The guidelines describe FDA-approved and off-label uses of bedaquiline in populations with multidrug-resistant tuberculosis that were not included in clinical trials.
Provisional guidelines from the Centers for Disease Control and Prevention (CDC) describe FDA-approved and off-label uses of bedaquiline fumarate (Sirturo, Janssen Therapeutics) in populations with multidrug-resistant tuberculosis (MDR TB) that were not included in clinical trials. The new recommendations regarding use of this oral diarylquinoline in children, pregnant women, or persons with extrapulmonary MDR TB were published in the October 25 issue of the Morbidity and Mortality Weekly Report.
Bedaquiline is in the first new class of TB drugs to be approved to treat TB in more than 4 decades.
"[MDR TB] is caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampin, the two most effective of the four first-line TB drugs (the other two drugs being ethambutol and pyrazinamide)," write Sundari Mase, MD, from the Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC, and colleagues. "MDR TB includes the subcategory of extensively drug-resistant TB (XDR TB), which is MDR TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, capreomycin, or amikacin). MDR TB is difficult to cure, requiring 18–24 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with toxic side effects, and carries a mortality risk greater than that of drug-susceptible TB."
New drugs to treat TB, especially drug-resistant TB, are urgently needed. On the basis of data from 2 phase 2b trials, the FDA approved use of bedaquiline on December 28, 2012, under the provisions of accelerated approval regulations for "serious or life-threatening illnesses."
As the clinical trials did not enroll children, pregnant women, or persons with extrapulmonary MDR TB, the CDC's Division of TB Elimination developed recommendations for these populations from expert opinion and evidence from systematic reviews and literature searches.
Because this protocol differs from the statutory standards used by the FDA for drug approvals and labeling, the guidelines are not identical to current FDA-approved labeling for bedaquiline.
Specific Recommendations
For adults aged 18 years or older diagnosed with laboratory-confirmed pulmonary MDR TB, bedaquiline should be administered by direct observation and used with clinical expert consultation as part of a combination treatment regimen containing at least 4 drugs.
When treatment options are limited, use of bedaquiline can be considered for individual persons with extrapulmonary TB, children, pregnant women, or persons with HIV or other comorbid conditions on a case-by-case basis. However, further research is needed before bedaquiline can be routinely recommended in these populations.
The new guidelines include recommendations for dosing and delivery: 400 mg once daily orally for 2 weeks, followed by 200 mg 3 times a week for 22 weeks, taken orally with food.
Unless the anticipated benefits outweigh the risks of inadequate treatment of MDR TB, the use of bedaquiline with rifamycins or other drugs that induce or suppress CYP3A4 should be avoided.
Because of the extremely long terminal half-life of bedaquiline, acquired resistance might occur when bedaquiline is the sole effective anti-TB drug in circulation. Discontinuing bedaquiline 4 to 5 months before scheduled termination of other drugs in the regimen should therefore be considered.
To track patient outcomes, adverse reactions, laboratory findings, drug susceptibility, development of drug resistance, use of concomitant medications, and comorbidities, Janssen Therapeutics has established a registry for persons treated with bedaquiline.
Clinicians should closely monitor patients for adverse reactions as well as for clinical outcomes. They should report suspected adverse reactions (any adverse event thought to be drug-related) and serious adverse events (resulting in death, hospitalization, permanent disability, or a life-threatening situation) to Janssen Therapeutics at 1-800-526-7736, to the FDA at 1-800-332-1088, or online at http://www.fda.gov/medwatch, and to the CDC's Emergency Operations Center at 1-770-488-7100.
You can download the provisional CDC guidelines from here.
The World Health Organization issued its guidance on use of the drug in June.
Source: Medscape