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HEPATITIS C PROTEASE INHIBITORS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Hepatitis C protease inhibitors are direct-acting antiviral agents, used in combination with ribavirin and peginterferon alfa, against genotype 1 chronic hepatitis C. The fixed-dose combination of grazoprevir, an HCV NS3/4A protease inhibitor with elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, are indicated for the treatment of patients with hepatitis C virus infection, genotypes 1 or 4 and in patients coinfected with HIV-1.

Specific Substances

    A) ASUNAPREVIR (SYNONYM)
    1) BMS-650032
    2) CAS 630420-16-5
    BOCEPREVIR (SYNONYM)
    1) Boceprevirum
    2) CAS 394730-60-0
    GRAZOPREVIR (SYNONYM)
    1) CAS 1350514-68-9
    SIMEPREVIR (SYNONYM)
    1) TMC435
    2) CAS 923604-59-5
    TELAPREVIR (SYNONYM)
    1) Telaprevirum
    2) VRT-127394
    3) LY-570310
    4) CAS 402957-28-2
    GENERAL TERMS
    1) Antiviral protease inhibitors, HCV
    2) HCV protease inhibitors
    3) Protease inhibitors, Hepatitis C
    4) HCV NS3/4A inhibitor

    1.2.1) MOLECULAR FORMULA
    1) BOCEPREVIR: C27H45N5O5
    2) DASABUVIR SODIUM: C26H26N3O5S.Na.H2O
    3) ELBASVIR: C49H55N9O7
    4) GRAZOPREVIR: C38H50N6O9S
    5) OMBITASVIR HYDRATE: C50H67N7O8.4.5H2O
    6) PARITAPREVIR DIHYDRATE: C40H43N7O7S.2H2O
    7) SIMEPREVIR: C38H47N5O7S2
    8) TELAPREVIR: C36H53N7O6

Available Forms Sources

    A) FORMS
    1) BOCEPREVIR is available as a 200 mg red-colored capsule packaged into a carton with 28 bottles containing 12 capsules per bottle (Prod Info VICTRELIS(TM) oral capsules, 2011).
    2) SIMEPREVIR is available as a 150 mg capsule (Prod Info OLYSIO(TM) oral capsules, 2013).
    3) TELAPREVIR is available as a 375 mg purple-colored tablet packaged as a bottle containing 168 tablets or as a 28-day blister card containing 7 blister strips (6 tablets per strip) (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    4) GRAZOPREVIR 100 mg/ELBASVIR 50 mg combination is available as oral tablets (Prod Info ZEPATIER(TM) oral tablets, 2016).
    B) USES
    1) Hepatitis C protease inhibitors are indicated, in combination with peginterferon alfa and ribavirin, for the treatment of genotype 1 chronic hepatitis C (CHC) in adults with compensated liver disease, including cirrhosis, who are treatment-naive or have been previously treated with interferon-based treatment, including null responders, partial responders, and relapsers (Prod Info OLYSIO(TM) oral capsules, 2013; Prod Info VICTRELIS(TM) oral capsules, 2011; Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    2) Grazoprevir/elbasvir combination is a fixed-dose combination indicated for the treatment of patients with hepatitis C virus infection, genotypes 1 or 4 and in patients coinfected with HIV-1 (Prod Info ZEPATIER(TM) oral tablets, 2016).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Hepatitis C protease inhibitors are used for the treatment of genotype 1 chronic hepatitis C virus (HCV), in combination with ribavirin and peginterferon alfa. This class includes boceprevir, simeprevir, and telaprevir. The fixed-dose combination of grazoprevir, an HCV NS3/4A protease inhibitor with elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, are indicated for the treatment of patients with hepatitis C virus infection, genotypes 1 or 4 and in patients coinfected with HIV-1.
    B) PHARMACOLOGY: Hepatitis C protease inhibitors specifically inhibit HCV nonstructural protein 3 (NS3/4A) serine protease. Inhibition of serine protease causes a disruption in viral replication by preventing protein cleavage of specific nonstructural proteins NS4A, NS4B, NS5A, and NS5B within the hepatitis C virus. These drugs are to be used in combination with peginterferon alfa and ribavirin and not as sole therapy.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) BOCEPREVIR: Alopecia, rash, dry skin, nausea, vomiting, dysgeusia, diarrhea, decreased appetite, dry mouth, anemia, neutropenia, arthralgia, fatigue, headache, dizziness, irritability, and dyspnea on exertion. SIMEPREVIR: COMMON (greater than 20%): Rash, photosensitivity, pruritus, and nausea. OTHER EFFECTS: Hyperbilirubinemia, myalgia, and dyspnea. TELAPREVIR: Nausea, vomiting, dysgeusia, rash, Sevens-Johnson syndrome, hemorrhoids or anal discomfort, anemia, and fatigue.
    2) DRUG INTERACTIONS: Hepatitis C inhibitors are strong inhibitors of cytochrome P450 3A4/5.
    E) WITH POISONING/EXPOSURE
    1) No reports of overdose have been found except for clinical trial data. BOCEPREVIR: Daily doses of 3600 mg have been taken by healthy volunteers for 5 days without untoward symptomatic effects. TELAPREVIR: In clinical trials, 1875 mg every 8 hours for 4 days in healthy subjects caused nausea, vomiting, diarrhea, headache, dysgeusia and decreased appetite.
    0.2.20) REPRODUCTIVE
    A) Hepatitis C protease inhibitors must be used in combination with another antiviral drug. Boceprevir and telaprevir used in combination with ribavirin or peginterferon alfa are classified as FDA pregnancy category X. Ribavirin has been shown to cause birth defects in animal studies, while peginterferon alfa is an abortifacient. The use of the simeprevir or elbasvir/grazoprevir combination with ribavirin is also contraindicated in pregnant women and men whose female partners are pregnant. Alone, boceprevir, dasabuvir, ombitasvir/paritaprevir/ritonavir, and telaprevir are classified as FDA pregnancy category B. It is not known if telaprevir or boceprevir are excreted into human milk.
    0.2.22) OTHER
    A) WITH THERAPEUTIC USE
    1) DRUG INTERACTIONS
    a) Hepatitis C protease inhibitors are strong inhibitors of cytochrome P450 3A4/5, which may result in increased plasma concentrations of medications metabolized by the same isozyme, such as antiarrhythmics, antidepressants, benzodiazepines, bosentan, calcium channel blockers, colchicine, HMG-CoA reductase inhibitors (ie, statins), prednisone (and other corticosteroids), PDE5 inhibitors (eg, sildenafil), salmeterol, and warfarin (Prod Info INCIVEK(TM) film coated oral tablets, 2011; Prod Info VICTRELIS(TM) oral capsules, 2011).

Laboratory Monitoring

    A) Monitor vital signs.
    B) Obtain a basic metabolic panel and CBC. Monitor for anemia and neutropenia.
    C) Monitor liver enzymes after significant overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor serum electrolytes, renal function, CBC and liver enzymes.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Supportive care remains the mainstay of therapy. Monitor serial CBC with differential. Transfusion of packed red cells may be needed in patients with severe anemia. Consider colony stimulating factors in patients with severe neutropenia. Monitor for infection. Stevens-Johnson Syndrome or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) should be treated with supportive care and corticosteroids. Hepatic failure should prompt consultation with a transplant center.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal in a patient with a recent, substantial ingestion who is awake and can protect the airway. Prehospital care should focus on assessment of vital signs and general supportive care.
    2) HOSPITAL: Activated charcoal may be considered for patients who present early after overdose and are awake and willing to drink the charcoal.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be useful in the management of overdose with hepatitis C protease inhibitors because of the large volume of distribution (boceprevir and telaprevir) or high protein binding (simeprevir).
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with an inadvertent minor ingestion (1 or 2 extra doses), and asymptomatic children with inadvertent ingestion of 1 or 2 pills of a protease inhibitor can be observed at home.
    2) OBSERVATION CRITERIA: All patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve.
    3) ADMISSION CRITERIA: Patients with significant fluid and electrolyte imbalance, anemia or neutropenia should be admitted. Patients with evidence of hepatic insufficiency or failure should be admitted. Patients with severe skin reactions should be admitted to a burn-unit setting.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear
    G) PITFALLS
    1) Failure to consider drug-drug interactions and toxicity of co-ingestants. Patients who are taking hepatitis C protease inhibitors must be on ribavirin and peginterferon alfa and adverse effects in the patient may be due to these medications, in addition to the hepatitis C protease inhibitor.
    H) PHARMACOKINETICS
    1) BOCEPREVIR: 75% protein bound, hepatitic metabolism mediated by CYP 3A4/5, 79% fecal elimination, 772 L volume of distribution, half-life 3.4 hours.
    2) SIMEPREVIR: Tmax: 4 to 6 hours. Protein binding: Greater than 99.9%. Metabolism: Simeprevir undergoes oxidative metabolism primarily via hepatic CYP3A enzymes. CYP2C8 and CYP2C19 may also be involved. Excretion: Renal: Insignificant; less than 1% of an administered dose recovered in the urine. Feces: About 91% of the dose. Elimination half-life: 10 to 13 hours (subjects without hepatitis C virus [HCV] infection); 41 hours (subjects with HCV infection).
    3) TELAPREVIR: Approximately, 59% to 76% protein bound, hepatic metabolism mediated by CYP 3A4/5, 82% fecal elimination, 252 L volume of distribution, half-life approximately 4.7 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Other agents that may cause anemia or neutropenia. Other etiologies of hepatic failure (ie, acetaminophen, iron, carbon tetrachloride, etc.) should be considered. Medical etiologies (ie, portal vein thrombosis, viral hepatitis, hepatic abscess, or Budd-Chiari malformation) should be ruled out in cases of adverse drug effect.

Range Of Toxicity

    A) TOXICITY: BOCEPREVIR: Healthy volunteers were given up to 3600 mg for 5 days without untoward symptomatic effects. TELAPREVIR: The highest documented dose of telaprevir was 1875 mg given every 8 hours for 4 days produced the following adverse effects: nausea, headache, diarrhea, decreased appetite, dysgeusia and vomiting.
    B) THERAPEUTIC DOSE: ADULT: BOCEPREVIR: 800 mg orally 3 times daily (every 7 to 9 hours). SIMEPREVIR: 150 mg orally once daily for 12 or 24 weeks. TELAPREVIR: 1125 mg orally 2 times daily (10 to 14 hours apart). PEDIATRIC: The safety and efficacy of boceprevir, simeprevir, or telaprevir in the pediatric population have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Hepatitis C protease inhibitors are used for the treatment of genotype 1 chronic hepatitis C virus (HCV), in combination with ribavirin and peginterferon alfa. This class includes boceprevir, simeprevir, and telaprevir. The fixed-dose combination of grazoprevir, an HCV NS3/4A protease inhibitor with elbasvir, a hepatitis C virus (HCV) NS5A inhibitor, are indicated for the treatment of patients with hepatitis C virus infection, genotypes 1 or 4 and in patients coinfected with HIV-1.
    B) PHARMACOLOGY: Hepatitis C protease inhibitors specifically inhibit HCV nonstructural protein 3 (NS3/4A) serine protease. Inhibition of serine protease causes a disruption in viral replication by preventing protein cleavage of specific nonstructural proteins NS4A, NS4B, NS5A, and NS5B within the hepatitis C virus. These drugs are to be used in combination with peginterferon alfa and ribavirin and not as sole therapy.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) BOCEPREVIR: Alopecia, rash, dry skin, nausea, vomiting, dysgeusia, diarrhea, decreased appetite, dry mouth, anemia, neutropenia, arthralgia, fatigue, headache, dizziness, irritability, and dyspnea on exertion. SIMEPREVIR: COMMON (greater than 20%): Rash, photosensitivity, pruritus, and nausea. OTHER EFFECTS: Hyperbilirubinemia, myalgia, and dyspnea. TELAPREVIR: Nausea, vomiting, dysgeusia, rash, Sevens-Johnson syndrome, hemorrhoids or anal discomfort, anemia, and fatigue.
    2) DRUG INTERACTIONS: Hepatitis C inhibitors are strong inhibitors of cytochrome P450 3A4/5.
    E) WITH POISONING/EXPOSURE
    1) No reports of overdose have been found except for clinical trial data. BOCEPREVIR: Daily doses of 3600 mg have been taken by healthy volunteers for 5 days without untoward symptomatic effects. TELAPREVIR: In clinical trials, 1875 mg every 8 hours for 4 days in healthy subjects caused nausea, vomiting, diarrhea, headache, dysgeusia and decreased appetite.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, dyspnea on exertion was reported in 8% and 11% of patients, respectively, receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 8% and 5%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) SIMEPREVIR: Dyspnea occurred in 12% of adult patients with chronic hepatitis C virus infection who received oral simeprevir 150 mg once daily (n=781) for 12 weeks combined with peginterferon alfa and ribavirin compared with 8% of patients who received placebo (n=397) with peginterferon alfa and ribavirin in clinical trials. All of the dyspnea events with simeprevir were mild or moderate in severity (grade 1 or 2), and 61% of the dyspnea events occurred in the first 4 weeks of therapy (Prod Info OLYSIO(TM) oral capsules, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Up to 58% of patients reported fatigue with the use of a hepatitis C protease inhibitor (Prod Info INCIVEK(TM) film coated oral tablets, 2011; Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, fatigue was reported in 58% and 55% of patients, respectively, receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 59% and 50%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    c) TELAPREVIR: Fatigue was reported in 56% (n=1797) of patients who were administered telaprevir in combination with ribavirin and peginterferon alfa, compared to 50% (n=493) who did not receive telaprevir (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    d) ELBASVIR/GRAZOPREVIR: In clinical trials, fatigue developed in 5% of 122 patients in the elbasvir/grazoprevir group and 8% of 113 patients in the placebo group (Prod Info ZEPATIER(TM) oral tablets, 2016)
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: Headache was reported as a common adverse effect in patients who used boceprevir (Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) ELBASVIR/GRAZOPREVIR: In clinical trials, headache developed in 11% of 122 patients in the elbasvir/grazoprevir group and 5% of 113 patients in the placebo group (Prod Info ZEPATIER(TM) oral tablets, 2016)
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, dizziness was reported in 19% and 16% of patients, respectively, receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 16% and 10%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, nausea developed 46% and 43% of patients receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 42% and 38%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) SIMEPREVIR: Nausea occurred in 22% of adult patients with chronic hepatitis C virus infection who received oral simeprevir 150 mg once daily (n=781) for 12 weeks combined with peginterferon alfa and ribavirin compared with 18% of patients who received placebo (n=397) with peginterferon alfa and ribavirin in clinical trials (Prod Info OLYSIO(TM) oral capsules, 2013).
    c) TELAPREVIR: Nausea was reported in 39% (n=1797) of patients who were administered telaprevir in combination with ribavirin and peginterferon alfa, compared to 28% (n=493) who did not receive telaprevir (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    d) ELBASVIR/GRAZOPREVIR: In clinical trials, nausea developed in 11% of 122 patients in the elbasvir/grazoprevir group and 8% of 113 patients in the placebo group (Prod Info ZEPATIER(TM) oral tablets, 2016)
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, vomiting developed 20% and 15% of patients receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 13% and 8%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) TELAPREVIR: Vomiting was reported in 13% (n=1797) of patients who were administered telaprevir in combination with ribavirin and peginterferon alfa, compared to 8% (n=493) who did not receive telaprevir (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    C) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, dysgeusia developed 35% and 44% of patients receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 16% and 11%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) TELAPREVIR: Dysgeusia was reported in 10% (n=1797) of patients who were administered telaprevir in combination with ribavirin and peginterferon alfa, compared to 3% (n=493) who did not receive telaprevir (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, diarrhea developed 25% and 24% of patients receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 22% and 16%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, decreased appetite developed 25% and 26% of patients, respectively, receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 24% and 16%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    F) HEMORRHOIDS
    1) WITH THERAPEUTIC USE
    a) TELAPREVIR: Up to 12% of patients taking telaprevir experienced hemorrhoids or anal discomfort compared with 3% of patients not taking telaprevir (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    G) APTYALISM
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, dry mouth developed 11% and 15% of patients, respectively, receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 10% and 9%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) SIMEPREVIR: Hyperbilirubinemia (grade 1) occurred in 27% of adult patients with chronic hepatitis C virus infection who received oral simeprevir 150 mg once daily (n=781) for 12 weeks combined with peginterferon alfa and ribavirin compared with 15% of patients who received placebo (n=397) with peginterferon alfa and ribavirin in clinical trials. Grade 2, 3, and 4 hyperbilirubinemia occurred in 18%, 4%, and less than 1% of simeprevir patients compared with 9%, 2%, and 0% of placebo patients, respectively. The laboratory abnormalities included elevations of both direct and indirect bilirubin, occurred early after treatment initiation (peaked by week 2), and were rapidly reversible upon cessation of therapy. Generally, the elevation in bilirubin levels was not associated with elevations in liver transaminases (Prod Info OLYSIO(TM) oral capsules, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Up to 50% of patients who received hepatitis C inhibitors experienced anemia (Prod Info INCIVEK(TM) film coated oral tablets, 2011; Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) Anemia can occur with peginterferon alfa and ribavirin therapy. An additional decrease in hemoglobin concentration has been observed when telaprevir or boceprevir was administered in combination with peginterferon alfa and ribavirin therapy (Prod Info INCIVEK(TM) film coated oral tablets, 2011; Prod Info VICTRELIS(TM) oral capsules, 2011).
    c) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, anemia developed 50% and 45% of patients, respectively, receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 30% and 20%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    d) TELAPREVIR: Anemia was reported in 36% (n=1797) of patients who were administered telaprevir in combination with ribavirin and peginterferon alfa, compared to 17% (n=493) who did not receive telaprevir (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, neutropenia developed 25% and 14% of patients, respectively, receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 19% and 10%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, alopecia developed 27% and 22% of patients receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 27% and 16%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, rash developed 17% and 16% of patients receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 19% and 6%, respectively, of patients receiving peginterferon and ribavirin alone(Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) SIMEPREVIR: Rash, including photosensitivity, occurred in 28% of adult patients with chronic hepatitis C virus infection who received oral simeprevir 150 mg once daily (n=781) for 12 weeks combined with peginterferon alfa and ribavirin compared with 20% of patients who received placebo (n=397) with peginterferon alfa and ribavirin in clinical trials. Most of the rash events with simeprevir were mild or moderate in severity (grade 1 or 2), and 56% of the rash events occurred in the first 4 weeks of therapy. A grade 3 rash occurred in 1% of simeprevir patients compared with none of the placebo patients. None of the patients had life-threatening (grade 4) rash events (Prod Info OLYSIO(TM) oral capsules, 2013).
    c) TELAPREVIR: Rash was reported in 56% (n=1797) of patients who were administered telaprevir in combination with ribavirin and peginterferon alfa, compared to 34% (n=493) who did not receive telaprevir (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) SIMEPREVIR: Pruritus occurred in 22% of adult patients with chronic hepatitis C virus infection who received oral simeprevir 150 mg once daily (n=781) for 12 weeks combined with peginterferon alfa and ribavirin compared with 15% of patients who received placebo (n=397) with peginterferon alfa and ribavirin in clinical trials (Prod Info OLYSIO(TM) oral capsules, 2013).
    D) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, dry skin developed 18% and 22% of patients receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 18% and 9%, respectively, of patients receiving peginterferon and ribavirin alone(Prod Info VICTRELIS(TM) oral capsules, 2011).
    E) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) TELAPREVIR: Less than 1% of patients taking telaprevir experienced Stevens-Johnson Syndrome while taking telaprevir, in combination with ribavirin and peginterferon alfa. Symptoms upon presentation include fever, target lesions, and mucosal erosions or ulcerations (eg, conjunctivae, lips) (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    F) DRUG HYPERSENSITIVITY SYNDROME
    1) WITH THERAPEUTIC USE
    a) TELAPREVIR: Less than 1% of patients taking telaprevir experienced Drug Rash with Eosinophilia and Systemic Syndrome (DRESS) while taking telaprevir, in combination with ribavirin and peginterferon alfa. Symptoms upon presentation include rash, fever, facial edema and evidence of internal organ involvement (eg, hepatitis, nephritis) with or without eosinophilia (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    G) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) SIMEPREVIR: Photosensitivity reactions, including serious events requiring hospitalization, were reported during clinical trials with simeprevir. Although the reactions may occur at any time, the highest frequency of events were reported during the first 4 weeks of therapy and the frequency increased with higher simeprevir exposures. The presentation may be similar to an exaggerated sunburn and usually affects the areas exposed to light, such as the face, V area of the neck, extensor surfaces of the forearms, and dorsa of the hands. Symptoms may include burning, erythema, exudation, blistering, and edema (Prod Info OLYSIO(TM) oral capsules, 2013).
    b) SIMEPREVIR: Photosensitivity occurred in 5% of adult patients with chronic hepatitis C virus infection who received oral simeprevir 150 mg once daily (n=781) for 12 weeks combined with peginterferon alfa and ribavirin compared with 1% of patients who received placebo (n=397) with peginterferon alfa and ribavirin in clinical trials. Most of the photosensitivity reactions with simeprevir were mild to moderate in severity (grade 1 or 2). Although none of the patients had life-threatening photosensitivity reactions, 2 patients who received simeprevir were hospitalized with serious reactions (Prod Info OLYSIO(TM) oral capsules, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) BOCEPREVIR: In the SPRINT-1/SPRINT-2 (n=1225) and the RESPOND-2 (n=323) clinical trials, arthralgia developed 19% and 23% of patients, respectively, receiving boceprevir along with peginterferon alpha 2-B and ribavirin, compared with 19% and 16%, respectively, of patients receiving peginterferon and ribavirin alone (Prod Info VICTRELIS(TM) oral capsules, 2011).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) SIMEPREVIR: Myalgia occurred in 16% of adult patients with chronic hepatitis C virus infection who received oral simeprevir 150 mg once daily (n=781) for 12 weeks combined with peginterferon alfa and ribavirin compared with 13% of patients who received placebo (n=397) with peginterferon alfa and ribavirin in clinical trials (Prod Info OLYSIO(TM) oral capsules, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Hepatitis C protease inhibitors must be used in combination with another antiviral drug. Boceprevir and telaprevir used in combination with ribavirin or peginterferon alfa are classified as FDA pregnancy category X. Ribavirin has been shown to cause birth defects in animal studies, while peginterferon alfa is an abortifacient. The use of the simeprevir or elbasvir/grazoprevir combination with ribavirin is also contraindicated in pregnant women and men whose female partners are pregnant. Alone, boceprevir, dasabuvir, ombitasvir/paritaprevir/ritonavir, and telaprevir are classified as FDA pregnancy category B. It is not known if telaprevir or boceprevir are excreted into human milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) SPECIFIC SUBSTANCE
    a) BOCEPREVIR
    1) In animal studies involving rats and rabbits given boceprevir alone, no effects on fetal development have been observed at boceprevir AUC exposures approximately 11.8 and 2.0 fold higher, respectively, than those in humans at the recommended dose of 800 mg 3 times daily (Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) DASABUVIR
    1) In animal studies, there was no evidence of teratogenicity when animals were administered dasabuvir at doses 24-fold or 6-fold the recommended human exposure in rats or rabbits, respectively (Prod Info VIEKIRA XR(TM) oral extended-release tablets, 2016; Prod Info VIEKIRA PAK(R) oral tablets, 2016).
    c) ELBASVIR/GRAZOPREVIR
    1) In animal studies, both elbasvir and grazoprevir crossed the placental barrier and no effects on embryofetal, prenatal, or postnatal development were seen after the oral administration of elbasvir or grazoprevir during organogenesis at doses up to 18- and 78-fold the recommended human dose, respectively (Prod Info ZEPATIER(TM) oral tablets, 2016).
    d) OMBITASVIR/PARITAPREVIR/RITONAVIR
    1) In animal studies, there was no evidence of teratogenicity when animals were administered ombitasvir and its major inactive human metabolites (M29, M36), or paritaprevir and ritonavir at doses higher than the recommended human exposure. These doses were 28-fold (mouse) or 4-fold (rabbit) the recommended human dose for ombitasvir, 26-fold the recommended human dose for ombitasvir metabolites, 98-fold (mouse) or 8-fold (rat) the recommended human dose for paritaprevir, and 17-fold (rat) the recommended human dose for paritaprevir and ritonavir combination (Prod Info VIEKIRA XR(TM) oral extended-release tablets, 2016; Prod Info VIEKIRA PAK(R) oral tablets, 2016).
    e) SIMEPREVIR
    1) In animal studies, there was no evidence of teratogenicity in rats or mice exposed to simeprevir 0.5 and 6 times the recommended dose of 150 mg once daily, based on AUC, respectively. However, early and late in utero fetal losses were observed following the administration of doses up to approximately 6 times the exposure than the mean AUC at the recommended human dose (RHD) of 150 mg/day in mice. Exposures approximately 4 times that of the mean AUC at the RHD also resulted in significantly increased fetal skeletal variations. Effects on developing rat offspring included significantly decreased body weight, physical growth delay, overall small size, and decreased motor activity from in utero exposure and during lactation via breast milk with a maternal exposure approximately equal to the mean AUC at the RHD (Prod Info OLYSIO(R) oral capsules, 2014).
    f) TELAPREVIR
    1) In animal studies involving mice and rats given telaprevir alone, no effects on the fetus were observed at the highest telaprevir dose tested, which produced exposures equal to 1.84- and 0.60-fold the recommended clinical dose, respectively (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) COMBINATION THERAPY
    a) Hepatitis C protease inhibitors must be used in combination with another antiviral drug. Boceprevir and telaprevir used in combination with ribavirin or peginterferon alfa are classified as FDA pregnancy category X. Ribavirin has been shown to cause birth defects in animal studies, while peginterferon alfa is an abortifacient (Prod Info OLYSIO(TM) oral capsules, 2013; Prod Info VICTRELIS(TM) oral capsules, 2011; Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    b) Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin and is contraindicated in pregnancy and in the male partners of women who are pregnant. Interferons are abortifacients in animal species and should be assumed to have the same potential in humans (Prod Info OLYSIO(TM) oral capsules, 2013; Prod Info VICTRELIS(TM) oral capsules, 2011; Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    c) Extreme caution should be taken to prevent pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using effective contraception (2 reliable forms) during treatment with ribavirin and for 6 months after treatment (Prod Info OLYSIO(TM) oral capsules, 2013). Systemic hormonal contraceptives may not be as effective in women while taking boceprevir or telaprevir. Two alternative and effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with boceprevir or telaprevir and concomitant ribavirin therapy (Prod Info VICTRELIS(TM) oral capsules, 2011; Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    d) ELBASVIR/GRAZOPREVIR
    1) There are no adequate data to establish whether elbasvir/grazoprevir adversely affects pregnancy outcomes. Use of this combination with ribavirin is contraindicated in pregnant women and men whose female partners are pregnant. Advise patients taking elbasvir/grazoprevir and ribavirin to avoid pregnancy during treatment and within 6 months of stopping treatment and to notify their healthcare professional immediately if pregnancy occurs (Prod Info ZEPATIER(TM) oral tablets, 2016)
    e) OMBITASVIR/PARITAPREVIR/RITONAVIR WITH DASABUVIR
    1) There are no adequate or well-controlled studies of ombitasvir/paritaprevir/ritonavir/dasabuvir use in pregnant women. Due to the potential for fetal risk, administer this drug during pregnancy only if clearly required. Advise patients using ombitasvir/paritaprevir/ritonavir/dasabuvir concomitantly with ribavirin to avoid pregnancy during therapy and within 6 months of discontinuation, as the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant (Prod Info VIEKIRA XR(TM) oral extended-release tablets, 2016; Prod Info VIEKIRA PAK(R) oral tablets, 2016).
    2) SPECIFIC SUBSTANCE
    a) BOCEPREVIR
    1) Alone, boceprevir is FDA pregnancy category B (Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) SIMEPREVIR
    1) Advise pregnant women of the potential for fetal harm if simeprevir is used during pregnancy. IN COMBINATION WITH RIBAVIRIN: Due to the risk of birth defects and fetal deaths with ribavirin, combination therapy including simeprevir, peginterferon alfa, and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. Advise patients to avoid pregnancy during treatment with ribavirin and within 6 months after completion of treatment in both female patients and in female partners of male patients. Advise women to contact their healthcare provider immediately in the event of a pregnancy (Prod Info OLYSIO(R) oral capsules, 2016).
    c) TELAPREVIR
    1) Alone, telaprevir is FDA pregnancy category B (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    B) ANIMAL STUDIES
    1) SPECIFIC SUBSTANCE
    a) ELBASVIR/GRAZOPREVIR
    1) In animal studies, both elbasvir and grazoprevir crossed the placental barrier and no effects on embryofetal, prenatal, or postnatal development were seen after the oral administration of elbasvir or grazoprevir during organogenesis at doses up to 18- and 78-fold the recommended human dose, respectively (Prod Info ZEPATIER(TM) oral tablets, 2016).
    b) SIMEPREVIR
    1) Early and late in utero fetal losses and early maternal deaths were observed following administration of doses up to approximately 6 times the exposure than the mean AUC at the recommended human dose (RHD) of 150 mg/day in mice. Exposures approximately 4 times that of the mean AUC at the RHD also resulted in significantly decreased fetal weights. Early deaths were also observed in rats exposed to doses approximately equivalent to the mean clinical AUC in humans during gestation and lactation. Doses 0.7 times the mean clinical exposure in humans in rats resulted in significantly reduced body weight gains. Effects on the developing rat offspring included significant decreased body weight, physical growth delay, and overall small size from in utero exposure and during lactation via breast milk with a maternal exposure approximately equal to the mean AUC at the RHD (Prod Info OLYSIO(R) oral capsules, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) SPECIFIC SUBSTANCE
    a) BOCEPREVIR
    1) It is not known if boceprevir 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 boceprevir, taking into account the importance of the therapy to the mother (Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) ELBASVIR/GRAZOPREVIR
    1) It is not known whether elbasvir or grazoprevir is excreted into human breast milk, affects milk production, or has an adverse effect on breastfed infants. Elbasvir and grazoprevir were detected in the milk of lactating rats but did not affect the growth or development of the nursing pups (Prod Info ZEPATIER(TM) oral tablets, 2016).
    c) OMBITASVIR/PARITAPREVIR/RITONAVIR WITH DASABUVIR
    1) It is unknown whether ombitasvir, paritaprevir, ritonavir, or dasabuvir are excreted into human milk. In animal studies, ombitasvir, paritaprevir and its metabolite M13, and dasabuvir were excreted into the milk of lactating rats with no effects to the nursing pup. Consider the benefits of breastfeeding, the mother's clinical need for this drug, and any potential adverse effects to the nursing infant when prescribing this drug to a woman who is breastfeeding (Prod Info VIEKIRA XR(TM) oral extended-release tablets, 2016; Prod Info VIEKIRA PAK(R) oral tablets, 2016).
    d) SIMEPREVIR
    1) It is unknown whether simeprevir or its metabolites are excreted into human milk. Simeprevir was detected in the plasma of nursing rat pups, likely due to its excretion into the milk. Consider the developmental and health benefits of breastfeeding, along with the mother's clinical need for the drug and potential adverse effects on the nursing infant before prescribing simeprevir to a lactating woman (Prod Info OLYSIO(R) oral capsules, 2016).
    e) TELAPREVIR
    1) It is not known if telaprevir is excreted in human breast milk. When administered to lactating rats, levels of telaprevir were higher in milk compared to those observed in plasma. Rat offspring exposed to telaprevir in utero showed no effects on body weight at birth. However, when fed via milk from telaprevir-treated dams, body weight gain of pups was lower than pups fed milk from control dams. After weaning, rat pup body weight gain was similar in offspring from telaprevir-treated and control dams. Because of the potential for adverse reactions in nursing infants, nursing must be discontinued prior to the initiation of treatment (Prod Info INCIVEK(TM) film coated oral tablets, 2011).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) SPECIFIC SUBSTANCE
    a) BOCEPREVIR
    1) Limited clinical monitoring has revealed no evidence of testicular toxicity in human subjects (Prod Info VICTRELIS(TM) oral capsules, 2011).
    B) ANIMAL STUDIES
    1) SPECIFIC SUBSTANCE
    a) BOCEPREVIR
    1) USE WITH RIBAVIRIN AND PEGINTERFERON ALFA: Fertility studies in male animals determined ribavirin to have reversible toxicity on testes. Peginterferon alfa may impair fertility in females. For specific reproductive information on both ribavirin and peginterferon alfa, please refer to the RIBAVIRIN and INTERFERONS managements(Prod Info VICTRELIS(TM) oral capsules, 2011).
    2) Boceprevir-induced reversible effects on fertility and early embryonic development in female rats, with no effects observed at a 75 mg/kg dose level. Boceprevir AUC exposures at 75 mg/kg are approximately 1.3-fold higher than those in humans at the recommended dose of 800 mg 3 times daily. Decreased fertility was also observed in male rats, most likely as a consequence of testicular degeneration. No testicular degeneration was observed at 15 mg/kg dose level resulting in boceprevir AUC exposures of less than those in humans at the recommended dose of 800 mg 3 times daily. Testicular degeneration was not observed in mice or monkeys administered boceprevir for 3 months at does of up to 900 or 1000 mg/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 3 times daily(Prod Info VICTRELIS(TM) oral capsules, 2011).
    b) DASABUVIR
    1) In animal studies, no effects on embryofetal viability or fertility were observed when dasabuvir was administered to rats at doses up to 800 mg/kg/day (approximately 16 or 33-fold the human exposure at the recommended clinical dose) (Prod Info VIEKIRA XR(TM) oral extended-release tablets, 2016; Prod Info VIEKIRA PAK oral tablets, 2014).
    c) ELBASVIR/GRAZOPREVIR
    1) In animal studies, no effects on male or female fertility, mating, or early embryonic development were noted at systemic exposures (AUC) up to 114 times the recommended human dose (Prod Info ZEPATIER(TM) oral tablets, 2016).
    d) OMBITASVIR/PARITAPREVIR/RITONAVIR
    1) In animal studies, no effects on embryofetal viability or fertility were observed when ombitasvir was administered to mice at doses up to 200 mg/kg/day (approximately 25-fold the human exposure at the recommended clinical dose) or when paritaprevir/ritonavir was administered to rats at doses up to 300/30 mg/kg/day (approximately 2 to 5-fold the human exposure at the recommended clinical dose for paritaprevir) (Prod Info VIEKIRA XR(TM) oral extended-release tablets, 2016; Prod Info VIEKIRA PAK oral tablets, 2014).
    e) SIMEPREVIR
    1) The effects of simeprevir on human fertility are unknown. Simeprevir treatment alone affected the fertility of 3 male rats in a rat fertility study. Nonmotile sperm, small testes and epididymides, and resulting infertility were observed in 2 of 24 rats treated with simeprevir approximately 0.2 times the mean AUC in humans and 1 of 24 rats who received 10 times that amount (500 mg/kg/day) (Prod Info OLYSIO(R) oral capsules, 2016).
    f) TELAPREVIR
    1) Telaprevir treatment alone had effects on fertility parameters in rats. The no observed adverse effect level for testicular toxicity was established at exposure of 0.17-fold the human exposures at the recommended clinical dose. Potential effects on sperm (eg, decreased percentage of motile sperm and increased nonmotile sperm count) were observed in a rat fertility study at exposures 0.30 fold the human exposures at the recommended clinical dose. Additional effects on fertility include minor increases in percent preimplantation loss, in percent of dams with nonviable embryos and percent of nonviable conceptuses per liter. Effects are most likely due to testicular toxicity; however, female effects cannot be ruled out (Prod Info INCIVEK(TM) film coated oral tablets, 2011).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) SPECIFIC SUBSTANCE
    1) BOCEPREVIR
    a) In animal studies, the use of boceprevir with ribavirin and peginterferon alfa did not result in oncogenic growth in mouse and rat carcinogenicity studies at doses less than the maximum recommended daily human dose; however, ribavirin alone is genotoxic in in vitro and in vivo assays. Two-year carcinogenicity studies with boceprevir alone in mice and rats did not show significant increases in drug-related neoplasms when dosages given were 500 mg/kg in male mice and 650 mg/kg in female mice, and 100 mg/kg in male rats and 125 mg/kg female rats. 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 3 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 3 tomes daily(Prod Info VICTRELIS(TM) oral capsules, 2011).
    2) OMBITASVIR/PARITAPREVIR/RITONAVIR AND DASABUVIR
    a) In a 6-month transgenic mouse study, no carcinogenic effects were observed with ombitasvir, paritaprevir/ritonavir, or dasabuvir at doses up to 150, 300/30, or 2,000 mg/kg/day, respectively. In a 2-year rat study, no carcinogenic effects were observed with paritaprevir/ritonavir at doses up to 300/30 mg/kg/day (approximately 9-fold the human exposure with a 150 mg dose) (Prod Info VIEKIRA PAK oral tablets, 2014)
    3) SIMEPREVIR
    a) Simeprevir has not been tested for carcinogenic potential (Prod Info OLYSIO(TM) oral capsules, 2013).
    4) TELAPREVIR
    a) Telaprevir has not been tested for carcinogenic potential (Prod Info INCIVEK(TM) film coated oral tablets, 2011).

Genotoxicity

    A) Boceprevir, ombitasvir, or dasabuvir were not genotoxic when tested in the in in vitro or in vivo assays, including bacterial mutagenicity, chromosomal aberration in human peripheral blood lymphocytes and mouse micronucleus assays (Prod Info VIEKIRA PAK oral tablets, 2014; Prod Info VICTRELIS(TM) oral capsules, 2011). Paritaprevir was not genotoxic when tested in the in vitro or in vivo assays, including bacterial mutagenicity and mouse micronucleus assays; however, it was positive in an in vitro chromosome aberration test with human lymphocytes (Prod Info VIEKIRA PAK oral tablets, 2014). Simeprevir was not genotoxic in the Ames test, the mammalian forward mutation assay in mouse lymphoma cells, or the in vivo mammalian micronucleus test (Prod Info OLYSIO(TM) oral capsules, 2013). Telaprevir was not genotoxic when tested in the bacterial mutagenicity assays, in vitro mammalian chromosomal aberration assay, or in vitro micronucleus mouse studies(Prod Info INCIVEK(TM) film coated oral tablets, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Obtain a basic metabolic panel and CBC. Monitor for anemia and neutropenia.
    C) Monitor liver enzymes after significant overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant fluid and electrolyte imbalance, anemia or neutropenia should be admitted. Patients with evidence of hepatic insufficiency or failure should be admitted. Patients with severe skin reactions should be admitted to a burn-unit setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with an inadvertent minor ingestion (or 1 or 2 extra doses), or asymptomatic children who inadvertently ingest 1 or 2 pills of a protease inhibitor can be observed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve.

Monitoring

    A) Monitor vital signs.
    B) Obtain a basic metabolic panel and CBC. Monitor for anemia and neutropenia.
    C) Monitor liver enzymes after significant overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) No prehospital decontamination is indicated. Prehospital care should focus on assessment of vital signs and general supportive care.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal may be considered for patients who present early after overdose and are alert and able to maintain their airway. Gastric lavage is not indicated as overdose is not life-threatening.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    2) Supportive care remains the mainstay of severe toxicity.
    3) Blood products may be indicated in patients with significant anemia.
    4) Stevens-Johnson Syndrome or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) should be treated with supportive care and corticosteroids.
    B) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) Obtain a basic metabolic panel, renal function, CBC and liver enzymes after significant overdose.
    C) ANEMIA
    1) Anemia can occur in patients treated with hepatitis C protease inhibitors, in combination with ribavirin and peginterferon alfa. In the case of severe anemia, treatment may require discontinuation of all implicated agents and transfusion of blood products.
    D) NEUTROPENIA
    1) Monitor serial CBC with differential. Discontinue all implicated agents. Consider colony stimulating factors in patients with severe neutropenia. Monitor for infection.
    2) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is unlikely to be useful in the management of overdose with hepatitis C protease inhibitors because of the large volume of distribution (boceprevir and telaprevir) or high protein binding (simeprevir).

Range Of Toxicity

Summary

    A) TOXICITY: BOCEPREVIR: Healthy volunteers were given up to 3600 mg for 5 days without untoward symptomatic effects. TELAPREVIR: The highest documented dose of telaprevir was 1875 mg given every 8 hours for 4 days produced the following adverse effects: nausea, headache, diarrhea, decreased appetite, dysgeusia and vomiting.
    B) THERAPEUTIC DOSE: ADULT: BOCEPREVIR: 800 mg orally 3 times daily (every 7 to 9 hours). SIMEPREVIR: 150 mg orally once daily for 12 or 24 weeks. TELAPREVIR: 1125 mg orally 2 times daily (10 to 14 hours apart). PEDIATRIC: The safety and efficacy of boceprevir, simeprevir, or telaprevir in the pediatric population have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) BOCEPREVIR
    a) 800 mg orally 3 times daily (every 7 to 9 hours) (Prod Info VICTRELIS(TM) oral capsules, 2011).
    2) ELBASVIR/GRAZOPREVIR
    a) 1 tablet (elbasvir 50 mg/grazoprevir 100 mg in each tablet) orally once daily. Duration varies by genotype in patients with or without cirrhosis (Prod Info ZEPATIER(TM) oral tablets, 2016).
    3) OMBITASVIR/PARITAPREVIR/RITONAVIR/DASABUVIR
    a) VIEKIRA PAK(TM) KIT: 2 tablets (ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg in each tablet) orally once every morning plus 1 tablet (dasabuvir 250 mg in each tablet) orally twice daily in the morning and evening. Duration varies by genotype in patients with or without cirrhosis (Prod Info VIEKIRA PAK oral tablets, 2014).
    b) VIEKIRA XR(TM) EXTENDED-RELEASE: 3 tablets (each containing dasabuvir 200 mg, ombitasvir 8.33 mg, paritaprevir 50 mg, and ritonavir 33.33 mg) orally once daily (Prod Info VIEKIRA XR(TM) oral extended-release tablets, 2016)
    4) OMBITASVIR/PARITAPREVIR/RITONAVIR
    a) 2 tablets (ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg) orally once daily for 12 weeks (Prod Info TECHNIVIE(TM) oral tablets, 2015).
    5) OMBITASVIR/PARITAPREVIR/RITONAVIR/RIBAVIRIN
    a) 2 tablets (ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg) orally once daily plus weight-based ribavirin (weight less than 75 kg, 1000 mg daily; weight 75 kg or more, 1200 mg daily; administered in 2 divided doses with food); continue treatment for 12 weeks (Prod Info TECHNIVIE(TM) oral tablets, 2015).
    6) SIMEPREVIR
    a) 150 mg orally once daily for 12 or 24 weeks (Prod Info OLYSIO(R) oral capsules, 2016).
    7) TELAPREVIR
    a) 1125 mg orally 2 times daily (10 to 14 hours apart) (Prod Info INCIVEK(R) oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of boceprevir, elbasvir/grazoprevir, ombitasvir/paritaprevir/ritonavir, dasabuvir, simeprevir, or telaprevir in the pediatric population have not been established (Prod Info VIEKIRA XR(TM) oral extended-release tablets, 2016; Prod Info ZEPATIER(TM) oral tablets, 2016; Prod Info OLYSIO(R) oral capsules, 2016; Prod Info TECHNIVIE(TM) oral tablets, 2015; Prod Info VIEKIRA PAK oral tablets, 2014; Prod Info VICTRELIS(TM) oral capsules, 2011; Prod Info INCIVEK(R) oral tablets, 2013).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) BOCEPREVIR
    a) Healthy volunteers were given up to 3600 mg for 5 days without untoward symptomatic effects (Prod Info VICTRELIS(TM) oral capsules, 2011).
    2) TELAPREVIR
    a) The highest documented dose of telaprevir was 1875 mg given every 8 hours for 4 days produced the following adverse effects: nausea, headache, diarrhea, decreased appetite, dysgeusia and vomiting (Prod Info INCIVEK(TM) film coated oral tablets, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Hepatitis C protease inhibitors specifically inhibit the hepatitis C virus (HCV) NS3/4A protease. Inhibition of serine protease causes a disruption in viral replication by preventing protein cleavage of specific nonstructural proteins NS4A, NS4B, NS5A, and NS5B within the hepatitis C virus. These drugs are to be used in combination with peginterferon alfa and ribavirin, and not as sole therapy for the treatment of Hepatitis C (Prod Info VICTRELIS(TM) oral capsules, 2011; Prod Info INCIVEK(TM) film coated oral tablets, 2011).

Physicochemical

Physical Characteristics

    A) BOCEPREVIR is a white to off-white amorphous powder that is freely soluble in methanol, ethanol, and isopropanol; slightly soluble in water (Prod Info VICTRELIS(R) oral capsules, 2013).
    B) DASABUVIR is a white, pale yellow, or pink powder that is very slightly soluble in methanol and isopropyl alcohol; slightly soluble in water (Prod Info VIEKIRA PAK oral tablets, 2014).
    C) ELBASVIR is very soluble in ethyl acetate and acetone, very slightly soluble in ethanol (0.2 mg/mL), and practically insoluble in water (less than 0.1 mg/mL) (Prod Info ZEPATIER(TM) oral tablets, 2016).
    D) GRAZOPREVIR is freely soluble in ethanol and some organic solvents (eg, acetone, tetrahydrofuran, and N,N-dimethylformamide), and practically insoluble in water (less than 0.1 mg/mL) (Prod Info ZEPATIER(TM) oral tablets, 2016).
    E) OMBITASVIR is a white, light yellow, or light pink powder that is soluble in ethanol and practically insoluble in aqueous buffers (Prod Info VIEKIRA PAK oral tablets, 2014).
    F) PARITAPREVIR is a white to off-white powder that has a very low solubility in water (Prod Info VIEKIRA PAK oral tablets, 2014).
    G) SIMEPREVIR is a white to almost-white powder that is freely soluble in some organic solvents (eg, tetrahydrofuran, N,N-dimethylformamide); soluble in dichloromethane; slightly soluble in acetone; very slightly soluble in ethanol; and practically insoluble in propylene glycol and in water (over wide pH range) (Prod Info OLYSIO(TM) oral capsules, 2013).
    H) TELAPREVIR is a white to off-white powder with a solubility in water of 0.0047 mg/mL (Prod Info INCIVEK(TM) film coated oral tablets, 2011).

Molecular Weight

    A) BOCEPREVIR: 519.7 (Prod Info VICTRELIS(R) oral capsules, 2013)
    B) DASABUVIR SODIUM: 533.57 (Prod Info VIEKIRA PAK oral tablets, 2014)
    C) ELBASVIR: 882.02 (Prod Info ZEPATIER(TM) oral tablets, 2016)
    D) GRAZOPREVIR: 766.9 (Prod Info ZEPATIER(TM) oral tablets, 2016)
    E) OMBITASVIR HYDRATE: 975.2 (Prod Info VIEKIRA PAK oral tablets, 2014)
    F) PARITAPREVIR DIHYDRATE: 801.91 (Prod Info VIEKIRA PAK oral tablets, 2014)
    G) SIMEPREVIR: 749.94 (Prod Info OLYSIO(TM) oral capsules, 2013)
    H) TELAPREVIR: 679.85 (Prod Info INCIVEK(TM) film coated oral tablets, 2011)

References

General Bibliography

    1) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    4) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    5) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    6) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    7) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    8) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    9) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    10) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    11) Product Information: INCIVEK(R) oral tablets, telaprevir oral tablets. Vertex Pharmaceuticals Incorporated (per FDA), Cambridge, MA, 2013.
    12) Product Information: INCIVEK(TM) film coated oral tablets, telaprevir film coated oral tablets. Vertex Pharmaceuticals Incorporated, Cambridge, MA, 2011.
    13) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    14) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    15) Product Information: OLYSIO(R) oral capsules, simeprevir oral capsules. Janssen Therapeutics (per FDA), Titusville, NJ, 2016.
    16) Product Information: OLYSIO(R) oral capsules, simeprevir oral capsules. Janssen Therapeutics (per manufacturer), Titusville, NJ, 2014.
    17) Product Information: OLYSIO(TM) oral capsules, simeprevir oral capsules. Janssen Therapeutics (per manufacturer), Titusville, NJ, 2013.
    18) Product Information: TECHNIVIE(TM) oral tablets, ombitasvir paritaprevir ritonavir oral tablets. AbbVie Inc. (per Manufacturer), North Chicago, IL, 2015.
    19) Product Information: VICTRELIS(R) oral capsules, boceprevir oral capsules. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2013.
    20) Product Information: VICTRELIS(TM) oral capsules, boceprevir oral capsules. Merck & Co, Inc, Whitehouse Station, NJ, 2011.
    21) Product Information: VIEKIRA PAK oral tablets, ombitasvir paritaprevir ritonavir oral tablets and dasabuvir oral tablets. AbbVie Inc. (per manufacturer), North Chicago, Il, 2014.
    22) Product Information: VIEKIRA PAK(R) oral tablets, ombitasvir paritaprevir ritonavir oral tablets, dasabuvir oral tablets. AbbVie Inc (per manufacturer), North Chicago, IL, 2016.
    23) Product Information: VIEKIRA XR(TM) oral extended-release tablets, dasabuvir, ombitasvir, paritaprevir, ritonavir oral extended-release tablets. AbbVie Inc (per FDA), North Chicago, IL, 2016.
    24) Product Information: ZEPATIER(TM) oral tablets, elbasvir, grazoprevir oral tablets. Merck Sharp & Dohme Corp. (per manufacturer), Whitehouse Station, NJ, 2016.
    25) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    26) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.