What is Victrelis (boceprevir)?
What are the important side effects of Victrelis (boceprevir)?
Victrelis (boceprevir) side effects list for healthcare professionals
What drugs interact with Victrelis (boceprevir)?

What is Victrelis (boceprevir)?

Victrelis (boceprevir) is a man-made antiviral medication that targets hepatitis C virus (HCV). Victrelis is called a direct-acting antiviral agent because it acts directly on hepatitis C virus.

Victrelis blocks the replication of hepatitis C virus in human cells by binding to and inhibiting protease enzymes that HCV use for reproducing. Inhibiting viral replication reduces HCV viral load in the body to undetectable levels in some patients.

Common side effects of Victrelis include:

hair loss,
dry skin,
diarrhea,
loss of appetite,
nausea,
altered taste senses,
sleeplessness,
irritability,
fatigue,
shivering,
anemia, and
low white blood cell count.

Serious side effects of Victrelis include serious skin reactions, including:

hives,
angioedema,
Stevens-Johnson syndrome (SJS),
drug reaction with eosinophilia and systemic symptoms (DRESS), and
exfoliative dermatitis.

Drug interactions of Victrelis include:

alfuzosin,
doxazosin,
sildosin,
tamsulosin,
sildenafil, and tadalafil because it can increase their blood levels, leading to increased side effects from these drugs.

Victrelis combined with carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort can decrease its effectiveness.

Victrelis combined with lovastatin and simvastatin may increase the risk of muscle aches, including rhabdomyolysis.

Victrelis combined with midazolam and triazolam can increase the risk of sedation and respiratory depression.

Victrelis used with HIV medications can lead to decreased effectiveness of Victrelis and the HIV medications.

Victrelis should be used with caution with arrhythmia medications because it can increase the risk of irregular heart rate and rhythm.

Victrelis should be used with caution with antifungal medications, certain antibiotics, and immunosuppressant medications because it can increase their levels in the body, leading to increased side effects and toxicity.

Victrelis should be used with caution with warfarin because it can increase or decrease the effect of warfarin.

Victrelis is combined with ribavirin and peginterferon alfa which cause fetal harm and birth defects if used in pregnant women or in male partners of women who are pregnant.

Female patients of childbearing potential and their male partners as well as male patients and their female partners must use two effective birth control methods during treatment and for 6 months after treatment. Female patients should have monthly pregnancy tests during treatment and for 6 months after stopping treatment.

It is unknown if Victrelis enters breast milk. To avoid any potential risk to the newborn, a decision must be made to discontinue breastfeeding or to discontinue the drug.

What are the important side effects of Victrelis (boceprevir)?

Side effects of boceprevir include:

hair loss,
dry skin,
diarrhea,
loss of appetite,
nausea,
altered sense of taste,
sleeplessness,
irritability,
fatigue,
shivering,
anemia, and
low white blood cell count.

Boceprevir can cause serious skin reactions, including

urticaria,
angioedema,
Stevens-Johnson syndrome (SJS),
drug reaction with eosinophilia and systemic symptoms (DRESS), and
exfoliative dermatitis.

Boceprevir should be discontinued if serious skin reactions occur.

Victrelis (boceprevir) side effects list for healthcare professionals

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
Neutropenia
Pancytopenia
Hypersensitivity

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.

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	Previously Untreated (SPRINT-1 and SPRINT-2)		Previous Treatment Failures (RESPOND-2)
	Percentage of Subjects Reporting Adverse Events		Percentage of Subjects Reporting Adverse Events
Body System Organ Class	Victrelis + PegIntron +Rebetol (n=1225)	PegIntron + Rebetol (n=467)	Victrelis + PegIntron +Rebetol (n=323)	PegIntron + Rebetol (n=80)
Median Exposure (days)	197	216	253	104
Blood and Lymphatic System Disorders
Anemia	50	30	45	20
Neutropenia	25	19	14	10
Gastrointestinal Disorders
Nausea	46	42	43	38
Dysgeusia	35	16	44	11
Diarrhea	25	22	24	16
Vomiting	20	13	15	8
Dry Mouth	11	10	15	9
General Disorders and Administration Site Conditions
Fatigue	58	59	55	50
Chills	34	29	33	30
Asthenia	15	18	21	16
Metabolism and Nutrition Disorders
Decreased Appetite	25	24	26	16
Musculoskeletal and Connective Tissue Disorders
Arthralgia	19	19	23	16
Nervous System Disorders
Dizziness	19	16	16	10
Psychiatric Disorders
Insomnia	34	34	30	24
Irritability	22	23	21	13
Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea Exertional	8	8	11	5
Skin and Subcutaneous Tissue Disorders
Alopecia	27	27	22	16
Dry Skin	18	18	22	9
Rash	17	19	16	6

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.

Gastrointestinal Disorders

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.

Laboratory Values

Changes in selected hematological parameters during treatment of adult subjects with the combination of Victrelis with PegIntron and Rebetol are described in Table 4.

Hemoglobin

Decreases in hemoglobin may require a decrease in dosage or discontinuation of ribavirin. If ribavirin is permanently discontinued, then peginterferon alfa and Victrelis must also be discontinued.

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. If peginterferon alfa is permanently discontinued, then ribavirin and Victrelis must also be discontinued.

Table 4
Selected 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
Hematological Parameters	Victrelis + PegIntron + Rebetol (n=1225)	PegIntron +Rebetol (n=467)	Victrelis + PegIntron + Rebetol (n=323)	PegIntron + Rebetol (n=80)
Hemoglobin (g/dL)
<10	49	29	49	25
<8.5	6	3	10	1
Neutrophils (x 10⁹/L)
<0.75	31	18	26	13
<0.5	8	4	7	4
Platelets (x 10⁹/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

Gastrointestinal Disorders: mouth ulceration, stomatitis

Infections and Infestations: pneumonia, sepsis

Skin and Subcutaneous Tissue Disorders: angioedema, urticaria; drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, exfoliative rash, exfoliative dermatitis, Stevens-Johnson syndrome, toxic skin eruption, toxicoderma

What drugs interact with Victrelis (boceprevir)?

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.

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. 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 ↑ 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) 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 ↑ 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. 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 ↑ 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	Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced steady-state exposures to boceprevir, lopinavir and ritonavir.
	↓ boceprevir	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.
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. 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. 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.
drospirenone/ethinyl estradiol*	↑ drospirenone ↓ ethinyl estradiol	Concentrations of drospirenone increased in the presence of boceprevir. Thus, the use of drospirenonecontaining products is contraindicated during treatment with Victrelis due to potential for hyperkalemia.
norethindrone/ethinyl estradiol*	↓ ethinyl estradiol ↔ norethindrone	Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Norethindrone Cmax decreased 17% in the presence of boceprevir. 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. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.
PDE5 inhibitors:		For contraindicated PDE5 enzyme inhibitors.
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. 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.
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.
* These combinations have been studied.

Summary

Victrelis (boceprevir) is a man-made antiviral medication that targets hepatitis C virus (HCV). Victrelis is called a direct-acting antiviral agent because it acts directly on hepatitis C virus. Common side effects of Victrelis include hair loss, dry skin, diarrhea, loss of appetite, nausea, altered taste senses, sleeplessness, irritability, fatigue, shivering, anemia, and low white blood cell count. Victrelis is combined with ribavirin and peginterferon alfa which cause fetal harm and birth defects if used in pregnant women or in male partners of women who are pregnant. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use two effective birth control methods during treatment and for 6 months after treatment. It is unknown if Victrelis enters breast milk.