Some recent updates from the American Society of Health-Systems Pharmacists of interest to people with colon and rectal cancer:

• Fluorouracil (5-FU) as of 8/31/11: On back order from Teva, APP Pharmaceuticals, and Mylan Institutional.  Manufacturing delays at Teva appear to have caused increased demand from other companies.
• Leucovorin as of 8/31/11:   Bedford has some powderized sizes available and limited allocations of others.  Teva is importing folinic acid solution and it is available for drop shipment, but powdered leucovorin is on back order. APP is releasing powderized leucovorin as it becomes available.
• Irinotecan as of 8/26/11:  Teva and Sandoz have back orders of some doses because of manufacturing problems.  Hospira shortages are due to increased demand.  Some dosage vials are available from APP and as Camptosar from Pfizer.  Three generic manufacturers stopped making irinotecan in 2010 and another one did so in May 2011.
• Fusilev as of 6/21/11:  Although it was in shortage previously, Spectrum has announced that they have ample supplies currently and for the future.  ASHP reminds physicians and pharmacists that dosing errors can occur when substituting Fusilev (levoleucovorin) for leucovorin.

Check the links to ASHP updated sites for more detailed information about which sizes are available, reasons given for shortages, and when shortages are expected to be resolved.

Take action!

Email your Members of Congress in support of legislation that would combat future drug shortages. We make it easy in our online action center.

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“What to do when your doc is out of 5-FU“  

Frequently Asked Questions

What drugs for colorectal cancer patients are in short supply?

The list of drugs on the short supply list can change week to week, but there are two drugs that have been low for some time: leucovorin and fluorouracil (5-FU).

Leucovorin is a folic acid that has long been used with 5-FU to treat colorectal and other cancers. Leucovorin boosts the effectiveness of 5-FU, by lengthening the time that the very short-acting 5-FU works to kill cancer cells.

Why are there leucovorin and 5-FU shortages?

For several years, manufacturing problems at the US companies that make and distribute generic leucovorin and 5-FU and have limited the amount of the drug that they are able to ship to pharmacies and doctors.  Many oncologists now cannot obtain it at all.  Others can only get limited supplies, so they are reducing doses for patients. Additionally, one of the companies that makes 5-FU has blamed their shortage on manufacturing delays.

Both the FDA and the American Society of Health-System Pharmacists track drug shortages, the reasons for those shortages, and when the shortage for each drug might be resolved. But the national picture does not always reflect day-to-day shortages in specific parts of the country or individual cancer centers.

What choices do I have if my doctor doesn’t have leucovorin?

The National Comprehensive Cancer Network (NCCN), which provides cancer treatment guidelines, has recommended that doctors do one of the following:

• Use a lower dose of leucovorin for all patients. (Several studies have shown equivalent effectiveness at lower doses.)
• Use Fusilev® (levoleucovorin) a brand-name drug with a chemical structure similar to leucovorin. Although the dosage is different, levoleucovorin has the same effectiveness as leucovorin when combined with 5-FU.  It was approved by the FDA in April 2011 to treat advanced colorectal cancer.
• If there are no other options, “treatment without leucovorin would be reasonable.” For patients who can tolerate it without side effects, NCCN suggests increasing the bolus dose of 5-FU in the range of 10 percent.

The FDA has also approved temporarily importing injectable calcium folinate–the form of leucovorin most commonly used in Europe.

What choices do I have if my doctor doesn’t have 5-FU?

The Association of Health System Pharmacists recommends that doctors:

• Evaluate the health-care system’s total supply of fluorouracil before beginning patients on combination chemotherapy regimens containing fluorouracil. If adequate supplies are not available, select an alternative regimen.
• Consult a Hematology/Oncology specialist for patient- and neoplasm-specific recommendations.
• Refer to the ASHP Guidelines on Managing Drug Product Shortages for more guidance on developing a multidisciplinary plan when the supply must be allocated.

What is Fight Colorectal Cancer doing to help patients, and to solve this problem?

• Our Research & Treatment News has been tracking this issue since 2008, and we will continue to keep you informed with frequent updates. Subscribe to receive our updates by email.
• The Answer Line (877-427-2111) has fielded over 100 calls on this topic and has assisted patients and families facing drug shortages.
• Fight Colorectal Cancer supports S. 296 and H.R. 2245, bills that would require manufacturers to report shortages as they arise and also require the FDA to take specific actions to ease drug shortage issues. Please email your Members of Congress in support of this legislation.
• Fight Colorectal Cancer continues to push both manufacturers and the FDA to increase the availability of generic oncology drugs.

Shortages of prescription drugs cost the United States more than $200 million.

In addition, shortages force doctors to delay or cancel treatment.  Patient safety is compromised when doctors have to use different or unfamiliar drugs when they can’t get the right ones.

In the six months from July to December of 2010, 240 drugs were either in short supply or completely unavailable.  More than 400 generics were back-ordered for more than five days.

Most of the medicines with shortages are necessary for emergency care, sedation, or chemotherapy — including leucovorin which is a backbone of most colorectal cancer treatment regimens.

The Premier healthcare alliance surveyed 311 pharmacy experts in 211 hospitals, surgery and oncology centers, and pharmacies.  They discovered that over the course of six months in 2010:

• 89 percent experienced shortages that could have caused a patient safety issue.
  • 53 percent had that problem more than 5 times.
• 80 percent experienced a shortage that caused them to delay or cancel patient care
  • 34 percent had that happen more than 5 times.
• 98 percent encountered a shortage that caused an increase in costs.
  • 88 percent spent more 5 or more times.
  • 41 percent spent more 20 0r more times.

Reasons for Drug Shortages

Quality of Raw Materials: Nearly half of shortages were related to quality issues including impurities, microbials contamination, and chemical instability.  Eighty percent of raw materials for medications manufactured in the United States come from outside of the US.

Manufacturer Financial Decisions: Nearly 1 in 5 of injectable drug shortages were due to a manufacturer stopping making the drug.  Pressures from patent expirations, cost of FDA compliance, and healthcare reform impact profits and financial decisions.

Enforcement of FDA Standards and Regulations: Meeting manufacturing inspections requirements and the high costs of FDA’s Unapproved Drug Initiative, launched in 2006, have led some manufacturers to cease production rather than invest to meet requirements and regulatory user fees inherent in the drug approval process.

Leaner Inventories: In recent years, “just-in-time” inventory management has led to lower quantities of raw materials and finished products.

Gray Market Price Gouging: During shortages distributors may buy up all available supplies and sell them at greatly inflated markups.  Premier members reported as much as a 335 percent markup for a drug in shortage.

Stockpiling by Users: Shortages can be worsened when hospitals and doctors try to protect themselves by ordering larger amounts of drugs than they really need.

Changes in Clinical Practice and Emergency Situations: Shortages of one drug can lead to shortages of a replacement medicine.

Leucovorin and Fusilev Shortage Update

The American Society of Health-Systems Pharmacists (ASHP) updated their information on leucovorin and Fusilev® (levoleucovorin) on March 23,2011.   At that time all three manufacturers of leucovorin were experiencing delays in shipping it, and Spectrum Pharmaceuticals had a shortage of Fusilev.

ASHP had personal communications with each of the companies and found:

• Bedford could provide no reason for the shortage.  They have some dosages on back order and don’t know what the release date will be.  For other dosages, they are estimating release late March, 2011.
• Teva says their shortage is due to manufacturing problems.  They cannot estimate a release date.
• APP has leucovorin on back order and estimates being able to release it late March or early April 2011.
• Spectrum Pharmaceuticals has Fusilev on back order due to increased demand.  They cannot estimate when they will release it. They will have supplies of imported levoleucovorin, but cannot estimate a release date.

The FDA has  authorized Spectrum to import levoleucovorin from a Pfizer manufacturing facility in Italy.  That facility has been inspected by the FDA, but it is the only approved foreign source of Fusilev.

Preserving Access to Life-Saving Medications Act

On February 7, 2011 Senators Amy Klobuchar (D-Minn.) and Robert Casey (D-Pa.)introduced a bill to address the issue of drug shortages.  The legislation, S.296, would require

• manufacturers to notify the FDA if they anticipate changes in supplies or production  that may lead to shortages .  If a company plans to discontinue making a drug, they have to inform the FDA at least 6 months in advance.  The FDA must develop penalties for manufacturers not complying with notifications.
• FDA to publish information about manufacturing problems and actual drug shortages on its website.
• FDA to develop evidence-based criteria for drugs that are vulnerable to shortage and publish that information on their website.  Factors that would make drugs vulnerable to shortages include the number of manufacturers, supply of raw materials, characteristics of the supply chain, and availability of other treatments.

ASHP has a summary of the legislation.

Fight Colorectal Cancer is doing all we can to keep pressure on the issue of drug shortages, particularly leucovorin and now Fusilev.  We will let you know as the situation changes.

Briefly: In research this week, human embryonic stem cells produced an immune response in mice with colon cancer, and discussing strong pain medicines with cancer patients reduces their pain by about 20 percent.

The Food and Drug Administration has found many dietary supplements contaminated with prescription drugs not listed on the label, some at several times higher than the recommended dose.  In other FDA news, Spectrum Pharmaceuticals was unable to get FDA approval for use of Fusilev® for metastatic colorectal cancer.

Research Reports

• Stem cell researchers at the University of Connecticut have laid groundwork for a possible cancer vaccine. Injecting human embryonic stem cells into mice with colon cancer induced a strong immune response that reduced tumor growth. Dr. Bei Liu, one of the study’s leaders said, “Although we have only tested the protection against colon cancer, we believe that stem cells might be useful for generating an immune response against a broad spectrum of cancers, thus serving as a universal cancer vaccine.
• Pooled analysis of 21 studies of cancer pain found that talking to patients about how the strong pain drugs worked, how best to take them, and myths about them improved pain relief by a full point on a 10 point scale.  In discussing the research at the United Kingdom’s National Cancer Research Institute’s Cancer Conference in Birmingham  on October 7, Professor Michael Bennett said, “Helping people manage pain is a major challenge for doctors and our research shows for the first time that education is an effective, easy and cheap way to do this.” Hear an interview with Professor Bennett from NCRI.

Other Headlines

• The FDA has identified over 140 contaminated dietary supplements, but this is only the tip of the iceberg according to American Roulette — Contaminated Dietary Supplements, an article in the New England Journal of Medicine. Many of the supplements contain drugs that aren’t listed on the label among so-called “natural” ingredients.  Supplements are regulated under the 1994 Dietary Supplement Health and Education Act (DSHEA) which does not require safety testing before dietary supplements can be placed on the market or label warnings about side effects.  However, they must include all ingredients on their labels and cannot have prescription medicine as an ingredient.  Some prescription stimulants in dietary supplements sold for weight loss are three times what would be a safe dose.
• The FDA has refused to approve Spectrum Pharmaceutical’s application to extend indications for Fusilev® (levoleucovorin) to include metastatic colorectal cancer. Their response to Spectrum said that the company’s submission did not demonstrate the Fusilev was not inferior to leucovorin.  However, they recommended that Spectrum meet with them to discuss options for continuing to seek approval for the use of the drug in colorectal cancer.  Spectrum says that they will seek an FDA meeting promptly.  Fusilev is the active part of the leucovorin (folinic acid) molecule and can be used at a lower dose than leucovorin.  Last year, when there was a shortage of leucovorin in the United States, some oncologists substituted Fusilev for leucovorin, which is a critical part of many colorectal cancer chemotherapy regimens.  Fusilev is FDA-approved to rescue overdoses of methotrexate but not to treat colorectal cancer.