Composition:
Utilisé dans le traitement:
Examiné médicalement par Oliinyk Elizabeth Ivanovna, Pharmacie Dernière mise à jour le 16.03.2022
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Tuberculose pulmonaire active
La Пентакокс® (rifapentine) est indiquée chez les adultes et les enfants de 12 ans et plus pour le traitement de la tuberculose pulmonaire active (TB) causée par Mycobacterium tuberculosis. Пентакокс doit toujours être utilisé en association avec un ou plusieurs médicaments antituberculeux (anti-TB) auxquels l'isolat est sensible.
Limitations d'utilisation
N'utilisez pas la monothérapie Пентакокс dans les phases initiale ou continue du traitement antitubérineux actif.
Пентакокс ne doit pas être utilisé une fois par semaine dans le schéma de phase de continuation en association avec l'isoniazide (INH) chez les patients infectés par le VIH atteints de tuberculose pulmonaire active en raison d'un taux plus élevé d'échec et / ou de rechute avec des organismes résistants à la rifampicine (RIF).
Пентакокс n'a pas été étudié dans le cadre du schéma thérapeutique de phase initial chez les patients infectés par le VIH atteints de tuberculose pulmonaire active.
Infection tuberculeuse latente
Пентакокс est indiqué chez les adultes et les enfants de 2 ans et plus pour le traitement de l'infection tuberculeuse latente causée par Mycobacterium tuberculosis chez les patients à haut risque de progression vers la tuberculose (y compris ceux en contact étroit avec des patients tuberculeux actifs, conversion récente à un test cutané à la tuberculine positif, Patients infectés par le VIH, ou ceux atteints de fibrose pulmonaire sur radiographie).
Limitations d'utilisation
La tuberculose active doit être exclue avant de commencer le traitement de l'infection tuberculeuse latente.
Пентакокс doit toujours être utilisé en association avec l'isoniazide comme régime hebdomadaire de 12 semaines pour le traitement de l'infection tuberculeuse latente.
- Пентакокс en association avec l'isoniazide n'est pas recommandé pour les individus présumés exposés à la rifamycine ou à la M. tuberculosis résistante aux isoniazides.
Posologie dans la tuberculose pulmonaire active
Пентакокс n'est recommandé que pour le traitement de la tuberculose pulmonaire active causée par des organismes sensibles aux médicaments dans le cadre de schémas thérapeutiques consistant en une phase initiale de 2 mois suivie d'une phase de continuation de 4 mois. Пентакокс ne doit pas être utilisé dans le traitement de la tuberculose pulmonaire active causée par des souches résistantes à la rifampicine.
Phase initiale (2 mois)
Пентакокс doit être administré à une dose de 600 mg deux fois par semaine pendant deux mois en tant que traitement directement observé (DOT) avec un intervalle d'au moins 3 jours consécutifs (72 heures) entre les doses, en association avec d'autres médicaments antituberculeux dans le cadre d'un régime approprié qui comprend des médicaments d'accompagnement quotidiens tels que l'isoniazide (INH) éthambutol (EMB) et pyrazinamide (PZA).
Phase de continuation (4 mois)
Après la phase initiale (2 mois), le traitement de la phase de continuation (4 mois) consiste en Пентакокс 600 mg une fois par semaine pendant 4 mois en association avec l'isoniazide ou un autre agent antituberculeux approprié pour les organismes sensibles administré en traitement directement observé.
Posologie dans une infection tuberculeuse latente
Пентакокс doit être administré une fois par semaine en association avec l'isoniazide pendant 12 semaines en tant que traitement directement observé.
Adultes et enfants de 12 ans et plus
La dose recommandée de Пентакокс doit être déterminée en fonction du poids du patient jusqu'à un maximum de 900 mg une fois par semaine (voir tableau 1). La dose recommandée d'isoniazide est de 15 mg / kg (arrondie à 50 mg ou 100 mg près) jusqu'à un maximum de 900 mg une fois par semaine pendant 12 semaines.
Enfants de 2 à 11 ans
La dose recommandée de Пентакокс doit être déterminée en fonction du poids du patient jusqu'à un maximum de 900 mg une fois par semaine (voir tableau 1). La dose recommandée d'isoniazide est de 25 mg / kg (arrondie à 50 mg ou 100 mg près) jusqu'à un maximum de 900 mg une fois par semaine pendant 12 semaines.
Tableau 1: Dose pondérale de Пентакокс dans le traitement de l'infection tuberculeuse latente
Plage de poids | Dose de Пентакокс | Nombre de comprimés de Пентакокс |
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 |
Administration
Prenez Пентакокс avec les repas. L'administration de Пентакокс avec un repas augmente la biodisponibilité orale et peut réduire l'incidence des troubles gastro-intestinaux, des nausées et / ou des vomissements..
Pour les patients qui ne peuvent pas avaler de comprimés, les comprimés peuvent être écrasés et ajoutés à une petite quantité d'aliments semi-solides, qui doivent tous être consommés immédiatement.
Hypersensibilité
Пентакокс est contre-indiqué chez les patients ayant des antécédents d'hypersensibilité aux rifamycines.
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.
Bien qu'il n'y ait aucune expérience dans le traitement d'un surdosage aigu avec Пентакокс, l'expérience clinique avec les rifamycines suggère que le lavage gastrique évacue le contenu gastrique (dans les quelques heures suivant une surdose) suivi d'une instillation d'un lisier de charbon activé dans l'estomac, peut aider à adsorber tout médicament restant du tractus gastro-intestinal.
La rifapentine et la 25-désacétyl rifapentine sont liées respectivement à 97,7% et 93,2% aux protéines plasmatiques. La rifapentine et les composés apparentés excrétés dans l'urine ne représentent que 17% de la dose administrée, par conséquent, ni l'hémodialyse ni la diurèse forcée ne devraient améliorer l'élimination systémique de la rifapentine inchangée du corps d'un patient présentant un surdosage de Пентакокс.
Lorsque des doses orales de Пентакокс ont été administrées une fois par jour ou une fois toutes les 72 heures à des volontaires sains pendant 10 jours, l'ASC (0-∞) à dose unique de rifapentine était similaire à son AUCss à l'état d'équilibre (0-24h) ou AUCss (0-72h) ), suggérant aucun effet d'auto-induction significatif sur la pharmacocinétique à l'état d'état d'état d'état d'état d'équilibre. Des conditions à l'état d'équilibre ont été atteintes au jour 10 après l'administration quotidienne de 600 mg de Пентакокс. Aucune accumulation plasmatique de rifapentine et de 25désacétyl rifapentine (métabolite actif) n'est attendue après l'administration hebdomadaire de Пентакокс.
Les paramètres pharmacocinétiques de la rifapentine et de la 25-désacétyl rifapentine au 10e jour après administration orale de 600 mg de Пентакокс toutes les 72 heures à des volontaires sains sont décrits dans le tableau 5.
Tableau 5: Pharmacocinétique et rifapentine et 25-désacétyl rifapentine chez les volontaires sains.
Paramètre | Rifapentine | Rifapentine 25-désacétyle |
Moyenne ± ET (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 | -- |
Les paramètres pharmacocinétiques de la rifapentine et de la rifapentine à 25 désacétyle après administration orale à dose unique de 900 mg de Пентакокс en association avec 900 mg d'isoniazide dans des conditions d'alimentation sont décrits dans le tableau 6.
Tableau 6: Paramètres pharmacocinétiques moyens ± ET de la rifapentine et de la 25-désacétyl rifapentine chez les volontaires sains lorsque Пентакокс est co-administré avec Isoniazid dans des conditions fédérales (N = 16).
Paramètre | Rifapentine | Rifapentine 25-désacétyle |
Cmax (μg / mL) | 25,8 ± 5,83 | 13,3 ± 4,83 |
AUC (μg * h / ml) | 817 ± 128 | 601 ± 187 |
T ½ (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 ** |
* Médiane (Min-Max) ** Sans objet |
Absorption
La biodisponibilité absolue de Пентакокс n'a pas été déterminée. La biodisponibilité relative (avec une solution buvable comme référence) de Пентакокс après une dose unique de 600 mg à des volontaires adultes en bonne santé était de 70%. Les concentrations maximales ont été atteintes de 5 heures à 6 heures après l'administration de la dose de 600 mg de Пентакокс.
L'administration de Пентакокс avec un repas riche en graisses a augmenté la Cmax et l'ASC de la rifapentine de 40% à 50% par rapport à celle observée lorsque Пентакокс a été administré à jeun.
L'administration de Пентакокс (dose unique de 900 mg) et d'isoniazide (dose unique de 900 mg) avec un petit-déjeuner faible en gras et riche en glucides, a entraîné une augmentation de 47% et 51% de la Cmax et de l'ASC de la rifapentine, respectivement. En revanche, l'ingestion du même repas a diminué la Cmax et l'ASC de l'isoniazide de 46% et de 23%, respectivement.
Distribution
Dans une analyse pharmacocinétique de population chez 351 patients tuberculeux ayant reçu 600 mg de Пентакокс en association avec l'isoniazide, le pyrazinamide et l'éthambutol, le volume de distribution apparent estimé était de 70,2 ± 9,1 L. Chez des volontaires sains, la rifapentine et les protéines de 25-désacétyle rifapentine étaient respectivement de 97,7,7,7% et 3. La rifapentine était principalement liée à l'albumine. Une mesure similaire de la liaison aux protéines a été observée chez des volontaires sains, des sujets infectés par le VIH asymptomatiques et des sujets atteints d'insuffisance hépatique.
Métabolisme / excrétion
Après une dose orale unique de 600 mg de rifapentine radiomarquée à des volontaires sains (n = 4), 87% du total 14La rifapentine C a été récupérée dans l'urine (17%) et les excréments (70%). Plus de 80% du total 14La dose de rifapentine C a été excrétée du corps dans les 7 jours. La rifapentine a été hydrolysée par une enzyme estérase pour former une rifapentine 25-désacétyle microbiologiquement active. La rifapentine et la rifapentine à 25 désacétyle représentaient 99% de la radioactivité totale dans le plasma. Les valeurs plasmatiques d'ASC (0-∞) et de Cmax du métabolite 25-désacétyl rifapentine étaient respectivement la moitié et le tiers de celles de la rifapentine. Basé sur un parent in vitro les activités et les valeurs de l'ASC (0∞), la rifapentine et la 25-désacétyl rifapentine contribuent potentiellement à 62% et 38% aux activités cliniques contre M. tuberculosis, respectivement.