"SILVER SPRING, MD â€” The US Food and Drug Administration (FDA) is updating labeling information for the hepatitis C antivirals ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and sofosbuvir (Sovaldi, Gilead Sciences) after th"...
See the peginterferon alfa and ribavirin prescribing information for description of adverse reactions associated with their use.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of VICTRELIS cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling:
- Anemia [see WARNINGS AND PRECAUTIONS]
- Neutropenia [see WARNINGS AND PRECAUTIONS]
- Pancytopenia [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
The most commonly reported adverse reactions (more than 35% of subjects regardless of investigator's causality assessment) in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when VICTRELIS was used in combination with PegIntron and REBETOL.
The safety of the combination of VICTRELIS 800 mg three times daily with PegIntron/REBETOL was assessed in 2095 subjects with chronic hepatitis C in one Phase 2, open-label trial and two Phase 3, randomized, double-blind, placebo-controlled clinical trials. SPRINT-1 (subjects who were previously untreated) evaluated the use of VICTRELIS in combination with PegIntron/REBETOL with or without a four-week lead-in period with PegIntron/REBETOL compared to PegIntron/REBETOL alone. SPRINT-2 (subjects who were previously untreated) and RESPOND-2 (subjects who had failed previous therapy) evaluated the use of VICTRELIS 800 mg three times daily in combination with PegIntron/REBETOL with a four-week lead-in period with PegIntron/REBETOL compared to PegIntron/REBETOL alone [see Clinical Studies]. The population studied had a mean age of 49 years (3% of subjects were older than 65 years of age), 39% were female, 82% were white and 15% were black.
During the four week lead-in period with PegIntron/REBETOL in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL, 28/1263 (2%) subjects experienced adverse reactions leading to discontinuation of treatment. During the entire course of treatment, the proportion of subjects who discontinued treatment due to adverse reactions was 13% for subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and 12% for subjects receiving PegIntron/REBETOL alone. Events resulting in discontinuation were similar to those seen in previous studies with PegIntron/REBETOL. Only anemia and fatigue were reported as events that led to discontinuation in more than 1% of subjects in any arm.
Adverse reactions that led to dose modifications of any drug (primarily PegIntron and REBETOL) occurred in 39% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL compared to 24% of subjects receiving PegIntron/REBETOL alone. The most common reason for dose
reduction was anemia, which occurred more frequently in subjects receiving the combination of VICTRELIS with PegIntron/REBETOL than in subjects receiving PegIntron/REBETOL alone.
Serious adverse events were reported in 11% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and in 8% of subjects receiving PegIntron/REBETOL.
Adverse events (regardless of investigator's causality assessment) reported in greater than or equal to 10% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and reported at a rate of greater than or equal to 5% than PegIntron/REBETOL alone in SPRINT-1, SPRINT-2, and RESPOND2 are presented in Table 3.
Table 3 : Adverse Events Reported in ≥ 10% of
Subjects Receiving the Combination of VICTRELIS with PegIntron/REBETOL and
Reported at a Rate of ≥ 5% than PegIntron/REBETOL alone
|Adverse Events Body System Organ Class||Previously Untreated (SPRINT-1 and SPRINT-2)||Previous Treatment Failures (RESPOND-2)|
|Percentage of Subjects Reporting Adverse Events||Percentage of Subjects Reporting Adverse Events|
|VICTRELIS + PegIntron + REBETOL
|PegIntron + REBETOL
|VICTRELIS + PegIntron + REBETOL
|PegIntron + REBETOL
|Median Exposure (days)||197||216||253||104|
|Blood and Lymphatic System Disorders|
|General Disorders and Administration Site Conditions|
|Metabolism and Nutrition Disorders|
|Musculoskeletal and Connective Tissue Disorders|
|Nervous System Disorders|
|Insomnia||34||34 1||1 30||24|
|Respiratory, Thoracic, and Mediastinal Disorders|
|Skin and Subcutaneous Tissue Disorders|
Other Important Adverse Reactions Reported in Clinical Trials
Among subjects (previously untreated subjects or those who failed previous therapy) who received VICTRELIS in combination with peginterferon alfa and ribavirin, the following adverse drug reactions were reported. These events are notable because of their seriousness, severity, or increased frequency in subjects who received VICTRELIS in combination with peginterferon alfa and ribavirin compared with subjects who received only peginterferon alfa and ribavirin.
Dysgeusia (alteration of taste) was an adverse event reported at an increased frequency in subjects receiving VICTRELIS in combination with peginterferon alfa and ribavirin compared with subjects receiving peginterferon alfa and ribavirin alone (Table 3). Adverse events such as dry mouth, nausea, vomiting and diarrhea were also reported at an increased frequency in subjects receiving VICTRELIS in combination with peginterferon alfa and ribavirin.
Changes in selected hematological parameters during treatment of adult subjects with the combination of VICTRELIS with PegIntron and REBETOL are described in Table 4.
Decreases in hemoglobin may require a decrease in dosage or discontinuation of ribavirin [see WARNINGS AND PRECAUTIONS and Clinical Studies] [see prescribing information for ribavirin]. If ribavirin is permanently discontinued, then peginterferon alfa and VICTRELIS must also be discontinued [see DOSAGE AND ADMINISTRATION].
Neutrophils and Platelets
The proportion of subjects with decreased neutrophil and platelet counts was higher in subjects treated with VICTRELIS in combination with PegIntron/REBETOL compared to subjects receiving PegIntron/REBETOL alone. Three percent of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL had platelet counts of less than 50 x 109 per L compared to 1% of subjects receiving PegIntron/REBETOL alone. Decreases in neutrophils or platelets may require a decrease in dosage or interruption of peginterferon alfa, or discontinuation of therapy [see prescribing information for peginterferon alfa and ribavirin]. If peginterferon alfa is permanently discontinued, then ribavirin and VICTRELIS must also be discontinued [see DOSAGE AND ADMINISTRATION].
Table 4 :Selected Hematological Parameters
|Hematological Parameters||Previously Untreated (SPRINT-1 and SPRINT-2)||Previous Treatment Failures (RESPOND-2)|
|Percentage of Subjects Reporting Selected Hematological Parameters||Percentage of Subjects Reporting Selected Hematological Parameters|
|VICTRELIS + PegIntron + REBETOL
|PegIntron + REBETOL
|VICTRELIS + PegIntron + REBETOL
|PegIntron + REBETOL
|Neutrophils (x 109/L)|
|Platelets (x 109/L)|
|< 25||< 1||0||0||0|
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.
Gastrointestinal Disorders: mouth ulceration, stomatitis
Skin and Subcutaneous Tissue Disorders: angioedema, urticaria [see WARNINGS AND PRECAUTIONS]; drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, exfoliative rash, exfoliative dermatitis, Stevens-Johnson syndrome, toxic skin eruption, toxicoderma
Read the Victrelis (boceprevir capsules) Side Effects Center for a complete guide to possible side effects
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].
Table 5 : Established and
Other Potentially Significant Drug Interactions
|Concomitant Drug Class: Drug Name||Effect on Concentration of Boceprevir or Concomitant Drug||Recommendations|
|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]. 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 coadministered with VICTRELIS. Monitor INR closely.|
|Antidepressants: trazodone, desipramine||↑ trazodone
|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
|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) x 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
|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]. No dose adjustment of prednisone is necessary when coadministered with VICTRELIS. Patients receiving prednisone and VICTRELIS should be monitored appropriately.|
|Corticosteroid, inhaled: budesonide, fluticasone||↑ budesonide
|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
|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
|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
|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: 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]. 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)]. The observed changes are not considered clinically relevant. No dose adjustment of buprenorphine/naloxone or VICTRELIS is recommended.|
|Oral hormonal contraceptives: 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].|
|norethindrone/ ethinyl estradiol*||↓ ethinyl estradiol
|Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Norethindrone Cmax decreased 17% in the presence of boceprevir [see CLINICAL PHARMACOLOGY]. 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]. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.|
|PDE5 inhibitors: sildenafil, tadalafil, vardenafil||↑ sildenafil
|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].
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: alprazolam; IV midazolam||↑ midazolam
|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.|
|* These combinations have been studied; see CLINICAL PHARMACOLOGY for magnitude of interaction.|
Read the Victrelis Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 8/11/2014
Additional Victrelis Information
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