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RIFABUTIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Rifabutin, an antimycobacterial agent, is a semi-synthetic ansamycin antibiotic derived from rifamycin S.

Specific Substances

    1) 1,4-Dihydro-1-deoxy-1',4-didehydro-5'-(2-methylpropyl)-1-oxorifamycin XIV
    2) 4-Deoxo-3,4-(2-spiro(N-isobutyl-4-piperidyl)-2,5-dihydro-1H-imidazo)-rifamycin S
    3) Ansamycin
    4) Ansamicin
    5) Rifabutine
    6) Rifabutinum
    7) Antibiotic LM 427
    8) LM-427
    9) CAS 72559-06-9
    1.2.1) MOLECULAR FORMULA
    1) C46-H62-N4-O11

Available Forms Sources

    A) FORMS
    1) Rifabutin is available as 150 mg capsules (Prod Info RIFABUTIN oral capsules, 2014).
    B) USES
    1) Rifabutin is indicated for the prevention of disseminated mycobacterium avium complex (MAC) disease in patients with advanced HIV infection (Prod Info RIFABUTIN oral capsules, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Uveitis, skin rashes, skin discoloration, and urine discoloration have been frequently reported with rifabutin therapy. Other reported adverse effects include neutropenia, nausea, vomiting, dyspepsia, and ageusia.
    B) WITH POISONING/EXPOSURE
    1) Overdose information of rifabutin is limited. Daily doses of 1 gram or greater have resulted in a syndrome of arthralgia/arthritis.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Hematologic abnormalities, including leukopenia and thrombocytopenia, have been reported with rifabutin therapy.
    0.2.15) MUSCULOSKELETAL
    A) WITH POISONING/EXPOSURE
    1) Arthralgia/arthritis syndrome has been reported with rifabutin monotherapy in doses greater than 1 gram daily.
    0.2.20) REPRODUCTIVE
    A) Rifabutin is classified as FDA pregnancy category B.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of rifabutin in humans.
    0.2.22) OTHER
    A) WITH THERAPEUTIC USE
    1) Rifabutin is a cytochrome P450 3A (CYP3A) enzyme inducer, resulting in increased metabolism of drugs principally metabolized by those enzymes. Rifabutin is also metabolized by CYP3A, resulting in increased plasma concentrations of rifabutin when administered with drugs that inhibit CYP3A enzymes.

Laboratory Monitoring

    A) Plasma rifabutin levels may be useful to confirm overdoses, but are not readily available and are not useful in guiding therapy.
    B) Monitor CBC, liver enzyme levels, and fluid/electrolyte status as indicated.
    C) Perform an ophthalmologic examination in patients with visual symptoms (eye pain, changes in visual acuity, etc.).

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) In case of rifabutin overdose, treatment is symptomatic and supportive.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.

Range Of Toxicity

    A) A specific toxic dose of rifabutin has not been established. A syndrome of arthralgia/arthritis has been reported following daily doses of at least 1 gram.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Uveitis, skin rashes, skin discoloration, and urine discoloration have been frequently reported with rifabutin therapy. Other reported adverse effects include neutropenia, nausea, vomiting, dyspepsia, and ageusia.
    B) WITH POISONING/EXPOSURE
    1) Overdose information of rifabutin is limited. Daily doses of 1 gram or greater have resulted in a syndrome of arthralgia/arthritis.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) UVEITIS
    a) Uveitis has been frequently reported with rifabutin therapy, in immunocompromised as well as in immunocompetent patients (Vaudaux & Guex-Crosier, 2002; Shafran et al, 1998; Chaknis et al, 1996; Shafran et al, 1996; Shafran et al, 1994; Havlir et al, 1994; Frank et al, 1994; Fuller et al, 1994). Rifabutin-associated uveitis is characterized by ocular pain, redness, and photophobia, with or without the presence of vitreous opacities (Shafran et al, 1998; Chaknis et al, 1996). It can develop over a wide range of time (less than 2 weeks to longer than 7 months) after initiating therapy with rifabutin (Vaudaux & Guex-Crosier, 2002). Ophthalmic corticosteroids and cycloplegic agents have been used to successfully treat uveitis (Arevalo & Freeman, 2000). Discontinuing rifabutin or decreasing the dose has also been reported to resolve uveitis (Prod Info Mycobutin(R), 2002; Nichols, 1996). Complete recovery of visual acuity is typical, within 6 days to upwards of 10 weeks after drug withdrawal and topical steroids (Vaudaux & Guex-Crosier, 2002).
    b) Typically, the incidence of uveitis is rare when rifabutin is used as a single agent at 300 mg/day for the prevention of MAC in HIV-infected patients; however, it has been postulated that fluconazole and macrolide antibiotics such as azithromycin and clarithromycin may inhibit hepatic metabolism via the cytochrome P450 enzyme system and increase serum rifabutin concentrations and thereby increase the incidence of uveitis (Prod Info Mycobutin(R), 2002; Nichols, 1996; Tseng & Walmsley, 1995).
    c) Three case reports describe uveitis in patients without human immunodeficiency virus receiving a rifabutin regimen for atypical mycobacterial infections. Rifabutin was dosed at 300 milligrams/day concomitantly with ethambutol (n=3), clarithromycin (n=2), isoniazid (n=1) and ciprofloxacin (n=1). Patients presented with unilateral vision loss and hypopyon with anterior chamber inflammation and vitreous infiltrate. The uveitis resolved with topical steroid and mydriatic therapy (Khan et al, 2000).
    2) CORNEAL DEPOSITS
    a) A prospective study of ophthalmologic changes in 25 children with human immunodeficiency virus (HIV) and low CD4 cell count (less than 50/cubic millimeter) reported bilateral, stellate corneal endothelial deposits without uveitis in 6 children (24%) during rifabutin prophylaxis of Mycobacterium avium complex (MAC) infection. In comparing patient characteristics, the only significant differences were longer mean duration of rifabutin therapy (27 versus 14 months, p=0.017) and follow-up (39 versus 18 months, p=0.001) in those who did and did not develop corneal deposits, respectively. Rifabutin dosing ranged from 5 to 15 milligrams/kilogram/day, with corneal abnormalities first diagnosed after 32.5 months (median). In children who subsequently discontinued rifabutin, the corneal deposits stabilized or decreased but did not disappear. No visual decrements were noted (Smith et al, 1999).
    1) The authors also reported rifabutin-associated corneal deposits in 11 of 63 HIV-positive children enrolled in other protocols, for an overall incidence rate of 19%. The mechanism of this adverse effect remains to be elucidated, but may involve a direct toxic effect of rifabutin, drug or disease interactions, and/or local corneal factors.
    3) CYSTOID MACULAR EDEMA
    a) A 56-year-old female, who received rifabutin 150 mg twice daily, as well as clarithromycin and ethambutol, for treatment of mycobacterium avium complex pulmonary infection, developed decreased visual acuity and a hypopyon associated with severe anterior uveitis. Although the hypopyon disappeared following discontinuation of rifabutin therapy and administration of prednisolone, peripheral opacities appeared and the patient's visual acuity continued to worsen. Fluorescein angiography and optical coherence tomography confirmed the presence of cystoid macular edema. The cystoid macular edema gradually resolved completely following administration of triamcinolone, diclofenac, and acetazolamide (Vaudaux & Guex-Crosier, 2002).
    4) OCULAR DISCOLORATION
    a) Rifabutin can cause a brown-orange discoloration of body fluids, including tears, which may permanently stain soft contact lenses (Prod Info Mycobutin(R), 2002).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal intolerance, including anorexia, diarrhea, dyspepsia, eructation, flatulence, nausea, and vomiting, occurs in approximately 3% of patients taking rifabutin (Prod Info Mycobutin(R), 2002).
    B) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) Taste perversion was reported in 3% of patients in clinical trials (Prod Info Mycobutin(R), 2002).
    b) Ageusia or loss of the sense of taste was reported in a patient receiving rifabutin for a pulmonary infection with Mycobacterium simiae. Six weeks after starting therapy the patient reported ageusia, arthralgias, and myalgias that resolved two weeks after discontinuing rifabutin. The patient was re-challenged and symptoms recurred (Morris & Kelly, 1993).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzyme levels have infrequently occurred following therapeutic administration of rifabutin and generally normalize following a decrease in the dosage or cessation of therapy (Prod Info Mycobutin(R), 2002; Griffith et al, 1995).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINE COLOR ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Rifabutin can cause brown-orange discoloration of urine and feces. Urine discoloration was reported in 30% of patients in clinical trials (Prod Info Mycobutin(R), 2002; Siegal et al, 1990).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hematologic abnormalities, including leukopenia and thrombocytopenia, have been reported with rifabutin therapy.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 68-year-old man was given initial treatment for mycobacterium avium complex with triple therapy including ethambutol (1600 mg/day), clarithromycin (500 mg twice daily), and rifabutin (600 mg/day). Three weeks after beginning treatment, his WBC had fallen from normal levels to 2,800 cells/mm(3), and on repeat one day later was 1,500. All drugs were discontinued and over the next two days, the WBC improved to 3,600. Two weeks later, WBC was well within normal range at 9,500. Drug therapy was restarted, but at rifabutin 300 mg daily. Two weeks later, WBC was 2,500 and drugs were once again discontinued. WBC improved to 7,600 one week later. Clofazimine was eventually substituted successfully for rifabutin (Chitre & Berenson, 2001).
    b) Neutropenia developed in 25% of patients (n=566) receiving rifabutin during clinical trials, as compared with 20% of patients (n=580) receiving placebo (Prod Info Mycobutin(R), 2002).
    c) Severe neutropenia (ANC 0.8 x 10(9) in one patient) occurred in several healthy volunteers approximately 9 days after beginning a 14-day clinical trial that was conducted to determine the possibility of pharmacokinetic interactions between rifabutin and azithromycin or clarithromycin. The neutropenia occurred in patients who received rifabutin (300 mg daily) with or without concomitant administration of azithromycin or clarithromycin; however, the neutropenia appeared to be more severe in individuals who received rifabutin and azithromycin or clarithromycin concurrently. The neutropenia gradually resolved following cessation of rifabutin therapy and administration of granulocyte colony stimulating factor (G-CSF) (Apseloff et al, 1996).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported with rifabutin use (5% versus placebo 4%) (Prod Info Mycobutin(R), 2002). Patients may be at increased risk of developing hematologic abnormalities such as leukopenia, anemia, and thrombocytopenia, when used in combination with either clarithromycin or azithromycin. Reducing the rifabutin dose to 300 mg/day when combining therapy with a macrolide may decrease this risk (Griffith et al, 1996; Tansey & Moe, 1996; Griffith et al, 1995).
    b) Healthy volunteers, receiving rifabutin (300 mg daily) as monotherapy or in combination with azithromycin or clarithromycin, experienced a 43% mean decrease in platelets following concomitant administration of rifabutin and clarithromycin (Apseloff et al, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash has been reported in approximately 11% of patients on rifabutin (Prod Info Mycobutin(R), 2002).
    B) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Rifabutin can cause brown-orange discoloration of perspiration. Discolored perspiration may cause staining of the skin (Prod Info Mycobutin(R), 2002).
    b) Pseudojaundice, characterized by yellow to orange-tan pigmentation of the skin but not the sclera, has been reported in several patients approximately 10 weeks after beginning rifabutin therapy. The pigmentation was not associated with pruritus. Serum bilirubin concentrations were normal in all but one patient, who had a slightly elevated level (46 mcmol/L) (Shafran et al, 1994; Siegal et al, 1990). The skin pigmentation gradually disappeared following cessation of rifabutin therapy.

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Arthralgia/arthritis syndrome has been reported with rifabutin monotherapy in doses greater than 1 gram daily.
    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) A polyarthralgia/arthritis syndrome was reported in 2 patients receiving rifabutin at standard doses of 300 milligrams (mg) to 450 mg daily, along with clarithromycin. One patient was infected with human immunodeficiency virus (HIV) and one was not. Serum tests for rheumatoid factor and antinuclear antibodies were negative in both patients. Symptoms resolved in 1 to 2 months after discontinuation of the rifabutin. The authors concluded that the reaction may have been due to increased rifabutin serum concentrations resulting from the concomitant clarithromycin, a known hepatic enzyme inhibitor (Le Gars et al, 1999).
    b) CASE REPORT - Arthralgias and myalgias were reported in a 71-year-old female approximately 6 weeks after beginning rifabutin and clarithromycin therapy. The symptoms resolved after cessation of rifabutin therapy. Two days after restarting rifabutin therapy, the patient reported worsening arthralgias and myalgias. The symptoms again resolved after discontinuation of rifabutin therapy (Morris & Kelly, 1993).
    2) WITH POISONING/EXPOSURE
    a) A syndrome of arthralgia/arthritis has been reported following administration of rifabutin, as monotherapy, in doses of 1050 to 2400 mg/day, and appeared to be reversible upon discontinuation of rifabutin (Prod Info Mycobutin(R), 2002; Siegal et al, 1990).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) Drug-induced lupus syndrome has occurred in three patients receiving rifabutin 300 milligrams daily for the treatment of mycobacterial infections. Symptoms occurred within 3 to 157 months of therapy and consisted of arthralgias, arthritis and extremity edema. All patients had positive antinuclear antibodies (ANAs) with titers of 1/160 or more and homogenous patterns. Discontinuation of rifabutin therapy resolved symptoms in 1 to 10 weeks. Patients were also receiving hepatic enzyme inhibitors, ciprofloxacin or clarithromycin, which may have altered rifabutin plasma concentrations (Berning & Iseman, 1997).

Reproductive

    3.20.1) SUMMARY
    A) Rifabutin is classified as FDA pregnancy category B.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no human data were available to assess the teratogenic potential of this agent. However, rifabutin did cause skeletal variants in rats and rabbits at doses approximately equal to human doses, based on comparison of body surface area and maternotoxicity occurred at doses approximately 5 times the human dose, based on comparison of body surface area (Prod Info Mycobutin(R) oral capsules, 2014).
    B) ANIMAL STUDIES
    1) RATS, RABBITS: Studies conducted in rats and rabbits did not result in teratogenic effects in either species when given doses of up to 200 mg/kg (approximately 6 times the recommended daily human exposure, based on comparison of body surface area) (Prod Info Mycobutin(R) oral capsules, 2014).
    2) RATS: An increase in fetal skeletal variants occurred in rats following rifabutin administration at a dose of 40 mg/kg/day (approximately equivalent to the recommended human daily dose, based on comparison of body surface area) (Prod Info Mycobutin(R) oral capsules, 2014).
    3) RABBITS: An increase in fetal skeletal anomalies occurred in rabbits following rifabutin administration at a dose of 80 mg/kg/day (approximately 5 times the recommended human daily dose, based on comparison of body surface area) (Prod Info Mycobutin(R) oral capsules, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info Mycobutin(R) oral capsules, 2014).
    B) PREGNANCY CATEGORY
    1) The manufacturer has classified rifabutin as FDA pregnancy category B (Prod Info Mycobutin(R) oral capsules, 2014).
    C) ANIMAL STUDIES
    1) RABBITS: Rabbits given 80 mg/kg/day (approximately 5 times the recommended daily human exposure, based on comparison of body surface area) had increased maternotoxicity (Prod Info Mycobutin(R) oral capsules, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether rifabutin is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Because many drugs are excreted in breast milk there is the potential for adverse effects in nursing infants. Due to the potential for adverse events in the nursing infant, a decision should be made to either discontinue nursing or discontinue rifabutin therapy. The importance of the drug to the mother should be taken into consideration (Prod Info Mycobutin(R) oral capsules, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Fertility was impaired in male rats given rifabutin at a dose of 160 mg/kg (32 times the recommended human daily dose) (Prod Info Mycobutin(R), 2002).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS72559-06-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of rifabutin in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Rifabutin was not carcinogenic in mice or rats following long-term administration at doses up to 180 mg/kg/day (approximately 36 times the recommended human daily dose) or 60 mg/kg/day (approximately 12 times the recommended human daily dose), respectively (Prod Info MYCOBUTIN(R) oral capsules, 2007).

Genotoxicity

    A) There was no evidence of genotoxicity in V-79 Chinese hamster cells, human lymphocytes in vitro, or mouse bone marrow cells in vivo. There was no evidence of mutagenicity in the Ames Test using rifabutin-susceptible and resistant strains or in Schizosaccharomyces pombe P1 (Prod Info MYCOBUTIN(R) oral capsules, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma rifabutin levels may be useful to confirm overdoses, but are not readily available and are not useful in guiding therapy.
    B) Monitor CBC, liver enzyme levels, and fluid/electrolyte status as indicated.
    C) Perform an ophthalmologic examination in patients with visual symptoms (eye pain, changes in visual acuity, etc.).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Plasma rifabutin levels may be useful to confirm overdoses, but are not readily available and are not useful in guiding therapy.
    B) Monitor CBC, liver enzyme levels, and fluid/electrolyte status as indicated.
    C) Perform an ophthalmologic examination in patients with visual symptoms (eye pain, changes in visual acuity, etc.).

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In case of rifabutin overdose, treatment should be symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor CBC, liver enzyme levels, and fluid/electrolyte status in symptomatic patients.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Rifabutin is highly protein-bound and is extensively distributed into tissues, therefore enhanced elimination techniques, including hemodialysis or forced diuresis, are not expected to be of any benefit following an overdose (Prod Info Mycobutin(R), 2002).

Range Of Toxicity

Summary

    A) A specific toxic dose of rifabutin has not been established. A syndrome of arthralgia/arthritis has been reported following daily doses of at least 1 gram.

Therapeutic Dose

    7.2.1) ADULT
    A) MAC INFECTIONS
    1) MYCOBACTERIUM AVIUM COMPLEX (MAC) INFECTIONS: The recommended adult dose of rifabutin is 300 mg once daily. For patients with gastrointestinal upset, 150 mg twice daily with food may be administered. The dose should be also reduced by 50% in patients with severe renal impairment (creatinine clearances less than 30 mL/min) (Prod Info Mycobutin(R) oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) MAC TREATMENT
    1) MYCOBACTERIUM AVIUM COMPLEX (MAC) TREATMENT The following dosages are based on limited treatment use in 22 HIV-positive children with MAC who received rifabutin in combination with other antimycobacterial agents for 1 to 183 weeks (Prod Info Mycobutin(R) oral capsules, 2014):
    AGEMEAN DOSE (RANGE)
    1 year 18.5 mg/kg (15 to 25)
    2 to 10 years 8.6 mg/kg (4.4 to 18.8)
    14 to 16 years 4 mg/kg (2.8 to 5.4)

    2) There is no evidence that doses greater than 5 mg/kg daily are more effective (Prod Info Mycobutin(R) oral capsules, 2014).
    B) MAC PROPHYLAXIS
    1) MYCOBACTERIUM AVIUM COMPLEX (MAC) PROPHYLAXIS: Safety and efficacy in pediatric patients have not been established (Prod Info Mycobutin(R) oral capsules, 2014).

Maximum Tolerated Exposure

    A) A syndrome of arthralgia/arthritis has been reported following administration of rifabutin in doses of 1050 to 2400 milligrams/day, and appeared to be reversible upon discontinuation of rifabutin (Prod Info Mycobutin(R), 2002; Siegal et al, 1990).

Workplace Standards

    A) ACGIH TLV Values for CAS72559-06-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS72559-06-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS72559-06-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS72559-06-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 3322 mg/kg (RTECS, 2003)
    B) LD50- (ORAL)RAT:
    1) > 5 g/kg (RTECS, 2003)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Rifabutin is an antibiotic with activity against tubercular and non-tubercular mycobacteria (Bruna et al, 1983; Woodley & Kilburn, 1982). Similar to rifampin, rifabutin is a member of a group of antibiotics known as rifamycins (also known as ansamycins or rifomycins).
    B) According to a comprehensive review of rifabutin's antimicrobial activity, rifabutin is active against almost all strains of mycobacteria with the notable exception of M. chelonae. Rifabutin has also exhibited activity against gram-positive cocci (staphylococci, group A streptococci), gram- negative bacteria (Neisseria, Legionella, and Hemophilus species; Campylobacter jejuni and Helicobacter pylori), Chlamydia trachomatis, and Toxoplasma gondii. Organisms displaying resistance to rifabutin include Enterobacteriaceae and Pseudomonas species. Its activity against yeasts and fungi has not been fully delineated (Kunin, 1996). Data from a rabbit model support the bactericidal activity of intravenous rifabutin in pneumococcal meningitis; human data are lacking (Schmidt et al, 1997).
    C) In addition to its antimycobacterial activity, rifabutin has been reported to inhibit reverse transcriptase and block the in vitro infectivity and replication of HIV (formerly HTLV-III), the virus thought to be responsible for the acquired immune deficiency syndrome (AIDS). Rifabutin in concentrations of 10 mcg/mL inhibit about 70% of viral production in lymphocytes. In the H-9 cell line, rifabutin inhibited 70% of virus production at 50 mcg/mL. Rifabutin was in solution with methanol; concentrations of methanol used had very little effect on live cell counts. The activity of rifabutin against HIV in vivo has not yet been tested (Anand et al, 1986).

Physicochemical

Physical Characteristics

    A) Rifabutin is a red-violet powder that is soluble in chloroform and methanol, very slightly soluble in water, and sparingly soluble in ethanol (Prod Info MYCOBUTIN(R) oral capsules, 2007).

Molecular Weight

    A) 847.02 (Prod Info MYCOBUTIN(R) oral capsules, 2007)

References

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