary of the Effect of Boceprevir on Co-administered Drugs in Healthy Subjects or HCV Positive Genotype-1 Subjects Co-administered Drug Co-administered Drug Dose/Schedule Boceprevir Dose/Schedule Ratio Estimate of Co-administered Pharmacokinetic Parameters (in Combination vs. Alone) (90% CI of the Ratio Estimate) * Change in mean C max Change in mean AUC(τ) Change in mean C min N/A = not available * No effect = 1.00 AUC 0-last AUC 0-inf C 8 hours 0-168 hours # Reported AUC is 200 mg and 400 mg cohorts combined. Þ C 12 hours Atazanavir/Ritonavir 300 mg/100 mg daily 22 days 800 mg three times daily 6 days Atazanavir: 0.75 (0.64-0.88) Ritonavir: 0.73 (0.64-0.83) Atazanavir: 0.65 (0.55-0.78) Ritonavir: 0.64 (0.58-0.72) Atazanavir: 0.51 (0.44-0.61) Ritonavir: 0.55 (0.45-0.67) Atorvastatin 40 mg single dose 800 mg three times daily 7 days 2.66 (1.81-3.90) 2.30 (1.84-2.88) N/A Buprenorphine/ Naloxone Buprenorphine: 8-24 mg + Naloxone: 2-6 mg daily 6 days 800 mg three times daily 6 days Buprenorphine: 1.18 (0.93-1.50) Buprenorphine: 1.19 (0.91-1.57) Buprenorphine: 1.31 (0.95-1.79) Naloxone: 1.09 (0.79-1.51) Naloxone: 1.33 (0.90-1.98) Naloxone: N/A Cyclosporine 100 mg single dose 800 mg three times daily 7 days 2.01 (1.69-2.40) 2.68 (2.38-3.03) N/A Darunavir/Ritonavir 600 mg/100 mg two times daily 22 days 800 mg three times daily 6 days Darunavir: 0.64 (0.58-0.71) Ritonavir: 0.87 (0.76-1.00) Darunavir: 0.56 (0.51-0.61) Ritonavir: 0.73 (0.68-0.79) Darunavir: 0.41 (0.38-0.45) Ritonavir: 0.55 (0.52-0.59) Digoxin 0.25 mg single dose 800 mg three times daily 10 days 1.18 (1.07-1.31) 1.19 (1.12-1.27) N/A Drospirenone/ Ethinyl estradiol Drospirenone: 3 mg + Ethinyl estradiol: 0.02 mg daily 14 days 800 mg three times daily 7 days Drospirenone: 1.57 (1.46-1.70) Ethinyl estradiol: 1.00 (0.91-1.10) Drospirenone: 1.99 (1.87-2.11) Ethinyl estradiol: 0.76 (0.73-0.79) N/A Efavirenz 600 mg daily 16 days 800 mg three times daily 6 days 1.11 (1.02-1.20) 1.20 (1.15-1.26) N/A Escitalopram 10 mg single dose 800 mg three times daily 11 days 0.81 (0.76-0.87) 0.79 (0.71-0.87) N/A Etravirine 200 mg two times daily 11-14 days 800 mg three times daily 11-14 days 0.76 (0.68-0.85) 0.77 (0.66-0.91) 0.71 (0.54-0.95) Lopinavir/Ritonavir 400 mg/100 mg two times daily 22 days 800 mg three times daily 6 days Lopinavir: 0.70 (0.65-0.77) Ritonavir: 0.88 (0.72-1.07) Lopinavir: 0.66 (0.60-0.72) Ritonavir: 0.78 (0.71-0.87) Lopinavir: 0.57 (0.49-0.65) Ritonavir: 0.58 (0.52-0.65) Methadone 20-150 mg daily 6 days 800 mg three times daily 6 days R -methadone: 0.90 (0.71-1.13) R -methadone: 0.85 (0.74-0.96) R -methadone: 0.81 (0.66-1.00) S -methadone: 0.83 (0.64-1.09) S -methadone: 0.78 (0.66-0.93) S -methadone: 0.74 (0.58-0.95) Midazolam 4 mg single oral dose 800 mg three times daily 6 days 2.77 (2.36-3.25) 5.30 (4.66-6.03) N/A Norethindrone/ Ethinyl estradiol Norethindrone: 1 mg + Ethinyl estradiol : 0.035 mg daily 21 days 800 mg three times daily 28 days Norethindrone: 0.83 (0.76-0.90) Ethinyl estradiol: 0.79 (0.75 -0.84) Norethindrone: 0.96 (0.87-1.06) Ethinyl estradiol: 0.74 (0.68-0.80) N/A Omeprazole 40 mg daily 5 days 800 mg three times daily 5 days 1.03 (0.85-1.26) 1.06 (0.90-1.25) 1.12 (0.75-1.67) Peginterferon alfa-2b 1.5 mcg/kg subcutaneous weekly 2 weeks 200 mg or 400 mg three times daily 1 week N/A 0.99 , # (0.83-1.17) N/A Pravastatin 40 mg single dose 800 mg three times daily 6 days 1.49 (1.03-2.14) 1.63 (1.01-2.62) N/A Prednisone 40 mg single dose 800 mg three times daily 6 days Prednisone: 0.99 (0.94-1.04) Prednisone: 1.22 (1.16-1.28) Prednisone: N/A Prednisolone: 1.16 (1.09-1.24) Prednisolone: 1.37 (1.31-1.44) Prednisolone: N/A Raltegravir 400 mg single dose 800 mg three times daily 10 days 1.11 (0.91-1.36) 1.04 (0.88-1.22) 0.75 Þ (0.45-1.23) Rilpivirine 25 mg every 24 hours 11 days 800 mg three times daily 11 days 1.15 (1.04, 1.28) 1.39 (1.27, 1.52) 1.51 (1.36, 1.68) Sirolimus 2 mg single dose 800 mg every 8 hours 9 days 4.84 (3.99, 5.88) 8.12 (7.08, 9.32) N/A Tacrolimus 0.5 mg single dose 800 mg three times daily 11 days 9.90 (7.96-12.3) 17.1 (14.0-20.8) N/A Tenofovir 300 mg daily 7 days 800 mg three times daily 7 days 1.32 (1.19-1.45) 1.05 (1.01-1.09) duties
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