Incivek

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Serious Skin Reactions/Rash

Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with INCIVEK combination treatment. Fatal cases have been reported in patients with progressive rash and systemic symptoms who continued to receive INCIVEK combination treatment after a serious skin reaction was identified.

For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must be discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients should be promptly referred for urgent medical care.

In clinical trials, serious skin reactions, including DRESS and 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 subjects recovered. The presenting signs of DRESS may include rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). 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).

TEN and Erythema Multiforme (EM) have been observed in post-marketing experience. Rash events (all grades) developed in 56% of subjects who received INCIVEK combination treatment and in 34% of subjects who received peginterferon alfa and ribavirin. Rash most frequently began during the first 4 weeks, but could occur at any time during INCIVEK combination treatment. Rash events led to discontinuation of INCIVEK alone in 6% of subjects and discontinuation of INCIVEK combination treatment in 1% of subjects. Severe rash (e.g., a generalized rash or rash with 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, 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.

Anemia

Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of INCIVEK to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. A decrease in hemoglobin levels occurred during the first 4 weeks of treatment, with 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. Hemoglobin values less than or equal to 10 g per dL were observed in 36% of subjects who received INCIVEK combination treatment compared to 17% of subjects who received peginterferon alfa and ribavirin. In clinical trials, the median time to onset of hemoglobin less than or equal to 10 g per dL was faster among subjects treated with INCIVEK combination treatment compared to those who received peginterferon alfa and ribavirin: 56 days (range 8-365 days) versus 63 days (range 13-341 days), respectively. Hemoglobin values less than 8.5 g per 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, 32% underwent a ribavirin dose modification (reduction, interruption or discontinuation) due to anemia, 6% received a blood transfusion, 4% discontinued INCIVEK, and 1% discontinued INCIVEK combination treatment. In subjects treated with peginterferon alfa and ribavirin alone, 12% underwent ribavirin dose modification due to anemia, 1% received a blood transfusion, and fewer than 1% discontinued treatment. Anemia requiring ribavirin dose reduction, blood transfusion, and/or erythropoiesis stimulating agent (ESA) has been reported to occur as soon as 10 days following initiation of INCIVEK combination treatment.

Hemoglobin should be monitored prior to and at least at weeks 2, 4, 8 and 12 during INCIVEK combination treatment and as clinically appropriate. Earlier and more frequent monitoring for some patients should be considered. 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 anemia, INCIVEK must also be permanently discontinued. Ribavirin may be restarted per the dosing modification guidelines for ribavirin. The dose of INCIVEK must not be reduced and INCIVEK must not be restarted if discontinued.

Pregnancy: Use with Ribavirin and Peginterferon Alfa

Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

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 have been demonstrated in all animal species exposed to ribavirin. Refer also to the prescribing information for ribavirin.

Female Patients

Hormonal contraceptives may be continued but may not be reliable during INCIVEK dosing and for up to 2 weeks following cessation of INCIVEK. During this time, female patients of childbearing potential should use 2 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 2 required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives.

Drug Interactions

See Table 3 for a listing of drugs that are contraindicated for use with INCIVEK due to potentially life-threatening adverse events or potential loss of therapeutic effect to INCIVEK. Refer to Table 5 for established and other potentially significant drug-drug interactions.

Laboratory Tests

HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated. Use of a sensitive real-time RT-PCR assay for monitoring HCV RNA levels during treatment is recommended. The assay should have a lower limit of HCV RNA quantification equal to or less than 25 IU per mL and a limit of HCV RNA detection of approximately 10-15 IU per mL. For the purpose of assessing response-guided therapy eligibility, an “undetectable” HCV RNA (Target Not Detected) result is required; a confirmed “detectable but below limit of quantification” HCV RNA result should not be considered equivalent to an “undetectable” HCV RNA result (reported as “Target Not Detected” or “HCV RNA Not Detected”).

Hematology evaluations (including hemoglobin, white cell differential, and platelet count) are recommended prior to and at weeks 2, 4, 8 and 12 and as clinically appropriate. Chemistry evaluations (including electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, and TSH) are recommended as frequently as hematology evaluations or as clinically appropriate.

Refer to the prescribing information for peginterferon alfa and ribavirin, 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.

There are no clinical data on re-treating patients who have failed an HCV NS3/4A protease inhibitor-based treatment, nor are there data on repeated courses of INCIVEK.

Hepatic Impairment

INCIVEK is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) or patients with decompensated liver disease. Refer to prescribing information for peginterferon alfa and ribavirin which must be co-administered with INCIVEK .

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide).

Serious Skin Reactions/Rash

Patients should be informed that INCIVEK combination treatment may cause rash. The rash can be serious, may be accompanied by fever and skin breakdown, may require urgent treatment in a hospital, and may result in death. Patients should promptly report any skin changes or itching to their healthcare provider. Patients should not stop INCIVEK due to rash unless instructed by their healthcare provider.

Pregnancy

Ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Ribavirin therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. Because INCIVEK must be used in combination with ribavirin and peginterferon alfa, the contraindications and warnings applicable to those drugs are applicable to combination treatment. INCIVEK combination treatment is contraindicated in women who are pregnant and in men whose female partners are pregnant (see also the prescribing information for ribavirin).

Patients must be advised of the teratogenic/embryocidal risks of ribavirin and should be advised that extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients—both during treatment and for 6 months after the completion of all treatment. Women of childbearing potential must be counseled about use of effective contraception (2 methods) prior to initiating treatment. Patients (both male and female) should be advised to notify their healthcare provider immediately in the event of a pregnancy.

Patients should also be advised that hormonal contraceptives may not be reliable during INCIVEK dosing and for up to 2 weeks following cessation of INCIVEK. During this time, female patients of childbearing potential should use 2 non-hormonal methods of effective birth control. Examples of non-hormonal methods of contraception include a male condom with spermicidal jelly OR female condom with spermicidal jelly (a combination of a male condom and a female condom is not suitable), a diaphragm with spermicidal jelly, a cervical cap with spermicidal jelly, or an intrauterine device (IUD).

Hepatitis C Virus Transmission

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

Importance of Hydration

Patients should be informed about the importance of hydration and fluid intake during INCIVEK combination treatment. Patients should be instructed to recognize the signs and symptoms of dehydration such as increased thirst, dry mouth, decreased urine output, and more concentrated urine. Patients should be advised to contact their healthcare provider if oral fluid intake is poor or if the patient is experiencing severe vomiting and/or diarrhea.

Administration

Patients should be advised INCIVEK must be administered in combination with both peginterferon alfa and ribavirin. If peginterferon alfa and/or ribavirin is discontinued for any reason, INCIVEK must also be discontinued.

Patients should be advised that the dose of INCIVEK must not be reduced or interrupted, as it may increase the possibility of treatment failure.

The recommended dose of INCIVEK tablets is 1125 mg (three 375-mg tablets) taken orally twice daily (10-14 hours apart) with food containing approximately 20 grams of fat. Patients should be advised that the fat content of the meal or snack is critical for the absorption of telaprevir. Food that is taken with INCIVEK should be ingested within 30 minutes prior to each INCIVEK dose. Examples of some foods that could be taken with INCIVEK include: a bagel with cream cheese, ½ cup nuts, 3 tablespoons peanut butter, 1 cup ice cream, 2 ounces American or cheddar cheese, 2 ounces potato chips, or ½ cup trail mix.

Patients should be instructed to swallow INCIVEK tablets whole (e.g., patients should not chew, crush, break, cut, or dissolve the tablets).

Patients should be informed about what to do in the event they miss a dose of INCIVEK:

• In case a dose of INCIVEK is missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of INCIVEK with food as soon as possible.
• If more than 6 hours has passed since INCIVEK is usually taken, the missed dose should NOT be taken and the patient should resume the usual dosing schedule.
• Patients should be advised to contact their healthcare provider if they have questions.

Patients should be advised that they can contact the local Poison Control Center in the event of an overdose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

INCIVEK /Peginterferon Alfa/Ribavirin Combination Treatment

Ribavirin was shown to be genotoxic in several in vitro and in vivo assays. Ribavirin was not oncogenic in a 6-month p53+/-transgenic mouse study or a 2-year carcinogenicity study in rat. See the prescribing information for ribavirin.

INCIVEK (telaprevir) Tablets

Evidence of genotoxicity was not observed in a bacterial mutagenicity assay, in vitro mammalian chromosomal aberration assay, or in vivo micronucleus study in mouse. Telaprevir has not been tested for its carcinogenic potential.

Impairment of Fertility

INCIVEK /Peginterferon Alfa/Ribavirin Combination Treatment

Animal studies have shown that ribavirin induced reversible toxicity in males while peginterferon alfa may impair female fertility. See the prescribing information for ribavirin and peginterferon alfa.

INCIVEK (telaprevir) Tablets

Telaprevir treatment alone had effects on fertility parameters in rats. The no observed adverse effect level (NOAEL) for degenerative testicular toxicity was established at exposures 0.17-fold the human exposures at the recommended clinical dose. Potential effects on sperm (e.g., decreased % motile sperm and increased non-motile 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, the percent of dams with nonviable embryos and percent of nonviable conceptuses per litter. These effects are likely associated with testicular toxicity in male rats but contributions of the female cannot be ruled out. Degenerative testicular toxicity was not observed in chronic toxicity studies in the dog. Furthermore, mean changes in proposed hormonal biomarkers of testicular toxicity among subjects who received telaprevir were comparable to placebo.

Use In Specific Populations

Pregnancy

Because INCIVEK must be used in combination with ribavirin and peginterferon alfa, the contraindications and warnings applicable to those drugs are applicable to combination treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients.

INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment

Pregnancy Category X

Animal studies have shown that ribavirin causes birth defects and/or fetal deaths while peginterferon alfa is abortifacient. See the prescribing information for ribavirin.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans (see peginterferon alfa prescribing information).

Extreme caution must be taken to avoid 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. Systemic hormonal contraceptives may not be as effective in women while taking INCIVEK. Therefore, 2 alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with INCIVEK and concomitant ribavirin.

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.

INCIVEK (telaprevir) Tablets

Pregnancy Category B

Telaprevir treatment alone in mice and rats did not result in harm to the fetus. The highest doses tested produced exposures equal to 1.84-and 0.60-fold the exposures in humans at the recommended clinical dose, respectively. Telaprevir treatment alone had effects on fertility parameters in rats. The no observed adverse effect level (NOAEL) for testicular toxicity was established at exposures 0.17-fold the human exposures at the recommended clinical dose. Potential effects on sperm (e.g., decreased % motile sperm and increased non-motile 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 litter. These effects are likely associated with testicular toxicity in male but contributions of the female cannot be ruled out. There are, however, no adequate and well-controlled trials in pregnant women.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients—both during treatment and for 6 months after the completion of all treatment. INCIVEK combination treatment should not be started unless a female patient has a negative pregnancy test immediately prior to initiation of treatment. Pregnancy testing should occur monthly during INCIVEK combination treatment and for 6 months after all treatment has ended. Pregnancy testing in non-pregnant female partners is recommended before INCIVEK combination therapy, every month during INCIVEK combination therapy, and for 6 months after ribavirin therapy has ended.

Hormonal contraceptives may be continued but may not be reliable during INCIVEK dosing and for up to 2 weeks following cessation of INCIVEK. During this time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception. Examples may include barrier methods or IUDs. Refer also to the prescribing information for ribavirin.

Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the 2 required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives. Refer also to the prescribing information for ribavirin.

Nursing Mothers

It is not known whether 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 initiation of treatment. See also the prescribing information for ribavirin.

Pediatric Use

The safety, efficacy and pharmacokinetic profile of INCIVEK in pediatric patients have not been established.

Geriatric Use

Clinical trials of INCIVEK did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of INCIVEK in geriatric patients reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy.

Hepatic Impairment

INCIVEK is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) because appropriate doses have not been established. No dose adjustment of INCIVEK is necessary for patients with mild hepatic impairment (Child-Pugh A, score 5-6). Refer also to the prescribing information for peginterferon alfa and ribavirin which must be co-administered with INCIVEK.

Renal Impairment

No dose adjustment is necessary for INCIVEK in HCV-infected patients with mild, moderate or severe renal impairment. INCIVEK has not been studied in HCV-infected patients with CrCl less than or equal to 50 mL per min.

The pharmacokinetics of telaprevir were assessed after administration of a single dose of 750 mg to HCV-negative subjects with severe renal impairment (CrCl less than 30 mL per min). INCIVEK has not been studied in subjects with end-stage renal disease (ESRD) or on hemodialysis. Refer also to the prescribing information for peginterferon alfa and ribavirin which must be co-administered with INCIVEK.

Liver Transplantation

The safety and efficacy of INCIVEK have not been established in liver transplant patients.

See Table 3 for a listing of drugs that are contraindicated for use with INCIVEK due to potentially life-threatening adverse events or potential loss of therapeutic effect to INCIVEK. Refer to Table 5 for established and other potentially significant drug-drug interactions.

Because INCIVEK must be used in combination with ribavirin and peginterferon alfa, the contraindications and warnings applicable to those drugs are applicable to combination treatment. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients.

INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment

Pregnancy Category X

Animal studies have shown that ribavirin causes birth defects and/or fetal deaths while peginterferon alfa is abortifacient. See the prescribing information for ribavirin.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans (see peginterferon alfa prescribing information).

Extreme caution must be taken to avoid 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. Systemic hormonal contraceptives may not be as effective in women while taking INCIVEK. Therefore, 2 alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with INCIVEK and concomitant ribavirin.

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.

INCIVEK (telaprevir) Tablets

Pregnancy Category B

Telaprevir treatment alone in mice and rats did not result in harm to the fetus. The highest doses tested produced exposures equal to 1.84-and 0.60-fold the exposures in humans at the recommended clinical dose, respectively. Telaprevir treatment alone had effects on fertility parameters in rats. The no observed adverse effect level (NOAEL) for testicular toxicity was established at exposures 0.17-fold the human exposures at the recommended clinical dose. Potential effects on sperm (e.g., decreased % motile sperm and increased non-motile 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 litter. These effects are likely associated with testicular toxicity in male but contributions of the female cannot be ruled out. There are, however, no adequate and well-controlled trials in pregnant women.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients—both during treatment and for 6 months after the completion of all treatment. INCIVEK combination treatment should not be started unless a female patient has a negative pregnancy test immediately prior to initiation of treatment. Pregnancy testing should occur monthly during INCIVEK combination treatment and for 6 months after all treatment has ended. Pregnancy testing in non-pregnant female partners is recommended before INCIVEK combination therapy, every month during INCIVEK combination therapy, and for 6 months after ribavirin therapy has ended.

Hormonal contraceptives may be continued but may not be reliable during INCIVEK dosing and for up to 2 weeks following cessation of INCIVEK. During this time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception. Examples may include barrier methods or IUDs. Refer also to the prescribing information for ribavirin.

Two weeks after completion of INCIVEK treatment, hormonal contraceptives are again appropriate as one of the 2 required effective methods of birth control; however, specific prescribing information recommendations should be followed for the contraceptives. Refer also to the prescribing information for ribavirin.

The following adverse reactions are discussed in greater detail in other sections of the label:

• Serious Skin Reactions/Rash
• Anemia
• Pregnancy: Use with Ribavirin and Peginterferon alfa

INCIVEK must be administered with peginterferon alfa and ribavirin. Refer to their respective prescribing information for their associated adverse reactions.

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 reactions. Rash, anemia, fatigue, pruritus, nausea, and vomiting were the most frequent adverse drug reactions leading to discontinuation of INCIVEK.

INCIVEK was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactions that occurred in subjects treated with INCIVEK with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone (Table 4).

Table 4: Clinical Adverse Drug Reactions Reported with at Least 5% Higher Frequency Among Subjects Receiving INCIVEK

Description of Selected Adverse Drug Reactions

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.

Laboratory abnormalities

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 subjects treated with INCIVEK 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 subjects treated with INCIVEK 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 per 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.

Additional Data from Clinical Trials

In the analysis of an additional study (Trial C211), the safety profile of combination treatment with INCIVEK 1125 mg twice daily was similar to the safety profile for patients receiving combination treatment with INCIVEK 750 mg every 8 hours (q8h). No new safety findings were identified.

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of INCIVEK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders: Toxic Epidermal Necrolysis (TEN) and Erythema Multiforme (EM)

Renal and Urinary Disorders: Pre-renal azotemia with or without acute renal insufficiency/failure, uric acid nephropathy

The highest documented dose administered is 1875 mg every 8 hours for 4 days in healthy subjects with INCIVEK alone. In that trial, the following common adverse events were reported more frequently with the 1875 mg q8h regimen compared to the 750 mg q8h regimen: nausea, headache, diarrhea, decreased appetite, dysgeusia, and vomiting.

No specific antidote is available for overdose with INCIVEK. Treatment of overdose with INCIVEK consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. In the event of an overdose, it is reasonable to employ the standard supportive measures, such as removing unabsorbed material from the gastrointestinal tract, employing clinical monitoring (including obtaining an electrocardiogram), and instituting supportive therapy if required.

It is not known whether telaprevir is dialyzable by peritoneal or hemodialysis.

ECG Evaluation

The effect of telaprevir 750 and 1875 mg on QTc interval was evaluated in a double-blind, double-dummy, randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 44 subjects. In the trial with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia correction method (QTcF) was below 10 ms, the threshold for regulatory concern. The dose of 1875 mg is adequate to represent the high exposure clinical scenario.

The pharmacokinetic properties of telaprevir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following multiple doses of telaprevir (750 mg every 8 hours) in combination with peginterferon alfa and ribavirin in treatment-naïve subjects with genotype 1 chronic hepatitis C, mean (SD) Cmax was 3510 (1280) ng/mL, Cmin was 2030 (930) ng/mL, and AUC8h was 22,300 (8650) ng•hr/mL.

Telaprevir total exposure (AUC24h,ss) was similar regardless of whether the total daily dose of 2250 mg was administered as 750 mg every 8 hours or 1125 mg twice daily.

Absorption and Bioavailability

Telaprevir is orally available, most likely absorbed in the small intestine, with no evidence for absorption in the colon. Maximum plasma concentrations after a single dose of telaprevir are generally achieved after 4 to 5 hours. In vitro studies performed with human Caco-2 cells indicated that telaprevir is a substrate of P-glycoprotein (P-gp). Exposure to telaprevir is higher during co-administration of peginterferon alfa and ribavirin than after administration of telaprevir alone.

Effects of Food on Oral Absorption

The systemic exposure (AUC) to telaprevir was increased by 237% when telaprevir was administered with a standard fat meal (containing 533 kcal and 21 g fat) compared to when telaprevir was administered under fasting conditions. In addition, the type of meal significantly affects exposure to telaprevir. Relative to fasting, when telaprevir was administered with a low-fat meal (249 kcal, 3.6 g fat) and a high-fat meal (928 kcal, 56 g fat), the systemic exposure (AUC) to telaprevir was increased by approximately 117% and 330%, respectively. Doses of INCIVEK were administered within 30 minutes of completing a meal or snack containing approximately 20 grams of fat in the Phase 3 trials. Therefore, INCIVEK should always be taken with food (not low fat).

Distribution

In vitro, within a concentration range of 0.1 μM (68 ng per mL) to 20 μM (13600 ng per mL), telaprevir is approximately 59% to 76% bound to plasma proteins. Telaprevir binds primarily to alpha 1-acid glycoprotein and albumin and the binding is concentration dependent, decreasing with increasing concentrations of telaprevir. After oral administration, the typical apparent volume of distribution (Vd/F) was estimated to be 252 L, with an inter-individual variability of 72%.

Metabolism

Telaprevir is extensively metabolized in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in feces, plasma, and urine. After repeated-oral administration, the R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the α-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir. In vitro studies using recombinant human cytochrome P450 (CYP) isoforms indicated that CYP3A4 was the major isoform responsible for CYP-mediated telaprevir metabolism. In vitro studies using recombinant aldo-ketoreductases indicated that these and potentially other reductases are also responsible for the reduction of telaprevir. Other proteolytic enzymes are also involved in the hydrolysis of telaprevir. These non-CYP mediated pathways of metabolism likely play a major role after multiple dosing of telaprevir.

Elimination

Following administration of a single oral dose of 750 mg ¹⁴C-telaprevir in healthy subjects, 90% of total radioactivity was recovered in feces, urine and expired air within 96 hours post-dose. The median recovery of the administered radioactive dose was approximately 82% in the feces, 9% in exhaled air and 1% in urine. The contribution of unchanged ¹⁴C-telaprevir and the R-diastereomer of telaprevir towards total radioactivity recovered in feces was 31.9% and 18.8%, respectively. After oral administration, the apparent total clearance (Cl/F) was estimated to be 32.4 L per hour with an inter-individual variability of 27.2%. The mean elimination half-life after single-dose oral administration of telaprevir 750 mg typically ranged from about 4.0 to 4.7 hours. At steady state, the effective half-life is about 9 to 11 hours.