Rifabutin

J04A - Drugs for treatment of tuberculosis ATC J04AB04 Small molecule approved 1992 Oral Natural product

JFDA label: MYCOBUTIN 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

Mycobacterium avium complex (MAC), prophylaxis

Off-label

Latent tuberculosis (LTBI) in HIV-infected patients (adolescents and adults)
Mycobacterium avium complex disease (disseminated) treatment in HIV-infected patients (adolescents and adults)
Tuberculosis, treatment (drug-susceptible) (excludes meningitis)
Tuberculosis, treatment in HIV-infected patients (adolescents and adults)

Antimicrobial Spectrum

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

Mycobacteria

Organism	Activity	MIC
Clostridioides difficile	Active	—
Helicobacter pylori	Active	—
Mycobacterium avium	Active	—
Pneumocystis carinii	Active	—

Contraindications

Source: Lexicomp

Clinically significant hypersensitivity to rifabutin, other rifamycins, 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

Renal and urinary disorders (1)

Very Common Discoloration of urine

Blood and lymphatic system disorders (3)

Very Common leukopenia · Neutropenia

Common Thrombocytopenia

Gastrointestinal disorders (7)

Common abdominal pain · dysgeusia · dyspepsia · eructation · flatulence · Nausea · vomiting

Skin and subcutaneous tissue disorders (1)

Very Common Skin rash

Musculoskeletal and connective tissue disorders (1)

Common Myalgia

General disorders and administration site conditions (1)

Common Fever

Dosing

Source: Lexicomp

Mycobacterium avium complex (MAC) disease (disseminated) in HIV-infected patients: Oral: Primary prophylaxis (patients with CD4 count 3): 300 mg once daily (HHS [OI adult 2017)]; alternatively, per the manufacturer, 150 mg twice daily with food may be used in patients with GI upset. May discontinue when CD4 count >100 cells/mm3 for ≥3 months in response to antiretroviral therapy (ART) (HHS [OI adult 2017]). Note: If effective ART is initiated immediately and viral suppression is achieved, some experts do not recommend routine initiation of MAC primary prophylaxis, regardless of initial CD4 count (IAS-USA [Gunthard 2016]). Treatment (off-label use): 300 mg once daily as optional adjunct therapy with clarithromycin or azithromycin (plus ethambutol) (HHS [OI adult 2017]) Tuberculosis (off-label use): Oral: Latent tuberculosis (LTBI) treatment (to prevent TB) in HIV-infected patients: Daily dose based on concomitant ART for 4 months (HHS [OI adult 2015]) Note: LTBI treatment is recommended in HIV-infected patients testing positive for LTBI (but have no evidence of TB disease or no prior history of treatment for active or LTBI) or in HIV-infected close contacts of anyone who has infectious TB (regardless of screening tests for LTBI). LTBI treatment is not associated with clinical benefit or recommended in HIV infected patients who are anergic and who have not had recent contact with anyone with infectious TB (HHS [OI adult 2015]) Treatment of drug-susceptible TB (excludes meningitis) ( as an alternative/substitute for rifampin ): Non-HIV-infected patients: 5 mg/kg/dose (usual dose: 300 mg) once daily as part of a multidrug regimen (Nahid 2016). HIV-infected patients (and not receiving protease inhibitors, efavirenz, rilpivirine or elvitegravir/cobicistat/emtricitabine/tenofovir): 5 mg/kg/day (usual dose: 300 mg) once daily or intermittently 3 times weekly as part of a multidrug regimen (HHS [OI adult 2015]).

(For additional information see "Rifabutin: Pediatric drug information") Mycobacterium avium complex disease in HIV-exposed/-infected patients (off-label use): Oral: Prophylaxis for recurrence of Mycobacterium avium complex (MAC): Infants and Children: 5 mg/kg (maximum dose: 300 mg) once daily as an optional add-on to primary therapy of clarithromycin and ethambutol (CDC 2009). Prophylaxis for first episode of MAC: Children ≥6 years: 300 mg once daily (CDC 2009). Treatment of severe MAC: Infants and Children: 10 to 20 mg/kg (maximum dose: 300 mg) once daily, in addition to primary therapy of clarithromycin and ethambutol (CDC 2009). Adolescents (disseminated disease): Refer to adult dosing. Tuberculosis, treatment of drug-susceptible disease (as an alternative/substitute for rifampin) (excludes meningitis) (off-label use): Oral: Non-HIV-infected patients: Children and Adolescents: Appropriate dosing is unknown; estimated at 5 mg/kg/dose once daily (Nahid 2016) HIV-exposed/-infected patients: Infants and Children: 10 to 20 mg/kg (maximum dose: 300 mg) once daily or intermittently 2 to 3 times weekly (CDC 2009). Adolescents (and not receiving protease inhibitors, efavirenz, rilpivirine or elvitegravir/cobicistat/emtricitabine/tenofovir): Refer to adult dosing. Tuberculosis, LTBI treatment (to prevent TB) in HIV-infected patients (alternative to preferred therapy) (off-label use): Adolescents: Refer to adult dosing.

Refer to adult dosing.

CrCl ≥30 mL/minute: No dosage adjustment necessary. CrCl

Mild impairment: No dosage adjustment necessary. Moderate to severe impairment: There are no dosage adjustments provided in manufacturer's labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Hematologic toxicity

May be associated with neutropenia and/or thrombocytopenia (rarely); consider periodic monitoring of hematologic parameters and discontinue permanently if signs of thrombocytopenia (eg, petechial rash) (HHS [OI adult 2015]).

Hypersensitivity reactions

Hypersensitivity reactions, including anaphylaxis, hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, and flu-like syndrome, may occur with rifamycins. Discontinue use and administer supportive care if hypersensitivity occurs.

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.

Uveitis

May occur; carefully monitor patients when used in combination with macrolides or azole antifungals. If uveitis is suspected, refer patient to an ophthalmologist and consider temporarily discontinuing treatment. Disease-related concerns:

Hepatic impairment

Use with caution in patients with hepatic impairment; discontinue in patients with ALT ≥3 x ULN (symptomatic) or ≥5 x ULN (regardless of symptoms) (HHS [OI adult 2017]).

Renal impairment

Use with caution in patients with renal impairment; dosage reduction recommended in severe impairment (CrCl 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. Other warnings/precautions:

Appropriate use

Must not be administered for MAC prophylaxis to patients with active tuberculosis since its use may lead to the development of TB resistant to both rifabutin and rifampin. Caution that active TB in the HIV-positive patient may present atypically (ie, negative PPD or extrapulmonary manifestations).

Contact lenses

Remove soft contact lenses during therapy since permanent staining may occur.

Brown/orange discoloration

Urine, feces, saliva, sweat, tears, sputum, and skin may be discolored to brown/orange.

Pregnancy & Lactation

Pregnancy

Adverse events were seen in some animal reproduction studies.

Lactation

Avoid

It is not known if rifabutin is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Females with HIV infection should completely avoid breastfeeding to decrease the potential transmission of HIV (HHS [perinatal] 2017).

LactMed: monitor the infant.

Monitoring

Clinical pearl	Periodic liver function tests, CBC with differential, platelet count, signs/symptoms of hypersensitivity or uveitis

Chemistry & Properties

Formula	C46H62N4O11
Molecular weight	847.02 g/mol
IUPAC name	[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(31),2,4,9,19,21,25(32),26,29-nonaene-28,4'-piperidine]-13-yl] acetate
PubChem CID	135415564
InChIKey	`ATEBXHFBFRCZMA-VXTBVIBXSA-N`
logP	4.62 (XLogP 5.6)
Polar surface area	205.55 Å²
H-bond acceptors / donors	14 / 5
Drug-likeness (QED)	0.26
Lipinski violations	2

SMILES

CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C2=NC3(CCN(CC(C)C)CC3)NC2=C(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)C4=O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.18 h
Volume of distribution	1.93 L/kg
Protein binding	81.0%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Abiraterone	major
Alpelisib	major
Axitinib	major
Bortezomib	major
Bosutinib	major
Brigatinib	major
Cabozantinib	major
Cobicistat	major
Cobimetinib	major
Crizotinib	major
Cyclosporine	major
Dasatinib	major
Deferiprone	major
Deflazacort	major
Dicoumarol	major
Eliglustat	major
Encorafenib	major
Entrectinib	major
Ethinylestradiol	major
Everolimus	major
Fedratinib	major
Glasdegib	major
Hydrocodone	major
Ibrutinib	major
Imatinib	major
Irinotecan	major
Irinotecan (liposomal)	major
Ivacaftor	major
Ixazomib	major
Ketoconazole	major
Larotrectinib	major
Lorlatinib	major
Neratinib	major
Nilotinib	major
Olaparib	major
Osilodrostat	major
Osimertinib	major
Palbociclib	major
Panobinostat	major
Praziquantel	major

Showing 40 of 100+.

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
MYCOBUTIN Tab	Tablet 150 mg	30 tab	Khoury Drug Store	83.990