Boceprevir

519.6767

519.68

1592732-453-0

89BT58KELH

C117292

White to off-white amorphous powder

J05AE|J - Antiinfectives for systemic use

150.70000

2.05

1.2±0.1 g/cm3

1.533

Slightly soluble in water

Boceprevir capsules should be refrigerated at 2-8 °C (36-46 °F) until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated capsules of boceprevir can remain stable until the expiration date printed on the label. Bboceprevir also be stored at room temperature up to 25 °C (77 °F) for 3 months. Keep container tightly closed.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including boceprevir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501|Aggregated GHS information provided by 13 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The most commonly reported adverse reactions in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when Boceprevir was used in combination with [DB00811] and [DB00008]/[DB00022].

In large randomized controlled trials, triple therapy with boceprevir, peginterferon and ribavirin was associated with a high rate of adverse events that often required dose adjustments and led to early discontinuation in 5% to 20% of patients. However, serum ALT elevations and clinically apparent liver injury were not generally mentioned as adverse events of therapy. The exception to this occurred in patients with preexisting cirrhosis in whom de novo, seemingly spontaneous hepatic decompensation occurred in a proportion of treated subjects. The cause of the decompensation was not clear and the separate role of boceprevir from peginterferon and ribavirin and from what might happen even without therapy could not be easily defined. Nevertheless, in postmarketing studies of triple therapy of chronic hepatitis C with cirrhosis, decompensation was reported in 3% to 8% of patients and deaths from hepatic failure in 1% to 3%.

Concomitant use of boceprevir and potent CYP3A4/5 inducers that may substantially reduce plasma boceprevir concentrations and efficacy (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort [Hypericum perforatum]) is contraindicated.|Potential pharmacokinetic interaction with alfuzosin (increased alfuzosin concentrations). Concomitant use of boceprevir and alfuzosin is contraindicated because increased alfuzosin concentrations may result in hypotension.|Potential pharmacokinetic interaction with antiarrhythmic agents (amiodarone, bepridil (no longer commercially available in US), flecainide, propafenone, quinidine) may result in increased concentrations of the antiarrhythmic agent; potential for serious and/or life-threatening adverse effects. If boceprevir and antiarrhythmic agents are used concomitantly, use caution and monitor plasma concentrations of the antiarrhythmic agent.|Potential pharmacokinetic interaction with warfarin (altered warfarin concentrations). Monitor international normalized ratio (INR) closely if warfarin is used concomitantly with boceprevir.|For more Interactions (Complete) data for Boceprevir (38 total), please visit the HSDB record page.

There is insufficient experience in patients 65 years of age or older to determine whether geriatric patients respond differently to boceprevir than younger adults. Boceprevir should be used with caution in geriatric patients due to the greater frequency of decreased hepatic function and of concomitant disease and drug therapy observed in this age group.

Bocepravir is approximately 75% bound to human plasma proteins following a single dose.

Boceprevir, when used in combination with [DB00811], [DB00008], and [DB00022] is indicated for use in the treatment of chronic HCV genotype 1 infection in adults.|FDA Label|Victrelis is indicated for the treatment of chronic hepatitis-C (CHC) genotype-1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.|Treatment of chronic hepatitis C

Boceprevir is an oral, direct acting hepatitis C virus (HCV) protease inhibitor that is used in combination with other antiviral agents in the treatment of chronic hepatitis C, genotype 1. Boceprevir has not been linked to instances of acute liver injury during therapy but, when combined with peginterferon and ribavirin, has been associated with cases of hepatic decompensation in patients with preexisting cirrhosis.

Hepatitis C Agents

Boceprevir is indicated for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy. /Included in US product label/|Boceprevir must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin. /Included in US product label/

FDA notified healthcare professionals that the boceprevir (Victrelis) drug label has been revised to state that co-administration of boceprevir, a hepatitis C virus (HCV) protease inhibitor, along with certain ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors, is not recommended. The findings of a drug-drug interaction study and clinical trial showed that co-administration increased of the possibility of reducing the effectiveness of the medicines, permitting the amount of HCV or HIV virus in the blood to increase. Ritonavir-boosted HIV protease inhibitors include ritonavir-boosted atazanavir (Reyataz), ritonavir-boosted darunavir (Prezista), and lopinavir/ritonavir (Kaletra).|FDA notified healthcare professionals of updates to the prescribing information concerning interactions between protease inhibitors and certain statin drugs. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal. BACKGROUND: Statins are a class of prescription drugs used together with diet and exercise to reduce blood levels of low-density lipoprotein (LDL) cholesterol ("bad cholesterol"). HIV protease inhibitors are a class of prescription anti-viral drugs used to treat HIV. HCV protease inhibitors are a class of prescription anti-viral drugs used to treat hepatitis C infection. RECOMMENDATION: Healthcare professionals should follow the recommendations in the prescribing information (drug labels) when prescribing HIV or HCV protease inhibitors with statins.|FDA notified healthcare professionals and patients that drug interactions between the hepatitis C virus (HCV) protease inhibitor boceprevir (Victrelis) and certain ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors (atazanavir, lopinavir, darunavir) can potentially reduce the effectiveness of these medicines when they are used together. A drug interaction study showed that taking boceprevir (Victrelis) with ritonavir (Norvir) in combination with atazanavir (Reyataz) or darunavir (Prezista), or with Kaletra (lopinavir/ritonavir) reduced the blood levels of the HIV medicines and boceprevir in the body. FDA will be updating the boceprevir drug label to include information about these drug interactions. BACKGROUND: Boceprevir is a hepatitis C virus (HCV) protease inhibitor used with the medicines peginterferon alfa and ribavirin to treat chronic (long-lasting) hepatitis C infection in adults. HIV protease inhibitors are a class of anti-viral drugs used to treat HIV infection. Ritonavir is an HIV protease inhibitor used to "boost" other HIV protease inhibitors, increasing their levels in the blood and making them more effective. RECOMMENDATION: Patients should not stop taking any of their medicines without talking to their healthcare professional. Patients should contact their healthcare professional if they have any questions or concerns. Healthcare professionals who have started patients infected with both chronic HCV and HIV on boceprevir and antiretroviral therapy containing a ritonavir-boosted protease inhibitor should closely monitor patients for HCV treatment response and for potential HCV and HIV virologic rebound.|Because boceprevir must be used in conjunction with peginterferon alfa and ribavirin, it is contraindicated in women who are or may become pregnant and in male partners of pregnant women. The contraindications, warnings, and precautions for all 3 drugs should be considered.|For more Drug Warnings (Complete) data for Boceprevir (21 total), please visit the HSDB record page.

Resistance to boceprevir was characterized in biochemical and HCV genotype 1b replicon assays. The activity of boceprevir against the HCV NS3/4A protease or genotype 1b replicon was reduced (2- to 10- fold) by the following amino acid substitutions in the NS3 protease domain: V36A/I/M, Q41R, F43C/S, T54A/S, V55A/I, R155K/M/Q, V158I, V170A/T and M175L. A greater than 15-fold reduction in boceprevir anti-HCV activity was conferred by the substitutions T54C, R155G/I/T and A156S/T/V. The fold decrease in boceprevir anti-HCV activity conferred by double resistance-associated substitutions was approximately equal to the product of that for the individual substitutions. In cell-based protease assays, an NS3 Q80K substitution did not reduce HCV sensitivity to boceprevir. In addition, the decreased sensitivity to boceprevir observed with R155K was not further decreased when combined with either Q80K or Q80R.|An as-treated, pooled genotypic resistance analysis was conducted for subjects who received four weeks of PegIntron/REBETOL followed by VICTRELIS 800 mg three times daily in combination with PegIntron/REBETOL in two Phase 3 studies, SPRINT-2 and RESPOND-2. Among VICTRELIS-treated subjects who did not achieve a sustained virologic response, and for whom samples were analyzed, 53% had one or more specific post-baseline, treatment-emergent NS3 protease domain amino acid substitutions detected by a population-based sequencing assay (Table 8). Nearly all of these substitutions have been shown to reduce boceprevir anti-HCV activity in cell culture or biochemical assays. Among VICTRELIS-treated subjects who did not achieve SVR and for whom post-baseline samples were analyzed, 31% of PegIntron/REBETOL-responsive subjects, as defined by greater than or equal to 1-log10 decline in viral load at Treatment Week 4 (end of 4-week PegIntron/REBETOL lead-in period), had detectable treatment-emergent substitutions, compared to 68% of subjects with less than 1-log10 decline in viral load at Treatment Week 4. Clear patterns of boceprevir treatment-emergent substitutions in the NS3 helicase domain or NS4A coding regions of the HCV genome were not observed.|Many of the treatment-emergent NS3 amino acid substitutions detected in boceprevir -treated subjects who did not achieve SVR in the Phase 3 clinical trials have been demonstrated to reduce the anti-HCV activity of other HCV NS3/4A protease inhibitors. The impact of prior exposure to VICTRELIS or treatment failure on the efficacy of other HCV NS3/4A protease inhibitors has not been studied. The efficacy of boceprevir has not been established for patients with a history of exposure to other NS3/4A protease inhibitors. Cross-resistance is not expected between boceprevir and interferons, or boceprevir and ribavirin.

Boceprevir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotype 1.

Boceprevir reaches peak plasma concentration 2 hours after administration. Absolute bioavailability has not been determined. When taken with food exposure increases up to 65%. In capsule, Boceprevir consists of two diaseromers in a 1:1 ratio. In plasma this ratio changes to 2:1 favoring the active diastereomer.|Boceprevir is mainly eliminated in the feces (79%) with a small amount eliminated in the urine (9%). Approximately 8% and 3% is excreted as the parent compound in the feces and urine respectively.|The mean apparent volume of distribution for Bocepravir is 772 litres at steady state.|Boceprevir has a mean total body clearance of 161 liters per hour.|In healthy subjects who received 800 mg three times daily alone, boceprevir drug exposure was characterized by AUC(T) of 5408 ng. hr per mL (n=71), Cmax of 1723 ng per mL (n=71), and Cmin of 88 ng per mL (n=71). Pharmacokinetic results were similar between healthy subjects and HCV-infected subjects.|Boceprevir was absorbed following oral administration with a median Tmax of 2 hours. Steady state AUC, Cmax, and Cmin 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.|Boceprevir 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, boceprevir may be taken without regard to either meal type or timing of the meal.|Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 772 L at steady state in healthy subjects.|For more Absorption, Distribution and Excretion (Complete) data for Boceprevir (10 total), please visit the HSDB record page.

Bocepravir is primarily metabolized via the aldo-ketoreductase-mediated pathway producing a diastereomeric mix of metabolites at a 4 fold greater exposure than the parent compound. Boceprevir also undergoes oxidative metabolism via CYP3A4/5, although to a lesser extent.|Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldo-ketoreductase (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 diasteriomeric 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.

Boceprevir has a mean half-life of elimination of 3.4 hours.|Boceprevir is eliminated with a mean plasma half-life (t1/2) of approximately 3.4 hours.

Boceprevir is a NS3/4a protease inhibitor used to inhibit viral HCV replication. NS3/4a protease is an integral part of viral replication and mediates the cleavage the virally encoded polyprotein to mature proteins (NS4A, NS4B, NS5A and NS5B). Boceprevir covalently but reversibly binds the serine (S139) resiude in the active site via a (α)-ketoamide functional group. This inhibits the proteolytic acitvity of the HCV 1a and 1b encoded enzyme.|Boceprevir is a selective hepatitis C virus (HCV) nonstructural (NS) 3/4A protease inhibitor. The drug is a direct-acting antiviral agent with activity against HCV. Boceprevir contains an alpha-ketoamide functional group that selectively, covalently, and reversibly binds the active serine site of HCV NS3 protease. By blocking proteolytic cleavage of NS4A, NS4B, NS5A, and NS5B from the HCV-encoded polyprotein, the drug inhibits HCV replication in host cells. Boceprevir has in vitro activity against HCV genotypes 1a and 1b, but is less active against genotypes 2, 2a, and 3a.|Boceprevir is an inhibitor of the HCV NS3/4A protease that is necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms of the NS4A, NS4B, NS5A and NS5B proteins. Boceprevir covalently, yet reversibly, binds to the NS3 protease active site serine (S139) through an (alpha)-ketoamide functional group to inhibit viral replication in HCV-infected host cells. In a biochemical assay, boceprevir inhibited the activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes, with Ki values of 14 nM for each subtype.|... Boceprevir is a ketoamide protease inhibitor that binds reversibly to the HCV nonstructural NS3 protease active site inhibiting intracellular viral replication. Phase III clinical studies have demonstrated that, in combination with the current standard of care, boceprevir significantly increases the a sustained virological response rate in both treatment-naive and previously treated patients with genotype 1 CHC. ...

There is no specific antidote for overdose with boceprevir. Treatment of overdosage with boceprevir should consist of general supportive measures, including monitoring of vital signs, and observation of the patient's clinical status.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Daily doses of 3600 mg have been taken by healthy volunteers for 5 days without untoward symptomatic effects.|/GENOTOXICITY/ Boceprevir was not genotoxic in a chromosomal aberration /assay using/ human peripheral blood lymphocytes.|/ALTERNATIVE and IN VITRO TESTS/ The hepatitis C virus protease inhibitor boceprevir is a strong inhibitor of cytochrome P450 3A4 and 3A5 (CYP3A4/5).|/OTHER TOXICITY INFORMATION/ Potential pharmacokinetic interaction (increased pimozide concentrations); potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias). Concomitant use of boceprevir and pimozide is contraindicated.|For more Human Toxicity Excerpts (Complete) data for Boceprevir (6 total), please visit the HSDB record page.

boceprevir

VICTRELIS 200 mg Capsules, red-colored cap with the Merck logo printed in yellow ink, and a yellow-colored body with "314" printed in red ink.

Manufactured as an approximately equal mixture of two diasteromers.

Human drugs -> Victrelis -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients