Brief Summary of Prescribing Information. See package insert for full prescribing information.
INDICATIONS AND USAGE
INCIVEKTM (telaprevir), in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in
adult patients with compensated liver disease, including cirrhosis, who are treatment-naïve or who have previously been treated with
interferon-based treatment, including prior null responders, partial responders, and relapsers.
The following points should be considered when initiating treatment with INCIVEK:
t; */$* 7&,;must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin.
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had telaprevir resistance–associated substitutions emerge on treatment with INCIVEK combination treatment.
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Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment.
INCIVEK combination treatment is contraindicated in:
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during pregnancy, or if the patient becomes pregnant while taking this drug treatment, the patient should be apprised of the potential
hazard to a fetus.
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concentrations are associated with serious and/or life-threatening events (narro w therapeutic index). INCIVEK is contraindicated when
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are listed below.
Drugs that are Contraindicated with INCIVEK
Drug Class Drugs within Class that are
Contraindicated with INCIVEK
Potential for hypotension or cardiac arrhythmia
Ergot derivatives Dihydroergotamine, ergonovine,
Potential for acute ergot toxicity characterized
by peripheral vasospasm or ischemia
Potential for cardiac arrhythmias
Herbal products St. John's wort
Plasma concentrations of telaprevir can be
reduced by concomitant use of the herbal
preparation St. John’s wort.
).(;$P";SFEVDUBTF;JOIJCJUPST Potential for myopathy including rhabdomyolysis
Neuroleptic Potential for serious and/or life-threatening
adverse reactions such as cardiac arrhythmias
secondary to increases in plasma concentrations
PDE5 inhibitor 4JMEFOBGJM;;3FWBUJP®) or tadalafil
"EDJSDB®) [for treatment of pulmonary
Potential for PDE5 inhibitor-associated
adverse events, including visual abnormalities,
hypotension, prolonged erection, and syncope
Sedatives/hypnotics Orally administered midazolamb,
Prolonged or increased sedation or respiratory
a See table under Drug Interactions for co-administration of sildenafil and tadalafil when dosed for erectile dysfunction.
b See table under Drug Interactions for parenterally administered midazolam.
WARNINGS AND PRECAUTIONS
Pregnancy: Use with Ribavirin and Peginterferon Alfa.;3JCBWJSJO;NBZ;DBVTF;CJSUI;EFGFDUT;BOE;PS;EFBUI;PG;UIF;FYQPTFE;GFUVT;;&YUSFNF;DBSF;
a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.
Because INCIVEK must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those
drugs are applicable to combination therapy. Female patients of childbearing potential and their male partners as well as male patients and
their female partners must use 2 effective contraceptive methods during treatment and for 6 months after all treatment has ended. Female
patients should have monthly pregnancy tests during treatment and during the 6-month period after stopping treatment. Extreme care must
be taken to avoid pregnancy in female patients and in female partners of male patients as significant teratogenic and/or embryocidal effects
Female Patients-Hormonal contraceptives may be continued but may not be reliable during INCIVEK dosing and for up to two weeks following
cessation of INCIVEK. During this time, female patients of childbearing potential should use two effective non-hormonal methods of
contraception. Examples may include barrier methods or intrauterine devices (IUDs). Two weeks after completion of INCIVEK treatment,
hormonal contraceptives are again appropriate as one of the two required effective methods of birth control; however, specific prescribing
information recommendations should be followed for the contraceptives.
Serious Skin Reactions. ;4FSJPVT; TLJO;SFBDUJPOT;;JODMVEJOH;%SVH;3BTI;XJUI;&PTJOPQIJMJB;BOE;4ZTUFNJD;4ZNQUPNT;;% 3& 44;;BOE;4UFWFOT;
Johnson Syndrome (SJS) were reported in less than 1% of subjects who received INCIVEK combination treatment compared to none who
received peginterferon alfa and ribavirin alone. These serious skin reactions required hospitalization, and all patients recovered. The
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Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations
(e.g., conjunctivae, lips).
If a serious skin reaction occurs, all components of INCIVEK combination treatment must be discontinued immediately and the patient should
be promptly referred for urgent medical care.
Rash. ;3BTI;EFWFMPQFE;JO;;;;;PG; TVCKFDUT;XIP;SFDFJWFE;*/$* 7&,;DPNCJOBUJPO;USFBUNFOU;;4FWFSF;SBTI;;F;H;;;B;HFOFSBMJ[FE;SBTI;PS;SBTI;XJUI;
vesicles or bullae or ulcerations other than SJS) was reported in 4% of subjects who received INCIVEK combination treatment compared to
less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a prominent eczematous component.
Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses
and becomes severe or if systemic symptoms develop, INCIVEK should be discontinued. Peginterferon alfa and ribavirin may be continued.
If improvement is not observed within 7 days of INCIVEK discontinuation, sequential or simultaneous interruption or discontinuation of
ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and
peginterferon alfa should be considered. Patients should be monitored until the rash has resolved. INCIVEK must not be reduced or restarted
if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but
effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended.
is associated with an additional decrease in hemoglobin concentrations. Hemoglobin values less than or equal to 10 g/dL were observed in
36% of subjects who received INCIVEK combination treatment compared to 17% of subjects who received peginterferon alfa and ribavirin.
Hemoglobin values less than 8. 5 g/dL were observed in 14% of subjects who received INCIVEK combination treatment compared to 5% of
subjects receiving peginterferon alfa and ribavirin.
In subjects receiving INCIVEK combination treatment, 4% discontinued INCIVEK, 1% discontinued INCIVEK combination treatment, and 32%
underwent a ribavirin dose modification (reduction, interruption or discontinuation) due to anemia. In subjects treated with peginterferon alfa
and ribavirin alone, there were two discontinuations and 12% underwent ribavirin dose modification due to anemia.
Hemoglobin should be monitored prior to and at least every 4 weeks during INCIVEK combination treatment. For the management of anemia,
ribavirin dose reductions should be used (refer to the prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose
reductions are inadequate, discontinuation of INCIVEK should be considered. If ribavirin is permanently discontinued for the management of
dose of INCIVEK must not be reduced and INCIVEK must not be restarted if discontinued.
Drug Interactions. See the table above for a listing of drugs that are contraindicated for use with INCIVEK due to potentially life-threatening
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potentially significant drug-drug interactions.
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Hematology evaluations (including white cell differential count) are recommended at weeks 2, 4, 8 and 12 or as clinically appropriate
thereafter. Chemistry evaluations (electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, and TSH) are recommended as
including pregnancy testing requirements.
General. INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin.
Therefore, the prescribing information for peginterferon alfa and ribavirin must be consulted before starting treatment with INCIVEK.
repeated courses of INCIVEK.
Hepatic Impairment. INCIVEK is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score
which must be co-administered with INCIVEK.
The following adverse reactions are discussed in greater detail in other sections of the label:
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot
be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety assessment is based on data from pooled adequate and well-controlled clinical trials including 1797 subjects who received
INCIVEK combination treatment and 493 who received peginterferon alfa and ribavirin.
Serious adverse drug reactions occurred in 3% of subjects who received INCIVEK combination treatment compared to none of the subjects
treated with peginterferon alfa and ribavirin. The most frequent serious adverse events in subjects treated with INCIVEK combination
treatment were skin disorders (rash and/or pruritus) and anemia. Fourteen percent of subjects discontinued INCIVEK due to adverse drug
INCIVEK was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactions that occurred
in INCIVEK-treated subjects with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone.
Clinical Adverse Drug Reactions Reported with at Least 5% Higher Frequency Among Subjects Receiving INCIVEK
INCIVEK, peginterferon alfa, and ribavirin
Peginterferon alfa and ribavirin
Fatigue 56% 50%
Pruritus 47% 28%
Nausea 39% 28%
Diarrhea 26% 17%
Vomiting 13% 8%
Hemorrhoids 12% 3%
"OPSFDUBM;EJTDPNGPSU 11% 3%
Dysgeusia 10% 3%
"OBM;QSVSJUVT 6% 1%
Description of Selected Adverse Drug Reactions
Rash. In controlled clinical trials, rash events (all grades) were reported in 56% of subjects who received INCIVEK combination treatment and
any time during INCIVEK combination treatment. Improvement of rash occurs after INCIVEK dosing completion or discontinuation; however,
rashes may take weeks for complete resolution.
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Anemia. In controlled clinical trials, the overall incidence and severity of anemia increased with INCIVEK combination treatment compared
to peginterferon alfa and ribavirin alone. The incidence of anemia adverse events was 36% with INCIVEK combination treatment compared
lowest values reached at the end of INCIVEK dosing. Hemoglobin values gradually returned to levels observed with peginterferon alfa and
ribavirin after INCIVEK dosing was completed.
Anorectal Signs and Symptoms. In the controlled clinical trials, 29% of subjects treated with INCIVEK combination treatment experienced
anorectal adverse events, compared to 7% of those treated with peginterferon alfa and ribavirin alone. The majority of these events (e.g.,
hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate in severity; less than 1% led to treatment
discontinuation and all resolved during or after completion of INCIVEK dosing.
White Blood Cells: Treatment with peginterferon alfa is associated with decreases in mean values for total white blood cell, absolute
neutrophil, and absolute lymphocyte count. More INCIVEK-treated subjects had decreases in lymphocyte counts to 499/mm3 or less (15%
compared to 5%). Decreases in total white cell counts to 1,499/mm3 or less were comparable (8% compared to 5%). The incidence of
decreases in absolute neutrophil counts to 749/mm3 or less was 15% in subjects treated with peginterferon alfa and ribavirin alone
compared to 12% among those treated with INCIVEK combination treatment.
Platelets: Treatment with peginterferon alfa is associated with decreases in mean platelet counts. More patients treated with INCIVEK
combination treatment had decreases in mean platelet values of all grades: 47% compared to 36% treated with peginterferon alfa and
ribavirin alone. Three percent of INCIVEK combination treatment subjects had decreases to 49,999/mm3 or less compared to 1% of those
treated with peginterferon alfa and ribavirin-treated alone.
Bilirubin: Forty one percent of INCIVEK-treated subjects compared to 28% of peginterferon alfa and ribavirin-treated subjects had all grade
elevations in bilirubin levels; 4% and 2% of subjects, respectively, had greater than or equal to 2. 6 x ULN elevations. Bilirubin levels increased
most steeply during the first 1 to 2 weeks of INCIVEK dosing, stabilized and between Weeks 12 and 16 were at baseline levels.
Uric Acid: During the INCIVEK combination treatment period, 73% of subjects had elevated uric acid levels compared to 29% for those treated
with peginterferon alfa and ribavirin alone. Shifts to greater than or equal to 12.1 mg/dL from baseline in uric acid levels were also more
frequent among subjects treated with INCIVEK (7%) compared to peginterferon alfa and ribavirin (1%). Less than 1% of subjects had clinical
events of gout/gouty arthritis; none were serious and none resulted in treatment discontinuation.
DRUG INTERAC TIONS
Potential for INCIVEK to Affect Other Drugs
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plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions. INCIVEK is also an
inhibitor of P-gp. Co-administration of INCIVEK with drugs that are substrates for P-gp transport may result in increased plasma
concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse reactions. If dose adjustments
of concomitant medications are made during INCIVEK treatment, they should be re-adjusted after administration of INCIVEK
Potential for Other Drugs to Affect INCIVEK
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Established and Other Potentially Significant Drug Interactions
The table below provides effect of concentration of INCIVEK or concomitant drug with INCIVEK. These recommendations are based on either
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adverse events or loss of efficacy.
Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on
Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class:
Effect on concentration
of INCIVEK or
Co-administration with telaprevir has the potential to produce serious and/
or life-threatening adverse events and has not been studied. Caution is
warranted and clinical monitoring is recommended when co-administered
Concentrations of both telaprevir and the antibacterial may be increased
during co-administration. Caution is warranted and clinical monitoring
is recommended when co-administered with telaprevir. QT interval
prolongation and Torsade de Pointes have been reported with
clarithromycin and erythromycin. QT interval prolongation has been
reported with telithromycin.
Concentrations of warfarin may be altered when co-administered with
when warfarin is co-administered with telaprevir.
Concentrations of the anticonvulsant may be altered and concentrations
of telaprevir may be decreased. Caution should be used when prescribing
carbamazepine, phenobarbital, and phenytoin.
Telaprevir may be less effective in patients taking these agents
Clinical or laboratory monitoring of carbamazepine, phenobarbital, and
phenytoin concentrations and dose titration are recommended to achieve
the desired clinical response.
Concentrations of escitalopram were decreased when co-administered
with telaprevir. Selective serotonin reuptake inhibitors such as
escitalopram have a wide therapeutic index, but doses may need to
be adjusted when combined with telaprevir.