Although azathioprine requires caution and ongoing patient monitoring, some say their side effects are less severe than many patients - and some dermatologists - think. Even some medically oriented dermatologists express the concern that "these pills will wreck your liver," which overstates the actual clinical risk, says Neil Shear, M.D.
Toronto - Although azathioprine requires caution and ongoing patient monitoring, some say their side effects are less severe than many patients - and some dermatologists - think.
It's not just cosmetic dermatologists who avoid prescribing azathioprine, says Neil Shear, M.D., professor and chief of dermatology, University of Toronto Medical School. When asked by patients about azathioprine, even some medically oriented dermatologists express the concern that "these pills will wreck your liver," which overstates the actual clinical risk, he says.
Dr. Shear says that in his practice, he frequently uses azathioprine in steroid-sparing regimens to help minimize patients' doses of prednisone, which can cause many worrisome side effects, or to transition patients off prednisone entirely.
Typically, Dr. Shear says, he prescribes doses up to 3 mg/kg of a patient's ideal body weight. "We never usually get that high because we're afraid of people getting severe reactions like aplastic anemia. But we know how to screen for that now, so we're not quite as afraid as we used to be," he says.
If genetic tests reveal that a patient has normal thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of azathioprine, the patient can take normal azathioprine doses without developing serious bone marrow toxicity, he says.
Dr. Shear says, however, that 0.3 percent of patients have virtually no TPMT activity.
"If I give them the regular dose, these people are at high risk of severe hematologic toxicity," he says.
Patients who have intermediate TMPT activity (which can occur because one allele in this pair is abnormal) also can develop problems.
"Generally I don't use azathioprine in either type of patient," he says. Dr. Shear says he recommends genetic testing for TPMT in all patients who are considering azathioprine.
"People will argue that doing this is optional. But a lawyer who's suing you would argue that you should follow what's in the product monograph," Dr. Shear says. And azathioprine's label states that physicians should consider TPMT testing for such patients. However, the label adds, they're no substitute for complete blood counts for monitoring patients on azathioprine.
Dr. Shear says he also counsels patients that if they develop flulike symptoms that disappear a day or two after stopping azathioprine - which can indicate azathioprine hypersensitivity syndrome - they must not resume taking it. If they do, "Their blood pressure can drop to zero. They end up in an intensive care unit, and people have died from it," he says.
Patients taking allopurinol also must avoid taking azathioprine, because allopurinol can produce severe hematological side effects, Dr. Shear says. A new alternative to allopurinol, Uloric (febuxostat, TAP Pharmaceuticals) avoids many of allopurinol's side effects. However, "You can't take febuxostat with azathioprine either. It's actually a more potent xanthine oxidase inhibitor, and even more dangerous than allopurinol," he says.
If a patient on azathioprine becomes pregnant, "The monograph says azathioprine is a category D drug, which means she shouldn't use it. But that advice may not be useful, because 50 percent of pregnancies aren't planned," Dr. Shear says. A patient could be on azathioprine well before she knows she's pregnant.
The monograph also mentions that pregnancy should be avoided while on azathioprine, and that azathioprine can cause fetal harm. "But it doesn't say it absolutely should not be given during pregnancy," Dr. Shear says.
Taken together, he says, these statements frighten patients but don't provide any specific directions.
"The Food and Drug Administration is changing the way it will write pregnancy guidelines and rules. But this is the way it stands right now," he says.
One survey has shown that even if pregnant women are prescribed penicillin and counseled that it's very safe during pregnancy, "They still think the risk is as high as that of thalidomide (Koren G, Bologa M, Long D, Feldman Y, Shear NH. Am J Obstet Gynecol. 1989 May;160(5 Pt 1):1190-1194)," Dr. Shear says.
In truth, Dr. Shear says that according to Motherisk, the world's largest program for tracking drug use in pregnancy, "Azathioprine is not a teratogen. The disconnect is that physicians might prescribe CellCept (mycophenolate mofetil, Hoffman-LaRoche), which can cause serious birth defects, because they think it's safer."
If azathioprine doesn't appear to be working for a particular patient, Dr. Shear says, he recommends asking when and how the patient takes the medication, because it's easy for patients to get confused about dosing.
"If you always write for azathioprine 50 mg, you shouldn't have to worry" about the pharmacy dispensing a higher dose, he says. Some azathioprine 50 mg tablets look like two round pills joined together with "50" written on one half of the tablet, however, which could erroneously suggest to patients that they must split the tablet, he says.
Disclosures: Dr. Shear reports no relevant financial interests.