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Morphine oral concentrate no longer available unless companies submit a new drug application

From the April 9, 2009 issue

Morphine (immediate release) oral solution concentrate (ROXANOL and generics) is being withdrawn from the market. Under a previously announced plan (www.fda.gov/cder/drug/unapproved_drugs/enforcement.htm) to ensure all US drugs are FDA approved, FDA sent letters on April 1 directing companies to stop making (within 60 days) and distributing (within 90 days) 14 narcotics in certain dosage forms that lack FDA approval, including Roxanol 20 mg/mL. Other opioids, including oxyCODONE and HYDROcodone, were listed in the letter (www.fda.gov/cder/drug/unapproved_drugs/narcoticsQA.htm), but it’s unclear whether ROXICODONE, the concentrated form of oxyCODONE (20 mg/mL), will remain available. It was not specifically mentioned in the FDA letter, and we have not reached the distributor, Xanodyne, for comment. 

FDA noted there are approved products and applications which contain the same active ingredients as the unapproved opioid analgesics; thus, a shortage is not anticipated. However, we believe the withdrawal of morphine oral concentrate will create problems for cancer patients, especially intermittently conscious patients near the end of life who require large doses of this drug to control pain. These patients may have difficulty swallowing the volume required using lower morphine concentrations.

It’s unlikely that morphine oral concentrate will go away entirely, as compounding pharmacies can prepare the drug. However, quality control standards in some pharmacies may not be equal to standards in the pharmaceutical industry, thus risking calculation, preparation, packaging, labeling, and dropper calibration errors. Some patients might be switched to morphine via injection or suppository—less comfortable for the patient and more difficult to administer. Others might be switched to another opioid, but miscalculation of equianalgesic doses, temporary intolerance to the new drug, or inadequate analgesia may result. 

Under a grandfather clause, a drug marketed prior to the 1938 Federal Food, Drug, and Cosmetic Act, and labeled with the same conditions of use as prior to the Act, was not considered a new drug. These drugs did not require an approved new drug application, but many thought tacit FDA approval was implied. It’s the drug company’s burden to prove an assertion that its product is grandfathered. But FDA believes few drugs are entitled to grandfather status because many differ from previous versions in some respect (e.g., formulation, strength, dosage form, route, indications, intended population).

Confusion between morphine oral concentrate (20 mg/mL) and conventional concentrations (20 mg/5 mL) has led to fatalities, as the concentrated version is without prominent warnings. Approved versions of opioids include labeling that reflects the risks, benefits, and safe use of these drugs. If morphine oral concentrate had undergone an FDA-approval process, there might have been labeling, packaging, or product changes to maximally protect against user error. For example, a required FDA-approval process may have led to labeling the concentrate as 100 mg/5 mL to help distinguish the high concentration from the lower 20 mg/5 mL strength. This is precisely the reason FDA is taking the current action—to compel submission of a new drug application and ensure safe use of unapproved opioids.  

Although FDA had announced it was going to address unapproved drugs, the withdrawal of these opioids was unexpected, particularly given a FDA directive earlier this year that led pharmaceutical companies to to create risk evaluation and mitigation strategies (REMS) for these opioids (www.fda.gov/cder/drug/infopage/opioids/default.htm). It’s unfortunate that the move by FDA couldn’t wait until the planned meetings about REMS were completed, allowing the pharmaceutical industry, medical community, and public a chance to interact with FDA. Hopefully, FDA and the companies will be able to collaborate so that morphine oral concentrate can remain on the market (with improved labeling). In fact, we understand that manufacturer-FDA communication is underway regarding this issue.
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