January 23, 2013
Rare Blood-Clotting Disease Could Be Linked to Misuse of Abuse-Deterrent Opioid

Atlanta—With the FDA releasing draft guidance to assist industry in developing new formulations of opioid drugs with abuse-deterrent properties, a report from the CDC has raised some troubling concerns.

The CDC’s Morbidity and Mortality Weekly Report (MMWR) noted earlier this month a report from Tennessee of a rare blood-clotting problem among people who injected the painkiller Opana ER (extended release) after crushing the pills. Tennessee health officials reported 15 cases of thrombotic thrombocytopenic purpura (TTP) from August to October last year, 14 specifically related to Opana ER.

FDA approved Opana ER for oral use in 2006, but released a new formulation into the market last February in response to the problem of the tablets being crushed to snort or dissolve for injection. The new formulation, designed to inhibit crushing and dissolving tablets, contains inactive ingredients not found in the original formulation, including polyethylene oxide (PEO) and polyethylene glycol, according to the CDC report.

“It is unclear what component or components of reformulated Opana ER might trigger TTP-like illness when injected and whether different methods of preparing the drug can increase or decrease the risk from injection,” the MMWR article said. “No human studies have evaluated the risk from injecting this new formulation, although in one study in rats, intravenously injected PEO caused thrombocytopenia. It is also possible that the pills in the Tennessee cases were adulterated by a drug dealer. However, at least two patients obtained the drugs directly from a licensed pharmacy with prescriptions, and the involved communities are far enough apart to make a single nonmedical source for other cases unlikely.”

The authors added, “In general, injection of any opioid pain reliever formulated for oral use presents risks for fatal toxicity and blood borne infection, but this is the first report of TTP-like illness associated with abuse of an opioid pain reliever by injection.”

CDC is recommending that patients with a TTP-like illness with unknown etiology be questioned about intravenous drug abuse, have a urine test to look for oxymorphone, and that their prescriptions for controlled substances be obtained from state prescription drug monitoring programs. The agency also is urging pharmacists and other health care providers to warn patients about the risk for recurrent TTP, blood borne infections, and overdose with use of injected Opana ER. Patients admitting to abuse should be referred to substance abuse treatment programs, and clinicians who prescribed them Opana ER should be notified, according to CDC, which said a standardized case report form is available at e-mail,

CDC said there have been no reports of cases of TTP-like illness following injection of reformulated OxyContin, available since Oct. 2010.

Reformulation of other opioids are likely to occur with release of the recent FDA document, “Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling.” It describes what studies should be conducted to demonstrate that an opioid formulation has abuse-deterrent properties, how those studies will be evaluated by the agency, and what labeling claims may be approved based on the results of those studies.

“While prescription opioids are an important component of pain management, abuse and misuse of these products have resulted in too many injuries and deaths across the United States,” said Douglas Throckmorton, MD, deputy director for regulatory programs in the FDA’s Center for Drug Evaluation and Research. “An important step towards the goal of creating safer opioids is the development of products that are specifically formulated to deter abuse.”

An FDA statement noted that “the science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving.”

FDA is seeking public comment on the draft guidance for 60 days, with instructions on how to submit comments to be announced in an upcoming Federal Register notice. One of the controversies expected to be discussed is how the FDA regulates generic versions of opioid analgesics that have been reformulated to deter abuse.

U.S. Pharmacist Social Connect