Roxane's Redesigned Morphine Carton Reflects Orderly Rollout After Safety Concern

FDA allows existing stock to be used up over the course of a year after the new color-coded container for the high-potency product was approved.

FDA's recent MedWatch alert about new packaging for Roxane Laboratories' high-potency 100 mg/5 mL morphine sulfate is the last chapter in a lengthy drug safety saga that reflects a close collaboration between the agency and the firm.

While the circumstance are of course unique, the techniques that Roxane used in dealing with the challenges can offer insight to other firms seeking to smoothly resolve regulatory or safety concerns with FDA. The resolution was not especially quick, but it could be seen as a very successful one from the firm's perspective.

The saga began in September 2007 when FDA learned that a patient had died due to a medication error involving Roxane's high-potency morphine sulfate and that three other mixups had been reported. After a collaborative effort, the redesigned container and carton labels with improved safety features were approved on Jan. 25, 2010. Roxane was allowed to use up the remaining stock of the previous packaging, and issued a "Dear Health Care Provider" letter in December 2010 announcing the change after the new carton became the only one in circulation.

Unapproved Drugs Initiative Leads The Way

The new labeling was approved along with the high-potency morphine sulfate product itself, which had previously been marketed as an unapproved drug. In recent years, FDA has been working to get previously unapproved and grandfathered-in drugs off the market or subject them to the NDA process (Also see "FDA Crackdown On Unapproved Drugs Has Incentives For Voluntary Submissions" - Pink Sheet, 12 Jun, 2006.). It was through this Unapproved Drugs Initiative that the medication error problem first came to FDA's attention.

Roxane had submitted an original NDA for morphine sulfate in lower dosages in May 2007 which was approved March 17, 2008. The company submitted a supplemental application for the 100 mg/5 mL product on Aug. 25, 2009, and received the approval for that five months later.

And while all seems relatively smooth in retrospect, there was a moment when FDA wanted to pull the high potency product from the market, but the agency reversed itself after palliative care doctors expressed concern ('FDA Adopts Interim Plan To Avoid Shortage Of Medically Necessary Opioid,' 'The Pink Sheet,' April 13, 2009). Former FDA Principal Deputy Commissioner Joshua Sharfstein highlighted that incident as one of the key motivators in his drive for transparency at the agency (Also see "From Beginning To End, FDA Transparency Weighed On Sharfstein’s Mind" - Pink Sheet, 10 Jan, 2011.).

The rapid review and smooth transition of Roxane's product can be contrasted with the difficult regulatory road that Lannett Co. is facing in its effort to re-launch its morphine products while it fights with the agency in court (Also see "FDA’s Unapproved Drugs Policy Draws Legal, Regulatory Responses From Lannett, To Little Success" - Pink Sheet, 17 Jan, 2011.).

Medication Errors Had Stopped Before New Package Rolled Out

One reason that Roxane and FDA were able to make such an orderly transition to the new carton may have been that the medication errors that had prompted the initial worries were not an acute ongoing concern.

"Through September 2007, we identified four cases of confusion with morphine concentrated oral solution (100 mg per 5 mL) and morphine sulfate oral solution (10 mg/5 mL and 20 mg/5 mL)," FDA said in an email. "One of the four cases resulted in death. In this case a technician chose the wrong product (20 mg/mL instead of 20 mg/5 mL) when entering the prescription into the computer, and the pharmacist did verify the order with the product prior to dispensing the medication."

There have been no additional deaths due to similar mixups with the 100mg/5 mL product since then, the agency says.

"Root cause analysis of the four errors suggested that the numerical similarity of the concentrations (20mg/mL versus 20mg/5mL) and visual similarity of the packaging may have contributed to the errors." The root cause analysis and resulting label redesign "may prevent" future errors, FDA added. The high-potency product is meant only for patients who have built up tolerance to opioids; it can stop other patients' breathing.

The redesigned label bears bold red and yellow colors, a boxed warning and other precautions to make sure prescribers and patients understand the dosage for Roxane's 100 mg/5 mL morphine sulfate oral solution and can distinguish it at a glance from lower-strength Roxane morphine products. The old label used brown lettering on a white background, similarly to other Roxane products.

Old Packaging Exits The Market Gracefully

Roxane issued a "Dear Health Care Professional" letter about the potential for medication error, and the fact that the label had been changed, on Dec. 30, 2010. FDA followed up with a MedWatch safety alert on Jan. 10, describing the approval as "recent." The agency said it issued the MedWatch notice "as a way to amplify the messages of the Dear HCP letter to a broader audience."

When asked why Roxane waited until December to send out the "Dear Health Care Professional" letter, the company declined to comment, but the agency said the product with the old label was still working its way through the market until then.

"The DHCP letter was written last year (sometime in the first quarter of 2010) soon after the higher strength morphine product was approved," the agency noted. "Prior to the approval, FDA's drug shortages staff worked closely with Roxane to ensure that Roxane had enough inventory to cover the market as CDER'S Office of Compliance pursued enforcement action on other marketed unapproved morphine products" (Also see "Roxane's Oral Morphine Sulfate Gets FDA Approval, But Also Inventory Oversight" - Pink Sheet, 26 Jan, 2010.)

It took Roxane longer than anticipated to use up the old inventory of morphine 100 mg/5 mL, so the firm "delayed the dissemination of the DHCP letter until the newly labeled product made it to the market," FDA says.

"The release of the DHCP letter was not in response to new cases of medication errors associated with morphine," the agency added. "The letter was delayed because it would have been erroneous to disseminate it before the newly labeled product was available. ...[T]he old product was not removed from the market, but was consumed before the newer product made it to the market."

As to why the product with the old labeling was allowed to remain on the market well into 2010, the agency said, "Cessation dates are determined on a case-by-case basis, and are directed towards manufacturers and distributors."

For the morphine oral solution 20 mg/ml, distribution of the unapproved versions of the products (including Roxane's own) was to cease 180 days after Roxane got approval, meaning that it should have been the only one moving through the channel was after July 25, 2010.

"Previously distributed unapproved morphine oral solution products may have been found on pharmacy shelves for a period of time," the agency added. "Health care providers can help protect the public's health by considering the approval status of a drug when prescribing, dispensing, or administering prescription drug products."

Agency Sees Collaboration With Industry As Key

During this lag time, on June 24, 2010, Carol Holquist, director of FDA's Division of Medication Error Prevention and Analysis, said at a public workshop that Roxane's standardized use of label colors had been causing confusion (Also see "Dangerous Clutter: FDA Takes On Errors Caused By Drug Labels, Packaging" - Pink Sheet, 5 Jul, 2010.).

[Editor's note: A previous story about Roxane's Dear Doctor letter incorrectly suggested that the remarks at the workshop occurred before the redesigned package was approved (Also see "FDA Noticed Labeling Problems With Roxane Drugs Six Months Before Morphine Alert" - Pink Sheet, 11 Jan, 2011.). ]

"Roxane and FDA worked collaboratively to improve the label of the 100 mg per 5 mL product six months before our public meeting," the agency said in a January 2011 email about the meeting. "In fact, one of the reasons that Melissa Craddock from Roxane was asked to participate in the public meeting was because the negotiation and implementation of these labeling changes were viewed as a successful partnership to reduce medication errors and we wanted her to share her firm's learnings in a public arena."

Craddock, a regulatory affairs/labeling specialist for Roxane, said at the meeting that the company uses brown on most of its drug labels, but distinguishes the highest strengths with red.

FDA is planning a guidance on avoiding medication errors, which was the reason for the June workshop. "Now [we] are reviewing comments and drafting guidance," the agency said.

The key point for the agency is that collaboration with industry is essential to reduce the risk of medication errors. "When a manufacturer becomes aware of a potential medication error problem, we encourage them to contact FDA to discuss the issue. Within CDER, the Division of Medication Error Prevention and Analysis (DMEPA) is routinely consulted to evaluate medication error issues. DMEPA has considerable knowledge of medication error causality from monitoring medication error cases reported to MedWatch."

-Martin Berman-Gorvine ([email protected])