Cadence’s (CADX) Ofirmev US approval provides an important missing adjunct, or alternative, to narcotic drugs for the relief of postoperative pain. The drug is an intravenous (IV) version of acetaminophen. Its antipyretic action makes it useful also for fever reduction in patients requiring emergency intervention. Preceding and following the Ofirmev approval, the Internet was bombarded with negative articles undermining Cadence and downplaying the value of Ofirmev, and, consequently, the value of its approval. We disagree with many of the negative arguments. In any case, sooner or later reality will surface.
The Ofirmev approval came eight years after the first approval of IV acetaminophen in France, which was followed by other European countries and 80 other countries approving the formulation over the following years. Since its introduction to hospitals, the drug has helped thousands of patients and generated millions of dollars in revenues under its European brand name Perfalgan.
Post-operative pain management illustrates the need for Ofirmev. The management of post-operative pain is facing a big dilemma. To begin with, current treatments are not adequately controlling post-operative pains, resulting in unwarranted complications following otherwise successful and safe surgeries. Uncontrolled post-operative pain, in addition to the side effects of the analgesics used, especially, the narcotics, impede the patients’ recovery and ability to return to their activities of daily living, such as walking, eating, sleeping, socializing, and working. These pursuits are necessary for expediting and enhancing the patients’ healing processes and expediting their recovery. Slower recovery increases patients’ hospital stays, and adds to the cost of healthcare.
The two classes of analgesics available for injectable use in the US are opioids and non-steroidal anti-inflammatory drugs (NSAIDs) which have side effects that limit their indications. The intravenous opioids: Morphine, fentanyl, hydromorphone, meperidine, sufentanil, and alfentanil cause nausea, vomiting, constipation, urinary retention, itchiness, chest wall rigidity, cognitive impairment, seizures and, potential respiratory depression, which can be life-threatening. The critical need for adjunctive non-opioid intravenous analgesics that allow for lower doses of opioids led to the choice of NSAID products as the most probable solution, as they do not cause respiratory depression or impair gastrointestinal motility. In the US injectable Toradol (ketorolac tromethamine) and Caldolor (ibuprofen) – NSAID drugs - were approved. Unfortunately, these drugs could not fill all the gaps as the two drugs inhibit platelet aggregation, which could cause bleeding. These NSAIDS are also associated with cardiovascular adverse events and renal toxicity. They are not indicated for use in children.
Cadence’s Ofirmev has advantages over the approved drugs. First it is approved in children. Second, the drug does not cause bleeding; hence surgeons and emergency room physicians are expected to welcome it. Besides the clinical trial data confirming the safety of Ofirmev, the safety of acetaminophen has been established through decades of use of its oral and suppository formulations and eight years of IV formulation use. Liver toxicity is recognized as a dose-dependent adverse effect and liver failure is rare to occur when acetaminophen is given at the recommended dosage. Also, there is an effective acetaminophen antidote known as N-acetylcysteine (NAC) for use in case of the drug toxicity. This product reverses the overdose, hence, reduces the risk of toxicity. Needless to mention that overdosing is less likely to occur with Ofirmev, as it is to be administered only by professionals in emergency rooms and hospital wards for a limited time.
Trial results: Multiple clinical studies demonstrated that given alone, and in combination with opioids, the drug was proven safe and successful in reducing use of morphine and other opioids. In other trals, with Ofirmev, results demonstrate that the average peak plasma concentration of acetaminophen was briefly higher for Ofirmev than for the same dose of oral acetaminophen. Good news is that the levels of the drug were not meaningful over time. Ofirmev proved not to accumulate over multiple doses after 12 hours. Urinary metabolites with potential to interact with the liver were not meaningfully different for Ofirmev than with oral acetaminophen at 12 and 24 hour measurements.
Market: Data published in 2008 by the independent marketing research firm IMS indicate that 400 million doses of intravenous acetaminophen have been distributed since its introduction in Europe. The drug has become the market leader among injectable analgesics with sales representing 20% of all injectable analgesic units, and an estimated 45% market share of all injectable analgesic dollar sales.
Statistical and other evidence from studies of the US and EU markets encourages us to agree with Cadence’s estimation that the US market is potentially larger than EU market with respect to potential unit market share and pricing. With regard to pricing, restrictive system pricing in many European countries has kept the prices under certain level. In some individual European countries, for example, the Scandinavian countries, which have less restrictive pricing controls, the price of the drug was 3.5 times the price of the drug in price restricting countries. Based on this remark and on other criteria, we estimate that the price of the drug will be almost four times the price in the European countries. A small calculation including the price and the market size leads us to believe that the Cadence sales of Ofirmev could reach over $800-$900 million/year.