Tuberculosis (TB) continues to be a leading infectious cause of death globally, but most patients can be cured by drug treatment. Isoniazid (INH) was introduced in 1951 as an anti-TB medicine and continues to be one of the leading drugs of choice. Only three suppliers provided this drug in 2012 and now one has stopped.
Mycobacterium tuberculosis is transmitted person-to-person via the airborne route. Before the introduction of anti-TB medications, patient isolation was the principal public health intervention to minimize the risk for TB transmission. The introduction of anti-TB medications revolutionized the treatment of TB and the approach to TB control.
TB disease is treated in most cases with a regimen of several drugs taken for six to nine months. Currently, ten drugs are approved by the FDA for the treatment of TB. Standard treatment worldwide for confirmed or suspected TB disease is based on the four first-line bactericidal drugs (INH, rifampin, ethambutol, and pyrazinamide), of which INH and rifampin are the most effective. Treatment of TB disease with second-line drugs can be less effective, more toxic, and more costly than treatment with first-line drugs. Thus, second-line drug treatment regimens are reserved for persons with TB disease caused by INH- and rifampin-resistant strains.
In November 2012, the United States began to experience a severe interruption in the supply of INH. To assess the extent of the problem and its impact on TB control programs, a nationwide survey of programs was conducted in January 2013 by the National Tuberculosis Controllers Association (NTCA). The results indicated that the INH shortage was interfering with patient care and could contribute to TB transmission in the United States.
This survey showed that 79% of the responding health departments reported difficulties with procuring INH within the last month, with 15% reporting that they no longer had INH and 41% reporting that they would no longer have a supply within 1 month of the survey. Because of local interruptions in INH supply, responding TB programs were changing INH suppliers (69%), prioritizing patients for treatment of latent TB infection (LTBI) (72%), delaying LTBI treatment (68%), and changing to alternative LTBI treatment regimens (88%). Additionally, INH is the recommended prophylaxis to prevent active TB disease in persons with LTBI. Alternative regimens for LTBI include rifampin and a combination of INH and rifapentine.
In 2012, three suppliers provided INH in the United States: Teva, VersaPharm, and Sandoz. A shortage of INH 300 mg tablets was first reported to CDC in November 2012; one supplier attributed the shortage, in part, to difficulty in procuring the active ingredient. The suppliers first reported an anticipated release of INH in late December 2012, but that forecast was changed to mid-January 2013. In December 2012, INH was available in 100 mg tablets, and CDC encouraged TB control programs to work with their pharmacies to obtain this formulation until the shortage of 300 mg tablets was resolved. The anticipated additional release by mid-January did not materialize, and the supply of INH 100 mg tablets also became limited.
In January 2013, VersaPharm announced it would not be producing INH until 2014, leaving two manufacturers in the U.S. market. Although the two remaining manufacturers were able to begin supplying limited quantities of INH as of February 2013, the INH shortage has continued to affect TB programs. In collaboration with the CDC and the FDA, Teva reserved 10% of its INH supply for emergency allocation for public health programs that have been unable to access INH through their usual procurement channels. The CDC and the NTCA assisted Teva with developing guidance for distribution of this emergency allocation and communicated the guidance to TB programs on February 1, 2013.
The NTCA survey results show that the INH shortage has affected TB control efforts nationally.
An INH shortage can directly affect patients and the community by necessitating treatment with alternative regimens that can be more expensive and, for the treatment of TB disease, more toxic. Currently a shortage also exists for two combination preparations of INH and rifampin (IsonaRif, VersaPharm; and Rifamate, Sanofi-Aventis). Increasing the use of rifampin as an alternative treatment regimen could lead to additional shortages of rifampin, the most effective drug for treating active TB. Also, interruptions in the supply of second-line anti-TB medications have been ongoing in the United States for several years.
The CDC, the NTCA, and state and local TB programs have been implementing short-term solutions to minimize the impact of the INH shortage by using strategies such as sharing of drugs among state and local programs, using alternative formulations (e.g., substituting INH 100 mg tablets for INH 300 mg tablets), and using alternative regimens for treatment of LTBI (e.g., rifampin 600 mg daily for 4 months or INH 900 mg plus rifapentine 900 mg once weekly for 12 weeks, instead of INH 300 mg daily for 9 months. Additionally, the CDC is investigating the prospect of obtaining INH from the Global Drug Facility that provides anti-TB medications to TB programs internationally. Such activities require significant investment of time and resources that could be used for other important TB control activities.
A 2011 presidential executive order, Reducing Prescription Drug Shortages, requires "drug manufacturers to provide adequate advance notice of manufacturing discontinuances that could lead to shortages of drugs that are life supporting or life sustaining, or that prevent debilitating disease". Such advance notification of a potential INH shortage could have helped TB programs anticipate the shortage and begin making programmatic modification. Some possible long-term solutions include the CDC maintaining a surveillance system to identify shortages and a U.S. distribution system for anti-TB drugs similar to the Global Drug Facility and to the CDC's Vaccines for Children Program, which supplies routinely used vaccines for eligible children and adolescents. Another possible strategy might be collaborating with the FDA to determine whether anti-TB drugs in the pipeline might qualify for orphan-drug designation, which provides incentives for manufacturers to develop products for the treatment, diagnosis, or prevention of rare diseases or conditions.
The INH shortage was unexpected, has affected U.S. TB control efforts, and has lasted months longer than predicted. How the increased use of alternative regimens and the rising cost of INH driven by increased demand might affect the future supply of INH and other first-line anti-TB medications is uncertain. Potential solutions for improving continuity of first-line anti-TB drug supplies include the sharing of drugs in short supply among state and local TB programs, creating a drug shortage early warning system, centralized drug distribution, obtaining drugs from foreign manufacturers when drugs are unavailable in the United States, and improving the timeliness of the reporting of drug shortages by drug suppliers.
See the CDC Report
See also Medical Law Perspectives, May 2013 Report: Drugs, Dosage, and Damage: Physician Liability for Prescribing or Administering Medication