Rifapentine is a rifamycin antibiotic that is similar in structure and activity to rifampin and rifabutin and that is used in combination with other agents as therapy of tuberculosis, particularly in once or twice weekly regimens. Rifapentine is associated with transient and asymptomatic elevations in serum aminotransferase and is a likely cause of clinically apparent acute liver injury.
Rifapentine (rif" a pen' teen) is a rifamycin antibiotic and a synthetic derivative of natural products of the bacterium, Amycolatopsis mediterranei. The rifamycins are complex macrocyclic antibiotics that have activity against several bacteria, but most prominently M. tuberculosis and several atypical mycobacterial species, probably as a result of inhibition of the DNA dependent RNA polymerase of mycobacteria. These agents are considered bactericidal and are active against both intracellular and extracellular organisms. Rifapentine has a longer half-life than rifampin and rifabutin, which allows for once or twice weekly dosing, which is its major advantage. Rifapentine was approved for use in treating active as well as latent tuberculosis in 1998. It is available as 150 mg film coated tablets under the trade names of Priftin. The recommended dose for active tuberculosis in adults is 600 mg twice weekly for 2 months, followed by 600 mg (~10 mg/kg) once weekly for 4 months as a part of directly observed therapy and in combination with isoniazid or other antituberculosis agents. The recommended regimen for latent tuberculsosis is a 12 week regimen of 600 mg once weekly in combination with isoniazid as directly observed therapy. Pyridoxine (vitamin B6) is commonly given with rifapentine and isoniazid to prevent neuropathy. Side effects of rifapentine are uncommon, but include rash, fever, flu-like symptoms, gastrointestinal upset and orange discoloration of urine and sweat. Rifapentine is intermediate between rifabutin and rifampin in activity as an inducer of the hepatic microsomal drug metabolizing P450 enzymes (CYP 1A2, 2C9, 2C19 and 3A4), the relative potencies being: rifampin (1.0), rifapentine (0.85) and rifabutin (0.4). For this reason, use of other medications (such as many antiretroviral agents, oral contraceptives, beta-blockers, benzodiazepines, cyclosporine, macrolide antibiotics and oral anticoagulants) with rifapentine should be carefully considered and monitored.
Because of its limited use, the effects of rifapentine on the liver have been less well defined than those of rifampin, but they are likely to be similar. Thus, long term therapy with rifapentine is associated with minor, transient elevations in serum aminotransferase levels in 2% to 7% of patients, abnormalities that usually do not require dose adjustment or discontinuation. Clinically apparent liver injury due to rifapentine has not been reported, but it is likely to be similar to rifampin in its potential for causing acute liver injury. Because rifapentine is usually given in combination with isoniazid and/or pyrazinamide, two other known hepatotoxic agents, the cause of the acute liver injury in patients on rifapentine containing regimens may be difficult to relate to a single agent, and some evidence suggests that these combinations are more likely to cause injury than the individual drugs. Typically, the onset of injury due to rifamycins is within 1 to 6 weeks and the serum enzyme pattern is usually hepatocellular at the onset of injury, but can cholestatic and mixed in contrast to isoniazid and pyrazinamide. Extrahepatic manifestations due to rifamycin hepatotoxicity such as fever, rash, arthralgias, edema and eosinophilia are uncommon as is autoantibody formation. This potential for hepatotoxicity has not been specifically demonstrated for rifapentine.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of rifamycin associated hepatotoxicity is not known, but these agents are extensively metabolized by the liver and induce multiple hepatic enzymes. Thus, the cause of injury is likely to be due to idiosyncratic metabolic products that are either directly toxic or induce an immunologic reaction.
Outcome and Management
For rifampin, the severity of hepatic injury ranges from asymptomatic elevations in serum aminotransferase levels, jaundice without apparent hepatic injury, symptomatic self-limited hepatitis to severe fulminant liver failure and death. Complete recovery is expected after stopping the drug and is usually rapid and complete. The rifamycins have not been associated with vanishing bile duct syndrome or chronic hepatitis. There is likely to be some cross sensitivity to liver injury among the rifamycins (rifampin, rifabutin, rifapentine), but not with the other first and second line antituberculosis agents. Routine monitoring for seurm enzyme elevations is not recommended except in high risk individuals. Nevertheless, routine monitoring for symptoms of liver disease is recommended for all regimens, whether for clinically active or latent tuberculosis.
Specific, regularly updated recommendations on therapy of tuberculosis can be found on the U.S. Centers for Disease Control and Prevention website: https://www.cdc.gov/tb/topic/treatment/
[First line medications used in the therapy of
tuberculosis in the US include ethambutol, isoniazid, pyrazinamide, rifabutin,
rifampin, and rifapentine. Second line medications include streptomycin,
capreomycin, cycloserine, ethionamide, fluoroquinolones such as levofloxacin and
moxifloxacin, aminoglycosides such as amikacin, and para-aminosalicylic acid
REPRESENTATIVE TRADE NAMES
Rifapentine – Priftin®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 14 June 2018
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Havlir DV, Dubé MP, Sattler FR, Forthal DN, Kemper CA, Dunne MW, Parenti DM, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group. N Engl J Med 1996; 335: 392-8. PubMed Citation (Controlled trial of azithromycin vs rifabutin vs both for prevention of MAC disease in 693 HIV infected patients; 1-2% of subjects developed laboratory abnormalities requiring discontinuation, a proportion being ALT elevations).
Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A, Chaisson R, Gordin F, et al.; Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002 17; 360: 528-34. PubMed Citation (Among 1004 patients treated with either rifapentine [once weekly] or rifampin [twice weekly] with isoniazid, ALT elevations >5 times ULN occurred in 2.6% on rifapentine and 3.5% on rifampin; no deaths due to liver injury).
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Centers for Disease Control and Prevention (CDC). Trends in tuberculosis—United States, 2008. MMWR Morb Mortal Wkly Rep 2009; 58 (10): 249-53. PubMed Citation (In 2008, 12,898 cases of active tuberculosis were reported in US, lowest rate since reporting began in 1953; incidence rate=3/100,000; 1.2% with multidrug resistant strains).
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Horne DJ, Spitters C, Narita M. Experience with rifabutin replacing rifampin in the treatment of tuberculosis. Int J Tuberc Lung Dis 2011; 15: 1485-9. PubMed Citation (Among 30 patients with tuberculosis switched from rifampin to rifabutin because of liver test abnormalities, only two redeveloped liver injury on rifabutin, whereas 6 of 15 who were switched because of rash had a recurrence).
Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, Hackman J, et al; TB Trials Consortium PREVENT TB Study Team. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011; 365: 2155-66. PubMed Citation (7731 subjects with latent tuberculosis at high risk for active disease were treated with either a 3 month course of directly observed once weekly isoniazid and rifapentine [3 mo INH/R] or standard therapy with 9 months of daily isoniazid [9 mo INH]; after 3 years rates of active tuberculosis were similar [0.19% after 3 mo INH/R and 0.43% after 9 mo INH], whereas hepatotoxicity was less with 3 mo INH/R [0.4%] than 9 mo INH [2.7%]).
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