NEW YORK — There's no doubt that systemic drugs used to treat skin disorders can interact in myriad ways, with results ranging from rashes to death, but some commonly held assumptions about drug interactions are either untrue or controversial.
At a meeting on medical and surgical dermatology sponsored by Mount Sinai School of Medicine, Dr. Mark G. Lebwohl offered his top 10 problematic or misconstrued combinations:
▸ Methotrexate and trimethoprim-sulfamethoxazole. “This is known as Kevorkian therapy for psoriasis,” Dr. Lebwohl said. Several deaths are reported every year from this combination, which can cause severe myelosuppression.
Many other interactions can occur with methotrexate. Aspirin and many of the NSAIDs—including salicylate, ibuprofen, and naproxen—can increase methotrexate levels. Moreover, the combination of methotrexate and naproxen also increases naproxen levels. The NSAIDs that do not affect methotrexate levels and are safe to use in combination are flurbiprofen, ketoprofen, and piroxicam. “And the [cyclo-oxygenase-2] inhibitors were fine until the lawyers got there,” he said.
▸ Bexarotene and gemfibrozil. “Bexarotene has been a godsend for patients with mycosis fungoides who are not doing well with PUVA or narrow-band UVB,” but the combination of bexarotene with gemfibrozil is dangerous and should never be given, said Dr. Lebwohl, professor and chairman of dermatology at Mount Sinai in New York.
Like other retinoids, bexarotene causes hyperlipidemia. The specific dyslipidemia associated with this agent is hypertriglyceridemia, and gemfibrozil is the best drug for lowering triglycerides. Unfortunately, gemfibrozil raises bexarotene levels, and there have been cases of patients developing massive hypertriglyceridemia and pancreatitis. Atorvastatin and simvastatin are acceptable alternatives to gemfibrozil.
▸ Erythromycin and theophylline. Erythromycin elevates levels of theophylline, and because the asthma drug has a narrow therapeutic window, toxicity can result. Manifestations of theophylline toxicity include sinus tachycardia, tremor, and gastrointestinal disturbances.
Numerous other interactions have been seen with erythromycin. There have been reports of inappropriate antidiuretic hormone secretion syndrome, which is characterized by hyponatremia and potentially lethal metabolic disturbances, when erythromycin is combined with carbamazepine, Dr. Lebwohl said.
Inhibitors of cytochrome P450 3A, including nitroimidazole antifungals and certain calcium channel blockers and antidepressants, also are hazardous for patients taking erythromycin because they can double plasma erythromycin concentrations.
Erythromycin prolongs cardiac repolarization, and a recent large review found that patients taking erythromycin plus a cytochrome P450 3A inhibitor had three sudden deaths in 194 person-years of follow-up, compared with no deaths in 254 person-years for those patients taking amoxicillin plus a cytochrome P450 3A inhibitor (N. Engl. J. Med. 2004;351:1089–96). If a macrolide antibiotic is needed, then azithromycin is a suitable choice, because it does not inactivate the cytochrome enzymes.
▸ Azathioprine and allopurinol. The gout medication allopurinol interferes with the metabolism of azathioprine, increasing plasma levels of 6-mercaptopurine; serious blood dyscrasias can result. There have been numerous reports of pancytopenia and death when these two agents were given together, Dr. Lebwohl said.
Approximately 11% of the population is partially or completely deficient in the enzyme thiopurine methyltransferase, which is involved in the metabolism of azathioprine. “If you really want to wipe out the bone marrow, give the combination of azathioprine and allopurinol to a patient who is genetically deficient in this enzyme,” he said. An assay for thiopurine methyltransferase should always be obtained before a patient is started on azathioprine.
▸ Cyclosporine and many drugs. Cyclosporine has numerous potential drug interactions, and elevated levels are associated with a host of side effects, Dr. Lebwohl said. Among the more common adverse effects are elevations of BUN and creatinine levels, and ultimately hypertension and renal failure. Drugs such as calcium channel blockers and erythromycin, when used in combination with cyclosporine, can cause elevated cyclosporine levels, but others such as phenobarbital and phenytoin can reduce cyclosporine levels.
Also be cautious in giving cyclosporine to patients on atorvastatin, and monitor the serum creatine phosphokinase levels. The concern is the possible development of rhabdomyolysis, he said.
▸ Retinoids and tetracycline. This combination can result in pseudotumor cerebri, in which patients present with severe headache, vision abnormalities, and nausea and vomiting. Ophthalmologic examination is needed, as papilledema can occur.
▸ Ampicillin and allopurinol. In virtually every survey, the frequency of morbilliform drug reaction on first-time exposure to ampicillin and amoxicillin is 5%. One report found that the rate increased to 22.5% when ampicillin was given with allopurinol, however, so that's another combination to avoid, he said.
▸ Epinephrine and β-blockers. This is an old story, Dr. Lebwohl said. There have been many reports of malignant hypertension among patients on β-blockers who are given epinephrine, but these have involved massive quantities of epinephrine. “We're not talking about a punch biopsy here,” he said.