Dosing and uses of Victrelis (boceprevir)
Adult dosage forms and strengths
capsule
- 200mg
Chronic Hepatitis C
Discontinued; sale and distribution of boceprevir will be discontinued in the United States by December 2015
Indicated for treatment of chronic hepatitis C (CHC) genotype 1 infection in combination with peginterferon alfa and ribavirin
Indication is specifically for adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy
Initiate therapy with peginterferon alfa and ribavirin for 4 weeks, THEn
Add boceprevir 800 mg PO q8hr (ie, q7-9hr) with food
Treatment Duration
Duration of treatment depends on HCV-RNA levels at treatment weeks 8, 12, and 24
HCV-RNA levels at 8 weeks
- Previously untreated and HCV-RNA levels undetectable: Complete 3-medication regimen at week 28
- Previously untreated and HCV-RNA levels detectable: Continue 3 medication regimen through week 36, then continue peginterferon alfa and ribavirin through week 48
- Partial responders or relapsed and HCV-RNA levels undetectable: Complete 3-medication regimen at week 36
- Partial responders or relapsed and HCV-RNA levels detectable: Continue 3 medication regimen through week 36, then continue peginterferon alfa and ribavirin through week 48
HCV-RNA levels at 12 weeks
- Response-guided therapy was not studied in individuals who had less than a 2-log10 HCV-RNA decline by treatment week 12 during prior therapy with peginterferon alfa and ribavirin
- If considered for treatment, these patients should receive peginterferon alfa and ribavirin x4 weeks followed by boceprevir x44 weeks in combination with peginterferon alfa and ribavirin
- In addition, consideration should be given to treating previously untreated patients who are poorly interferon responsive (as determined at TW 4) with 4 weeks peginterferon alfa and ribavirin followed by boceprevir x44 weeks in combination with peginterferon alfa and ribavirin in order to maximize rates of a sustained virologic response
HCV-RNA levels at 24 weeks
- If HCV-RNA levels are undetectable at treatment week 24, continue with treatment regimen identified at week 8
Treatment futility
- Discontinuation of therapy is recommended in all patients with any of the following circumstances:
- If HCV-RNA levels ≥1000 IU/mL at week 8, discontinue 3-medication regimen, OR
- If HCV-RNA levels ≥100 IU/mL at week 12, discontinue 3-medication regimen, OR
- If confirmed, detectable HCV-RNA levels at week 24, discontinue 3-medication regimen
Compensated cirrhosis
- Peginterferon alfa and ribavirin x 4 weeks followed by boceprevir x44 weeks in combination with peginterferon alfa and ribavirin
Renal or Hepatic Impairment
No dose adjustment for boceprevir is required
See peginterferon alfa and ribavirin monographs for recommended dose adjustments
Administration
Must be administered in combination with peginterferon alfa and ribavirin
Administer with a meal or light snack
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established
Victrelis (boceprevir) adverse (side) effects
>10%
Fatigue (55-58%)
Anemia (45-50%)
Nausea (43-46%)
Headache (>35%)
Dysgeusia (35-44%)
Insomnia (30-34%)
Chills (33-34%)
Alopecia (22-27%)
Diarrhea (25%)
Anorexia (25%)
Neutropenia (14-25%)
Arthralgia (19-23%)
Irritability (21-22%)
Dry skin (18-22%)
Asthenia (15-21%)
Vomiting (15-20%)
Dizziness (16-19%)
Rash (16-17%)
Xerostomia (11-15%)
Exertional dyspnea (8-11%)
Postmarketing Reports
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
Warnings
Contraindications
Coadministration with 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
Potent CYP3A4/5 inducers where significantly reduced boceprevir plasma concentrations may be associated with reduced efficacy
Hypersensitivity
Also consider contraindications to peginterferon alfa and ribavirin
Because ribavirin may cause birth defects and fetal death, boceprevir in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant
Cautions
Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients; patients must have a negative pregnancy test prior to therapy; use 2 or more forms of contraception, 1 of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone (lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated)
Perform monthly pregnancy tests in sexually active women
Serious acute hypersensitivity reactions (eg, urticaria, angioedema) reported
Anemia: Addition of boceprevir to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared with peginterferon alfa and ribavirin alone
Neutropenia: Addition of boceprevir to peginterferon alfa and ribavirin may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone
Pancytopenia reported; obtain CBC pretreatment and at treatment weeks 2, 4, 8, and 12, and periodically thereafter as clinically appropriate
Safety and efficacy not established with decompensated cirrhosis, organ transplant, or coinfection with HIV or HBV
Potential inhibitor of p-glycoprotein (P-gp) based on in vitro studies; the potential for a drug interaction with sensitive substrates of p-glycoprotein (eg, digoxin) has not been evaluated in a clinical triaL
Pregnancy and lactation
Pregnancy category: X
Boceprevir is coadministered with ribavirin; significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant
Lactation: Unknown whether distributed in breast milk; because of the potential for adverse reaction, breastfeeding is not recommended
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Victrelis (boceprevir)
Mechanism of action
Inhibits HCV NS3/4A protease needed for proteolytic cleavage of the HCV encoded polyprotein into mature forms, which in turn inhibits replication of the hepatitis C virus
Absorption
Peak plasma time: 2 hr peak
Plasma concentration: 1723 ng/mL
AUC: 5408 ng•hr/mL Should be administered with food; food enhanced the exposure of boceprevir by up to 65%
Distribution
Protein bound: 75%
Vd: 772 L (at steady state)
Metabolism
Primarily undergoes metabolism through the aldoketoreductase (AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV; also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5
Metabolized by aldoketoreductase (AKR), CYP3A4/5 (partial)
Enzymes inhibited: Strong CYP3A4/5 inhibitor
Elimination
Half-life: 3.4 hr
Total body clearance: 161 L/hr
Excretion: feces (79%), urine (9%)
Pharmacogenomics
A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C to T change) is a strong predictor of response to peginterferon and ribavirin
Sustained virologic response rates tended to be lower with the C/T and T/T genotypes compared to those with the C/C genotype, particularly among previously untreated subjects receiving 48 weeks of peginterferon and ribavirin
