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| |  Actiq Proven Effective For Breakthrough Pain In Cancer Patients SALT LAKE CITY, May 20, 1997 -- Results from pivotal studies with Actiq(TM) (oral transmucosal fenranyl citrate) show better results in blocking breakthrough pain in cancer patients than with the patients’ previous breakthrough pain medication. These results were presented by clinical investigators at the annual meeting of the American Society of Severe flares of breakthrough pain affect more than 50% of cancer pain patients and are often difficult to treat. These study results are a subset of the Actiq New Drug Application (NDA) currently under review by the Food and Drug Administration (FDA), submitted by Anesta Corp. in November 1996. In summary, Actiq provided better pain relief scores than patients' previous breakthrough pain medication, and the differences were highly statistically significant (p equal to or < 0.0003) at all time points studied. Most patients consistently rated the global performance of Actiq better than their previous medications. Patient preference for Actiq was demonstrated by 92% of eligible patients electing to continue using Actiq instead of their previous breakthrough medication in a long-term safety study. In the long- term study, Actiq remained effective over time and patients safely used the product in multiple stages of disease progression. In previously reported studies, Actiq has been shown to provide rapid onset of pain relief, within five to 10 minutes, a key factor in treating breakthrough pain effectively. Side-effects observed in all studies were those typical of potent opioid analgesics and did not limit the use of Actiq in this patient population. The NDA for Actiq is the first ever to include a breakthrough pain indication and, if approved, Actiq will be the first, and to this point, the only product specifically cleared for this indication. Abbott Laboratories Hospital Products Division manufactures and intends to market Actiq under license from Anesta in the United States. Breakthrough Pain Background Most patients with advanced cancer experience moderate to severe pain, which often has two components; persistent pain and breakthrough pain. Breakthrough pain occurs when transitory episodes of moderate to severe pain "break through" a baseline of otherwise pharmacologically controlled persistent pain. Breakthrough pain is highly prevalent, impacting over 800,000 people in the U.S. alone. Patients typically have one to four breakthrough pain episodes each day. These episodes frequently reach maximal intensity in three minutes and have a relatively short duration. Breakthrough pain is often one of the most agonizing, debilitating and difficult to manage symptoms faced by cancer pain patients. Persistent cancer pain can usually be controlled by analgesic medications that are dosed on a regular schedule (around-the-clock or ATC). Episodes of breakthrough pain, however, are not managed effectively by using and ATC analgesic alone. Currently available short-acting analgesic tablets, capsules and elixirs do not provide rapid pain relief. Instead, they are relatively slow in taking effect, creating a "pain-relief gap" between onset of breakthrough pain and onset of pain relief. While invasive methods (injections or infusions) of analgesic administration can address this gap, they have limitations in the home environment. Clinical Practice Guidelines recommend against the routine use of invasive methods, reserving them primarily for situations when all other means to achieve pain relief have failed. With this unmet medical need for non-invasive, rapid pain relief, Actiq has been developed as the product which provides clinically proven effectiveness to rapidly and safely control breakthrough pain. Cancer Pain Program Overview Anesta's cancer pain clinical research program, designed to demonstrate the safety and efficacy of Actiq, was developed in conjunction with leading cancer pain experts and the FDA. The clinical program included three pivotal trials and comprised 257 outpatients with cancer. In a follow-on, long-term safety trial, 155 patients used Actiq and average of 91 days. In addition to the studies in cancer patients, the Actiq NDA included studies evaluating multiple-dose pharmacokinetics, dose proportionally, and efficacy in other pain models. Cancer patients recruited into Anesta's multi-center pivotal trials were taking stable doses of ATC opioid analgesics for their persistent pain and a second medication on an "as needed" basis for their breakthrough pain. Two of these studies involved a blinded titration phase and were designed to demonstrate that a titration process can be used to identify a dose of Actiq to safely and effectively treat breakthrough pain. These studies also included a comparison of Actiq to the patients' previous breakthrough pain medications. A third pivotal study was a double-blind, placebo-controlled efficacy trial performed at 26 sites nationwide. "The U.S. Government Guidelines for treating cancer pain teach that if possible, cancer pain treatment should be non-invasive and simple in nature," said Dr. Richard Payne, Chief of the Section of Pain and Symptom Management, University of Texas, M.D. Anderson Cancer Center in Houston, Texas. "Actiq is the first oral product ever studied for breakthrough pain that matches the time to produce pain relief with the rapid onset of breakthrough pain,” Dr. Payne added. "The Actiq clinical program has broken new ground in increasing our understanding of, and ability to, relieve breakthrough pain -- one of the significant challenges faced by those caring for cancer patients today." Blinded Titration Studies In the first phase of the blinded titration studies, patients assessed their current breakthrough pain medication using pain intensity, pain relief, and global performance measures. In the second phase, patients were randomized to start at either 200 or 400 mcg of Actiq and were then titrated until a dose was reached at which one unit of Actiq effectively controlled a typical episode of breakthrough pain. Once an effective dose was found, patients evaluated Actiq for two days, again using pain intensity, pain relief and global performance measures. At the ASCO annual meeting, Dr. Paul Coluzzi, The Breast Care and Oncology Care Center at St. Joseph's Medical Plaza, Orange, California, presented data from a study in 65 patients who were receiving long-acting oral opioid analgesics as their ATC medication. Dr. Mary Simmonds, Pennsylvania State University, Hershey, Pennsylvania, presented data from a study in 62 patients who were receiving transdermal fentanyl as their ATC analgesic. In these studies, 74 - 76% of patients found an effective dose of Actiq. Open-label comparisons revealed that Actiq scored significantly better (p equal to or < 0.0003) than the patient's previous medications on pain relief scores at 15, 30 and 60 minutes. Importantly, pain relief was achieved more rapidly with Actiq than with the patients' previous breakthrough medications. Patients also rated global performance of Actiq significantly better than their previous breakthrough pain medications. Global performance is a measure of the patients overall satisfaction with a product and incorporates efficacy, side-effects, dosage form, and convenience. The most common side-effects experienced during Actiq use were the common opioid associated side-effects of somnolence, nausea, and dizziness. Placebo-Controlled Efficacy Study The third Actiq pivotal study presented at the ASCO annual meting by Dr. James Cleary, University of Wisconsin Medical Center, Madison, Wisconsin, compared the efficacy of Actiq against placebo in 130 patients. After an open-label, dose titration phase, patients entered a double-blind, placebo-controlled crossover phase where they received either active or placebo Actiq units according to a randomization schedule. Patients were allowed to rescue with their previous breakthrough medication if they did not achieve adequate pain relief. Dr. Cleary reported that Actiq provided significantly better analgesia than placebo (p equal to or < 0.0001), as measured by pain intensity and pain relief scores at 15, 30, 45 and 60 minutes. Global performance with Actiq was also significantly better than placebo. The most commonly reported side-effects were dizziness, nausea, and somnolence. Long-Term Safety Study After completing one of three pivotal studies, patients were screened to determine their eligibility to enroll in a safety study and continue the use of Actiq for their breakthrough pain for an extended time period. Of the patients eligible to participate in the study, 92% chose to continue using Actiq to treat their breakthrough pain rather than return to their previously used medications. At the ASCO annual meeting, Dr. Alan Lyss, Missouri Baptist Cancer Center, St. Louis, Missouri, reported data from 155 patients who had participated in the long-term study. In this study, patients recorded the number of breakthrough pain episodes each day, the number successfully treated with Actiq, global satisfaction, and side-effects. The number of treatment days ranged from 1 to 423 days (mean 91 days). Patients in the study used 41,766 units of Actiq to treat 38,595 episodes of breakthrough pain. Actiq treatment was rated by the patients as successful in 92% of the episodes treated with Actiq. Global performance was consistently rated in the very good to excellent range. The most common side-effects were somnolence, constipation, nausea, and dizziness. The Actiq dosage unit consists of a drug matrix attached to a handle, which is designed to facilitate dissolution and absorption of the drug within the mouth. Actiq enables the patients to individually control drug delivery, which can help achieve effective pain relief while minimizing side-effects in a patient friendly, non-invasive delivery system.
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