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Issue: March 25, 2009
March 25, 2009
9 min read
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Leucovorin shortage easing

Oncologists have turned to alternative treatment options as manufacturing delays, increased demand limit access to the drug.

Issue: March 25, 2009

Is there a shortage of leucovorin? Yes and no. As recently as January, the FDA issued alerts that supplies are low nationwide. Teva Pharmaceuticals, a manufacturer of leucovorin, warned that its stockpiles are low due to increased demand, but it has informed the FDA that it is working at full capacity to fill orders. Jeffrey Herzfeld, senior vice president–general manager of Teva Health Systems, said in January that the company expected to meet market demand within a few months.

Bedford Laboratories, the only other manufacturer of leucovorin, said manufacturing delays due to expansion at its Bedford, Ohio, facility have indefinitely stopped production.

Jeffery W. Clark, MD, medical director for clinical trials operations at Dana-Farber Harvard Cancer Center, told HemOnc Today early last month that, “to date, and at least for the next month, we have had sufficient supply to treat all patients both for clinical trials and standard therapy.”

Michael Nuess, MD
Michael Nuess

“There remains a national shortage, so the way that this (supply) has been maintained is through vigilant contact by the pharmacists with suppliers,” he said.

Carmen Allegra, MD, head of clinical and translational research for the University of Florida Shands Cancer Center, expressed doubts about a shortage. Michael Neuss, MD, a clinician in private practice with Hematology-Oncology Care in Cincinnati, Ohio, and chair-elect of the ASCO Clinical Practice Committee, echoed that opinion. Neuss termed the talk of a shortage as perhaps “much ado about nothing.”

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“It appears for many people that this shortage was more about the threat of the drug disappearing than the drug literally disappearing from their grasp,” Neuss said recently.

“I have only talked to people in big practices, and people in big practices who have buying-group leverage seem to be able to get a supply of the drug, as our practice has. That has not been the case with other drug shortages in the past. In past shortages, drugs have literally disappeared, and that has created a very big problem,” he said.

Sounding the warning

The FDA first issued a warning about the pending shortage on Nov. 20, 2008. Al Benson III, MD, associate director for clinical investigations at Robert H. Lurie Comprehensive Cancer Center of Northwestern University, was one of the physicians who first called attention to the problem.

Al Benson III, MD
Al Benson III

“What raised the concern was that people started calling saying they were out or would soon run out of their supply,” Benson said.

“We don’t have a good handle as to how many patients were actually affected by this in the long run — how many patients had their regimens altered, how many patients did not participate in clinical trials because of the shortage — but given the widespread use of leucovorin for standard regimens as well as clinical trials, it was felt that we should be very proactive, particularly because the initial announcement gave no timeframe whatsoever.”

Benson said the concern was highest in early December 2008, but the shortage appears to have eased. “It looks like that shortage is now subsiding,” he said. “It appears that the supply is now becoming more available.”

However, that is not the case everywhere. Jennifer Davis, PharmD, a clinical oncology pharmacy specialist at Hospital University of Pennsylvania, said her hospital has not been able to order the drug in bulk and is limiting the number of patients assigned to leucovorin.

“We have reserved all of our leucovorin for patients in the adjuvant setting or for patients receiving it on a research protocol,” she said. “For patients receiving leucovorin for other reasons, such as the metastatic setting, we’ve gone away from giving them infusions to save the drug.”

Richard L. Schilsky, MD
Richard L. Schilsky, MD, ASCO President, says it is unclear how long the shortage of leucovorin will last.

Photo by David Christopher

Richard L. Schilsky, MD, ASCO president and a professor of medicine at the University of Chicago, said oncologists will likely have to deal with limited amounts of leucovorin at least in the short term.

“We first heard about the shortage back in December,” Schilsky told HemOnc Today in late February. “It had been going on for at least a few weeks at that point and we don’t know how long it’s going to continue. It’s been a few months already and it’s unclear how long it will last.”

Available options

The form of leucovorin in question is the leucovorin calcium injection USP, a sterile, preservative-free solution indicated for intramuscular or IV administration in a 50-mL single-dose vial. It is used to counteract the toxic effects of folic acid antagonists such as methotrexate and to enhance the therapeutic efficacy of 5-FU.

“Leucovorin is crucial in regimens for patients with colon cancers receiving adjuvant treatment with curative intent,” Davis said. “It works simultaneously with 5-FU to increase the efficacy of 5-FU.”

Leucovorin is used by the majority of patients with gastrointestinal cancers, but physicians also have a few other drug options.

“The basic options the doctor has are leaving out leucovorin altogether, which could possibly diminish the effectiveness of the treatment,” Schilsky said, “or substituting levoleucovorin, which could preserve the effectiveness but increase the cost of treatment. Or you could switch out the 5-FU/leucovorin for capecitabine.”

The oral form of leucovorin is still available, according to the American Society of Health-System Pharmacists. A clinical alert issued to ASCO members in late 2008, however, noted that the FDA has not approved the use of the tablet to treat malignancies except in the case of methotrexate rescue for osteosarcoma. There are other problems with the tablets, according to Schilsky.

“The oral leucovorin is very variable as to how it gets absorbed into the body, and we’re not exactly sure what dose to recommend as a substitute for IV leucovorin,” he said.

A single-source drug approved last May, levoleucovorin (Fusilev, Spectrum Pharmaceuticals) is a novel folate analog formulation and the pharmacologically active isomer of calcium leucovorin.

“Levoleucovorin is commercially available as a branded product. If you substitute in levoleucovorin, there should be no impact on anything related to treatment except cost,” Schilsky said, “because it’s a lot more difficult to produce and it’s not a generic. It’s a lot more expensive, but it can be substituted any place leucovorin would be used.”

The average cost of leucovorin is 89.4 cents for a one 50-mg vial, according to a report in The Cancer Letter. The clinical equivalent dose of levoleucovorin, 25 mg, costs $52.35, or $1.047 per 0.5 mg.

“The levo is way more expensive,” Allegra said. “The racemic has been around forever.”

Lee Newcomer, business leader of Oncology Services for UnitedHealthcare of Minneapolis, told The Cancer Letter: “Oncologists have called to say ‘I can’t access anymore leucovorin. I’ve got to use levo, will you cover it?’ And we will cover it on a temporary basis until the shortage is resolved. What we won’t do is cover levo as a long-term substitute. As soon as this shortage is over, this drug is going to lose coverage because there is no reason for it.”

Another option, capecitabine

The last option Schilsky mentioned was oral capecitabine (Xeloda, Roche). Capecitabine, an oral fluoropyrimidine carbamate, converts to 5-FU within the body. In its alert to members about the leucovorin shortage, ASCO said capecitabine has been found noninferior to IV 5-FU/leucovorin as a single agent for both metastatic colorectal cancer and adjuvant therapy for stage III colon cancer.

In a study published in The Journal of Clinical Oncology in 2001, Van Custem et al said, “… because each step of the metabolic conversion occurs with successively greater specificity for tumor cells, capecitabine potentially reduces systemic exposure to 5-FU while maximizing the dose intensity within tumor tissue.”

Results from the BICC-C trial published in The Journal of Clinical Oncology in 2007, however, showed that IV 5-FU/leucovorin and irinotecan was safer and more effective than similar doses of capecitabine.

Fast Facts

Results published in the same journal in 2008 found that capecitabine plus oxaliplatin (XELOX) was noninferior to the combination of fluorouracil, folinic acid and oxaliplatin (FOLFOX-4) as first-line therapy for metastatic colorectal cancer.

Hoff et al published data in 2001 indicating that the investigator-assessed response rate for patients with advanced colorectal cancer assigned capecitabine (24.8%; 95% CI, 20.1%-30.1%) was superior to that of patients assigned IV 5-FU and leucovorin (15.5%; 95% CI, 11.6%-20.1%). There was no survival benefit for patients assigned capecitabine, researchers said, but “response rates were consistently higher for capecitabine than for 5-FU/LV in almost all sub-groups.”

Hoff et al also concluded that capecitabine had a generally better toxicity profile, although patients assigned the drug had a higher incidence of hand-foot syndrome. Other studies have noted that patients found it more convenient to take capecitabine tablets than IV 5-FU and leucovorin.

ASCO has stated that there are no efficacy data testing capecitabine with oxaliplatin in the adjuvant therapy setting for colon cancer.

“There are some regimens in the metastatic setting that use capecitabine, and it’s being tested more and more in the adjuvant setting, but to my knowledge it has not become standard of care,” Davis said.

“Also, the scheduling of the treatment is different if you combine with capecitabine,” Benson said. “It would be a fairly chaotic change, and most certainly in the adjuvant setting, we don’t feel that’s an appropriate substitution.”

Recent drug shortages

It is not uncommon for shortages to occur with cancer drugs. In 2005, there was a shortage of methotrexate, a key component of treatment for a variety of adult and pediatric cancers as well as for arthritis, lupus, psoriasis and Crohn’s disease. The shortage was the result of quality control issues that led to the shutdown of the Swiss manufacturing plant that provided 85% of the injectable methotrexate in the United States.

Davis said a recent shortage of vinblastine, used to treat Hodgkin’s lymphoma, was more of hardship than this current shortage of leucovorin. She said only patients being treated for curable Hodgkin’s were administered the drug, and even those patients received a flat dose.

Schilsky recalled a recent shortage of dacarbazine, a treatment for melanoma and part of the ABVD regimen for Hodgkin’s lymphoma. Prior to that, there was a shortage of bleomycin, another component of the ABVD regimen, he said.

“Sometimes it’s a problem at the manufacturing plant. I think the dacarbazine shortage was attributed to a fire at one of the major manufacturing facilities,” he said.

“Also, the shortage can sometimes be the result of a problem with the manufacturing process, such as impurities introduced into the drug, prompting the manufacturer to solve the problem before the drug can go back online. I’m not sure precisely what reasons these drugs periodically drop off the market, but obviously when they do, it can introduce a significant problem,” Schilsky said.

Davis, however, is convinced that shortages are more frequent. The FDA issued a warning about a shortage of cisplatin — manufactured by Teva, Bedford and APP Pharmaceuticals — on Dec. 24, 2008. She said that the Hospital University of Pennsylvania has felt the effect.

“We have definitely had to deal with a shortage of cisplatin,” she said. “There are some drugs the pharmacy can make ahead of time, but we’ve stopped doing that so that we don’t waste drugs if the patient doesn’t arrive for treatment. We really try to limit the amount we give.”

Occasional shortages are probably inevitable. A report by the BBC last year warned that farmers are having trouble keeping up with demand for the yew tree. Bark from the yew tree is used to make paclitaxel.

FDA’s role

Pharmaceutical companies have no legal obligation to produce any drug and are obligated only to report discontinuations of single-source, medically necessary drugs to the FDA. The agency has limited control over many of the factors that can lead to drug shortages, and it has no power to punish companies who fail to report such shortages.

Neuss said that he believes the FDA should be stronger in its response to drug supply interruption and noted that the FDA did not appear to be able to effect changes in pharmaceutical company behavior despite its charge to ensure an uninterrupted drug supply to our citizens.

“Every drug that has a limited number of suppliers is at risk of being in short supply when the demand for it goes up or one of the suppliers is required to decrease production,” Neuss said.

“These are established drugs that should have a sturdy chain of supply that should have companies that are smart enough to figure out what the market needs and have enough product to sell.” – by Jason Harris

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