The FDA issued a warning to physicians and pharmacists that administering a proton pump inhibitor (PPI) in conjunction with IV methotrexate could lead to elevated serum levels of the IV agent, potentially resulting in methotrexate toxicity. The warning cited case reports and pharmacokinetic studies.
But experts say that PPIs represent just the tip of the iceberg in terms of commonly used medications that may pose serious hazards when given concomitantly with methotrexate, a chemotherapy drug that also is used in the treatment of rheumatoid arthritis (RA).
In addition to PPIs, other drugs that can delay the elimination of methotrexate from the body, potentially with toxic consequences, include:
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Salicylic acid (aspirin)
Many antibiotics, including penicillin, vancomycin and amoxicillin.
“We’ve had several cases of methotrexate toxicities in our setting,” Dr. McBride said. “We treat a lot of acute leukemic patients, and also lymphoma patients who require high-dose methotrexate. With this drug, in oncology, we use a high dose, it gets into the cell, and then we use leucovorin to rescue the cells that aren’t replicating as quickly as the cancer cells. In that protocol, you have to maintain the patient’s urine pH at greater than 7.0 in order to maximize the elimination of the drug and prevent any toxic side effects.” But patients taking PPIs, NSAIDs, antibiotics and/or aspirin may have a difficult time maintaining that pH, he noted.
The signs of acute methotrexate toxicity can include the following:
Severe vomiting, diarrhea, or mucositis
Low white cell count
Low blood platelets
Renal failure
Although the potential for a toxic interaction may be more significant with the high doses of methotrexate used in chemotherapy, these risks are still present with the low doses of the drug used to treat RA—but they are likely to be less well understood, experts note.
“Patients with rheumatoid arthritis are also commonly taking NSAIDs as well,” said Robert Ignoffo, PharmD, FASHP, FCSHP, clinical professor emeritus at the University of California, San Francisco and professor of pharmacy at Touro University College of Pharmacy in Vallejo, Calif. “And if you’re taking an NSAID, you may also be taking a PPI because you have GI [gastrointestinal] side effects from the NSAIDs. So you have a double whammy—the NSAID and the PPI both interact with the methotrexate to delay its elimination.”
Although these drugs also may be prescribed concomitantly for cancer patients, the interaction is less likely to be missed, Dr. Ignoffo noted. “It’s highly unusual to see someone getting high-dose methotrexate and an NSAID, because it’s an oncology unit overseeing the administration. Up until the FDA alert, however, they would have been less familiar with the PPI interaction, so I think the FDA is on the mark here in issuing it.”
The dose and duration of methotrexate therapy that trigger toxic drug interactions have yet to be determined, according to Dr. McBride. “That’s the question everyone is still trying to figure out,” he said. “There are case reports where someone taking a low dose of methotrexate for rheumatoid arthritis has signs of toxicity even with only two to four weeks of NSAIDs.”
Until such questions are resolved, experts recommend a high degree of caution when prescribing the drug combinations—not just for the patient’s safety, but in order to avoid the high cost of complications.
“We had a patient taking methotrexate who was on a PPI and had delayed elimination. He had low platelets and acute renal failure and had a seizure, and ended up in the hospital for 33 days,” Dr. McBride said. “We had to use an investigational drug, carboxypeptidase G2, which costs tens of thousands of dollars. If someone had caught this early on and changed the drug, we could have prevented this interaction.”
Barnes-Jewish was lucky to get the rescue drug in time, Dr. Ignoffo added. “The ability to get carboxy within 24 hours is an issue,” he noted, adding that because it’s experimental, permission to use it must be obtained from the FDA. “If your institution is in California, it’s going to take 12 hours to get to you,” Dr. Ignoffo said. “That may be too late. But even without that, there are a number of costly complications. If the interaction results in extreme myelosuppression, then the patient has to be hospitalized, given broad-spectrum antibiotics and monitored for at least a week. That’s costly to the system and unnecessary for the patient.”
Help at Hand
Fortunately, getting access to the rescue drug, also known as glucarpidase, may soon get easier. On Jan. 17, the FDA approved the medication (Voraxaze, BTG plc) for the treatment of toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function. Although it will likely be a few months before the drug is available commercially, the approval “represents a significant gain in the limited arsenal for treating methotrexate toxicity,” said Leigh Boehmer, PharmD, BCOP, also clinical pharmacist in medical oncology at Barnes-Jewish.
Dr. Ignoffo said he wouldn’t be surprised if pharmacists and prescribing physicians were missing methotrexate interactions at least 10% of the time. “It may go unnoticed if the patient doesn’t have an extreme reaction,” he said.
Moreover, drug–drug interactions may not be the only problem with methotrexate therapy. Anything that increases the acidity of urine may impair elimination of the drug—such as carbonated beverages. A 2010 case report in the British Journal of Clinical Pharmacology (2010;70:762-764) found that unexplained low urinary pH in a lymphoma patient being treated with high-dose methotrexate was resolved in part by the elimination of cola drinks from the patient’s diet.
In St. Louis, Dr. McBride had a similar experience. “We had a patient who was set to begin a regimen for acute lymphocytic leukemia that included methotrexate, but we couldn’t get this patient’s pH within range to start the treatment. It turned out that he was constantly drinking those huge containers of Pepsi that you get at the 7-Eleven. We told him to switch to water; he did, and his pH levels resolved.”
Dr. Ignoffo added, “The warning should go out to all oncologists, oncology pharmacists and nurses, as well as rheumatology [specialists]: These drugs should be put on the checklist of red-flag items prior to the administration of methotrexate in any form.”
by
Akshaya Srikanth
Pharm.D Intern
Hyderabad, India
But experts say that PPIs represent just the tip of the iceberg in terms of commonly used medications that may pose serious hazards when given concomitantly with methotrexate, a chemotherapy drug that also is used in the treatment of rheumatoid arthritis (RA).
In addition to PPIs, other drugs that can delay the elimination of methotrexate from the body, potentially with toxic consequences, include:
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Salicylic acid (aspirin)
Many antibiotics, including penicillin, vancomycin and amoxicillin.
“We’ve had several cases of methotrexate toxicities in our setting,” Dr. McBride said. “We treat a lot of acute leukemic patients, and also lymphoma patients who require high-dose methotrexate. With this drug, in oncology, we use a high dose, it gets into the cell, and then we use leucovorin to rescue the cells that aren’t replicating as quickly as the cancer cells. In that protocol, you have to maintain the patient’s urine pH at greater than 7.0 in order to maximize the elimination of the drug and prevent any toxic side effects.” But patients taking PPIs, NSAIDs, antibiotics and/or aspirin may have a difficult time maintaining that pH, he noted.
The signs of acute methotrexate toxicity can include the following:
Severe vomiting, diarrhea, or mucositis
Low white cell count
Low blood platelets
Renal failure
Although the potential for a toxic interaction may be more significant with the high doses of methotrexate used in chemotherapy, these risks are still present with the low doses of the drug used to treat RA—but they are likely to be less well understood, experts note.
“Patients with rheumatoid arthritis are also commonly taking NSAIDs as well,” said Robert Ignoffo, PharmD, FASHP, FCSHP, clinical professor emeritus at the University of California, San Francisco and professor of pharmacy at Touro University College of Pharmacy in Vallejo, Calif. “And if you’re taking an NSAID, you may also be taking a PPI because you have GI [gastrointestinal] side effects from the NSAIDs. So you have a double whammy—the NSAID and the PPI both interact with the methotrexate to delay its elimination.”
Although these drugs also may be prescribed concomitantly for cancer patients, the interaction is less likely to be missed, Dr. Ignoffo noted. “It’s highly unusual to see someone getting high-dose methotrexate and an NSAID, because it’s an oncology unit overseeing the administration. Up until the FDA alert, however, they would have been less familiar with the PPI interaction, so I think the FDA is on the mark here in issuing it.”
The dose and duration of methotrexate therapy that trigger toxic drug interactions have yet to be determined, according to Dr. McBride. “That’s the question everyone is still trying to figure out,” he said. “There are case reports where someone taking a low dose of methotrexate for rheumatoid arthritis has signs of toxicity even with only two to four weeks of NSAIDs.”
Until such questions are resolved, experts recommend a high degree of caution when prescribing the drug combinations—not just for the patient’s safety, but in order to avoid the high cost of complications.
“We had a patient taking methotrexate who was on a PPI and had delayed elimination. He had low platelets and acute renal failure and had a seizure, and ended up in the hospital for 33 days,” Dr. McBride said. “We had to use an investigational drug, carboxypeptidase G2, which costs tens of thousands of dollars. If someone had caught this early on and changed the drug, we could have prevented this interaction.”
Barnes-Jewish was lucky to get the rescue drug in time, Dr. Ignoffo added. “The ability to get carboxy within 24 hours is an issue,” he noted, adding that because it’s experimental, permission to use it must be obtained from the FDA. “If your institution is in California, it’s going to take 12 hours to get to you,” Dr. Ignoffo said. “That may be too late. But even without that, there are a number of costly complications. If the interaction results in extreme myelosuppression, then the patient has to be hospitalized, given broad-spectrum antibiotics and monitored for at least a week. That’s costly to the system and unnecessary for the patient.”
Help at Hand
Fortunately, getting access to the rescue drug, also known as glucarpidase, may soon get easier. On Jan. 17, the FDA approved the medication (Voraxaze, BTG plc) for the treatment of toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function. Although it will likely be a few months before the drug is available commercially, the approval “represents a significant gain in the limited arsenal for treating methotrexate toxicity,” said Leigh Boehmer, PharmD, BCOP, also clinical pharmacist in medical oncology at Barnes-Jewish.
Dr. Ignoffo said he wouldn’t be surprised if pharmacists and prescribing physicians were missing methotrexate interactions at least 10% of the time. “It may go unnoticed if the patient doesn’t have an extreme reaction,” he said.
Moreover, drug–drug interactions may not be the only problem with methotrexate therapy. Anything that increases the acidity of urine may impair elimination of the drug—such as carbonated beverages. A 2010 case report in the British Journal of Clinical Pharmacology (2010;70:762-764) found that unexplained low urinary pH in a lymphoma patient being treated with high-dose methotrexate was resolved in part by the elimination of cola drinks from the patient’s diet.
In St. Louis, Dr. McBride had a similar experience. “We had a patient who was set to begin a regimen for acute lymphocytic leukemia that included methotrexate, but we couldn’t get this patient’s pH within range to start the treatment. It turned out that he was constantly drinking those huge containers of Pepsi that you get at the 7-Eleven. We told him to switch to water; he did, and his pH levels resolved.”
Dr. Ignoffo added, “The warning should go out to all oncologists, oncology pharmacists and nurses, as well as rheumatology [specialists]: These drugs should be put on the checklist of red-flag items prior to the administration of methotrexate in any form.”
by
Akshaya Srikanth
Pharm.D Intern
Hyderabad, India
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