Incivo

慢性C型肝炎

Incivo®(テラプレビル)は、ペグインターフェロンアルファおよびリバビリンと組み合わせて、肝硬変を含む代償性肝疾患の成人患者、治療歴がない、または以前に治療を受けたことがある遺伝子型1慢性C型肝炎の治療に適応されます以前のヌルレスポンダー、部分レスポンダー、および再発者を含むインターフェロンベースの治療。.

Incivoによる治療を開始するときは、次の点を考慮する必要があります。

• Incivoは単剤療法として投与してはならず、ペグインターフェロンアルファとリバビリンの両方でのみ処方されなければなりません。.
• 以前のヌルレスポンダー(特に肝硬変のレスポンダー)の高い割合は、持続的ウイルス学的応答(SVR)を達成せず、インシボ併用治療による治療でテラプレビル耐性関連の置換が現れました。.
• Incivoまたは他のHCV NS3 / 4Aプロテアーゼ阻害剤を含む治療計画による治療が以前に失敗した患者には、Incivoの有効性は確立されていません。.

インシボ/ペグインターフェロンアルファ/リバビリン併用治療。

Incivoタブレットの推奨用量は、1日2回(10〜14時間間隔で)食物と一緒に経口摂取する1125 mg(3つの375 mgタブレット)です(低脂肪ではありません)。. ペグインターフェロンアルファとリバビリンの具体的な投与方法については、それぞれの処方情報を参照してください。.

治療期間。

Incivoによる治療の推奨期間は、ペグインターフェロンアルファおよびリバビリンと組み合わせて12週間です。. HCV RNAレベルは、4週目と12週目に監視して、併用治療期間を決定し、治療の無益性を評価する必要があります(表1および2)。.

表1:推奨される治療期間(治療能力ルールについては、表2も参照してください)。

4週目と12週目の応答誘導療法の適格性を評価するため。 (表1を参照してください。) 「検出不能」HCV RNA。 (ターゲットは検出されません。) 結果が必要です。; 確認された「検出可能だが定量限界未満」HCV RNAの結果は、「検出不能」HCV RNAと同等と見なされるべきではありません。 (ターゲットは検出されません。) 結果。.

Incivo併用治療の4週目と12週目にHCV RNA(ターゲット未検出)が検出されない肝硬変の治療患者には、さらに36週間のペグインターフェロンアルファとリバビリン(合計48週間)の恩恵を受ける可能性があります。.

線量削減。

治療の失敗を防ぐために、Incivoの用量を減らしたり中断したりしてはなりません。. ペグインターフェロンアルファとリバビリンの用量変更については、それぞれの処方情報を参照してください。.

投与の中止。

ウイルス反応が不十分な患者は、SVRを達成する可能性が低く、治療に伴う耐性の代替を開発する可能性があります。. 治療の中止は、(1)HCV RNAレベルが治療週4または12で1000 IU / mLを超えるすべての患者に推奨されます。または(2)治療週24で検出可能なHCV RNAレベルが確認された(表2を参照)。.

表2:治療効用ルール:すべての患者。

何らかの理由でペグインターフェロンアルファまたはリバビリンが中止された場合、Incivoも中止する必要があります。.

ペグインターフェロンアルファとリバビリンの禁 ⁇ は、インシボ併用治療にも適用されます。.

Incivo併用治療は以下では禁 ⁇ です。

• 妊娠している、または妊娠する可能性のある女性。. リバビリンは、妊婦に投与すると胎児に害を及ぼす可能性があります。. この薬物が妊娠中に使用された場合、または患者がこの薬物治療を受けている間に妊娠した場合、患者は胎児への潜在的な危険を知らされるべきです。.
• 女性パートナーが妊娠している男性。.

IncivoはCYP3Aの強力な阻害剤です。クリアランスをCYP3Aに大きく依存し、血漿濃度の上昇が深刻なおよび/または生命を脅かすイベント(狭い治療指数)に関連している薬物と組み合わせると、Incivoは禁 ⁇ です。. Incivoは、CYP3Aを強く誘発する薬物と組み合わせると禁 ⁇ となり、したがって、曝露が減少し、Incivoの有効性が失われる可能性があります。. 禁 ⁇ 薬は以下の表3にリストされています[参照]。 薬物相互作用。、表5および。

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 Incivo combination treatment. Fatal cases have been reported in patients with progressive rash and systemic symptoms who continued to receive Incivo combination treatment after a serious skin reaction was identified.

For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, Incivo, 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 Incivo 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 Incivo 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 Incivo combination treatment. Rash events led to discontinuation of Incivo alone in 6% of subjects and discontinuation of Incivo 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 Incivo 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, Incivo should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of Incivo 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. Incivo 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 Incivo 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 Incivo dosing. Hemoglobin values gradually returned to levels observed with peginterferon alfa and ribavirin after Incivo dosing was completed. Hemoglobin values less than or equal to 10 g per dL were observed in 36% of subjects who received Incivo 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 Incivo 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 Incivo combination treatment compared to 5% of subjects receiving peginterferon alfa and ribavirin.

In subjects receiving Incivo combination treatment, 32% underwent a ribavirin dose modification (reduction, interruption or discontinuation) due to anemia, 6% received a blood transfusion, 4% discontinued Incivo, and 1% discontinued Incivo 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 Incivo combination treatment.

Hemoglobin should be monitored prior to and at least at weeks 2, 4, 8 and 12 during Incivo 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 Incivo should be considered. If ribavirin is permanently discontinued for the management of anemia, Incivo must also be permanently discontinued. Ribavirin may be restarted per the dosing modification guidelines for ribavirin. The dose of Incivo must not be reduced and Incivo 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 Incivo 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 Incivo dosing and for up to 2 weeks following cessation of Incivo. 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 Incivo 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 Incivo due to potentially life-threatening adverse events or potential loss of therapeutic effect to Incivo. 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

Incivo 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 Incivo.

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 Incivo.

Hepatic Impairment

Incivo 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 Incivo.

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide).

Serious Skin Reactions/Rash

Patients should be informed that Incivo 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 Incivo 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 Incivo must be used in combination with ribavirin and peginterferon alfa, the contraindications and warnings applicable to those drugs are applicable to combination treatment. Incivo 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 Incivo dosing and for up to 2 weeks following cessation of Incivo. 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 Incivo 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 Incivo must be administered in combination with both peginterferon alfa and ribavirin. If peginterferon alfa and/or ribavirin is discontinued for any reason, Incivo must also be discontinued.

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

The recommended dose of Incivo 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 Incivo should be ingested within 30 minutes prior to each Incivo dose. Examples of some foods that could be taken with Incivo 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 Incivo 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 Incivo:

• In case a dose of Incivo is missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of Incivo with food as soon as possible.
• If more than 6 hours has passed since Incivo 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

Incivo /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.

Incivo (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

Incivo /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.

Incivo (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 Incivo 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.

Incivo/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 Incivo. Therefore, 2 alternative effective methods of contraception, including intrauterine devices and barrier methods, should be used in women during treatment with Incivo 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.

Incivo (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.

Hormonal contraceptives may be continued but may not be reliable during Incivo dosing and for up to 2 weeks following cessation of Incivo. 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 Incivo 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 Incivo in pediatric patients have not been established.

Geriatric Use

Clinical trials of Incivo 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 Incivo in geriatric patients reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy.

Hepatic Impairment

Incivo 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 Incivo 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 Incivo.

Renal Impairment

No dose adjustment is necessary for Incivo in HCV-infected patients with mild, moderate or severe renal impairment. Incivo 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). Incivo 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 Incivo.

Liver Transplantation

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

以下の副作用については、ラベルの他のセクションで詳しく説明します。

• 深刻な皮膚反応/発疹。
• 貧血。
• 妊娠:リバビリンとペグインターフェロンアルファと一緒に使用してください。

Incivoはペグインターフェロンアルファとリバビリンと一緒に投与する必要があります。. 関連する副作用については、それぞれの処方情報を参照してください。.

臨床試験の経験。

臨床試験はさまざまな条件下で行われるため、薬物の臨床試験で観察された副作用率は、他の薬物の臨床試験の率と直接比較することはできず、臨床診療で観察された率を反映しない場合があります。.

安全性評価は、インシボ併用治療を受けた1797人の被験者とペグインターフェロンアルファとリバビリンを受けた493人の被験者を含む、プールされた適切で適切に管理された臨床試験のデータに基づいています。.

ペグインターフェロンアルファとリバビリンで治療された被験者のどれとも比較せずに、インシボ併用治療を受けた被験者の3%で深刻な薬物副作用が発生しました。. Incivo併用治療で治療された被験者で最も頻繁に見られる深刻な有害事象は、皮膚疾患(発疹および/またはそう ⁇ )と貧血でした。. 被験者の14%は、薬物副作用のためにIncivoを中止しました。. 発疹、貧血、疲労、 ⁇ 、吐き気、 ⁇ 吐は、Incivoの中止につながる最も頻繁な副作用でした。.

インシボはペグインターフェロンアルファおよびリバビリンと組み合わせて投与されました。. 次の表は、ペグインターフェロンアルファとリバビリンのみを投与された被験者よりも少なくとも5%高い発生率でIncivoで治療された被験者で発生した薬物副作用を示しています(表4)。.

表4:Incivoを投与されている被験者の間で少なくとも5%高い頻度で報告された臨床有害薬物反応。

選択された有害薬物反応の説明。

食欲抑制剤と症状。

対照臨床試験では、インシボ併用治療で治療された被験者の29%が食欲不振の有害事象を経験したのに対し、ペグインターフェロンアルファとリバビリンのみで治療された被験者の7%が経験しました。. これらのイベントの大部分(例:.、 ⁇ 、食欲不振、 ⁇ 門 ⁇ 、直腸 ⁇ 熱傷)は、重症度が軽度から中程度でした。 1%未満が治療の中止につながり、すべてIncivo投与の完了中または完了後に解決しました。.

実験室の異常。

白血球。: ペグインターフェロンアルファによる治療は、総白血球、絶対好中球、および絶対リンパ球数の平均値の減少と関連しています。. Incivoで治療されたより多くの被験者は、リンパ球数の減少が499 /mm³以下でした(5%と比較して15%)。. 白血球総数の減少が1,499 /mm³以下であった(5%に対して8%)。. 好中球絶対数の減少が749 /mm³以下になる発生率は、ペグインターフェロンアルファとリバビリンのみで治療された被験者では15%でしたが、Incivo併用治療で治療された被験者では12%でした。.

血小板。: ペグインターフェロンアルファによる治療は、平均血小板数の減少と関連しています。. Incivo併用治療で治療された患者の数は、すべてのグレードの平均血小板値が47%減少しました。. インシボ併用治療被験者の3%は、ペグインターフェロンアルファとリバビリン単独で治療された患者の1%と比較して、49,999 /mm³以下に減少しました。.

ビリルビン。: ペグインターフェロンアルファとリバビリンで治療された被験者の28%と比較して、インシボで治療された被験者の41%は、ビリルビンレベルのすべてのグレードの上昇を示しました。被験者のそれぞれ4%と2%は、2.6 x ULN以上の上昇を示しました。. ビリルビンレベルは、最初の1〜2週間のインシボ投与中に最も急激に増加し、安定し、12週目と16週目の間にベースラインレベルでした。.

尿酸。: Incivo併用治療期間中、被験者の73%が尿酸値の上昇を示したのに対し、ペグインターフェロンアルファとリバビリンのみで治療された被験者は29%でした。. 尿酸レベルのベースラインから12.1 mg / dL以上のシフトも、ペグインターフェロンアルファおよびリバビリン(1%)と比較して、インシボ(7%)で治療された被験者の間でより頻繁でした。. 痛風/痛風性関節炎の臨床事象があった被験者は1%未満でした。深刻なものはなく、治療の中止に至ったものもありませんでした。.

臨床試験からの追加データ。

追加の研究(試験C211)の分析では、1日2回のIncivo 1125 mgによる併用治療の安全性プロファイルは、8時間ごとにIncivo 750 mgによる併用治療を受けている患者の安全プロファイルと同様でした(q8h)。. 新しい安全に関する所見は確認されていません。.

市販後の経験。

Incivoの承認後の使用中に、以下の副作用が確認されました。. これらの反応は不確実なサイズの集団から自発的に報告されるため、その頻度を確実に推定したり、薬物曝露との因果関係を確立したりすることは常に可能ではありません。.

皮膚および皮下組織障害:。 毒性表皮壊死症(TEN)および多形紅斑(EM)。

腎および尿路障害:。 急性腎不全/障害の有無にかかわらず、腎性アゾチマ、尿酸腎症。

投与された最高記録用量は、Incivoのみの健康な被験者で、8時間ごとに4日間1875 mgです。. その試験では、750 mg q8hレジメンと比較して、1875 mg q8hレジメンで次の一般的な有害事象がより頻繁に報告されました:吐き気、頭痛、下 ⁇ 、食欲低下、味覚異常、 ⁇ 吐。.

Incivoでの過剰摂取に対して特定の解毒剤はありません。. Incivoによる過剰摂取の治療は、バイタルサインのモニタリングや患者の臨床状態の観察などの一般的な支援策で構成されています。. 過剰摂取の場合、胃腸管から吸収されなかった物質を除去する、臨床モニタリングを採用する(心電図の取得を含む)、必要に応じて支持療法を開始するなど、標準的な支援策を採用するのが妥当です。.

テラプレビルが腹膜または血液透析によって透析可能かどうかは不明です。.

ECG評価。

QTc間隔に対するテラプレビル750および1875 mgの効果は、44人の被験者を対象とした二重盲検、二重ダミー、無作為化、プラセボおよびアクティブコントロール(モキシフロキサシン400 mg)の4期クロスオーバー徹底QT試験で評価されました。. 小さな影響を検出する能力を示した試験では、フリデリシア補正法(QTcF)に基づく最大のプラセボ調整ベースライン補正QTcの片側95%信頼区間の上限は、規制のしきい値である10ミリ秒未満でした懸念。. 1875 mgの用量は、高暴露の臨床シナリオを表すのに十分です。.

テラプレビルの薬物動態特性は、健康な成人被験者と慢性C型肝炎の被験者で評価されています。テラプレビルの複数回投与後。 (8時間ごとに750 mg。) 遺伝子型1の慢性C型肝炎の治療歴のない被験者のペグインターフェロンアルファおよびリバビリンとの併用。, 平均。 (SD。) Cmaxは3510でした。 (1280。) ng / mL。, Cminは2030年でした。 (930。) ng / mL。, AUC8hは22,300でした。 (8650。) ng•hr / mL .

テラプレビルの総暴露量(AUC24h、ss)は、2250 mgの1日の総投与量が8時間ごとに750 mgとして投与されたか、1日2回1125 mgとして投与されたかに関係なく、類似していた。.

吸収とバイオアベイラビリティ。

テラプレビルは経口で入手可能であり、おそらく小腸に吸収され、結腸に吸収される証拠はありません。. テラプレビルの単回投与後の最大血漿濃度は、通常4〜5時間後に達成されます。. ヒトCaco-2細胞を用いて行われたin vitro試験では、テラプレビルがP糖タンパク質(P-gp)の基質であることが示されました。. テラプレビルへの曝露は、テラプレビル単独の投与後よりも、ペグインターフェロンアルファとリバビリンの同時投与中に高くなります。.

経口吸収に対する食物の影響。

テラプレビルが空腹時に投与された場合と比較して、テラプレビルが標準的な脂肪食(533 kcalと21 gの脂肪を含む)とともに投与された場合、テラプレビルへの全身曝露(AUC)は237%増加しました。. さらに、食事の種類はテラプレビルへの曝露に大きな影響を与えます。. 空腹時と比較して、テラプレビルが低脂肪食(249 kcal、3.6 g脂肪)と高脂肪食(928 kcal、56 g脂肪)とともに投与された場合、テラプレビルへの全身曝露(AUC)は約117増加しましたそれぞれ%と330%。. インシボの用量は、フェーズ3試験で約20グラムの脂肪を含む食事またはスナックを完了してから30分以内に投与されました。. したがって、Incivoは常に食物と一緒に摂取する必要があります(低脂肪ではありません)。.

分布。

In vitro。、0.1μM(68 ng / mL)〜20μM(13600 ng / mL)の濃度範囲内で、テラプレビルは血漿タンパク質に約59%〜76%結合しています。. テラプレビルは主にアルファ1酸糖タンパク質とアルブミンに結合し、結合は濃度に依存し、テラプレビルの濃度が上昇すると減少します。. 経口投与後、典型的な見かけの分布量(Vd / F)は252 Lと推定され、個人間の変動は72%でした。.

代謝。

テラプレビルは肝臓で広範囲に代謝され、加水分解、酸化、還元を伴います。. ⁇ 便、血漿、尿中に複数の代謝産物が検出されました。. 反復経口投与後、テラプレビル(活性30分の1)、ピラジノ酸、およびテラプレビル(活性ではない)のα-ケトアミド結合で還元された代謝産物のR-ジアステレオマーが、テラプレビルの主要な代謝物であることが判明しました。. 組換えヒトチトクロームP450(CYP)アイソフォームを使用したin vitro試験では、CYP3A4がCYP媒介テラプレビル代謝に関与する主要なアイソフォームであることが示されました。. 組換えアルドケトレダクターゼを使用したin vitro試験では、これらおよび他の可能性のあるレダクターゼもテラプレビルの減少の原因であることが示されました。. 他のタンパク質分解酵素もテラプレビルの加水分解に関与しています。. これらの非CYP媒介代謝経路は、テラプレビルの複数回投与後に主要な役割を果たす可能性があります。.

除去。

750 mgの単回経口投与後。 ¹⁴健康な被験者のC-テラプレビル、総放射能の90%は、投与後96時間以内に ⁇ 便、尿、呼気で回収されました。. 投与された放射性線量の回復の中央値は、 ⁇ 便で約82%、呼気で9%、尿で1%でした。. 変更なしの貢献。 ¹⁴ ⁇ 便で回収された総放射能に対するテラプレビルのCテラプレビルとRジアステレオマーは、それぞれ31.9%と18.8%でした。. 経口投与後、見かけの総クリアランス(Cl / F)は1時間あたり32.4 Lと推定され、個人間の変動は27.2%でした。. テラプレビル750 mgの単回投与経口投与後の平均排出半減期は、通常約4.0〜4.7時間の範囲でした。. 定常状態では、有効半減期は約9〜11時間です。.