Fixed-dosed drug therapy grows slowly despite strong support among experts
Experts call for more use of Rifater and Rifamate
More than three years after it was approved for sale in the United States, the fixed-dose combination pill Rifater has shown lackluster sales. Increasingly, however, some of TB’s most eminent experts are arguing that fixed-dose combination treatment should be established as the standard for self-administered tuberculosis therapy.
The most recent challenge comes from John Sbarbaro, MD, professor of medicine at University of Colorado Health Sciences Center in Denver. In a recent issue of Tubercle and Lung Disease, Sbarbaro allied himself with the World Health Organization and the International Union Against Tuberculosis and Lung Disease by writing that single-formulation drugs should be avoided altogether for self-administered therapy.1
"Perhaps it is time for us to actively support drug companies’ efforts to sell quality controlled combination medications and to attack any competing effort to sell single anti-tuberculosis medications," he writes. "What better way to establish combination medications as the standard for self-administered treatment?"
Rifater combines three drugs rifampin, isoniazid, and pyrazinamide in one tablet. Hoechst Marion Roussel of Kansas City, MO, also makes a two-drug fixed combination of rifampin and isoniazid, called Rifamate. Fixed-dose combinations not only eliminate the problems that come with monotherapy, they make compliance easier because they cut down on the number of pills a patient must take. The drug has been used extensively in poor countries where supervised therapy is less available, but it has been used less than is needed, Sbarbaro tells TB Monitor.
"In other countries, where the resources do not even permit one worker per 200,000 TB patients, what is the alternative?" he asks. "If America says the proper way of treating is combination pills when DOT is not available, then that will be aped by folks in developing countries because they all want to be like Americans as far as quality of care."
Prominent TB experts have long argued that fixed-dose combination therapy offers substantial advantages over individual drug therapy, even in wealthier countries like the United States. They chastise drug manufacturers, the Centers for Disease Control and Prevention in Atlanta, and the American Thoracic Society in New York City for not having endorsed and publicized the preparations more energetically. Although Hoechst introduced Rifater in the early 1980s, it was not offered in the United States until 1994 because the market for TB drugs was small and unprofitable.
"In 1980, when we first recommended isoniazid and rifampin, we should have [instead] recommended fixed-dose combinations," says Thomas Moulding, MD, professor of clinical medicine at Harbor/UCLA Medical Center in Los Angeles. "If we had, the situation in ew York City wouldn’t have gotten as bad as it did."
Latecomer to the U.S.
Indeed, it took the resurgence of TB and a concerted effort by the medical community and the U.S. Food and Drug Administration to persuade the company to seek marketing approval here. The company supported the U.S. launch with advertising and education efforts, but the timing may have been too late as directly observed therapy (DOT) soon was being promoted as the standard of care.
"Now that DOT is recognized and supported and part of current practice, a combination product like Rifater may not offer what was initially thought when it was developed," says Lonnie Moulder, the company’s product group manager.
U.S. sales of fixed-dose combinations have not risen in the past two years, with Rifater accounting for only about 5% of the TB drugs offered by Hoechst, Moulder says. Some large TB programs, however, have been relying extensively on fixed-dose combinations, particularly Rifamate, which has been available here longer than Rifater and is easier to use.
In Los Angeles, fixed-dose combinations have been provided to patients for nine years. There, resistance rates are low, even when therapy fails. "Fixed doses not only prevent resistance, they’re easier to work with," says Paul Davidson, MD, TB controller for the Los Angeles Health Department. "We’ve been using Rifamate a long time. It’s easier for the community outreach and the patient, too, since the patient has to take fewer pills."
The TB department rarely uses Rifater because pharmacies tend not to stock it, and it is harder than Rifamate to calculate the doses with some schedules, he adds.
In Massachusetts, fixed-dose combination therapy recently has been established as the standard of care. The state’s TB controller and chief of pulmonary medicine at Harvard Medical School, Ed Nardell, MD, has spent years arguing that combination drugs, not universal DOT, should be the cornerstone of a well-run TB control program.2
DOT overshadows need for fixed-dose drugs
The CDC has advocated the use of fixed-dose combinations, particularly when therapy is not supervised. But its advocacy has been low-keyed, and even the CDC’s Advisory Committee for the Elimination of TB has never come out with a strong position. (See related story in TB Monitor, November 1994, p. 148.)
"The problem is that our whole strategy now is geared toward pushing for supervised therapy, which obviously is quite effective, and so maybe we have been ignoring the other [fixed-dose combinations]," says Rick O’Brien, MD, chief of the TB division’s research and evaluation branch. "There is a legitimate perspective that if you have a good DOT program and your health care staff are well-trained, then providing medications in combinations adds costs."
Several TB experts who have experience with fixed-dose combination drugs say cost is not a significant issue. According to 1995 purchase prices negotiated by Massachusetts, Rifamate costs the same as rifampin plus isoniazid purchased individually, says Nardell. Rifater is a bit more expensive, Nardell says. Assuming that therapy for a hypothetical patient weighing 60 kg is self-administered, for six months’ therapy, Rifater costs $44, or 7% more than its three constituent drugs purchased a la carte, he calculates.
A decision analysis published recently by Richard Moore, MD, MSc, associate professor of medicine at Johns Hopkins Institute in Baltimore, projected that the cost of treatment per patient was about the same for fixed-dose combination therapy ($13,959) as for DOT ($13,925).3 Conventional therapy was projected as least cost-effective, at $15,003. However, when Moore looked at morbidity and mortality, combination therapy came out looking better than conventional therapy, though not quite as good as DOT. Per 1,000 patients treated, Moore projected 31 relapses and 3 deaths with DOT; 96 relapses and 8 deaths with combination therapy; and 133 relapses and 13 deaths with conventional therapy.
"My study was a model," Moore adds, "and a model’s only as good as the data you put in. There’s not a lot of data on fixed-dose combinations."
Dosage concerns unfounded
One problem that has haunted Rifater in the United States is concerns that the formulation (the company has at least three for Rifater) approved in this country did not match those used for individual drugs. Specifically, the formulation had a slightly higher dose of rifampin, O’Brien says. Patients may end up getting doses of rifampin that exceed those commonly given in the United States but it is offset by the decreased bioavailability of the drug when taken in combination with pyrazinamide, he adds.
"It can be a problem in other countries where one is not sure of the quality of the product and degree of monitoring," he explains, "but here they have to satisfy very rigorous requirements set by the FDA."
In San Francisco, which also has extensive experience with fixed-dose combination therapy, the city’s former TB controller says clinicians should set aside their misgivings about dosages, and trust that tests have established the proper formulation.
"The CDC has been pushing certain doses of rifampin and isoniazid, so that when you look at the dosages on the fixed-dose combinations, the numbers look as if they don’t add up," says Gisela Schecter, MD, MPH. However, a search of the literature shows they work, and "the drug companies need to publicize that and the CDC needs to reinforce it," she says.
At the October, 1996, meeting of the International Union Against Tuberculosis and Lung Disease in Paris, Lee Reichman, MD, MPH, professor of medicine at the New Jersey Medical School and executive director of the National Tuberculosis Center in Newark, NJ, also said that bioavailability should not be a concern. Fixed-dose combination drugs that don’t measure up cannot be marketed in the U.S., he said. When unscrupulous drug manufacturers try to sell such drugs, the companies should be prosecuted; otherwise, the test results should be accepted as valid, he added. Around the world, at least 19 fixed-dose combinations are being sold.
The lack of any definitive, large-scale trials on fixed-dose combination drugs may be one reason they have not received strong U.S. endorsement, says Moulding. Such a trial would be difficult and unethical to conduct because it would require a poorly run TB control program, with lots of treatment failures, to show convincingly that even in such extreme cases using fixed-combination therapy could keep resistance rates low, he adds.
Even fixed-dose combination drugs’ strongest supporters concede potential snags in using them. First, there is the possibility that doctors or pharmacies will confuse the sound-alike names of Rifater, Rifamate, rifampin, and rifapentine. Some name changes are in order, suggests Moulding.
The second problem is that the combination pills make it harder and more time-consuming to figure out which constituent medication is at fault when adverse reactions occur. Stopping the fixed doses and reintroducing the pills one at a time is the obvious solution, Moulding says.
These barriers are secondary, however, to lack of education about their benefits. Says Moulding: "Sbarbaro’s idea is to get these preparations on pharmacists’ computers, so that whenever a doctor orders rifampin, a message pops up: Ask the doctor if they wouldn’t prefer Rifamate.’"
References
1. Sbarbaro J (editorial). A challenge to our practices and to our principles. Tubercle Lung Dis 1996; 77:2-3.
2. Nardell E (editorial). Beyond four drugs: Public health policy and the treatment of the individual patient with tuberculosis. Am Rev Respir Dis 1993; 148:2-5.
3. Moore R, Chaulk C, Griffiths R, et al. Cost-effectiveness of directly observed versus self-administered therapy for tuberculosis. Am J Resp Crit Care Med 1996; 154:1013-1019.
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