Subsys is a prescription fentanyl spray designed to be applied under the tongue for rapid pain relief. It was FDA-approved exclusively for managing breakthrough cancer pain in adults who are already taking round-the-clock opioid medication. The drug became widely known not just for its medical use but for the massive legal scandal surrounding its manufacturer, Insys Therapeutics, which paid kickbacks to doctors and pushed the drug for patients who didn’t have cancer.
How Subsys Works
Fentanyl is a synthetic opioid that is roughly 50 to 100 times more potent than morphine. Subsys delivers fentanyl as a liquid spray under the tongue, where it absorbs quickly through the thin tissue lining the mouth and enters the bloodstream. This sublingual route allows the drug to bypass the digestive system, reaching peak blood levels in roughly 40 to 75 minutes depending on the dose. The effects of a single dose can last several hours, with the drug remaining active in the body for 5 to 12 hours.
The spray came in seven dose strengths ranging from 100 to 1,600 micrograms of fentanyl. Patients always started at the lowest dose, with gradual increases until they found the amount that controlled their breakthrough pain. A minimum four-hour gap was required between doses.
Who It Was Approved For
Subsys had one of the narrowest patient populations of any prescription painkiller. It was approved only for cancer patients 18 and older who were already opioid-tolerant, meaning their bodies had adapted to regular opioid use. The FDA defines opioid-tolerant as someone who has been taking at least 60 mg of morphine daily, 30 mg of oral oxycodone daily, or equivalent doses of another opioid for a week or longer.
Breakthrough cancer pain is the term for sudden, intense pain flares that cut through the baseline pain relief provided by a patient’s regular medication. These episodes can come on within minutes and be severe enough to require fast-acting treatment, which is why a sublingual spray format was chosen over a standard pill.
The TIRF REMS Safety Program
Because of the extreme risks of fentanyl products taken through the mouth, the FDA required Subsys and similar medications to be dispensed only through a special safety program called TIRF REMS (Transmucosal Immediate-Release Fentanyl Risk Evaluation and Mitigation Strategy). Under this program, prescribing doctors had to be certified and had to document that a patient was opioid-tolerant with every prescription. Pharmacies dispensing the drug also needed certification and were required to verify opioid tolerance at every fill. Patients themselves had to sign an agreement form and be enrolled in a registry.
These safeguards existed because fentanyl at these doses can cause fatal respiratory depression, where breathing slows or stops entirely. That risk is especially high in people who haven’t built up a tolerance to opioids. Even accidental exposure to a single dose could be lethal for a child or an opioid-naive adult.
The Insys Therapeutics Scandal
Subsys became one of the most notorious drugs of the American opioid crisis, largely because of the criminal behavior of its manufacturer, Insys Therapeutics. The U.S. Department of Justice found that between August 2012 and June 2015, Insys ran fraudulent “speaker programs” that were supposed to be educational events for healthcare providers. In reality, these dinners and lunches were vehicles for paying bribes and kickbacks to doctors in exchange for writing more Subsys prescriptions at higher doses.
The company also encouraged doctors to prescribe Subsys to patients who did not have cancer, directly violating the drug’s approved use. To get insurers to pay for these off-label prescriptions, Insys employees lied about patients’ diagnoses, submitting false claims to Medicare and TRICARE (the military health system).
In 2019, Insys agreed to a $225 million settlement to resolve both criminal and civil investigations. The company’s operating subsidiary pleaded guilty to five counts of mail fraud. Insys was also placed under a five-year Corporate Integrity Agreement with federal oversight. The company’s founder, John Kapoor, was convicted of racketeering along with several other executives, marking one of the first times pharmaceutical executives faced criminal prosecution for fueling the opioid epidemic. Insys later filed for bankruptcy.
Current Availability
Subsys is no longer being manufactured. In August 2024, the makers of all TIRF medicines, the category that included Subsys, announced that production would be discontinued as of September 30, 2024. The TIRF REMS program stopped accepting new enrollments for patients, prescribers, and pharmacies after that date. For cancer patients who relied on fast-acting fentanyl products, alternative formulations and pain management approaches have taken their place.