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Oliinyk Elizabeth Ivanovna 、薬局による医学的評価、 最終更新日:16.03.2022
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活動性肺結核。
⁇ ентакокс®(リファペンチン)は、結核菌によって引き起こされる活動性肺結核(TB)の治療のために12歳以上の成人と子供に適応されます。. ⁇ ентакоксは、分離株が感受性のある1つ以上の抗結核薬(抗TB)と組み合わせて常に使用 する必要があります。.
使用の制限。
⁇ ентакокс単剤療法は、活発な抗結核治療の初期段階または継続段階のいずれにも使用しないでください。.
⁇ ентакоксは、リファンピン(RIF)耐性菌による失敗および/または再発率が高いため、活動性肺結核のHIV感染患者のイソニアジド(INH)と組み合わせた継続相レジメンで週1回使用しないでください。.
⁇ ентакоксは、活動性肺結核のHIV感染患者における初期段階治療計画の一部として研究されていません。.
潜伏結核感染。
⁇ ентакоксは、結核への進行のリスクが高い患者の結核菌によって引き起こされる潜在的な結核感染症の治療のために2歳以上の成人と子供に適応されます。 (活動性結核患者と密接に接触している人を含む。, ツベルクリン陽性皮膚検査への最近の変換。, HIV感染患者。, またはX線写真で肺線維症の人。).
使用の制限。
潜在的な結核感染症の治療を開始する前に、活動性結核症を除外する必要があります。.
⁇ ентакоксは、潜在的な結核感染症の治療のための12週間の週1回のレジメンとして、イソニアジドと組み合わせて常に使用 する必要があります。.
- isoniazidと組み合わせた ⁇ ентакоксは、リファマイシンまたはイゾニアジド耐性結核に曝露されていると推定される個人には推奨されません。.
活動性肺結核の投与量。
⁇ ентакоксは、2か月の初期段階とそれに続く4か月の継続段階からなるレジメンの一部として、薬物感受性生物によって引き起こされる活動性肺結核の治療にのみ推奨されます。. ⁇ ентакоксは、リファンピン耐性株によって引き起こされる活動性肺結核の治療には使用しないでください。.
初期段階(2か月)。
⁇ ентакоксは、直接観察された治療として、週2回600 mgの用量で2か月間投与する必要があります。 (DOT。) 連続3日以上の間隔で。 (72時間。) 投与間。, イソニアジドなどの毎日のコンパニオンドラッグを含む適切なレジメンの一部として、他の抗結核薬と組み合わせて。 (INH。) エタンブトール。 (EMB。) ピラジンアミド。 (PZA。).
継続フェーズ(4か月)。
初期段階(2か月)に続いて、継続段階(4か月)の治療は、イソニアジドまたは直接観察された治療として投与された感受性生物に対する別の適切な抗結核剤と組み合わせて、週1回4か月間 ⁇ ентакокс600 mgで構成されます。.
潜伏結核感染の投与量。
⁇ ентакоксは、直接観察された治療として、イソニアジドと組み合わせて週1回12週間投与する必要があります。.
大人と12歳以上の子供。
⁇ ентакоксの推奨用量は、患者の体重に基づいて、週に1回最大900 mgまで決定する必要があります(表1を参照)。. イソニアジドの推奨用量は15 mg / kg(最も近い50 mgまたは100 mgに四捨五入)で、1週間に1回、12週間、最大900 mgです。.
2-11歳の子供。
⁇ ентакоксの推奨用量は、患者の体重に基づいて、週に1回最大900 mgまで決定する必要があります(表1を参照)。. イソニアジドの推奨用量は25 mg / kg(最も近い50 mgまたは100 mgに四捨五入)で、1週間に1回、12週間、最大900 mgです。.
表1:潜在性結核感染症の治療における ⁇ ентакоксの体重ベースの用量。
重量範囲。 | ⁇ ентакокс線量。 | ⁇ ентакоксタブレットの数。 |
10-14 kg。 | 300 mg。 | 2 |
14.1-25 kg。 | 450 mg。 | 3 |
25.1-32 kg。 | 600 mg。 | 4 |
32.1-50 kg。 | 750 mg。 | 5 |
> 50 kg。 | 900 mg。 | 6 |
管理。
食事と一緒に ⁇ ентакоксを服用してください。. 食事とともに ⁇ ентакоксを投与すると、口腔のバイオアベイラビリティが向上し、胃腸の不調、吐き気、および/または ⁇ 吐の発生率が低下する可能性があります。..
錠剤を飲み込むことができない患者の場合、錠剤を粉砕して少量の半固形食品に加えることができ、そのすべてをすぐに摂取する必要があります。.
過敏症。
⁇ ентакоксは、リファマイシンに対する過敏症の病歴のある患者には禁 ⁇ です。.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Hepatotoxicity
Elevations of liver transaminases may occur in patients receiving Пентакокс. Patients on Пентакокс should be monitored for symptoms of liver injury.
Patients with abnormal liver tests and/or liver disease or patients initiating treatment for active pulmonary tuberculosis should only be given Пентакокс in cases of necessity and under strict medical supervision. In such patients, obtain serum transaminase levels prior to therapy and every 2-4 weeks while on therapy. Discontinue Пентакокс if evidence of liver injury occurs.
Hypersensitivity And Related Reactions
Hypersensitivity reactions may occur in patients receiving Пентакокс. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of anaphylaxis.
Monitor patients receiving Пентакокс therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue Пентакокс.
Relapse In The Treatment Of Active Pulmonary Tuberculosis
Пентакокс has not been evaluated as part of the initial phase treatment regimen in HIV-infected patients with active pulmonary TB.
Do not use Пентакокс as a once-weekly continuation phase regimen in HIV-infected patients with active pulmonary tuberculosis because of a higher rate of failure and/or relapse with rifampinresistant organisms.
Higher relapse rates may occur in patients with cavitary pulmonary lesions and/or positive sputum cultures after the initial phase of active tuberculosis treatment and in patients with evidence of bilateral pulmonary disease. Monitor for signs and symptoms of TB relapse in these patients.
Poor adherence to therapy is associated with high relapse rate. Emphasize the importance of compliance with therapy
Drug Interactions
Rifapentine is an inducer of CYP450 enzymes. Concomitant use of rifapentine with other drugs metabolized by these enzymes, such as protease inhibitors, certain reverse transcriptase inhibitors, and hormonal contraception may cause a significant decrease in plasma concentrations and loss of therapeutic effect.
Discoloration Of Body Fluids
Пентакокс may produce a red-orange discoloration of body tissues and/or fluids (e.g., skin, teeth, tongue, urine, feces, saliva, sputum, tears, sweat, and cerebrospinal fluid). Contact lenses or dentures may become permanently stained.
Clostridium difficile-Associated Diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including Пентакокс, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, discontinue antibacterial use not directed against C. difficile if possible. Institute appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation as clinically indicated.
Porphyria
Porphyria has been reported in patients receiving rifampin, attributed to induction of delta amino levulinic acid synthetase. Because Пентакокс may have similar enzyme induction properties, avoid the use of Пентакокс in patients with porphyria.
Patient Counseling Information
Treatment Adherence
Emphasize the importance of compliance with the full course of therapy, and the importance of not missing any doses of Пентакокс or companion medications in the treatment of active pulmonary tuberculosis or the treatment of latent tuberculosis infection.
Hypersensitivity Reactions
Inform patients that Пентакокс may cause hypersensitivity reactions. Signs and symptoms of this reaction may include a flu-like illness, hypotension, urticaria, angioedema, bronchospasm, conjunctivitis, thrombocytopenia or neutropenia. Anaphylaxis may also occur.
Inform patients of signs and symptoms of hypersensitivity reactions and advise them to stop the medication and contact their healthcare provider if they experience any of these symptoms.
Hepatitis
Instruct patients to stop the medication and notify their physician promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and pain or swelling of the joints.
Drug Interactions
Rifapentine may increase the metabolism and decrease the activity of other drugs that are metabolized by the P4503A4 and 2C8/9 pathways. Dosage adjustments of the co-administered drugs may be necessary. Advise patients to discuss with their physician any other medications they are taking before starting treatment with Пентакокс.
Concomitant use of Пентакокс with protease inhibitors or reverse transcriptase inhibitors may cause a significant decrease in plasma concentrations and loss of therapeutic effect of the protease inhibitor or reverse transcriptase inhibitor.
Rifapentine may reduce the effectiveness of hormonal contraceptives. Advise patients using oral, transdermal patch, or other systemic hormonal contraceptives to change to non-hormonal methods of birth control.
Discoloration Of Body Fluids
Inform the patient that Пентакокс produces a reddish coloration of the urine, sweat, sputum, tears, and breast milk. Contact lenses or dentures may be permanently stained..
Administration With Food
Advise patients to take Пентакокс with food.
Nursing Mothers
Advise nursing mothers that breastfeeding is not recommended with Пентакокс use.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Hepatocellular carcinomas were increased in male NMRI mice (Harlan Winklemann) which were treated orally with rifapentine for two years at or above doses of 5 mg/kg/day (0.04 times the recommended human dose based on body surface area conversions). In a two year rat study, there was an increase in nasal cavity adenomas in Wistar rats treated orally with rifapentine at 40 mg/kg/day (0.6 times human dose based on body surface area conversions).
Rifapentine was negative in the following genotoxicity tests: in vitro gene mutation assay in bacteria (Ames test); in vitro point mutation test in Aspergillus nidulans; in vitro gene conversion assay in Saccharomyces cerevisiae; host-mediated (mouse) gene conversion assay with Saccharomyces cerevisiae; in vitro Chinese hamster ovary cell/hypoxanthineguaninephosphoribosyl transferase (CHO/HGPRT) forward mutation assay; in vitro chromosomal aberration assay utilizing rat lymphocytes; and in vivo mouse bone marrow micronucleus assay.
The 25-desacetyl metabolite of rifapentine was positive in the in vitro mammalian chromosome aberration test in V79 Chinese Hamster cells, but was negative in the in vitro gene mutation assay in bacteria (Ames test), the in vitro Chinese hamster ovary cell/hypoxanthine-guaninephosphoribosyl transferase (CHO/HGPRT) forward mutation assay, and the in vivo mouse bone marrow micronucleus assay. Fertility and reproductive performance were not affected by oral administration of rifapentine to male and female rats at doses of up to 20 mg/kg/day (one-third of the human dose based on body surface area conversions).
Use In Specific Populations
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well controlled trials of Пентакокс in pregnant women; however, there are limited pregnancy outcome data reported from women enrolled in clinical trials of various Пентакокс treatment regimens for active tuberculosis and latent tuberculosis infection. The reported rate of spontaneous abortion following Пентакокс exposure did not represent an increase over the background rate of spontaneous abortion reported in the general population. Further interpretation of these data is limited by the quality of clinical trial adverse event reporting. In animal reproduction and developmental toxicity studies, rifapentine produced fetal harm and was teratogenic at doses less than and similar to the recommended human dose. Because animal studies are not always predictive of human response, Пентакокс should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Labor or Delivery
When administered during the last few weeks of pregnancy, rifampin, another rifamycin product, may increase the risk for maternal postpartum hemorrhage and bleeding in the exposed neonate. Monitor prothrombin time of pregnant women and neonates, who are exposed to Пентакокс during the last few weeks of pregnancy. Treatment with Vitamin K may be indicated.
Human Data
Fourteen patients with active tuberculosis treated with multiple anti-tuberculosis drugs including Пентакокс became pregnant during clinical studies. Six delivered normal infants; four had first trimester spontaneous abortions (of these, one patient abused ethanol and another patient was HIV-infected); one had an elective abortion; and outcome was unknown in three patients. These data are, however, limited by the quality of reporting and confounded by co-morbid medical conditions and multiple anti-tuberculosis drug exposures.
In the trial that compared the safety and effectiveness of Пентакокс in combination with isoniazid to isoniazid alone for the treatment of latent tuberculosis infection, a total of 45 (2.5%) women in the Пентакокс/isoniazid arm and 71 (4.1%) women in the isoniazid arm became pregnant. Among the 46 total pregnancies in the Пентакокс/isoniazid arm, there were 31 live births, six elective abortions, seven spontaneous abortions, and two unknown outcomes. Of the 31 live infants, 21 were reported healthy while in the other ten cases no further details were available. No congenital anomalies were reported. The rate of spontaneous abortion in the Пентакокс/isoniazid arm (15%), and the rate of spontaneous abortion in the isoniazid arm (19%), did not represent an increase over the background rate of 15 to 20 percent reported in the general population. Further interpretation of these results is limited by the quality of adverse event reporting.
Animal Data
Animal studies in rats and rabbits revealed embryofetal toxicity in both species. Pregnant rats given oral rifapentine during organogenesis at 40 mg/kg/day (0.6 times the human dose of 600 mg based on body surface area), produced pups with cleft palates, right aortic arch, increased incidence of delayed ossification, and increased numbers of ribs. When rifapentine was administered orally to mated female rats late in gestation, at 20 mg/kg/day (0.3 times the human dose based on body surface area), pup weights and gestational survival (live pups born/pups born) were reduced compared to controls. Increased resorptions and post implantation loss, decreased mean fetal weights, increased numbers of stillborn pups, and slightly increased pup mortality during lactation were also noted. When pregnant rabbits received oral rifapentine at 10 mg/kg to 40 mg/kg (0.3 times to 1.3 times the human dose based on body surface area), major fetal malformations occurred including: ovarian agenesis, pes varus, arhinia, microphthalmia and irregularities of the ossified facial tissues. At the higher dose, there were increases in post-implantation loss and the incidence of stillborn pups.
Nursing Mothers
It is not known whether Пентакокс is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Since Пентакокс may produce a red-orange discoloration of body fluids, there is a potential for discoloration of breast milk.
A slight increase in rat pup mortality was observed during lactation when dams were dosed late in gestation through lactation.
Pediatric Use
The safety and effectiveness of Пентакокс in the treatment of active pulmonary tuberculosis have not been established in pediatric patients under the age of 12.
The safety and effectiveness of Пентакокс in combination with isoniazid once-weekly regimen has been evaluated in pediatric patients (2-17 years of age) for the treatment of latent tuberculosis infection. In clinical studies, the safety profile in children was similar to that observed in adult patients.
In a pharmacokinetic study conducted in 2 year to 11 year-old pediatric patients with latent tuberculosis infection, Пентакокс was administered once-weekly based on weight (15mg/kg to 30 mg/Kg, up to a maximum of 900 mg). Exposures (AUC) in children 2 years-11 years with latent tuberculosis infection were higher (average 31%) than those observed in adults receiving Пентакокс 900mg once-weekly.
Geriatric Use
Clinical studies with Пентакокс did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In a pharmacokinetic study with Пентакокс, no substantial differences in the pharmacokinetics of rifapentine and 25desacetyl metabolite were observed in the elderly compared to younger adults.
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Hepatotoxicity
- Hypersensitivity
- Discoloration of Body Fluids
- Clostridium difficile-Associated Diarrhea
- Porphyria
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 practice.
Active Pulmonary Tuberculosis
Пентакокс was studied in a randomized, open label, active-controlled trial of HIV-negative patients with active pulmonary tuberculosis. The population consisted of primarily of male subjects with a mean age of 37 ± 11 years. In the initial 2 month phase of treatment, 361 patients received Пентакокс 600 mg twice a week in combination with daily isoniazid, pyrazinamide, and ethambutol and 361 subjects received rifampin in combination with isoniazid, pyrazinamide and ethambutol all administered daily. Ethambutol was discontinued when drug susceptibly testing was known. During the 4 month continuation phase, 317 patients in the Пентакокс group continued to receive Пентакокс 600 mg dosed once-weekly with isoniazid and 304 patients in the rifampin group received twice weekly rifampin and isoniazid. Both treatment groups received pyridoxine (Vitamin B6) over the 6 month treatment period.
Because Пентакокс was administered as part of a combination regimen, the adverse reaction profile reflects the entire regimen.
Twenty-two deaths occurred in the study, eleven in the rifampin combination therapy group and eleven in the Пентакокс combination therapy group. 18/361 (5%) rifampin combination therapy patients discontinued the study due to an adverse reaction compared to 11/361 (3%) Пентакокс combination therapy patients. Three patients (two rifampin combination therapy patients and one Пентакокс combination therapy patient) were discontinued in the initial phase due to hepatotoxicity. Concomitant medications for all three patients included isoniazid, pyrazinamide, ethambutol, and pyridoxine. All three recovered without sequelae.
Five patients had adverse reactions associated with Пентакокс overdose. These reactions included hematuria, neutropenia, hyperglycemia, ALT increased, hyperuricemia, pruritus, and arthritis.
Table 2 presents selected treatment-emergent adverse reactions associated with the treatment regimens which occurred in at least 1% of patients during treatment and post-treatment through the first three months of follow-up.
Table 2: Selected Treatment Emergent Adverse Reactions During Treatment of Active Pulmonary Tuberculosis and Through Three Months Follow-up
System Organ Class Preferred Term | Initial Phase1 | Continuation Phase2 | ||
Пентакокс Combination (N=361) N (%) | Rifampin Combination (N=361) N (%) | Пентакокс Combination (N=317) N (%) | Rifampin Combination (N=304) N (%) | |
BLOOD AND LYMPHATICS | ||||
Anemia | 41 (11.4) | 41 (11.4) | 5 (1.6) | 10 (3.3) |
Lymphopenia | 38 (10.5) | 37 (10.2) | 10 (3.2) | 9 (3.) |
Neutropenia | 22 (6.1) | 21 (5.8) | 27 (8.5) | 24 (7.9) |
Leukocytosis | 6 (1.7) | 13 (3.6) | 5 (1.6) | 2 (0.7) |
Thrombocytosis | 20 (5.5) | 13 (3.6) | 1 (0.3) | 0 (0.0) |
Thrombocytopenia | 6 (1.7) | 6 (1.7) | 4 (1.3) | 6 (2) |
Lymphadenopathy | 4 (1.1) | 2 (0.6) | 0 (0.0) | 2 (0.7) |
Nonprotein Nitrogen Increased | 4 (1.1) | 3 (0.8) | 10 (3.2) | 15 (4.9) |
EYE | ||||
Conjunctivitis | 8 (2.2) | 2 (0.6) | 1 (0.3) | 1 (0.3) |
GASTROINTESTINAL | ||||
Dyspepsia | 6 (1.7) | 11 (3) | 4 (1.3) | 6 (2) |
Vomiting | 6 (1.7) | 14 (3.9) | 3 (0.9) | 3 (1) |
Nausea | 7 (1.9) | 3 (0.8) | 2 (0.6) | 1 (0.3) |
Diarrhea | 5 (1.4) | 2 (0.6) | 2 (0.6) | 0 (0.0) |
GENERAL | ||||
Back Pain | 15 (4.2) | 11 (3) | 11 (3.5) | 4 (1.3) |
Abdominal Pain | 3 (0.8) | 3 (0.8) | 4 (1.3) | 4 (1.3) |
Fever | 5 (1.4) | 7 (1.9) | 1 (0.3) | 1 (0.3) |
Anorexia | 14 (3.9) | 18 (5) | 8 (2.5) | 6 (2) |
HEPATIC & BILIARY | ||||
ALT Increased | 18 (5) | 23 (6.4) | 7 (2.2) | 10 (3.3) |
AST Increased | 15 (4.2) | 18 (5) | 7 (2.2) | 8 (2.6) |
MUSCULOSKELETAL | ||||
Arthralgia | 13 (3.6) | 13 (3.6) | 3 (0.9) | 5 (1.6) |
NEUROLOGIC | ||||
Headache | 11 (3) | 13 (3.6) | 3 (0.9) | 7 (2.3) |
Dizziness | 5 (1.4) | 5 (1.4) | 1 (0.3) | 1 (0.3) |
RESPIRATORY | ||||
Hemoptysis | 27 (7.5) | 20 (5.5) | 6 (1.9) | 6 (2) |
Coughing | 21 (5.8) | 8 (2.2) | 9 (2.8) | 11 (3.6) |
SKIN | ||||
Rash | 15 (4.2) | 26 (7.2) | 8 (2.5) | 8 (2.6) |
Sweating Increased | 19 (5.3) | 18 (5) | 5 (1.6) | 4 (1.3) |
Pruritus | 10 (2.8) | 16 (4.4) | 3 (0.9) | 0 (0.0) |
Rash Maculopapular | 6 (1.7) | 3 (0.8) | 0 (0.0) | 1 (0.3) |
1Initial phase consisted of therapy with either Пентакокс twice weekly or rifampin daily combined with daily isoniazid, pyrazinamide, and ethambutol for 60 days. 2Continuation phase consisted of therapy with either Пентакокс once weekly or rifampin twice weekly combined with daily isoniazid for 120 days. |
The following selected treatment-emergent adverse reactions were reported in less than 1% of the Пентакокс combination therapy patients during treatment and post-treatment through the first three months of follow-up.
Blood and Lymphatics: lymphocytosis, hematoma, purpura, thrombosis.
Cardiovascular: syncope, tachycardia, palpitation, orthostatic hypotension, pericarditis.
Metabolic & Nutritional: BUN increased, alkaline phosphatase increased.
Gastrointestinal: gastritis, esophagitis, pancreatitis, salivary gland enlargement.
General: asthenia, facial edema.
Hepatobiliary: bilirubinemia, hepatomegaly, jaundice.
Infectious Disease: infection fungal.
Musculoskeletal: myalgia, myositis.
Neurologic: somnolence, dysphonia.
Pregnancy, Puerperium and Perinatal conditions: abortion
Psychiatric: anxiety, confusion
Reproductive Disorders: vaginitis, vaginal hemorrhage, leukorrhea.
Respiratory: dyspnea, pneumonitis, pulmonary fibrosis, asthma, bronchospasm, laryngeal edema, laryngitis.
Skin: urticaria, skin discoloration,
In another randomized, open-label trial, 1075 HIV non-infected and infected patients with active pulmonary tuberculosis who had completed an initial 2 month phase of treatment with 4 drugs were randomly assigned to receive either Пентакокс 600 mg and isoniazid once weekly or rifampin and isoniazid twice weekly for the 4 month continuation phase. 502 HIV non-infected and 36 HIV-infected patients were randomized to receive the Пентакокс regimen and 502 HIVnoninfected and 35 HIV-infected patients were randomized to receive the rifampin regimen. The death rate was 6.5% for the Пентакокс combination regimen compared to 6.7% for the rifampin combination regimen.
Latent Tuberculosis Infection
Main Study
Пентакокс in combination with isoniazid given once-weekly for 3 months (3RPT/INH) was compared to isoniazid given once daily for 9 months (9INH) in an open-label, randomized trial in patients with a positive tuberculin skin test, and at high risk for progression from latent tuberculosis infection to active tuberculosis disease. Пентакокс was dosed by weight, and isoniazid mg/kg dose was determined according to age to a maximum of 900 mg each.
A total of 4040 patients received at least one dose of the 3RPT/INH regimen, including 348 children 2-17 years of age and 105 HIV-infected individuals. A total of 3759 received at least one dose of the 9INH regimen, including 342 children 2 years-17 years of age and 95 HIV-infected individuals.
Patients were followed for 33 months from the time of enrollment. Treatment-emergent adverse reactions were defined as those occurring during treatment and 60 days after the last dose of treatment. 161 (4%) 3RPT/INH subjects had a rifamycin hypersensitivity reaction, defined as either: a) one of the following: hypotension, urticaria, angioedema, acute bronchospasm, or conjunctivitis occurring in relation to study drug or b) at least four of the following symptoms occurring in relation to the study drug, with at least one symptom being CTCAE Grade 2 or higher: weakness, fatigue, nausea, vomiting, headache, fever, aches, sweats, dizziness, shortness of breath, flushing or chills. No specific definition was used for isoniazid hypersensitivity; 18 (0.5%) 9INH subjects were classified as having a hypersensitivity reaction. Hepatotoxicity was defined as AST ≥ 3x upper limit of normal in the presence of specific signs and symptoms of hepatitis, or AST > 5x upper limit of normal regardless of signs or symptoms. 113 (3%) 9INH subjects and 24 (0.6%) 3RPT/INH subjects developed hepatotoxicity.
196 subjects (4.9%) in the 3RPT/INH arm discontinued treatment due to a treatment related adverse reaction patients and 142 (3.8%) in the 9INH arm discontinued treatment due to a treatment related adverse reaction. In the 3RPT/INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hypersensitivity reaction, occurring in 120 (3%) patients. In the 9INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hepatotoxicity, occurring in 76 (2%) patients.
Seventy one deaths occurred, 31/4040, 0.77% in the 3RPT/INH group and 40/3759 (1.06%) in the 9INH group) during the 33 month study period. During the treatment emergent period, 11 deaths occurred, 4 in the 3RPT/INH group and 7 in the 9INH group. None of the reported deaths were considered related to treatment with study drugs or were attributed to tuberculosis disease.
Table 3 presents select adverse reactions that occurred during the treatment emergent period in the main study in LTBI patients treated with 3RPT/INH or 9INH at a frequency greater than 0.5%.
Table 3 : Select Adverse Reactions occurring in 0.5% or greater of patients* in the Latent Tuberculosis Infection Main Study
System Organ Class Preferred Term | 3RPT/INH (N=4040) N (%) | 9INH (N=3759) N (%) |
Immune system disorders | ||
Hypersensitivity | 161 (4) | 18 (0.5) |
Hepatobiliary disorders | ||
Hepatitis | 24 (0.6) | 113 (3) |
Nervous system disorders | ||
Headache | 26 (0.6) | 17 (0.5) |
Skin and subcutaneous tissue disorders | ||
Skin reaction | 31 (0.8) | 21 (0.6) |
*Includes events reported through 60 days after last dose of study drug |
Pediatric Substudy
Six-hundred and ninety children 2 years-17 years of age received at least one dose of study drugs in the main study. An additional 342 children 2 years-17 years of age received at least one dose in the pediatric extension study (total 1032 children; 539 received 3RPT/INH and 493 received 9INH).
No children in either treatment arm developed hepatotoxicity. Using the same definition for rifamycin hypersensitivity reaction as in the main study, 7 (1.3%) of children in the 3RPT/INH group experienced a rifamycin hypersensitivity reaction. Adverse reactions in children 2 years11 years of age and 12 years-17 years of age were similar.
HIV Substudy
Two-hundred HIV-infected patients with latent tuberculosis infection received at least one dose of study drugs in the main study and an additional 193 patients received at least one dose in the extension study (total of 393; 207 received 3RPT/INH and 186 received 9INH). Compared to the HIV-negative patients enrolled in the main study, a higher proportion of HIV-infected patients in each treatment arm experienced a treatment emergent adverse reaction, including a higher incidence of hepatotoxicity. Hepatotoxicity occurred in 3/207 (1.5%) patients in the 3RPT/INH arm and in 14/186 (7.5%) in the 9INH arm. Rifamycin hypersensitivity occurred in only one HIV-infected patient.
Eleven deaths occurred during the 33 month follow up period (6/207 in the 3RPT/INH group and 5/186 in the 9INH group) including one death in the 9INH arm during the treatment emergent period. None of the reported deaths were considered related to treatment with study drugs or tuberculosis disease.
Selected treatment-emergent adverse reactions reported during treatment and 60 days posttreatment in less 0.5% of the 3RPT/INH combination-therapy group in the main study are presented below by body system.
Eye Disorders: conjunctivitis.
Blood and Lymphatic System Disorders: leukopenia, anemia, lymphadenopathy, neutropenia.
Gastrointestinal Disorders: nausea, diarrhea, vomiting, abdominal pain constipation, dry mouth, dyspepsia, esophageal irritation, gastritis, pancreatitis.
General Disorders and Administration Site Conditions: fatigue, pyrexia, asthenia, chest pain, chills, feeling jittery.
Infections and Infestations: pharyngitis, viral infection, vulvovaginal candidiasis.
Metabolism and Nutrition Disorders: hyperglycemia, gout, hyperkalemia, decreased appetite, hyperlipidemia.
Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia, back pain, rhabdomyolysis.
Nervous system Disorders: dizziness, convulsion, paresthesia, headache, neuropathy peripheral, syncope.
Psychiatric Disorders: depression, anxiety, disorientation, suicidal ideation.
Renal and Urinary Disorders: azotemia.
Reproductive System and Breast Disorders: vulvovaginal pruritus.
Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnea, oropharyngeal pain, asthma, bronchial hyperactivity, epistaxis.
Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, urticaria.
⁇ ентакоксによる急性過剰摂取の治療の経験はありません。, リファマイシンの臨床経験は、胃内容物を排出するための胃洗浄を示唆しています。 (過剰摂取から数時間以内に。) その後、活性炭スラリーを胃に注入します。, 消化管から残っている薬物を吸着するのを助けるかもしれません。.
リファペンチンと25-デサセチルリファペンチンは、それぞれ97.7%と93.2%の血漿タンパク質結合です。. 尿中に排 ⁇ されるリファペンチンおよび関連化合物は、投与量の17%しか占めていないため、血液透析も強制利尿も、 ⁇ ентакокс過剰摂取患者の体から変化のないリファペンチンの全身排 ⁇ を促進すると予想されます。.
⁇ ентакоксの経口投与量が1日1回または72時間に1回健康なボランティアに10日間投与された場合、リファペンチンの単回投与AUC(0-∞)は、定常状態のAUCss(0-24h)またはAUCss(0- 72h)値、定常状態の薬物動態に対する有意な自動誘導効果がないことを示唆しています。アペントリフェント. 定常状態は、 ⁇ ентакокс600 mgを毎日投与した後、10日目までに達成されました。. ⁇ ентакоксを週1回投与した後、リファペンチンと25デサセチルリファペンチン(活性代謝物)の血漿蓄積は予想されません。.
健康なボランティアに72時間ごとに600 mg ⁇ ентакоксを経口投与した後の10日目のリファペンチンと25-デサセチルリファペンチンの薬物動態パラメーターを表5に示します。.
表5:健康なボランティアにおける薬物動態とリファペンチンおよび25-デサセチルリファペンチン。.
パラメータ。 | リファペンチン。 | 25-デサセチルリファペンチン。 |
平均±SD(n = 12)。 | ||
Cmax(M-g / mL)。 | 15.05±4.62。 | 6.26±2.06。 |
AUC(0-72h)(Mg * h / mL)。 | 319.54±91.52。 | 215.88±85.96。 |
T½(h)。 | 13.19±1.38。 | 13.35±2.67。 |
Tmax(h)。 | 4.83±1.80。 | 11.25±2.73。 |
Cl / F(L / h)。 | 2.03±0.60。 | -- |
摂食状態で900 mgのイソニアジドと組み合わせた900 mg ⁇ ентакоксの単回投与経口投与後のリファペンチンと25-デサセチルリファペンチンの薬物動態パラメーターを表6に示します。.
表6: ⁇ ентакоксが連邦機関の条件下でイソニアジドと同時投与された場合の、健康なボランティアにおけるリファペンチンと25-デサセチルリファペンチンの平均±SD薬物動態パラメーター(N = 16)。.
パラメータ。 | リファペンチン。 | 25-デサセチルリファペンチン。 |
Cmax(μg/ mL)。 | 25.8±5.83。 | 13.3±4.83。 |
AUC(μg* h / mL)。 | 817±128。 | 601±187。 |
T½(h)。 | 16.6±5.02。 | 17.5±7.42。 |
Tmax(h)*。 | 8(3-10)。 | 24(10-36)。 |
Cl / F(L / h)。 | 1.13±0.174。 | NA **。 |
*中央値(Min-Max)。 **該当なし。 |
吸収。
⁇ ентакоксの絶対バイオアベイラビリティは決定されていません。. 健康な成人ボランティアへの600 mg単回投与後の ⁇ ентакоксの相対的バイオアベイラビリティ(参照として経口溶液を使用)は70%でした。. 最大濃度は、600 mg ⁇ ентакокс用量の投与後5時間から6時間に達成されました。.
高脂肪食を含む ⁇ ентакоксの投与により、リファペンチンCmaxとAUCが、空腹時に ⁇ ентакоксを投与したときに観察されたものよりも40%から50%増加しました。.
低脂肪、高炭水化物の朝食で ⁇ ентакокс(900 mg単回投与)とイソニアジド(900 mg単回投与)を投与すると、リファペンチンCmaxとAUCがそれぞれ47%と51%増加しました。. 対照的に、同じ食事の摂取により、イソニアジドCmaxとAUCはそれぞれ46%と23%減少しました。.
分布。
イソニアジド、ピラジナミド、エタンブトールと組み合わせて600 mg ⁇ ентакоксを投与された351人の結核患者の母集団薬物動態分析では、推定見かけの分布量は70.2±9.1 Lでした。健康なボランティアでは、リファペンチンと25-デサセチルリファペンチンはそれぞれ97.7%と93。. リファペンチンは主にアルブミンに結合していました。. 健康なボランティア、無症候性のHIV感染被験者、および肝障害のある被験者でも同様のタンパク質結合が観察されました。.
代謝/排 ⁇ 。
健康なボランティアへの放射性標識リファペンチンの600 mg単回経口投与後(n = 4)、全体の87%。 14Cリファペンチンは尿(17%)と ⁇ 便(70%)で回収されました。. 全体の80%以上。 14Cリファペンチンの投与量は7日以内に体から排 ⁇ されました。. リファペンチンは、エステラーゼ酵素によって加水分解され、微生物学的に活性な25-デスアセチルリファペンチンを形成しました。. リファペンチンと25-デサセチルリファペンチンは、血漿中の総放射能の99%を占めました。. 25-デサセチルリファペンチン代謝産物の血漿AUC(0-∞)およびCmax値は、それぞれリファペンチンの半分および3分の1でした。. 相対に基づいています。 in vitro。 活動とAUC(0∞)値、リファペンチンと25-デサセチルリファペンチンは、結核菌に対する臨床活動にそれぞれ62%と38%貢献する可能性があります。.