Safety Overview of Postmarketing and Clinical Experience of Sodium Oxybate (Xyrem): Abuse, Misuse, Dependence, and Diversion
2009; American Academy of Sleep Medicine; Volume: 05; Issue: 04 Linguagem: Inglês
10.5664/jcsm.27549
ISSN1550-9397
AutoresY. Grace Wang, Todd J. Swick, Lawrence P. Carter, Michael J. Thorpy, Neal L. Benowitz,
Tópico(s)Forensic Toxicology and Drug Analysis
ResumoFree AccessAlcoholSafety Overview of Postmarketing and Clinical Experience of Sodium Oxybate (Xyrem): Abuse, Misuse, Dependence, and Diversion Y. Grace Wang, M.D., Todd J. Swick, M.D., Lawrence P. Carter, Ph.D., Michael J. Thorpy, M.D., Neal L. Benowitz, M.D. Y. Grace Wang, M.D. Address correspondence to: Grace Wang, M.D., Drug Safety & Pharmacovigilance, Jazz Pharmaceuticals, Inc., 3180 Porter Drive, Palo Alto CA 94304(650) 496-2687(650) 496-2721 E-mail Address: [email protected] Jazz Pharmaceuticals, Inc. Palo Alto, CA , Todd J. Swick, M.D. The Houston Sleep Center, University of Texas-Houston, School of Medicine, Houston, TX , Lawrence P. Carter, Ph.D. Psychiatric Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR , Michael J. Thorpy, M.D. Montefiore Medical Center, Bronx, NY Albert Einstein School of Medicine, Bronx, NY , Neal L. Benowitz, M.D. University of California, San Francisco, San Francisco, CA Published Online:August 15, 2009https://doi.org/10.5664/jcsm.27549Cited by:65SectionsAbstractPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTStudy Objectives:This study reviewed the cumulative postmarketing and clinical safety experience with sodium oxybate (Xyrem®), a treatment approved for cataplexy and excessive daytime sleepiness in narcolepsy. Study objectives were to investigate the occurrence of abuse/misuse of sodium oxybate since first market introduction in 2002, classify cases using DSM-IV criteria for substance abuse and dependence, and describe specific characteristics of these cases.Methods:We retrospectively reviewed postmarketing spontaneous adverse event (AE) reports from 15 countries for all cases containing reporting terminology related to abuse/misuse to determine its occurrence. All death cases independent of causality were reviewed to identify associated risk factors.Results:Approximately 26,000 patients worldwide received sodium oxybate from first market introduction in 2002 through March 2008. Of those 26,000 patients, 0.2% reported ≥ 1 of the events studied. These included 10 cases (0.039%) meeting DSM-IV abuse criteria, 4 cases (0.016%) meeting DSM-IV dependence criteria, 8 cases (0.031%, including 3 of the previous 4) with withdrawal symptoms reported after discontinuation of sodium oxybate, 2 confirmed cases (0.008%) of sodium oxybate–facilitated sexual assault, 8 cases (0.031%) of overdose with suicidal intent, 21 deaths (0.08%) in patients receiving sodium oxybate treatment with 1 death known to be related to sodium oxybate, and 3 cases (0.01%) of traffic accidents involving drivers taking sodium oxybate. During this period, approximately 600,000 bottles of sodium oxybate were distributed, and 5 incidents (0.0009%) of diversion were reported.Conclusion:Cumulative postmarketing and clinical experience indicates a very low risk of abuse/misuse of sodium oxybate.Citation:Wang YG; Swick TJ; Carter LP; Thorpy MJ; Benowitz NL. Safety overview of postmarketing and clinical experience of sodium oxybate (xyrem): abuse, misuse, dependence, and diversion. J Clin Sleep Med 2009;5(4):365-371.INTRODUCTIONSodium oxybate (Xyrem) is the sodium salt of gamma-hydroxybutyric acid (GHB), an endogenous short-chain fatty acid with properties consistent with those of a neurotransmitter and/or neuromodulator.1 GHB is found throughout the brain as well as in tissues outside the central nervous system (CNS). GHB is a rapidly acting CNS depressant. In the 1990s, GHB gained a reputation as a club drug because of its use at raves and dance parties, and as a date rape drug because of reports of intoxication, obtundation, and amnesia.2,3 The concentration or doses of illicitly produced GHB are often unknown and can be contaminated with GHB prodrugs such as 1,4-butanediol (1,4-BD) or gamma-butyrolactone (GBL).4 Illicit GHB, particularly in combination with alcohol, can result in greater than intended effects for both the voluntary and involuntary (assault victim) user. The FDA has issued warnings stating that GBL and 1,4-BD, analogs of GHB, which are metabolized to GHB when ingested, also have the potential for abuse and are a danger to public health.5 Illicit GHB has been reported to decrease level of consciousness to varying degrees and has been associated with overdose,6,7 likely because of its relatively steep dose-effect relationship.8GHB and the pharmaceutical product sodium oxybate have been evaluated for abuse liability in non-human species and humans, respectively, using well-established laboratory methodologies. Most non-human studies have shown that GHB is not self-administered to the same extent as other drugs of abuse,9 although Weerts et al. showed GHB self-administration under conditions of infrequent and extended access.10 Similarly, human abuse liability studies have shown that the abuse liability of sodium oxybate is comparable to that of other scheduled and unscheduled depressant drugs such as triazolam and alcohol.11,12 However, national surveys of drug use, illicit drug confiscation, and emergency room and poison control center calls in the U.S. indicate that the prevalence of illicit use of GHB is very low, has declined since 2000,4 and is much lower than that of the major drugs of abuse and club drugs including 3,4,-methylenedioxymethamphetamine (MDMA, street name: ecstasy).13 Both epidemiological and laboratory studies have reported that frequent, around-the-clock patterns of GHB administration can produce physical dependence, as evidenced by a withdrawal syndrome.14 Physical dependence (characterized by the emergence of withdrawal signs and/or symptoms upon cessation of use) was reported with daily use of illicit GHB at supratherapeutic doses of 18 to 250 g/day15–17 (therapeutic doses of sodium oxybate for narcolepsy range from 4.5 to 9 g/night). In patients who ingested these high doses of illicit GHB around the clock, withdrawal signs and symptoms included psychosis, agitation, tachycardia, hypertension, delirium with auditory and visual hallucinations, diaphoresis, nausea, and vomiting. The onset of these reactions occurred within 1 to 6 hours after the last dose of GHB and lasted 5 to 15 days. One death of a hospitalized patient occurred as the withdrawal symptoms were resolving.16In a randomized double-blind placebo-controlled trial designed to evaluate the effects of abrupt discontinuation of sodium oxybate on patients with narcolepsy with cataplexy after a mean nighttime exposure of 21 months, 17% of the patients (5 of 26 patients) withdrawn from active drug reported symptoms of anxiety (2), dizziness (1), insomnia (1), and somnolence (1). These symptoms were interpreted as possibly representing the return of the narcoleptic symptoms or mild withdrawal. This further suggests that when taken under approved and appropriate prescribing conditions, sodium oxybate has little in the way of significant discontinuation effects.18Early studies with GHB and later studies with pharmaceutical grade sodium oxybate demonstrated increased duration and intensity of slow wave activity and slow wave sleep in non-human species19,20 and in patients with narcolepsy,21 fibromyalgia,22 Parkinson disease,23 and obstructive sleep apnea.24,25 The pivotal clinical trials supporting approval of sodium oxybate for cataplexy and excessive daytime sleepiness (EDS) in patients with narcolepsy demonstrated its clinical efficacy in decreasing the number of cataplectic attacks, and objective and subjective measures of EDS.17 These studies also demonstrated that sodium oxybate reduced nocturnal awakenings and had an acceptable safety profile, with no long-term safety concerns when used as recommended.17,26Sodium oxybate has been approved by the FDA for the treatment of cataplexy (July 2002) and EDS (November 2005) in patients with narcolepsy. In 2005, sodium oxybate was also approved for the treatment of cataplexy in patients with narcolepsy by Health Canada's Therapeutic Products Directorate, and for the treatment of cataplexy in adult patients with narcolepsy by the European Medicines Agency for the European Union (EU) and the Swiss Agency, Swissmedic, for Therapeutic Products. In 2006, sodium oxybate received an expanded indication for narcolepsy with cataplexy in the EU. Sodium oxybate is currently marketed as Xyrem (sodium oxybate) oral solution in 15 countries.Narcolepsy is a condition that has been documented worldwide, with a prevalence ranging from 0.002% in Israel27 to 0.18% in Japan.28 Prevalence in the US is approximately 0.05%.29 The pentad of clinical symptoms includes: EDS, cataplexy, hypnagogic hallucinations, sleep paralysis, and fragmented sleep. EDS and cataplexy are the most common daytime symptoms of narcolepsy. Historically, treatment of narcolepsy involved the use of one medication to address EDS and a different medication to control cataplexy. This paradigm changed with the availability of sodium oxybate for the treatment of both EDS and cataplexy. Sodium oxybate is the only product approved for the treatment of cataplexy with narcolepsy and is a first-line therapy for patients with narcolepsy.30In the US, sodium oxybate is classified as a Schedule III controlled substance for medicinal use under the Controlled Substances Act, with illicit use subject to Schedule I penalties. In Canada and the EU, it is classified as a Schedule III and a Schedule IV controlled substance, respectively.As part of the current US risk management program, sodium oxybate is available through a unique prescribing and dispensing program, using a centralized pharmacy for all prescriptions. The Xyrem Success Program (the risk management program) provides educational materials to the prescriber and the patient explaining the risks and proper use of the product. Once the central pharmacy has documented that the patient has read and/or understood the materials, the pharmacy ships the drug directly to the patient. The Success Program also recommends patient follow-up with the prescribing physician every 3 months. Physicians are expected to report all serious adverse events to the manufacturer directly or through the Success Program. Each patient and each prescribing physician is registered with the central pharmacy in a secure database. To minimize abuse and diversion, the central pharmacy always verifies the legitimacy of any requests for early refills with the prescribing physician.Since sodium oxybate is a sodium salt of GHB, and illicit GHB is a street drug with a history of abuse and criminal misuse, there has been a perception among some physicians and patients that all of the risks associated with illicit GHB also apply to sodium oxybate. Pharmaceutical sodium oxybate can differ from illicit GHB in accessibility, purity, and dosing.13 Therefore, it is important to determine whether the adverse events and abuse/misuse associated with sodium oxybate also differ from those reported with the use of illicit GHB. To determine whether the dangers and concerns attributed to illicit GHB use reflect risks associated with marketed sodium oxybate, we systemically reviewed worldwide postmarketing data on the overall safety and on the occurrence of the abuse/misuse of this product, including abuse, dependence, sexual assault, suicide-related overdose, automobile accidents, death, and diversion.METHODOLOGYThe postmarketing safety of sodium oxybate is monitored through the spontaneous adverse event reporting system, which collects reports on all marketed pharmaceutical products in the US. In addition, a Post-Marketing Evaluation Program (PMEP) for Xyrem was implemented from 2002 to November 2005 to solicit safety data on an additional 1,000 patients after market introduction. In addition to reporting adverse events through the MedWatch system, under the PMEP, physicians were asked to see their patients at least every 3 months and to write prescriptions that covered no more than 3 months of therapy. Physicians were asked to follow up with patients, to provide adverse event information for the first 6 months of therapy, and to reevaluate patients after 3 and 6 months. Physicians used a company-provided questionnaire to query patients specifically about any instances of vomiting, incontinence, sleepwalking, confusion, and convulsions, and generally, about any other adverse events. The PMEP also captured reports of patients who had not experienced any adverse events while receiving sodium oxybate treatment.In addition to adverse event reporting, physicians were asked to report any potentially inappropriate use of the product, including ingestion of excessive quantities by the patient, accidental or deliberate use by someone else, and any uncertain dosing resulting from difficulty in dose preparation of the liquid solution. Physicians were asked to record and report to the company all early or overly frequent requests for prescription refills; requests to replace spilled, lost, or stolen product; and patient requests for inappropriate dose increases.Cases were collected through spontaneous adverse event reporting after market introduction. In addition to spontaneous reports from consumers, healthcare providers, literature case reports, and other sources, the central pharmacy is required to report to the manufacture all adverse events received during contact with consumers or physicians. As part of the central pharmacy's follow-up, a nurse from the pharmacy contacts each patient after the first shipment and at 3 other times during the first 2 months of treatment. Because the pharmacy is required to initiate and maintain initial and longitudinal contact with both patients and physicians, patients have more frequent opportunities to report events than is the case with other products.We searched all the adverse event cases that were reported to Jazz Pharmaceuticals since the US launch of Xyrem in 2002 through March 2008, which included cases from the US, the EU, Switzerland, and Canada. We reviewed cases with the terms from the Medical Dictionary for Regulatory Activities (MedDRA) that contained the following complete or partial words for adverse events: "abuse""misuse""dependence""withdraw""toleran""overdose" (based on reporter's verbatim: cases for attempted or successful suicide)"suicid""accident""sleepwalking""somnambulism""breathing-related sleep disorder"Additionally, we searched for cases with an outcome of "death" or "fatal." We reviewed all risk management reports from the central pharmacy to identify incidents of diversion. We further analyzed cases reported as possible "abuse" or "dependence" for satisfying the DSM-IV criteria for substance abuse and/or dependence. All reported abuse or dependence cases were rated on a scale of 1 to 4 by a physician, with 1 being least likely to be a case of abuse or dependence, and 4 being most likely to be a case of abuse or dependence. All reports were reviewed by the authors.Rating ScaleReported abuse or dependence case with no supported evidence or the description was not consistent with an abuse or dependence case. The case did not satisfy DSM-IV criteria for abuse or dependence.Reported abuse or dependence case with some, but not significant, information suggesting the case might be an abuse or dependence case. The case description did not satisfy DSM-IV criteria for abuse or dependence.Reported abuse or dependence case with some information suggesting the case might be an abuse or dependence case. The case description likely satisfied DSM-IV criteria for abuse or dependence.Reported abuse or dependence case with information suggesting the case was very likely to be an abuse or dependence case. The case description satisfied DSM-IV criteria for abuse or dependence.RESULTSOverall SafetyA total of 928 PMEP reports were received by July 2006, representing 692 unique patients. Of those reports, 64% (593/928) reported no adverse event. The 10 most commonly reported adverse events from solicited and spontaneous reports were nausea, insomnia, headache, dizziness, vomiting, somnolence, initial insomnia, feeling abnormal, confusional state, and tremor/anxiety. After data from these 692 patients were collected, the PMEP requirement was terminated with the agreement of the FDA (November 2005) because the data were consistent with the adverse events reported in the clinical trials and because of the relatively low rate of physician response. The PMEP results as of September 2004 were summarized by Wedin et al. in 2006.31From product introduction in the US, the EU, and Canada through March 2008, an estimated 26,000 patients have received treatment with commercial sodium oxybate at different doses. During that period, 3,781 adverse event reports were reported to the manufacturer worldwide, representing 973 unique adverse events (excluding reports of ineffectiveness). Given the limitations of postmarketing adverse event reporting, the assessment of causality is usually limited, making causation and/or association in many cases speculative at best. Table 1 lists the 20 most frequent adverse events reported during the period under study. As is typical with postmarketing spontaneous reporting, the incidence of postmarketing adverse events has been lower than that from the clinical trials. Overall, there were no new significant safety findings from the postmarketing adverse event profile compared to what was reported in controlled clinical trials as described in the product prescribing information.Table 1 Twenty Most Frequently Reported Adverse Events in Postmarketing Use Through March 2008Events (MedDRA Preferred Term)Number of Reports (Incidence)Nausea578 (2.2%)Insomnia365 (1.4%)Headache362 (1.4%)Dizziness339 (1.3%)Vomiting264 (1.0%)Somnolence234 (0.9%)Initial insomnia207 (0.8%)Feeling abnormal195 (0.8%)Weight decreased169 (0.7%)Confusional state166 (0.6%)Tremor164 (0.6%)Anxiety162 (0.6%)Depression158 (0.6%)Fatigue149 (0.6%)Diarrhea111 (0.4%)Dyspnea110 (0.4%)Hyperhidrosis100 (0.4%)Blood pressure increased99 (0.4%)Paresthesias99 (0.4%)Sleep walking94 (0.4%)Motor Vehicle AccidentsSodium oxybate is a CNS depressant, with dizziness as one of the most frequently reported postmarketing adverse events. Sleepwalking/somnambulism, which is among the 20 most frequently reported events, might be associated with the drug's reported effect in increasing slow wave sleep.21 Episodes of somnambulism can range from simply sitting up in bed, to walking and attempting to leave one's home. Cases of more complex behavior such as driving, with or without confusional states, have been posited to be associated with slow wave sleep (NREM parasomnias). Because sedation, dizziness, and somnambulism raise concern about traffic accidents in patients taking sodium oxybate, we reviewed all traffic accident and/or somnambulism cases involving driving during the day and/or night.Through March 2008, 3 cases (0.01% of the 26,000 patients who received sodium oxybate treatment) involving motor vehicle accidents (MVAs) were reported. In one case, the MVA occurred during the day, and it could not be determined whether the patient was receiving sodium oxybate therapy at the time of the accident. A second case concerned a patient who reported dizziness, cold sweats, vomiting, chills, and the inability to think clearly after the first night of sodium oxybate therapy and had an MVA during the day, 36 hours after the last dose of sodium oxybate; the half-life of the drug is 60–90 minutes. The third case concerned a patient who experienced an episode of somnambulism with driving, resulting in an MVA. The patient had experienced sleepwalking and sleep eating on 5 previous occasions during stressful times, and reported being stressed at the time of the event. The patient had ingested Adderall (amphetamine and dextroamphetamine) the previous morning and alcohol 1.5 hours before taking sodium oxybate on the night of the incident. Sodium oxybate therapy was continued, and somnambulism did not reoccur. This is the only case reported of somnambulism with driving.AbuseThrough March 2008, 14 cases of abuse of sodium oxybate were reported worldwide after market introduction. These cases were reported as possible abuse because they had one or more of the following characteristics (reason for reporting in Table 2): Patient intentionally took more doses and/or more frequently than prescribed.Patient continued to take sodium oxybate after being instructed to stop by the physician.Patient inappropriately used the drug during daytime.Patient attempted to obtain a dose higher than prescribed.Patient engaged in inappropriate activities, such as driving too soon after dosing.Patient exhibited inappropriate behavior.Patient had intentional non-suicidal overdose.Patient used this drug inappropriately with other drugs.Patient provided the drug to others.Table 2 Reported Abuse Cases Through March 2008Prescribed Use/Dose/FrequencyReported Actual Dose/frequencyReason for ReportingaOther Concomitant Psychoactive DrugsReported Other Substance Abuse HistoryAdequate description of Abuse/ Abuse rating per DSM-IV (1-4)bResolutionCommentNarcolepsy/6 g/nightlyUnknown doses during the dayC, EFluoxetineYYes/4Drug discontinued, event resolvedSocial anxiety/4 g/twice nightlyUnknown doses throughout the dayD, IFluoxetineYYes/4Physician was notifiedNarcolepsy/4.5 g/qid or 9 g/bidVaries, 9 g/ qid was reportedA, C, E, G, HZolpidem, alprazolam, escitalopram oxalate, acetaminophen and hydrocodone, trazodone, oxcarbazepineYYes/4Drug discontinuedDepression/NIcUnknown doses anytime during the dayCUnknownYes/4Drug discontinued and restarted without problem of abuseCataplexy/3 g/twice nightlyMore than prescribed and during the dayA, B, CModafinil, dextroamphetamine, venlafaxine hydrochlorideNYes/4Drug discontinuedLikely abuse case per DSM-IVSleep problem/NIMore than prescribedAZolpidem, duloxetine, cyclobenzaprine, tramadol, primidone, buprenorphine/naloxone, Benzedrine, varenicline,YYes/4Drug discontinuedPatient was abusing multiple drugs.Narcolepsy with cataplexy/4.5 g/twice nightlyUnknown dose anytime during the dayC, EMethylphenidate, alprazolamNYes/4Physician's office was notifiedLikely abuse case per DSM-IVUnknown/NI3 times prescribed doseAUnknownUnknownYes/4Drug discontinuedLikely abuse case per DSM-IVNarcolepsy and cataplexy/9 g/unknown frequencyNIBTopiramate, oxcarbazepineYNo/3Drug discontinued, admitted for detoxificationNarcolepsy/NIMore frequent than prescribedA, FUnknownNo/3Drug discontinuedReported taking doses more frequently than prescribedNI/NIMore than prescribedAUnknownUnknownNo/2Drug discontinuedPhysician reported patient was taking more medication than was prescribed. No other information.Insomnia/4.5 g/ nightly6 g/nightlyASertraline hydrochlorideNNo/1NANo evidence of recurrent maladaptive pattern of Xyrem useNarcolepsy/2.5 g/twice nightly13.5 g throughout the dayCFluoxetine, alprazolamNYes/1Physician was notifiedThis case is a dependence case; therefore, the case is not counted as abuse per DSM-IV.Alpha intrusion associated with fibromyalgia/NINIFMethadone, tizanidine, clonazepamPossibleNo/1Drug discontinuedXyrem was discontinued in Feb 2007. The patient was exhibiting inappropriate behavior in July 2007. Patient was on other medications that may have caused the symptoms.areasons for reports coded as follows: Patient intentionally took more doses and/or more frequently than prescribed.Patient continued to take sodium oxybate after being instructed to stop by the physician.Patient inappropriately used the drug during daytime.Patient attempted to obtain a dose higher than prescribed.Patient engaged in inappropriate activities, such as driving too soon after dosing.Patient exhibited inappropriate behavior.Patient had intentional non-suicidal overdose.Patient used this drug inappropriately with other drugs.Patient provided the drug to others.brating scale: Reported abuse or dependence case with no supported evidence or the description was not consistent with an abuse or dependence case. The case did not satisfy DSM-IV criteria for abuse or dependence.Reported abuse or dependence case with some but not significant information suggesting the case might be an abuse or dependence case. The case description did not satisfy DSM-IV criteria for abuse or dependence.Reported abuse or dependence case with some information suggesting the case might be an abuse or dependence case. The case description likely satisfied DSM-IV criteria for abuse or dependence.Reported abuse or dependence case with information suggesting the case was very likely to be an abuse or dependence case. The case description satisfied DSM-IV criteria for abuse or dependence.cNI – no informationOf these 14 cases, 10 (0.039%) of the patients who took the commercial product during the time evaluated satisfied DSM-IV criteria for substance abuse and 1 case satisfied DSM-IV criteria for substance dependence, which is discussed separately in the section on dependence. The remaining 3 cases contained no definitive evidence of abuse and were considered suspicious of abuse. All 14 cases were either reported by or to the physicians who prescribed sodium oxybate at the time of reporting. During clinical trials with sodium oxybate in individuals with narcolepsy, 781 patients received the drug at different dosages in controlled clinical trials. No cases of abuse of sodium oxybate were reported in these clinical trials.DependencePhysical dependence refers to adaptations resulting in withdrawal signs or symptoms when the drug is discontinued.32 Dependence per DSM-IV criteria (i.e., addiction) refers to the loss of control over the desire to acquire and use the drug regardless of adverse consequences associated with obtaining and using it. Physical dependence and dependence per DSM-IV criteria are distinct phenomena, and the terminology should not be used interchangeably.In worldwide postmarketing adverse event reporting, there have been 20 cases of dependence on, withdrawal from, or tolerance to sodium oxybate from 2002 through March 2008. In reviewing these 20 cases, we found 4 cases (0.016% of patients who took the commercial product during the time evaluated) that satisfied DSM-IV criteria for substance dependence. Three of these cases also satisfied DSM-IV criteria for physical dependence. One patient reported taking 20 g sodium oxybate at bedtime followed by 20 g throughout the day; one patient reported taking sodium oxybate 8 to 10 times during a 24-hour period at doses from 1.5 g to 4.5 g; and one patient reported taking sodium oxybate 13.5 g (unknown whether this was the total daily dose or one dose) throughout the day. A fourth case involved a patient who had already developed dependence on Alcover (a formulation of sodium oxybate available in Europe) before starting Xyrem. When Alcover was no longer available in that country, the physician prescribed Xyrem.We examined all the remaining cases of reported abuse and dependence that did not satisfy DSM-IV criteria for abuse or dependence for evidence of withdrawal signs or symptoms from sodium oxybate. Five of these remaining cases included adverse events that were reported after sodium oxybate was discontinued, which add to a total of 8 (0.031%) physical dependence cases. The doses in these 5 cases were reported as 4.5 g nightly (2 cases), 9 g nightly, and unknown (2 cases; Table 3). Withdrawal signs and symptoms included headache, dizziness, auditory hallucinations, questionable psychotic behavior, thought disturbance, agitation, anxiety, tremors, rebound fatigue and sleepiness, confusion, and paranoia (see Table 3).Table 3 Cases of Dependence/Withdrawal/Tolerance Reported Through March 2008Prescribed Use and Dose – Frequency at the Time of Dependence/ Titration Exceeds PIa GuidelinesOther Concomitant Psychoactive DrugsOther Sub-stance Abuse HistoryWithdrawal SymptomsResolutionDependence Rating per DSM-IV (1-4)b/ Physical Dependence (withdrawal after discontinuation) (1-4)bCommentsDSM-IV DEPENDENCE CASESNarcolepsy 13.5 g throughout the day/YFluoxetine, alprazolamNsweating, weakness, dizziness, upset stomachPhysician was notified4/4Narcolepsy with cataplexy 40 g per day/NIcUnknownYperipheral tingling, goose bumps, sweating, inability to sleepDrug discontinued4/4Cataplexy and Alcoverd dependence 4.5 g bid plus 3g tid/NAeAlcoverYweakness, shaking, nausea, disorientationDrug treatment on-going4/4Patient had pre-existing dependence to Alcover. Xyrem was prescribed for Alcover dependence.Insomnia 4.5 g 8-10 times a day/YHydrocodoneYNo withdrawal symptomsDrug discontinued3/1PHYSICAL DEPENDENCE CASESInsomnia 6 g nightly/NSertraline hydrochlorideNVisual hallucination, agitation, tremors, tachycardia, nausea, dilated pupils, "picking", increased muscle tone, hyperreflexia, dehydrationDrug discontinued1/3Patient was taking 6 g nightly instead of prescribed 4.5 g for several nights prior to discontinuation. The patient was discontinuing other medications at the same time.Narcolepsy with cataplexy 4.5 g nightly/NGabapentin, topiramateNHeadache after 9 days discontinuationDrug continued1/3Narcolepsy 9 g nightly/YMethylphenidateNdizziness, auditory hallucinations, chest pain, paranoia, and thought disturbanceDrug discontinued1/3Symptoms started four days after the discontinuation of sodium oxybateIdiopathic hypersomnia Unknown/NIFluoxetine, methylphenidateYConfusion, paranoiaDrug discontinued1/3Sleeping disorder Unknown/NIVenlafaxineUnknownheadache, feeling agitated anxious, tremulous, rebound, and sleepinessUnknown1/4OSAf 2 g, 2.5 g, 3.5 g, 3.5 g nightly/NAUnknownNNo withdrawal symptomsDrug continued1/1Narcolepsy 3 g three times a night/YUnknownNanxiety, tightening of abdomen, the urge to defecateDrug continued1/1Symptoms occurred every morning after taking XyremFibromyalgia 6.5 g, then 5 g nightly/YUnknownNNo withdrawal symptomsUnknown1/1Fibromyalgia 5.5 g twice n
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