Fidaxomicin

1060.01198

1058.04

Z5N076G8YQ

C66979

A07AA12|A - Alimentary tract and metabolism

267 Ų

1.3±0.1 g/cm3

1046.4

586.7±34.3 °C

1.590

|Warning|H302 (97.3%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 37 companies from 2 notifications to the ECHA C&L Inventory.

In rats, the LD50 of fidaxomicin was approximately 200 mg/kg and the no observed adverse effect level (NOAEL) was determined to be 62.5 mg/kg following administration of a single intravenous dose. There is limited clinical data on acute overdose in humans.

In large clinical trials, therapy with fidaxomicin for ten days was associated with a low rate of serum aminotransferase elevations [1% to 3.2%], but rates with comparator agents such as vancomycin were similar [up to 2.7%]. There have been no reports of clinically apparent liver injury attributed to fidaxomicin. However, other oral macrolide antibiotics have been linked to many episodes of acute liver injury which can be severe and have resulted in fatalities. The onset of macrolide associated liver injury is typically 1 to 3 weeks after starting the drug and can arise after it is stopped. The injury is typically cholestatic, but can be mixed or hepatocellular. The hepatocellular cases are more likely to be severe and can result in acute liver failure. However, in most instances, recovery occurs within 4 to 8 weeks of withdrawal of the macrolide. No such cases, however, have been linked to use of fidaxomicin, which unlike the other macrolides is not absorbed orally.

Since fidaxomicin has minimal systemic absorption following oral administration, there is limited information on the plasma protein binding profile of fidoxamicin.

Fidaxomicin is indicated for the treatment of _Clostridioides_ (formerly _Clostridium_) _difficile_-associated diarrhea in adult and pediatric patients 6 months of age and older. Fidaxomicin should only be used in patients with proven or strongly suspected _C. difficile_ infection to reduce the risk of development of drug-resistant bacteria and maximize the therapeutic effectiveness of fidaxomicin and other antimicrobial agents.|FDA Label|Dificlir film-coated tablets is indicated for the treatment of Clostridioides difficile infections (CDI) also known as C. difficile-associated diarrhoea (CDAD) in adult and paediatric patients with a body weight of at least 12.5 kg.Consideration should be given to official guidelines on the appropriate use of antibacterial agents.Dificlir granules for oral suspension is indicated for the treatment of Clostridioides  difficile infections (CDI) also known as C. difficile-associated diarrhoea (CDAD) in adults and paediatric patients from birth to < 18 years of age.Consideration should be given to official guidelines on the appropriate use of antibacterial agents.|Treatment of enterocolitis caused by Clostridium difficile

Fidaxomicin is a semisynthetic macrolide antibiotic used to treat Clostridium difficile-associated diarrhea in adults. Fidaxomicin has minimal systemic absorption and has not been linked to serum enzyme elevations during therapy or to instances of clinically apparent, acute liver injury.

Antiinfective Agents

Fidaxomicin has a narrow-spectrum antibacterial profile, with potent bactericidal activity specifically against C. difficile. The minimum inhibitory concentration for 90% of organisms for fidaxomicin against _C. difficile_ ranged from 0.0078 to 2 μg/mL _in vitro_. The bactericidal activity of fidaxomicin is time-dependent. Other than _C. difficile_, fidaxomicin has moderate inhibitory activity against Gram-positive bacteria (_S. aureus_ and _Enterococcus spp._) and poor activity against normal colonic flora, including anaerobes and enteric Gram-negative bacilli. Isolates of _C. difficile_ that are resistant to rifamycins or other antimicrobial classes (such as cephalosporins, fluoroquinolones, clindamycin) were not shown to be cross-resistant to fidaxomicin.

Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)

Following oral administration of a single dose of 200 mg fidaxomicin in healthy adults, the C_max of fidaxomicin and its main metabolite OP-1118 were 5.20 ± 2.81 ng/mL and 12.0 ± 6.06, respectively. The median T_max of fidaxomicin was 2 hours. The systemic absorption of fidaxomicin following oral administration is minimal. In a food-effect study involving healthy adults in either with a high-fat meal versus under fasting conditions, the C_max of fidaxomicin and OP-1118 were decreased by 21.5% and 33.4%, respectively; however, this effect is deemed to be clinically insignificant as the therapeutic action of fidaxomicin does not depend on drug concentrations in the systemic circulation.|Following oral administration, fidaxomicin is mainly excreted in feces. More than 92% of the dose was recovered in the faces as either the unchanged parent drug or metabolites in one study consisting of healthy adults receiving single doses of 200 mg and 300 mg of fidaxomicin. In another study of healthy adults, approximately 0.59% fo the oral dose (200 mg) administered was recovered in the urine as the main metabolite, OP-1118.|Fidaxomicin is mainly confined to the gastrointestinal tract when orally administered. There is limited information on the volume of distribution of fidaxomicin.|There is limited information on the clearance of fidaxomicin.

Following oral administration, fidaxomicin is transformed to its main and pharmacologically active metabolite, OP-1118, via hydrolysis at the isobutyryl ester. As cytochrome enzymes are not involved in the metabolism of fidaxomicin, it is speculated that this biotransformation is mediated by gastric acid or enzymatic activity of intestinal microsomes.

Following oral administration of a single dose of 200 mg fidaxomicin in healthy adults, the elimination half-life of fidaxomicin was approximately 11.7 ± 4.80 hours.

_Clostridium difficile_ is a Gram-positive bacterium that causes various gastrointestinal complications, such as antibiotic-associated diarrhea. _C. difficile_ infection can be caused by antibiotic therapy, resulting in the disruption of the human gut flora leads to an overgrowth of _C. difficile_. The consequences of _C. difficile_ infection can be mild to severe and sometimes fatal. Fidaxomicin gets hydrolyzed to its active metabolite, OP-1118, upon oral administration. Both compounds mediate a bactericidal activity against _C. difficile_ by inhibiting bacterial RNA polymerase at the initiation phase of the transcription cycle. The RNA polymerase is an essential bacterial enzyme that regulates gene expression, catalyzes nucleic acid interactions, and promotes several bacterial enzymatic reactions critical for bacterial survival. The core RNA polymerase is composed of a complex of different subunits and contains the active site. To initiate bacterial transcription, the active site of the core RNA polymerase binds to a promoter-specificity σ initiation factor, which locates and binds to a promoter region of the DNA. The DNA-RNA polymerase interaction promotes subsequent steps of transcription, which involves the separation of DNA strands. Fidaxomicin binds to the DNA template-RNA polymerase complex, thereby preventing the initial separation of DNA strands during transcription and inhibiting messenger RNA synthesis. The narrow spectrum of antimicrobial activity of fidaxomicin may be explained by the unique target site of fidaxomicin and differing σ subunits of the core structure of RNA polymerase among bacterial species.

Dificid

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