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Victrelis

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Victrelis

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Embryofetal Toxicity (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. Refer to the prescribing information for ribavirin for additional information.

Women of childbearing potential and men must use at least two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. One of these 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. Routine monthly pregnancy tests must be performed during this time [see CONTRAINDICATIONS and DRUG INTERACTIONS].

Anemia (Use With Ribavirin And Peginterferon Alfa)

Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. Complete blood counts (with white blood cell differential counts) should be obtained pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. If hemoglobin is less than 10 g per dL, a decrease in dosage of ribavirin is recommended; and if hemoglobin is less than 8.5 g per dL, discontinuation of ribavirin is recommended [see ADVERSE REACTIONS and Clinical Studies]. If ribavirin is permanently discontinued for management of anemia, then peginterferon alfa and VICTRELIS must also be discontinued [see DOSAGE AND ADMINISTRATION].

Refer to the prescribing information for ribavirin for additional information regarding dose reduction and/or discontinuation.

In clinical trials with VICTRELIS, the proportion of subjects who experienced hemoglobin values less than 10 g per dL and less than 8.5 g per dL was higher in subjects treated with the combination of VICTRELIS with PegIntron®/REBETOL® than in those treated with PegIntron/REBETOL alone (see Table 4). W ith the interventions used for anemia management in the clinical trials, the average additional decrease of hemoglobin was approximately 1 g per dL.

In clinical trials, the median time to onset of hemoglobin less than 10 g per dL from the initiation of therapy was similar among subjects treated with the combination of VICTRELIS and PegIntron/REBETOL (71 days with a range of 15-337 days), compared to those who received PegIntron/REBETOL (71 days with a range of 8-337 days). Certain adverse reactions consistent with symptoms of anemia, such as dyspnea, exertional dyspnea, dizziness and syncope were reported more frequently in subjects who received the combination of VICTRELIS with PegIntron/REBETOL than in those treated with PegIntron/REBETOL alone [see ADVERSE REACTIONS].

In clinical trials with VICTRELIS, dose modifications (generally of PegIntron/REBETOL) due to anemia occurred twice as often in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL (26%) compared to PegIntron/REBETOL (13%). The proportion of subjects who discontinued study drug due to anemia was 1% in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL and 1% in subjects who received PegIntron/REBETOL. The use of erythropoiesis stimulating agents (ESAs) was permitted for management of anemia, at the investigator's discretion, with or without ribavirin dose reduction in the Phase 2 and 3 clinical trials. The proportion of subjects who received an ESA was 43% in those treated with the combination of VICTRELIS with PegIntron/REBETOL compared to 24% in those treated with PegIntron/REBETOL alone. The proportion of subjects who received a transfusion for the management of anemia was 3% of subjects treated with the combination of VICTRELIS with PegIntron/REBETOL compared to less than 1% in subjects who received PegIntron/REBETOL alone.

Thromboembolic events have been associated with ESA use in other disease states; and have also been reported with peginterferon alfa use in hepatitis C patients. Thromboembolic events were reported in clinical trials with VICTRELIS among subjects receiving the combination of VICTRELIS with PegIntron/REBETOL, and among those receiving PegIntron/REBETOL alone, regardless of ESA use. No definite causality assessment or benefit risk assessment could be made for these events due to the presence of confounding factors and lack of randomization of ESA use.

A randomized, parallel-arm, open-label clinical trial was conducted in previously untreated CHC subjects with genotype 1 infection to compare use of an ESA versus ribavirin dose reduction for initial management of anemia during therapy with VICTRELIS in combination with peginterferon alfa-2b and ribavirin. Similar SVR rates were reported in subjects who were randomized to receive ribavirin dose reduction compared to subjects who were randomized to receive an ESA. In this trial, use of ESAs was associated with an increased risk of thromboembolic events including pulmonary embolism, acute myocardial infarction, cerebrovascular accident, and deep vein thrombosis compared to ribavirin dose reduction alone. The treatment discontinuation rate due to anemia was similar in subjects randomized to receive ribavirin dose reduction compared to subjects randomized to receive ESA (2% in each group). The transfusion rate was 4% in subjects randomized to receive ribavirin dose reduction and 2% in subjects randomized to receive ESA.

Ribavirin dose reduction is recommended for the initial management of anemia.

Neutropenia (Use With Ribavirin And Peginterferon Alfa)

In Phase 2 and 3 clinical trials, seven percent of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL had neutrophil counts of less than 0.5 x 109 per L compared to 4% of subjects receiving PegIntron/REBETOL alone (see Table 4). Three subjects experienced severe or life-threatening infections associated with neutropenia, and two subjects experienced life-threatening neutropenia while receiving the combination of VICTRELIS with PegIntron/REBETOL. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Decreases in neutrophil counts may require dose reduction or discontinuation of peginterferon alfa and ribavirin. If peginterferon alfa and ribavirin are permanently discontinued, then VICTRELIS must also be discontinued [see DOSAGE AND ADMINISTRATION].

Refer to the prescribing information for peginterferon alfa and ribavirin for additional information regarding dose reduction or discontinuation.

Pancytopenia (Use With Ribavirin And Peginterferon Alfa)

Serious cases of pancytopenia have been reported postmarketing in patients receiving VICTRELIS in combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.

Refer to the prescribing information for ribavirin and peginterferon alfa for guidelines for discontinuation of therapy based on laboratory parameters.

Hypersensitivity

Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with VICTRELIS, peginterferon alfa and ribavirin. If such an acute reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted [see CONTRAINDICATIONS and ADVERSE REACTIONS].

Drug Interactions

See Table 2 for a listing of drugs that are contraindicated for use with VICTRELIS due to potentially life-threatening adverse events, significant drug interactions or loss of virologic activity [see CONTRAINDICATIONS]. Please refer to Table 5 for established and other potentially significant drug interactions [see DRUG INTERACTIONS].

Laboratory Tests

HCV-RNA levels should be monitored at Treatment Weeks 4, 8, 12, and 24, at the end of treatment, during treatment follow-up, and for other time points as clinically indicated. Use of a sensitive real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification of equal to or less than 25 IU per mL, and a limit of HCV-RNA detection of approximately 10 to 15 IU per mL. For the purposes of assessing Response-Guided Therapy milestones, 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”).

Complete blood count (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.

Refer to the prescribing information for peginterferon alfa and ribavirin for pre-treatment, on-treatment and post-treatment laboratory testing recommendations including hematology, biochemistry (including hepatic function tests), and pregnancy testing requirements.

Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Medication Guide)

VICTRELIS must be used in combination with peginterferon alfa and ribavirin, and thus all contraindications and warnings for peginterferon alfa and ribavirin also apply. If peginterferon alfa or ribavirin is permanently discontinued, VICTRELIS must also be discontinued [see DOSAGE AND ADMINISTRATION].

Pregnancy

Ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Ribavirin therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks of ribavirin and must be instructed to practice effective contraception during therapy and for 6 months post-therapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Women of childbearing potential and men must use at least two forms of effective contraception during treatment and for at least 6 months after treatment has been stopped; routine monthly pregnancy tests must be performed during this time. 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 and WARNINGS AND PRECAUTIONS].

To monitor maternal and fetal outcomes of pregnant women exposed to ribavirin, the Ribavirin Pregnancy Registry has been established. Patients should be encouraged to register by calling 1-800593-2214.

Anemia

Patients should be informed that anemia may be increased when VICTRELIS is administered with peginterferon alfa and ribavirin [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS].

Neutropenia

Patients should be informed that neutropenia may be increased when VICTRELIS is administered with peginterferon alfa and ribavirin [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS].

Pancytopenia

Patients should be informed that serious cases of pancytopenia have been reported during postmarketing when VICTRELIS was administered with peginterferon alfa and ribavirin [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS].

Hypersensitivity

Patients should be informed that serious acute hypersensitivity reactions have been observed during combination therapy with VICTRELIS, peginterferon alfa, and ribavirin therapy [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. If symptoms of acute hypersensitivity reactions (e.g., itching; hives; swelling of the face, eyes, lips, tongue, or throat; trouble breathing or swallowing) occur, patients should seek medical advice promptly.

Usage Safeguards

Patients should be advised that VICTRELIS must not be used alone due to the high probability of resistance without combination anti-HCV therapies [see INDICATIONS AND USAGE]. See the prescribing information for peginterferon alfa and ribavirin for additional patient counseling information on the use of these drugs in combination with VICTRELIS.

Patients should be informed of the potential for serious drug interactions with VICTRELIS, and that some drugs should not be taken with VICTRELIS [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Patients should be advised that the total daily dose of VICTRELIS is packaged into a single bottle containing 12-capsules and the patient should take four capsules three times daily with food.

Missed VICTRELIS Doses

If a patient misses a dose and it is less than 2 hours before the next dose is due, the missed dose should be skipped. If a patient misses a dose and it is 2 or more hours before the next dose is due, the patient should take the missed dose with food and resume the normal dosing schedule.

Hepatitis C Virus Transmission

Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus should be taken.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis and Mutagenesis

Use with Ribavirin and Peginterferon alfa: Ribavirin is genotoxic in in vitro and in vivo assays. Ribavirin was not oncogenic in mouse and rat carcinogenicity studies at doses less than the maximum recommended daily human dose. Please refer to the prescribing information for ribavirin for additional information.

Two-year carcinogenicity studies in mice and rats were conducted with boceprevir. Mice were administered doses of up to 500 mg per kg in males and 650 mg per kg in females, and rats were administered doses of up to 125 mg per kg in males and 100 mg per kg in females. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested resulting in boceprevir AUC exposures approximately 2.3-and 6.0-fold higher in males and females, respectively, than those in humans at the recommended dose of 800 mg three times daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest doses tested resulting in boceprevir AUC exposures similar to those in humans at the recommended dose of 800 mg three times daily.

Boceprevir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosomal aberration in human peripheral blood lymphocytes and mouse micronucleus assays.

Impairment of Fertility

Use with Ribavirin and Peginterferon alfa: In fertility studies in male animals, ribavirin induced reversible testicular toxicity; while peginterferon alfa may impair fertility in females. Please refer to the prescribing information for ribavirin and peginterferon alfa for additional information.

Boceprevir-induced reversible effects on fertility and early embryonic development in female rats, with no effects observed at a 75 mg per kg dose level. At this dose, boceprevir AUC exposures are approximately 1.3-fold higher than those in humans at the recommended dose of 800 mg three times daily. Decreased fertility was also observed in male rats, most likely as a consequence of testicular degeneration. No testicular degeneration was observed at a 15 mg per kg dose level resulting in boceprevir AUC exposures of less than those in humans at the recommended dose of 800 mg three times daily. Testicular degeneration was not observed in mice or monkeys administered boceprevir for 3 months at doses of up to 900 or 1000 mg per kg, respectively. At these doses, boceprevir AUC exposures are approximately 6.8-and 4.4-fold higher in mice and monkeys, respectively, than those in humans at the recommended dose of 800 mg three times daily. Additionally, limited clinical monitoring has revealed no evidence of testicular toxicity in human subjects.

Use In Specific Populations

Pregnancy

VICTRELIS must be administered in combination with peginterferon alfa and ribavirin [see DOSAGE AND ADMINISTRATION].

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 and WARNINGS AND PRECAUTIONS] [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. W omen 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 and WARNINGS AND PRECAUTIONS].

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]. 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].

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].

Renal Impairment

No dosage adjustment of VICTRELIS is required for patients with any degree of renal impairment [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

No dose adjustment of VICTRELIS is required for patients with mild, moderate or severe hepatic impairment [see CLINICAL PHARMACOLOGY]. 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/mm³ 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/mm³ 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 and CLINICAL PHARMACOLOGY.

Last reviewed on RxList: 8/11/2014
This monograph has been modified to include the generic and brand name in many instances.

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