Rifaximin

A07A - Intestinal antiinfectives ATC A07AA11 Small molecule approved 2004 Oral Natural product

JFDA label: Xifaxan 200mg tab

Mechanism of Action

Inhibitor of Bacterial DNA-directed RNA polymerase — Bacterial DNA-directed RNA polymerase inhibitor

Target	Action	Gene / class
Bacterial DNA-directed RNA polymerase efficacy	INHIBITOR

Indications

Approved

Hepatic encephalopathy
Irritable bowel syndrome with diarrhea
Traveler's diarrhea

Off-label

Clostridium difficile infection (recurrent)
Overt hepatic encephalopathy episodes (treatment)

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: openfda-label.

Bacteria

Organism	Activity	MIC
Escherichia coli	Active	—

Contraindications

Source: Lexicomp

Hypersensitivity to rifaximin, other rifamycin antibiotics, or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Very Common Peripheral edema

Nervous system disorders (4)

Very Common Dizziness · fatigue

Common depression · Headache

Hepatobiliary disorders (2)

Very Common Ascites

Common Increased serum ALT

Gastrointestinal disorders (3)

Very Common Nausea

Common Abdominal pain · pseudomembranous colitis

Skin and subcutaneous tissue disorders (2)

Common Pruritus · skin rash

Musculoskeletal and connective tissue disorders (3)

Common arthralgia · increased creatine phosphokinase, dyspnea, epistaxis · Muscle spasm

General disorders and administration site conditions (1)

Common Fever

Other (5)

Common Clostridium difficile associated diarrhea · exfoliative dermatitis · flushing · hypersensitivity reaction · urticaria

Dosing

Source: Lexicomp

Hepatic encephalopathy: Oral: Reduction of overt hepatic encephalopathy recurrence: 550 mg 2 times daily. Note: Supporting clinical trial evaluated efficacy over 6-month treatment period. Treatment of hepatic encephalopathy (off-label use): 400 mg every 8 hours for 5 to 10 days (Mas 2003) Irritable bowel syndrome with diarrhea (IBS-D): Oral: 550 mg 3 times daily for 14 days; may be retreated up to 2 times with the same dosing regimen if symptoms recur. Traveler's diarrhea: Oral: 200 mg 3 times daily for 3 days Clostridium difficile -associated diarrhea (off-label use): Oral: 200 to 400 mg 2 to 3 times daily for 14 days (Johnson 2007)

(For additional information see "Rifaximin: Pediatric drug information") Traveler's diarrhea: Oral: Children ≥12 years and Adolescents: Refer to adult dosing.

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

No dosage adjustment necessary. Use with caution in severe impairment (Child-Pugh class C); however, systemic absorption is limited and pharmacokinetic parameters are highly variable.

Warnings & Precautions

Source: Lexicomp

Hypersensitivity

Hypersensitivity reactions (eg, exfoliative dermatitis, rash, urticaria, flushing, angioneurotic edema, pruritus, anaphylaxis) have occurred; these events have occurred as early as within 15 minutes of drug administration.

Superinfection

Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. Disease-related concerns:

Diarrhea

Appropriate use: Avoid use in diarrhea with fever and/or blood in the stool and in the treatment of diarrhea due to pathogens other than E. coli, including C. jejuni, Shigella, and Salmonella (efficacy has not been established). Consider alternative therapy if symptoms persist or worsen after 24 to 48 hours of treatment.

Hepatic impairment

Efficacy for prevention of encephalopathy has not been established in patients with a Model for End-Stage Liver Disease (MELD) score >25; use caution in patients with severe hepatic impairment (Child-Pugh class C). Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Propylene glycol

Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). Other warnings/precautions:

Appropriate use

Not for treatment of systemic infections;

Pregnancy & Lactation

Pregnancy

Adverse events have been observed in some animal reproduction studies. Due to the limited oral absorption of rifaximin in patients with normal hepatic function, exposure to the fetus is expected to be low.

Lactation

It is not known if rifaximin is excreted in human milk. According to the manufacturer, the decision to breast-feed during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother. Because of the limited oral absorption of rifaximin in patients with normal hepatic function, exposure to the nursing infant is expected to be low.

Monitoring

Clinical pearl	Hypersensitivity reactions, temperature, blood in stool, change in symptoms; monitor changes in mental status in hepatic encephalopathy

Chemistry & Properties

Formula	C43H51N3O11
Molecular weight	785.89 g/mol
IUPAC name	[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,36-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22,30-octamethyl-6,23-dioxo-8,37-dioxa-24,27,33-triazahexacyclo[23.10.1.14,7.05,35.026,34.027,32]heptatriaconta-1(35),2,4,9,19,21,25(36),26(34),28,30,32-undecaen-13-yl] acetate
CAS	80621-81-4
PubChem CID	6436173
InChIKey	`NZCRJKRKKOLAOJ-XRCRFVBUSA-N`
logP	6.16 (XLogP 6.9)
Polar surface area	198.38 Å²
H-bond acceptors / donors	13 / 5
Drug-likeness (QED)	0.11
Lipinski violations	3

SMILES

CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c5c(nc6cc(C)ccn65)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C8	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (48, DDInter)

Interacting drug	Severity	Management
Typhoid vaccine (live)	major
Vibrio cholerae CVD 103-HgR strain live antigen (live)	major
Alpelisib	moderate
Anisindione	moderate
Apalutamide	moderate
Bempedoic acid	moderate
Bifidobacterium longum infantis	moderate
Brigatinib	moderate
Cabozantinib	moderate
Capmatinib	moderate
Cyclosporine	moderate
Daclatasvir	moderate
Darolutamide	moderate
Dicoumarol	moderate
Elagolix	moderate
Elexacaftor	moderate
Eliglustat	moderate
Enasidenib	moderate
Encorafenib	moderate
Entrectinib	moderate
Enzalutamide	moderate
Erdafitinib	moderate
Flibanserin	moderate
Fostamatinib	moderate
Fostemsavir	moderate
Gemfibrozil	moderate
Gilteritinib	moderate
Glasdegib	moderate
Ibrutinib	moderate
Istradefylline	moderate
Lactobacillus acidophilus	moderate
Lasmiditan	moderate
Ledipasvir	moderate
Lonafarnib	moderate
Midostaurin	moderate
Neratinib	moderate
Nilotinib	moderate
Picosulfuric acid	moderate
Ponatinib	moderate
Rolapitant	moderate

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Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Xifaxan	Tablet 200 mg	12 tab	Almutanabbe Drug Store	6.410