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ISSUE: JANUARY 2004 | VOLUME: 31:01

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Clinical

Cancer Experts Urge More Vigilance To StemAdverse Rx Interactions

by Mark Fuerst

Phoenix--It's not just grapefruit juice any more.

There has been a sharp escalation in the number

and types of oncologic drug combinations and

ancillary agents that may muddle one another's

effects, particularly by interference with the

cytochrome P450 3A4 (CYP3A4) isoenzyme during

first-pass metabolism.

Imatinib mesylate (Gleevec, Novartis), for example--

a vitally important drug for treating chronic myeloid leukemia and gastrointestinal stromal

tumors--is inhibited by a popular herbal medication used for depression, St. John's wort. In

many cases, patients do not like to mention to their oncologists that they take herbals. St.

John's wort induces CYP3A4 activity with the effect of reducing imatinib mesylate's plasma

concentration. Several other drugs--dexamethasone, phenytoin, carbamazepine, rifampin

(Rifadin, Aventis) and phenobarbital--can also do the same when coadministered with imatinib

mesylate. Conversely, ketoconazole, a CYP3A4 inhibitor, may increase imatinib mesylate's

plasma concentration.

These are just a few of the potentially troublesome oncologic drug interactions that clinicians

need to be aware of in order to steer clear of trouble, according to Robert Ignoffo, PharmD,

Clinical Professor, Department of Clinical Pharmacy, University of California, San Francisco,

School of Pharmacy.

Cancer patients, in particular, are at risk for experiencing drug interactions because they are

treated with so many medications in combination plus other agents aimed at preventing

chemotherapy-related symptoms, Dr. Ignoffo told attendees of the 2003 Annual Conference of

Oncology Pharmacy meeting. In addition, a large proportion of cancer patients are elderly,

making them particularly susceptible to drug interactions.

The financial impact of these drug interactions is impressive, Dr. Ignoffo stressed, citing anestimated $136 billion per year being spent on adverse drug events. Pharmacists, he said,

are often the sentinels, or outcomes assessors, for drug interactions. Pharmacists, more than

physicians, are likely to be aware of the changes in patient symptoms and unusual reactions
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that can be related to enhanced drug effects and interactions.

"Our job is to be at the forefront in preventing these events by advising patients on

medications they can take, or not take, with chemotherapy," he said. Because cancer drugs

can have serious toxicities, and many have a narrow therapeutic index, synergistic drug

interactions can lead to worsening side effects and antagonistic drug interactions can lead to

silent progression of a malignancy.

Thus, it is extremely important for pharmacists to recognize well-known drug interactions,

which often is easier with inpatients than outpatients, Dr. Ignoffo said. "Be aware of other

concurrent problems and which drugs may be interactive," he added. "Our role as outcome

assessors is to look at anything unusual in the patient and possibly attribute that to drugs."

Some commonly reported drug interactions with chemotherapy drugs include:

cyclophosphamide (Cytoxan, Bristol-Myers Squibb [oral]; Neosar, Pfizer [injection]) and

phenytoin, which leads to increased phenytoin toxicity. The coadministration of mercapto-

purine (Purinethol, GlaxoSmithKline) and allopurinol has the effect of increasing

mercaptopurine's toxicity and can be avoided by decreasing the dose by one-third, Dr. Ignoffo

noted. Procarbazine (Matulane, Sigma-Tau) and tricyclics may lead to a hypertensive crisis.

The sequence of a chemotherapy combination may be important. If carboplatin (Paraplatin,

Bristol-Myers Squibb) precedes paclitaxel, patients will have more bone marrow toxicity and

mucositis. Similarly, cisplatin given before topotecan (Hycamtin, GlaxoSmithKline) increases

the risk of bone marrow toxicity, Dr. Ignoffo pointed out.

Herbs, Vitamins May Be Culprits

As mentioned, a drug interaction may result from an unexpected source, such as herbal

products or vitamins, which most patients do not consider to be drugs. "Today, I have noticed

that cancer patients are taking more and more ancillary medications," Dr. Ignoffo said. "A

thorough medications history is necessary, asking about nutritional supplements, and may

help raise some red flags about potential interactions with drugs."

In addition to imatinib mesylate, St. John's wort reduces the plasma concentrations of

irinotecan (Camptosar, Pfizer), taxanes and vinca alkaloids.

Not all drug interactions are bad. Some are well-known therapeutic strategies known to

enhance antitumor effects or decrease disease- or therapy-related toxicities. For example,

leucovorin enhances the binding of 5-fluorouracil. Another such desirable drug interaction

involves the combination of oral paclitaxel, available in Europe, with cyclosporine to increase

the availability of paclitaxel. "When the taxanes become available orally, we will see a lot of

pharmacokinetic interactions because they affect cytochrome P450 absorption in the gut," Dr.

Ignoffo said.

CPOE Can Help

Computerized prescriber order entry systems can help eliminate more serious drug

interactions, commented Pat Willman, PharmD, Oncology Clinical Specialist at Gwinnett

Hospital in Lawrenceville, Ga. Her hospital has been a forerunner in this area, with software


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installed for computerized data entry and bedside charting.

"We have eliminated transcripts, either verbally or by fax," Dr. Willman said. Some interactions

are caught as data are being entered into the system, and more serious drug interactions

may become apparent even before a prescription is written. "Dose limits with chemotherapy

will also show up and system blocks will require an override," she said. "This helps us be more

aware of interactions, allows us time to check a reference and then make a therapeutic

choice."

Dr. Willman agrees with Dr. Ignoffo's contention that "pharmacists need to be aware of the

potential of drug interactions so we can help educate practitioners. We are usually the ones to

draw attention to it in patients."

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