Componenti:
Metodo di azione:
Opzione di trattamento:
Revisione medica di Fedorchenko Olga Valeryevna, Pharmacy Ultimo aggiornamento in data 21.03.2022
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Ridurre lo sviluppo di batteri resistenti ai farmaci e mantenere l'efficacia di Mai E Ke Si e di altri farmaci antibatterici, Mai E Ke Si quando usato per trattare l'infezione deve essere usato solo per trattare o prevenire infezioni che sono comprovate o fortemente sospettate di essere causate da batteri sensibili. Quando sono disponibili informazioni sulla coltura e sulla suscettibilità, devono essere prese in considerazione nella scelta o modifica della terapia antibatterica. In assenza di tali dati, i modelli locali di epidemiologia e suscettibilità possono contribuire alla selezione empirica della terapia.
Diarrea dei viaggiatori
Mai E Ke Si è indicato per il trattamento della diarrea dei viaggiatori (TD) causata da ceppi non invasivi di Escherichia coli negli adulti e nei pazienti pediatrici di età pari o superiore a 12 anni.
Limitazioni d'uso
Mai E Ke Si non deve essere usato in pazienti con diarrea complicata da febbre o sangue nelle feci o diarrea a causa di agenti patogeni diversi dall'Escherichia coli.
Encefalopatia epatica
Mai E Ke Si è indicato per la riduzione del rischio di recidiva di encefalopatia epatica palese (HE) negli adulti.
Negli studi su Mai E Ke Si per HE, il 91% dei pazienti utilizzava contemporaneamente lattulosio. Non è stato possibile valutare le differenze nell'effetto del trattamento di quei pazienti che non usano contemporaneamente lattulosio.
Mai E Ke Si non è stato studiato in pazienti con MELD (Modello per la malattia epatica allo stadio terminale) con punteggi> 25 e solo l'8,6% dei pazienti nello studio controllato aveva punteggi MELD superiori a 19. Vi è una maggiore esposizione sistemica in pazienti con disfunzione epatica più grave.
Sindrome dell'intestino irritabile con diarrea
Mai E Ke Si è indicato per il trattamento della sindrome dell'intestino irritabile con diarrea (IBS-D) negli adulti.
Dosaggio per la diarrea dei viaggiatori
La dose raccomandata di Mai E Ke Si è una compressa da 200 mg assunta per via orale tre volte al giorno per 3 giorni.
Dosaggio per encefalopatia epatica
La dose raccomandata di Mai E Ke Si è una compressa da 550 mg assunta per via orale due volte al giorno.
Dosaggio per la sindrome dell'intestino irritabile con diarrea
Le sezioni o le sottosezioni omesse dalle informazioni complete sulla prescrizione non sono elencate.
La dose raccomandata di Mai E Ke Si è una compressa da 550 mg assunta per via orale tre volte al giorno per 14 giorni.
I pazienti che manifestano una ricorrenza dei sintomi possono essere ritirati fino a due volte con lo stesso regime posologico.
Amministrazione
Mai E Ke Si può essere assunto con o senza cibo.
Mai E Ke Si è controindicato nei pazienti con ipersensibilità alla rifaximina, a uno qualsiasi degli agenti antimicrobici della rifamicina o a uno qualsiasi dei componenti di Mai E Ke Si. Le reazioni di ipersensibilità hanno incluso dermatite esfoliativa, edema angioneurotico e anafilassi.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Travelers’ Diarrhea Not Caused By Escherichia Coli
Mai E Ke Si was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli.
Discontinue Mai E Ke Si if diarrhea symptoms get worse or persist more than 24 to 48 hours and alternative antibiotic therapy should be considered.
Mai E Ke Si is not effective in cases of travelers' diarrhea due to Campylobacter jejuni. The effectiveness of Mai E Ke Si in travelers' diarrhea caused by Shigella spp. and Salmonella spp. has not been proven. Mai E Ke Si should not be used in patients where Campylobacter jejuni, Shigella spp., or Salmonella spp. may be suspected as causative pathogens.
Clostridium Difficile-Associated Diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Mai E Ke Si, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to 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 antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Development Of Drug-Resistant Bacteria
Prescribing Mai E Ke Si for travelers' diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Severe (Child-Pugh Class C) Hepatic Impairment
There is increased systemic exposure in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering Mai E Ke Si to patients with severe hepatic impairment (Child-Pugh Class C).
Concomitant Use With P-glycoprotein Inhibitors
Concomitant administration of drugs that are P-glycoprotein inhibitors with Mai E Ke Si can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of Mai E Ke Si and a P-glycoprotein inhibitor such as cyclosporine is needed. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-glycoprotein inhibitors may further increase the systemic exposure to rifaximin.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Malignant schwannomas in the heart were significantly increased in male Crl:CD® (SD) rats that received rifaximin by oral gavage for two years at 150 to 250 mg/kg per day (doses equivalent to 2.4 to 4 times the recommended dose of 200 mg three times daily for TD, and equivalent to 1.3 to 2.2 times the recommended dose of 550 mg twice daily for HE, based on relative body surface area comparisons). There was no increase in tumors in Tg.rasH2 mice dosed orally with rifaximin for 26 weeks at 150 to 2000 mg/kg per day (doses equivalent to 1.2 to 16 times the recommended daily dose for TD and equivalent to 0.7 to 9 times the recommended daily dose for HE, based on relative body surface area comparisons).
Rifaximin was not genotoxic in the bacterial reverse mutation assay, chromosomal aberration assay, rat bone marrow micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay. There was no effect on fertility in male or female rats following the administration of rifaximin at doses up to 300 mg/kg (approximately 5 times the clinical dose of 600 mg per day for TD, and approximately 2.6 times the clinical dose of 1100 mg per day for HE, adjusted for body surface area).
Use In Specific Populations
Pregnancy
Risk Summary
There are no available data on Mai E Ke Si use in pregnant women to inform any drug associated risks. Teratogenic effects were observed in animal reproduction studies following administration of rifaximin to pregnant rats and rabbits during organogenesis at doses approximately 0.9 to 5 times and 0.7 to 33 times, respectively of the recommended human doses of 600 mg to 1650 mg per day. In rabbits, ocular, oral and maxillofacial, cardiac, and lumbar spine malformations were observed. Ocular malformations were observed in both rats and rabbits at doses that caused reduced maternal body weight gain. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Advise pregnant women of the potential risk to a fetus.
Data
Animal Data
Rifaximin was teratogenic in rats at doses of 150 to 300 mg/kg (approximately 2.5 to 5 times the recommended dose for TD [600 mg per day], and approximately 1.3 to 2.6 times the recommended dose  for HE [1100 mg per day], and approximately 0.9 to 1.8 times the recommended dose for IBS-D [1650 mg per day] adjusted for body surface area). Rifaximin was teratogenic in rabbits at doses of 62.5 to 1000 mg/kg (approximately 2 to 33 times the recommended dose for TD [600 mg per day], and approximately 1.1 to 18 times the recommended dose for HE [1100 mg per day], and approximately 0.7 to 12 times the recommended dose for IBS-D [1650 mg per day] adjusted for body surface area). These effects include cleft palate, agnathia, jaw shortening, hemorrhage, eye partially open, small eyes, brachygnathia, incomplete ossification, and increased thoracolumbar vertebrae.
A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses of rifaximin up to 300 mg/kg per day (approximately 5 times the recommended dose for TD [600 mg per day], and approximately 2.6 times the recommended dose for HE [1100 mg per day], and approximately 1.8 times the recommended dose for IBS-D [1650 mg per day] adjusted for body surface area).
Lactation
Risk Summary
There is no information regarding the presence of rifaximin in human milk, the effects of rifaximin on the breastfed infant, or the effects of rifaximin on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Mai E Ke Si and any potential adverse effects on the breastfed infant from Mai E Ke Si or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness of Mai E Ke Si has not been established in pediatric patients less than 12 years of age with TD or in patients less than 18 years of age for HE and IBS-D.
Geriatric Use
Of the total number of patients in the clinical study of Mai E Ke Si for HE, 19% of patients were 65 and over, while 2% were 75 and over. In the clinical studies of IBS-D, 11% of patients were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either indication. Clinical studies with Mai E Ke Si for TD did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Renal Impairment
The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.
Hepatic Impairment
Following administration of Mai E Ke Si 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC τ) of rifaximin was about 10-, 14-, and 21-fold higher in those patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) and severe (Child- Pugh Class C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when Mai E Ke Si is administered to patients with severe hepatic impairment.
Clinical Studies 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.
Travelers' Diarrhea
The safety of Mai E Ke Si 200 mg taken three times a day was evaluated in patients with travelers' diarrhea consisting of 320 patients in two placebo-controlled clinical trials with 95% of patients receiving three or four days of treatment with Mai E Ke Si. The population studied had a mean age of 31.3 (18-79) years of which approximately 3% were ≥65 years old, 53% were male and 84% were White, 11% were Hispanic.
Discontinuations due to adverse reactions occurred in 0.4% of patients. The adverse reactions leading to discontinuation were taste loss, dysentery, weight decrease, anorexia, nausea and nasal passage irritation.
The adverse reaction that occurred at a frequency ≥2% in Mai E Ke Si-treated patients (n=320) at a higher rate than placebo (n=228) in the two placebo-controlled trials of TD was:
- headache (10% Mai E Ke Si, 9% placebo)
Hepatic Encephalopathy
The data described below reflect exposure to Mai E Ke Si in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days). The safety of Mai E Ke Si 550 mg taken two times a day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n=140) and in a long term followup study (n=280). The population studied had a mean age of 56 (range: 21 to 82) years; approximately 20% of the patients were ≥65 years old, 61% were male, 86% were White, and 4% were Black. Ninetyone percent of patients in the trial were taking lactulose concomitantly. The most common adverse reactions that occurred at an incidence ≥5% and at a higher incidence in Mai E Ke Si-treated subjects than in the placebo group in the 6-month trial are provided in Table 1.
Table 1: Most Common Adverse Reactions in HE Trial
MedDRA Preferred Term | Number (%) of Patients | |
Mai E Ke Si Tablets 550 mg TWICE DAILY n=140 | Placebo n=159 | |
Peripheral edema | 21 (15%) | 13 (8%) |
Nausea | 20 (14%) | 21 (13%) |
Dizziness | 18 (13%) | 13 (8%) |
Fatigue | 17 (12%) | 18 (11%) |
Ascites | 16 (11%) | 15 (9%) |
Muscle spasms | 13 (9%) | 11 (7%) |
Pruritus | 13 (9%) | 10 (6%) |
Abdominal pain | 12 (9%) | 13 (8%) |
Anemia | 11 (8%) | 6 (4%) |
Depression | 10 (7%) | 8 (5%) |
Nasopharyngitis | 10 (7%) | 10 (6%) |
Abdominal pain upper | 9 (6%) | 8 (5%) |
Arthralgia | 9 (6%) | 4 (3%) |
Dyspnea | 9 (6%) | 7 (4%) |
Pyrexia | 9 (6%) | 5 (3%) |
Rash | 7 (5%) | 6 (4%) |
* reported in ≥5% of Patients Receiving Mai E Ke Si and at a higher incidence than placebo |
Irritable Bowel Syndrome With Diarrhea
The safety of Mai E Ke Si for the treatment of IBS-D was evaluated in 3 placebo-controlled studies in which 952 patients were randomized to Mai E Ke Si 550 mg three times a day for 14 days. Across the 3 studies, 96% of patients received at least 14 days of treatment with Mai E Ke Si. In Trials 1 and 2, 624 patients received only one 14-day treatment. Trial 3 evaluated the safety of Mai E Ke Si in 328 patients who received 1 open-label treatment and 2 double-blind repeat treatments of 14 days each over a period of up to 46 weeks. The combined population studied had a mean age of 47 (range: 18 to 88) years of whom approximately 11% of the patients were ≥65 years old, 72% were female, 88% were White, 9% were Black and 12% were Hispanic.
The adverse reaction that occurred at a frequency ≥2% in Mai E Ke Si-treated patients at a higher rate than placebo in Trials 1 and 2 for IBS-D was:
- nausea (3% Mai E Ke Si, 2% placebo)
The adverse reactions that occurred at a frequency >2% in Mai E Ke Si-treated patients (n=328) at a higher rate than placebo (n=308) in Trial 3 for IBS-D during the double-blind treatment phase were:
ALT increased (Mai E Ke Si 2%, placebo 1%)
- nausea (Mai E Ke Si 2%, placebo 1%)
Less Common Adverse Reactions
The following adverse reactions, presented by body system, were reported in less than 2% of patients in clinical trials of TD and IBS-D and in less than 5% of patients in clinical trials of HE:
Hepatobiliary disorders: Clostridium colitis
Investigations: Increased blood creatine phosphokinase
Musculoskeletal and connective tissue disorders: myalgia
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Mai E Ke Si. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, reported in ≥5% of Patients Receiving Mai E Ke Si and at a higher incidence than placebo frequency of reporting or causal connection to Mai E Ke Si.
Infections And Infestations
Cases of C. difficile-associated colitis have been reported.
General
Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration.
Non sono disponibili informazioni specifiche sul trattamento del sovradosaggio con Mai E Ke Si. Negli studi clinici a dosi superiori alla dose raccomandata (superiore a 600 mg al giorno per TD, superiore a 1100 mg al giorno per HE o superiore a 1650 mg al giorno per IBS-D) le reazioni avverse sono state simili nei soggetti che hanno ricevuto dosi superiori alla dose raccomandata e al placebo. In caso di sovradosaggio, interrompere Mai E Ke Si, trattare in modo sintomatico e istituire misure di supporto come richiesto.
Assorbimento
In soggetti sani, il tempo medio per raggiungere le concentrazioni plasmatiche di picco di rifaximina è stato di circa un'ora e la Cmax media variava da 2,4 a 4 ng / mL dopo una singola dose e dosi multiple di Mai E Ke Si 550 mg.
Viaggiatori Diarrea
L'assorbimento sistemico di Mai E Ke Si (200 mg tre volte al giorno) è stato valutato in 13 soggetti con problemi di shigellosi nei giorni 1 e 3 di un ciclo di trattamento di tre giorni. Le concentrazioni plasmatiche e le esposizioni di Rifaximin erano basse e variabili. Non sono state riscontrate prove di accumulo di rifaximina dopo somministrazione ripetuta per 3 giorni (9 dosi). Le concentrazioni plasmatiche di picco di rifaximina dopo 3 e 9 dosi consecutive variavano da 0,81 a 3,4 ng / mL il giorno 1 e da 0,68 a 2,26 ng / mL il giorno 3. Allo stesso modo, le ultime stime dell'AUC0 erano 6,95 ± 5,15 ng • h / mL il giorno 1 e 7,83 ± 4,94 ng • h / mL il giorno 3. Mai E Ke Si non è adatto per il trattamento di infezioni batteriche sistemiche a causa della limitata esposizione sistemica dopo somministrazione orale.
Encefalopatia epatica
L'esposizione media alla rifaximina (AUC τ) nei pazienti con anamnesi di HE era circa 12 volte superiore a quella osservata in soggetti sani. Tra i pazienti con anamnesi di HE, l'AUC media nei pazienti con compromissione epatica di classe C Child-Pugh era 2 volte superiore rispetto ai pazienti con compromissione epatica di classe A Child-Pugh.
Sindrome dell'intestino irritabile con diarrea
Nei pazienti con sindrome dell'intestino irritabile con diarrea (IBS-D) trattati con Mai E Ke Si 550 mg tre volte al giorno per 14 giorni, la Tmax mediana era di 1 ora e la Cmax e l'AUCtau medie erano generalmente comparabili con quelle in soggetti sani. Dopo dosi multiple, l'AUC era 1,65 volte superiore a quella del primo giorno nei pazienti con IBS-D (Tabella 2).
Tabella 2: Parametri farmacocinetici medi (± DS) di Rifaximin dopo Mai E Ke Si 550 mg tre volte al giorno in pazienti con IBS-D e soggetti sani
Soggetti sani | Pazienti IBS-D | |||
Dose singola (giorno 1) n = 12 | Dose multipla (giorno 14) n = 14 | Dose singola (giorno 1) n = 24 | Dose multipla (giorno 14) n = 24 | |
C max (ng / mL) | 4.04 (1.51) | 2,39 (1,28) | 3,49 (1,36) | 4,22 (2,66) |
T max (h) * | 0,75 (0,5-2,1) | 1,00 (0,5-2,0) | 0,78 (0-2) | 1,00 (0,5-2) |
AUC tau (ng • h / mL) | 10,4 (3,47) | 9.30 (2.7) | 9,69 (4,16) | 16,0 (9,59) |
Emivita (h) | 1,83 (1,38) | 5,63 (5,27) | 3.14 (1.71) | 6.08 (1.68) |
* Mediana (intervallo) |
Effetto alimentare in soggetti sani
Un pasto ricco di grassi consumato 30 minuti prima della somministrazione di Mai E Ke Si in soggetti sani ha ritardato il tempo medio al picco della concentrazione plasmatica da 0,75 a 1,5 ore e ha aumentato l'esposizione sistemica (AUC) della rifaximina di 2 volte, ma non ha influenzato in modo significativo Cmax.
Distribuzione
La rifaximina è moderatamente legata alle proteine plasmatiche umane. In vivo, il rapporto medio di legame con le proteine era del 67,5% in soggetti sani e del 62% in pazienti con compromissione epatica quando veniva somministrato Mai E Ke Si.
Eliminazione
L'emivita media di rifaximina in soggetti sani allo stato stazionario era di 5,6 ore ed era di 6 ore nei pazienti con IBSD.
Metabolismo
In uno studio in vitro la rifaximina è stata metabolizzata principalmente dal CYP3A4. La rifaximina rappresentava il 18% della radioattività nel plasma, suggerendo che la rifaximina assorbita subisce un ampio metabolismo.
Escrezione
In uno studio sul bilancio di massa, dopo somministrazione di 400 mg 14C-rifaximina per via orale a volontari sani, del recupero totale del 96,94%, il 96,62% della radioattività somministrata è stato recuperato nelle feci principalmente come farmaco immodificato e lo 0,32% è stato recuperato nelle urine principalmente come metaboliti con lo 0,03% come farmaco immodificato.
L'escrezione biliare di rifaximina è stata suggerita da uno studio separato in cui la rifaximina è stata rilevata nella bile dopo colecistectomia in pazienti con mucosa gastrointestinale intatta.
However, we will provide data for each active ingredient