Posted by djmmm on October 16, 2003, at 7:44:20
From Club Drug to Orphan Drug: Sodium Oxybate (Xyrem) for the Treatment of Cataplexy
Posted 10/09/2003
David E. Fuller, M.D., Carl S. Hornfeldt, Ph.DAbstract and Introduction
Abstract
Narcolepsy, a rare disease with a prevalence of 0.05% in the general population, affects an estimated 140,000 patients in the United States. Patients have been able to lead fuller personal and professional lives since the Food and Drug Administration approved sodium oxybate (Xyrem) in 2002 for treatment of cataplexy in patients with narcolepsy. Previously, γ-hydroxybutyrate (GHB), the active ingredient of sodium oxybate, had been a substance of abuse, most notoriously as a date-rape drug. Public Law 106-172, the date-rape prohibition act enacted in 2000, was modified to allow the drug to be legally administered for medical purposes. Because of the apprehension regarding the risk of possible drug diversion after the approval of sodium oxybate and concerns about safety, the Xyrem Risk Management Program was created. This program has been successful in satisfying the needs of patients and physicians while ensuring responsible distribution of the drug.Introduction
On July 17, 2002, the Food and Drug Administration (FDA) approved sodium oxybate (Xyrem; Orphan Medical, Inc., Minnetonka, MN) for treatment of cataplexy in patients with narcolepsy. The FDA approval made this novel drug available to an estimated 140,000 patients with narcolepsy in the United States, despite the reputation of its active ingredient, g-hydroxybutyrate (GHB), as a substance of abuse. Indeed, two articles emphasizing GHB abuse and addiction have appeared in recent issues of this journal.[1, 2] We describe the development of sodium oxybate as an orphan drug for treatment of cataplexy in a patient population with a rare disease.Narcolepsy
Narcolepsy is a sleep disorder classically described as consisting of a tetrad of symptoms: excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations believed to represent the outward manifestations of a disrupted sleep-wake cycle.[3] In addition, patients with narcolepsy may experience fragmented nighttime sleep, automatic behaviors, problems with mental concentration and memory, and visual and other sensory disturbances.[3, 4]Excessive daytime sleepiness, the most common and disabling symptom of narcolepsy,[5] is present in all patients with the disease. Sleepiness often becomes irresistible, resulting in involuntary sleep attacks, even during activities such as talking, eating, standing, walking, and driving in traffic.[6] Although patients with narcolepsy may fall asleep easily at night, as many as 90% report severely disrupted nocturnal sleep, with frequent awakenings.[3, 6]
Cataplexy is the second most common symptom of narcolepsy. Although it has been reported to be present in up to 93% of patients,[7] its prevalence is probably 30-50%. Cataplexy is manifested by sudden episodes of bilateral skeletal muscle weakness induced by an emotional trigger such as laughter, anger, embarrassment, surprise, or even sexual arousal.[8] The frequency of attacks ranges from a few attacks/month to many attacks/day.[3] Partial cataplexy attacks may involve only certain muscle groups, resulting in head drooping or knee buckling; complete cataplexy attacks may involve total skeletal muscle atonia, resulting in collapse, although breathing and consciousness remain unaffected.[8]
Sleep paralysis is the inability to move at sleep onset or on awakening; episodes may last up to 10 minutes and are especially distressing when coupled with hypnagogic hallucinations. Patients with narcolepsy experience sleep paralysis with varying degrees of frequency, sometimes daily.[6]
Hypnagogic hallucinations occur while falling asleep, whereas hypnopompic hallucinations occur on waking, usually lasting 10 minutes or less. These hallucinations are usually visual but can also involve auditory, tactile, or other sensory components. They are usually bizarre or terrifying[3] and occur at least weekly in about 50% of patients.[9]
Narcolepsy has an estimated prevalence of 0.05% in the general population.[10] Thus, with an estimated 140,000 patients with the disorder in the United States, it is, by definition, a rare or orphan disease. Prevalence varies among races but cases are equally distributed between the sexes.
Narcolepsy symptoms generally appear at 15-30 years of age; disease onset after 55 years of age is uncommon. Excessive daytime sleepiness is the primary symptom in 90% of patients. Other symptoms of narcolepsy may occur abruptly soon after disease onset, gradually over a period of years, or not at all. Once narcolepsy symptoms occur, they generally persist without remission.[3]
Pathophysiology
Although the cause of human narcolepsy remains unknown, research suggests that the disease is caused by the loss of a discrete group of neurons that secrete the neuropeptide hypocretin.[11, 12] The cell bodies of hypocretin-containing neurons are located in the posterolateral hypothalamus, from which they project throughout the central nervous system (CNS).[13] Hypocretin has several important functions, such as sleep-wake regulation, maintenance of the normal waking state, and suppression of entry into rapid-eye-movement (REM) sleep. The loss of hypocretin[14] and hypocretin-secreting cells[11, 15] has been demonstrated in patients with narcolepsy. The mechanism responsible for the loss of hypocretin-producing neurons is not known but is thought to involve a combination of genetic and autoimmune factors.[3]Pharmacotherapy
Because no cure has been found for narcolepsy, patients rely on pharmacologic agents to enable them to lead the fullest personal and professional lives possible. Excessive daytime sleepiness is treated with CNS stimulants such as dextroamphetamine, methylphenidate, or modafinil.[3]The symptoms of narcolepsy that are related to REM sleep, such as cataplexy, may be treated with sodium oxybate or off-label use of antidepressant drugs, such as tricyclic anti-depressants and serotonin selective reuptake inhibitors.[16] The mechanism by which these antidepressant drugs alleviate the REM-related symptoms of narcolepsy is not clear, but they are potent REM sleep suppressants.[3] Although some patients report symptomatic relief with these drugs, tolerance may occur. A special concern is that sudden withdrawal of tricyclic antidepressants and serotonin selective reuptake inhibitors may precipitate a marked increase in the number and severity of cataplexy attacks, a condition known as rebound cataplexy. In its most severe form, this condition is known as status cataplecticus.[16]
γ-Hydroxybutyrate
First synthesized in 1960,[17] GHB was later discovered to occur naturally in the CNS.[18] It has been extensively studied since that time, and evidence suggests that it meets the criteria necessary to be considered a neurotransmitter. The neurotransmitter properties of GHB are reviewed elsewhere.[19]In the United States, GHB was marketed as an unregulated dietary supplement in health food stores, training gyms, and fitness centers, and on the Internet during the 1980s. Because anabolic effects were allegedly produced due to the ability of GHB to stimulate growth hormone release, it was taken to enhance body building and strength training. In addition, it was promoted as a natural treatment for insomnia and to induce weight loss. In 1990, the FDA warned against consumption of the substance after several reports of overdose[20] and later that year banned the sale of GHB-containing nutritional supplements.[21]
By that time, GHB had developed notoriety as a substance of abuse at "raves," the popular all-night dance parties.[2] Those who took the drug claimed to experience disinhibition, sexual arousal, and euphoria similar to that associated with alcohol consumption, without unpleasant hangover effects. However, an increasing number of persons taking GHB experienced overdose requiring hospital emergency care; many had combined GHB with ethanol, which produces synergistic CNS depressant effects.[22]
γ-hydroxybutyrate was also implicated in an increasing number of drug-facilitated sexual assaults and was labeled a "date-rape" drug.[23] Like many other CNS depressants, GHB can cause anterograde amnesia, especially when combined with ethanol, leaving the assault victim unable to recall details of the event.
By the end of the 1990s, severe withdrawal symptoms after abrupt cessation of long-term GHB abuse were being reported. This phenomenon has occurred in persons taking GHB every 30 minutes-3 hours over periods of 6 months-2.5 years.[1, 24] Symptoms such as nausea, vomiting, anxiety, confusion, tremor, insomnia, agitation, psychosis, auditory and visual hallucinations, tachycardia, and hypertension after long-term abuse of illicit GHB have been reported
Legal Status
Despite the ban on sales, GHB continued to be abused and misused, eventually leading to enactment of the Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act of 2000 (Public Law 106-172), which amended the Controlled Substances Act, making GHB a schedule I agent.[25] This legislation threatened to greatly hinder future development of GHB for therapeutic applications; however, successful lobbying efforts on behalf of physicians and patients led to modification of Public Law 106-172, creating for the first time a bifurcated or split schedule for GHB-sodium oxybate. Provisions of this act allowed sodium oxybate for medical purposes to be controlled under schedule III after FDA approval while retaining severe schedule I penalties for illegal use.Sodium Oxybate Oral Solution
The formal clinical development of sodium oxybate (Xyrem) for treatment of cataplexy in narcolepsy began in 1994 when Orphan Medical, Inc., was approached by the National Organization of Rare Disorders and the FDA Orphan Products Development Division; both suggested the development of GHB (now called sodium oxybate, its official generic name) for treatment of cataplexy. This suggestion was based on promising results obtained by several independent investigators who reported the efficacy of sodium oxybate as a treatment of narcolepsy. In early clinical trials, nocturnal administration of sodium oxybate greatly improved the quality of nighttime sleep in patients with narcolepsy with an associated reduction in daytime sleep attacks, cataplexy, and other symptoms of narcolepsy.[26-30]Orphan Medical established the safety and efficacy of sodium oxybate for treatment of cataplexy associated with narcolepsy in two randomized, double-blind, placebo-controlled studies (Trials 1 and 2).[31-33] Additional safety data were provided by a long-term, open-label trial (Trial 3).[34] (All studies described in this article were conducted in accordance with the ethical principles delineated in the Helsinki Declaration of 1975, as revised in 1997.)
Trial 1, a 4-week, double-blind, placebo-controlled, multicenter trial, involved 136 narcoleptic patients.[31] Compared with placebo, sodium oxybate produced significant reductions in the number of cataplexy attacks at dosages of 6.0-9.0 g/night, reducing the median frequency of cataplexy attacks by 44% (p=0.045) and 69% (p=0.0016) for placebo and sodium oxybate, respectively.
Trial 2 was a multicenter, randomized, double-blind, placebo-controlled study.[32, 33] The long-term efficacy of sodium oxybate was demonstrated using a withdrawal paradigm in 55 patients who previously had taken the drug in an open-label fashion for cataplexy associated with narcolepsy. Sodium oxybate remained effective after an average of 21 months of previous treatment as demonstrated by the return of cataplexy symptoms in patients who abruptly discontinued taking it and began taking placebo (p<0.001).[32] The frequency of cataplexy gradually returned to baseline levels over a 2-week period but did not exceed them; that is, no evidence indicated rebound cataplexy, commonly associated with abrupt discontinuation of tricyclic antidepressants.[3] Furthermore, no overt abstinence symptoms, such as those seen after long-term abuse, were noted. Several patients reported symptoms that may have been related to termination of sodium oxybate, such as anxiety (2 patients), dizziness (1), insomnia (1) and somnolence (1). However, these may have been related to the return of narcolepsy symptoms.[33]
Trial 3 was a 12-month, open-label extension of Trial 1, in which sodium oxybate dosage was titrated to optimal clinical response for each patient.[34] Clinical response was maximal after approximately 8 weeks of treatment. The median reduction in cataplexy at 12 months was 80-90% in all dosage groups; these beneficial effects were maintained over the 12-month trial without evidence of tolerance.
In Trial 1,[31] adverse events reported more frequently with sodium oxybate than placebo were dizziness (23% of patients), headache (20%), nausea (16%), pain (12%), somnolence (9%), sleep disorder (9%), confusion (7%), infection (7%), vomiting (6%), and urinary incontinence (5%). Data from this trial suggest that the frequency of dizziness, nausea, urinary incontinence, and vomiting may be dose related.[31]
Xyrem Risk Management Program
Because of the apprehension regarding the risk of possible drug diversion after the approval of Xyrem and concerns about safety, Orphan Medical collaborated with the FDA, experts in drug diversion and drug abuse prevention, and clinicians to create the Xyrem Risk Management Program. The program goals are to ensure responsible distribution of sodium oxybate to patients with narcolepsy and provide education to physicians and patients about safe and responsible administration of the drug. Elements of the program include the following:A single, centralized pharmacy housed in a secure facility
Physician and patient registries to help identify inappropriate activities, such as overprescribing and "doctor shopping"
Xyrem Success Program educational materials for patients and physicians to support informed prescribing and patient information on product preparation and administration
Access 24 hours/day to a dedicated team of Xyrem pharmacists providing physician and patient support regarding administration of the drug
Postmarketing surveillance of adverse events associated with Xyrem.
Unlike traditional pharmacies, the central pharmacy maintains comprehensive patient and physician registries and verifies the eligibility of every prescribing physician before honoring Xyrem prescriptions. Pharmacists are trained to be alert for compliance issues and suspicious questions or behavior on the part of patients and physicians, such as rapidly escalating drug dosage and short intervals between refills. They also provide support for patients and ongoing counseling to monitor patient safety and compliance.
Each physician who wishes to prescribe the drug is sent materials describing the Xyrem Physician Success Program. These materials provide guidelines for physicians to consider when prescribing the drug. Physicians are encouraged to provide dosing, preparation, and administration counseling for their patients; evaluate patients every 3 months; and rewrite prescriptions for Xyrem at least every 3 months.
On receipt of their first Xyrem prescription, patients are sent materials describing the Patient Success Program, which contains written educational information as well as an instructional videotape. Patients are taught important aspects about the efficacy and safety of the product, cautioned about the dangers of combining it with alcohol or other sedating drugs, and encouraged not to drive a car until 6 hours after taking the second dose. Before shipping the drug, a Xyrem pharmacist contacts patients to confirm that they understand the information in the Patient Success Program and to address any additional patient questions or concerns.
Xyrem is shipped to patients by overnight shipping service. Each patient or designee must be available to sign for the prescription, or it will be returned to the pharmacy. Xyrem pharmacists contact patients to ensure that prescriptions have been received. The central pharmacy investigates all cases in which a Xyrem prescription is lost or stolen in transit to the patient or drug diversion is suspected.
Postmarketing Surveillance
As a condition of FDA approval, Orphan Medical created the Xyrem Postmarketing Evaluation Program, which provides the FDA with safety information regarding the initial 6 months of therapy for the first 1000 patients prescribed the drug. All physicians are requested to discuss possible adverse events with their patients at clinic visits 3 and 6 months after starting the drug. All information obtained is recorded on evaluation forms provided in the Physician Success Program materials. In addition, physicians may use these forms to record information about patients suspected of abusing or misusing the drug.A review of the current data suggests that no new or clinically significant safety issues have arisen that would affect the recognized adverse-effect profile of the product.
Conclusion
In addition to the difficulties normally associated with development of an orphan drug for a patient population with a rare disease, the clinical development of sodium oxybate was challenged by the popularity of illicit GHB as a substance of abuse. Working cooperatively with federal authorities and drug diversion experts, the Xyrem Risk Management Program was developed to satisfy the needs of patients and physicians while ensuring responsible distribution of the drug. Based on the initial 6 months of operation, the Xyrem Success Program appears to be successful in ensuring appropriate distribution and administration of this important drug
poster:djmmm
thread:269920
URL: http://www.dr-bob.org/babble/20031015/msgs/269920.html