Health - Canadian SBD report on Xyrem (GHB)

Discussion in 'GHB' started by MrG, Dec 21, 2006.

  1. MrG

    MrG Platinum Member & Advisor

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    Key points highlighted in red by MrG. For your reading pleasure.


    SUMMARY BASIS OF DECISION (SBD)

    XYREM®

    Sodium oxybate, 500 mg/mL, Oral solution
    Orphan Medical, Inc.
    Submission Control No. 088659


    Dated Issued2006/03/22

    Health Products and Food Branch
    Our mission is to help the people of Canada maintain and improve their health.
    Health Canada
    HPFB's Mandate is to take an integrated approach to the management of the risks and benefits to health related to health products and food by:
    • Minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and,
    • Promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.
    Health Products and Food Branch
    Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), XYREMMD , Sodium oxybate, 500 mg/mL, Solution orale, Orphan Medical, Inc. No de contrôle de la présentation 088659
    FOREWORD

    Health Canada 's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within reviewer reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
    Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada '. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document. These documents are all available on the Health Canada website.
    The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. For information related to post-market warnings or advisories as a result of adverse events, interested parties are advised to access the Health Canada website.
    For further information on a particular product, readers may also access websites of other regulatory jurisdictions, available under 'Related Links' on the Health Canada website. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
    Other Policies and Guidance:

    Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
    TABLE OF CONTENTS

    1 PRODUCT AND SUBMISSION INFORMATION
    2 NOTICE OF DECISION
    3 SCIENTIFIC AND REGULATORY BASIS FOR DECISION
    3.1 Quality Basis for Decision
    3.1.1 Drug Substance (Medicinal Ingredient)
    3.1.2 Drug Product
    3.1.3 Facilities and Equipment
    3.1.4 Adventitious Agents Safety Evaluation
    3.1.5 Summary and Conclusion
    3.2 Non-clinical Basis for Decision
    3.2.1 Pharmacokinetics
    3.2.2 Toxicology
    3.2.3 Summary and Conclusion
    3.3 Clinical Basis for Decision
    3.3.1 Pharmacodynamics
    3.3.2 Pharmacokinetics
    3.3.3 Clinical Efficacy
    3.3.4 Clinical Safety
    3.4 Benefit/risk Assessment and Recommendation
    3.4.1 Benefit/risk assessment
    3.4.2 Recommendation
    4 SUBMISSION MILESTONES
    1 PRODUCT AND SUBMISSION INFORMATION

    Brand Name Xyrem® Manufacturer/Sponsor Orphan Medical, Inc.Medicinal Ingredient Sodium oxybateInternational Non-proprietary Name Sodium oxybateStrength500 mg/mLDosage form SolutionRouteOral DIN02268272Pharmaco-therapeutic group (ATC Code) Central nervous system (CNS) depressantNon-medicinal Ingredients Purified water, malic acid, sodium hydroxideSubmission Type and Control No. New Drug Submission,
    Control No. 088659
    Date of Submission 2003/12/09Date of Authorization 2005/08/05Xyrem® (sodium oxybate) oral solution is a registered trademark of Orphan Medical, Inc. Canadian Patent No. 2,355,293 issued on August 16, 2005.
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    2 NOTICE OF DECISION

    On August 5, 2005, Health Canada issued a Notice of Compliance for the drug product Xyrem to Orphan Medical Inc., a wholly owned subsidiary of Jazz Pharmaceuticals. Xyrem contains the medicinal ingredient sodium oxybate and is a central nervous system (CNS) depressant. Sodium oxybate is also known as gamma-hydroxybutyrate (GHB), a known drug of abuse. Xyrem is indicated for the treatment of cataplexy in patients with narcolepsy. The mechanism by which sodium oxybate produces its anti-cataplectic effects is unknown. Due to the abuse potential of GHB and propensity for serious and possibly fatal adverse events, Xyrem is not recommended for use in other indications as safety and efficacy have not been established outside of cataplexy.
    Contraindications include concurrent use of Xyrem with sedative hypnotic agents or alcohol. Xyrem is also contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. This rare disorder is an inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia.
    The market authorization was based on data from quality control studies (drug substance and drug product), as well as data from pre-clinical and clinical studies. Efficacy as an anti-cataplectic agent was established in two randomized, double-blind, placebo-controlled trials with a total enrolment of 191 narcoleptic patients. Adverse reactions were assessed with 448 narcoleptic patients exposed to sodium oxybate.
    Abuse of GHB has been associated with serious CNS adverse events, including death. Even at recommended doses, sodium oxybate use has been associated with confusion, depression, and other neuropsychiatric events. Reports of respiratory depression occurred in clinical trials. Most patients receiving sodium oxybate during clinical trials maintained concomitant stimulant use.
    Xyrem is an oral solution with a concentration of 500 mg/mL sodium oxybate. Xyrem is only available to prescribing physicians, pharmacists, and patients through the Xyrem Success Program, a risk management program that includes the following: information necessary for the safe use, storage, and handling of the drug; maintenance of a registry of prescribing physicians, pharmacists, and patients; and restricted distribution through a single wholesaler. Xyrem should only be prescribed by physicians who have experience in treating cataplexy in patients with narcolepsy, and who have completed the Xyrem Success Program.
    Detailed dosing guidelines for the use of Xyrem and the core components of the Xyrem Success Program are described in the Product Monograph. Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Xyrem is favourable only for the treatment of cataplexy in patients with narcolepsy under the proposed conditions of use.
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    3 SCIENTIFIC AND REGULATORY BASIS FOR DECISION

    3.1 Quality Basis for Decision

    3.1.1 Drug Substance ( Medicinal Ingredient )

    Manufacturing Process and Process Controls
    Sodium oxybate is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
    • The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
    • The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
    • The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
    Characterisation
    Sodium oxybate is a white to off-white powder. The structure of sodium oxybate has been adequately explained and the representative spectra have been provided. Physical and chemical properties have been described and found to be satisfactory.
    The sponsor has provided a summary of all drug-related impurities. Impurities arising from manufacturing were reported and characterized. These products were found to be within ICH established limits, and therefore considered to be acceptable.
    Control of Drug Substance
    Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of the drug substance, and to justify the specification of the drug substance.
    Data from batch analyses were reviewed and considered to be acceptable according to the specification of the drug substance.
    Stability
    Based upon the real-time and accelerated stability study data submitted, the proposed shelf-life, storage and shipping conditions for the drug substance were supported and considered to be satisfactory.
    3.1.2 Drug Product

    Description and Composition
    Xyrem has been authorized in one strength, 500 mg/mL. The marketed drug product is packaged in an 8 oz. (240 mL) amber polyethylene terephthalate (PET) bottle with a child-resistant closure. The bottle is contained in a carton with security tape placed on the top and bottom flaps. A Press-In-Bottle-Adapter (PIBA) will be supplied and will be inserted into the container at the pharmacy. A 10 mL Exacta-Med syringe dispenser and two child-resistant dosing containers will also be supplied at the time of dispensing.
    All excipients found in the drug product are acceptable for use in drugs by the Canadian Food and Drug Regulations. The compatibility of sodium oxybate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
    Pharmaceutical Development
    Pharmaceutical developmental data, including pH and microbiological attributes, were considered acceptable. Studies which justified the type and proposed concentration of preservative/excipient to be used in the drug product were reviewed and these verified that no potential toxicological or immunological effects can be expected.
    Manufacturing Process and Process Controls
    The manufacturing process for Xyrem includes formulation, mixing, filtration to remove particulates, filling, and labelling.
    All equipment, operating parameters, in-process tests and detailed instructions are adequately defined in the documentation. The manufacturing process was considered to be adequately controlled within justified limits.
    Control of Drug Product
    Xyrem is tested to verify its identity, appearance, content uniformity, and the presence of degradation products and microbiological impurities. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products are within acceptable limits.
    The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product, and no anomalies were present. The results for all of the batches were within the proposed specification limits.
    Stability
    Stability data show that amber PET bottles with child-resistant closures are acceptable container/closure systems for the finished product.
    Based upon the real-time and accelerated stability study data submitted, the proposed 48 month shelf-life at 15-30oC for the drug product is considered acceptable.
    3.1.3 Facilities and Equipment

    The design, operations, and controls of the facility and equipment are considered to be suitable for the activities and products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
    3.1.4 Adventitious Agents Safety Evaluation

    N/A
    3.1.5 Summary and Conclusion

    The Chemistry and Manufacturing information submitted for Xyrem has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial process.
    3.2 Non-clinical Basis for Decision

    3.2.1 Pharmacokinetics and Pharmacodynamics

    The precise mechanism of action of sodium oxybate is not known. Gamma-hydroxybutyrate (GHB) produces dose-dependent sedation and anesthesia in laboratory animals. It has a rapid onset and short duration of action, depending on dose and route of administration. Endogenous GHB satisfies the criteria for a neuromodulator or neurotransmitter in the central nervous system (CNS). It binds reversibly, selectively, and with high affinity to two different receptor sites that show a heterogeneous distribution in the CNS different from that of gamma-aminobutyric acid (GABA) receptors. Activation of GHB receptors results in alterations in secondary messenger systems, including elevated cyclic guanosine monophosphate (cGMP) levels, inositol phosphate turnover, and nitric oxide synthesis. GHB can influence the activity of GABA as well as other amino acids (glutamate, glycine) in the brain by affecting their levels and/or release and also influences the dopaminergic system. Although GHB does not appear to directly influence dopamine synthesis or degradation, it can influence the firing of dopaminergic neurons, the release of dopamine, and the expression of dopamine D1 and D2 receptors. A GHB-mediated influence on endogenous opioid peptides has also been demonstrated.
    Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate however no active metabolites have been identified. Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not significantly inhibit the activities of human isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A at doses considerably higher than those intended for therapeutic use.
    3.2.2 Toxicology

    Acute Toxicity
    The acute toxicity of GHB has been studied in mice, rats, rabbits, and dogs, primarily by parenteral routes of administration. Reported lethality (from respiratory depression) in the rat ranges from an LD50 of 1700 mg/kg (intraperitoneal injection) to 9990 mg/kg (oral).
    Long-Term Toxicity
    In a 90-day study in rats, there were no toxicological effects attributed to sodium oxybate at a dose of 350 mg/kg/day (2.7 times the maximum recommended daily human dose). At the high dose of 1000 mg/kg/day, treatment-related effects included transient post-dose hypoactivity and prostration, and decreased body weight, body weight gain and food consumption. There were no histopathological changes seen in any tissue.
    Twenty-six week oral treatment in rats again produced hypoactivity, decreased body weight, and decreased food consumption at the high dose of 1000 mg/kg/day. No changes in the other parameters (gross pathology, organ weights, microscopic pathology) were reported. The no-effect dose was 350 mg/kg/day (2.7 times the maximum human dose).
    In the 90-day study in dogs, emesis was seen as the dose limiting effect. At 350 mg/kg/day, the incidence of emesis was low and this dose was considered to be a no-adverse-effect level (NOAEL). Histopathological evaluation of tissues revealed atrophy of the mandibular salivary glands and submucosal glands of the esophagus at 600 mg/kg/day.
    In a 52-week study in dogs, initial doses were 150, 350 and 600 mg/kg/day; however, the high dose was subsequently raised to 900 mg/kg/day during Week 32. Clinical signs (emesis, soft feces, tremors, thin appearance, hypoactivity, ataxia, salivation, prostration) were reported at 350 and 600/900 mg/kg/day. Body weight loss and decreased weight gain occurred in the high-dose animals. The only other effect was atrophy of the mandibular salivary glands and the submucosal mucous glands of the esophagus at 350 and 600 mg/kg/day. No gender differences or changes due to repeated dosing were observed. The no-effect level in this study was 150 mg/kg/day (1.2 times the maximum human dose).
    Carcinogenicity
    Oral carcinogenicity studies have been conducted in rats and mice with gamma-butyrolactone (GBL), a compound that is metabolized to sodium oxybate in vivo, with no clear evidence of carcinogenic potential. Plasma levels (AUC) of sodium oxybate achieved in these studies were estimated to be approximately 1/2 (mice and female rats) and 1/10 (male rats) those seen in humans receiving the maximum recommended daily dose of sodium oxybate.
    A sponsor-initiated, two-year rat carcinogenicity study compared daily oral (gavage) sodium oxybate dosages of 0, 200, 500, and 1000 mg/kg. Decreased survival of males at 1000 mg/kg/day during the second half of the second year of the study resulted in discontinuance of test article administration beginning in Week 83 of the study. No test article-related organ weight or macroscopic and microscopic pathology changes were observed. No oncogenic effect was observed.
    Mutagenicity
    Sodium oxybate was negative in three mutagenicity assays: the Ames test, the in vitro chromosomal aberration assay, and the in vivo rat micronucleus assay.
    Reproductive Toxicity
    A fertility study was conducted in rats at doses of 150, 350 and 1000 mg/kg/day from 28 days (males) and 14 days (females) prior to mating. Females were treated through Day 7 of gestation. No effect on the overall reproductive performance was observed in this study.
    Teratology studies indicated that sodium oxybate was not teratogenic. In rats and rabbits no developmental toxicity was reported at dosages of up to 1000 and 1200 mg/kg/day, respectively.
    In a study of perinatal and postnatal effects, sodium oxybate was administered to pregnant rats at doses of 150, 350 and 1000 mg/kg/day from Day 6 of gestation through Day 20 of lactation. Pregnancy, implantation sites, and live birth indices were unaffected by treatment at any dose. There was an increase in postnatal mortality at 1000 mg/kg/day, and surviving pups showed lower rates of growth. Post-weaning behavioral and maturational assessments, including fertility, showed no drug related effects. The no-effect dose in this study was 350 mg/kg/day.
    3.2.3 Summary and Conclusion

    Preclinical studies with Xyrem did not identify a specific mechanism of action for sodium oxybate, but did indicate that metabolism was the primary method of excretion of the drug and that no active metabolites are formed. Toxicology studies in animals generally did not indicate adverse effects up to approximately three times the maximum dose allowable in humans. Adverse effects were observed however, at dose levels of approximately 4.5 to 8 times the maximum dose in humans. Clinical effects included hypoactivy, prostration, decreased body weight, body weight gain, and food consumption, tremors, thin appearance, soft feces, ataxia, and salivation. Atrophy of the mandibular salivary glands and submucosal glands of the esophagus was also seen, and postnatal mortality was found to be increased in reproductive studies, with the pups showing decreased growth rates. No gender differences were observed, and Xyrem was not found to have carcinogenic, teratogenic, or mutagenic potential. However, due to the very low margin of safety between therapeutic doses and those showing adverse effects in animals, extreme caution should be taken in the prescribing and use of this drug.
    3.3 Clinical Basis for Decision

    3.3.1 Pharmacodynamics

    No specific pharmacodynamic studies were conducted by the sponsor but a number of published studies from the literature examining the pharmacology of sodium oxybate (GHB) were submitted in their place.
    In the treatment of narcolepsy, investigators found nightly divided doses from 3-9 grams were effective in treating subjective symptoms and were reflected in polysomnograph (PSG) measures of sleep architecture. The subjective daytime symptoms of narcolepsy also improved greatly with the nighttime dosing of GHB.
    Studies monitoring a variety of liver enzymes prior to and following high-dose GHB administration showed no evidence of hepatocellular injury. In chronic studies, following daily treatment, enzyme levels of alcoholic patients were significantly decreased, frequently to within normal limits, but improvements were likely a reflection of decreased alcohol consumption.
    Based on a limited number of studies available, it appears that GHB has no detrimental renal effects after acute or chronic exposure.
    It is evident however, that GHB can produce alterations in endocrine function. It has been shown to consistently elevate human growth hormone, cortisol, and prolactin, while having little or no effect on thyroid stimulating hormone, thyroxine, insulin, melatonin, or leutinizing hormone. Studies with cocaine and alcoholic patients suggest that chronic high level use of cocaine and alcohol results in persistent disruption of GHB-induced human growth hormone increase even after periods of abstinence.
    Gastrointestinal effects included nausea and vomiting, which were most likely centrally mediated as GHB can also produce dizziness and vertigo. Incidence of nausea and vomiting increased following high, anaesthetic doses and appeared to be influenced by the speed of administration and concurrent medications. No long-term gastrointestinal problems were noted.
    3.3.2 Pharmacokinetics

    Eight clinical pharmacokinetic studies and two in vitro studies were conducted. All were open-label, single-centre studies and none used biomarkers or surrogate endpoints. The oral solution to be marketed was used in the studies.
    Oxybate shows non-linear pharmacokinetics. The elimination of oxybate from the human body is dose-dependent and systemic exposure to oxybate increases disproportionately as the Xyrem dose increases. The elimination half-life also increases as the dose increases, but does not result in excessive drug accumulation when given on a divided nocturnal administration schedule. Plasma oxybate is detectable at negligible levels 8 hours after the ingestion of the highest recommended daily Xyrem. Oxybate is almost exclusively cleared by biotransformation, eventually being degraded to carbon dioxide via 2 distinct pathways. Renal excretion plays a minor role in the elimination of oxybate and < 5 % of a dose is recovered as unchanged drug in urine following oral administration.
    In vitro studies with pooled human liver microsomes show that oxybate does not significantly inhibit or enhance the activities of human CYP isozymes nor are there significant pharmacokinetic interactions observed between Xyrem and zolpidem (Ambien), protriptyline (Vivactil), or modafinil (Provigil) in healthy volunteers. However, pharmacodynamic interactions cannot be ruled out.
    The kinetics of Xyrem are similar in males and females and are comparable between narcoleptic patients and healthy volunteers as well as alcohol-dependent patients. Accumulation of oxybate has not been observed with chronic therapeutic dosing. However, severe cirrhosis has demonstrated significant modifications of oxybate disposition kinetics. As a precaution, the initial Xyrem dose in hepatically impaired patients should be one-half of that used in non-hepatically impaired patients.
    3.3.3 Clinical Efficacy

    The sponsor submitted two pivotal, well-controlled studies (OMC-GHB-2 and OMC-SXB-21), two supporting controlled studies (Scrima trial and Lammers trial) and supportive data from three uncontrolled studies (OMC-GHB-3, OMC-SXB-6 and OMC-SXB-20). These studies provide data in support of the indication for sodium oxybate in the treatment of cataplexy associated with narcolepsy.
    Study OMC-GHB-2
    This study was designed as a prospective, randomized, double-blind, placebo- controlled, parallel-group, multi-centre trial with three doses of sodium oxybate and a placebo in narcoleptic patients meeting specific American Sleep Disorders Association (ASDA) criteria for narcolepsy. The objectives of the trial were to evaluate and compare the efficacy and safety of three doses (3, 6 and 9 grams) of sodium oxybate and placebo in the treatment of the symptoms of narcolepsy. A rating of the change in the severity of the patient's narcolepsy symptoms as measured by the Clinical Global Impression of Change was provided by the investigator at the end of the four-week treatment period, compared to the rating of Clinical Global Impression of Severity of Disease at the end of the baseline period.
    The study was conducted at sixteen centers, and a total of 136 patients were enrolled. One dose was taken at bedtime, and the second dose was taken 2.5 to 4 hours later. The primary efficacy variable was the change from baseline in the total number of cataplexy attacks (complete and partial) recorded by patients from the last two weeks before study commencement to the end of the study period. Patients on stimulants were permitted to continue taking them at an unchanged dose.
    The primary reason for withdrawal from the study was the development of adverse events (10 patients) which was more frequent in the high-dose group. A significant reduction from baseline to endpoint in total number of cataplexy attacks per week was found among patients in the mid- and high-dose groups. Significant acute rebound cataplexy was not apparent during the 3-5 day period after abruptly stopping treatment.
    Study OMC-SXB-21
    This study was a Phase III, randomized, double-blind, placebo-controlled, parallel-group, multi-centre trial to assess the long-term efficacy of orally administered Xyrem, as compared to a placebo, in the treatment of narcolepsy. The primary efficacy variable was the return of cataplexy symptoms upon cessation of a minimum of 6 months of open-label treatment with sodium oxybate. Patients were dosed with either 3, 4.5, 6, 7.5, or 9 grams per night in divided doses, or with a placebo. There was no statistical difference between treatment groups in the mean number of cataplexy attacks at baseline.
    Results showed that patients given the placebo had significantly more cataplexy attacks than did patients who continued on active Xyrem treatment which suggests that Xyrem is effective in the long-term treatment of the narcolepsy symptom of cataplexy.
    3.3.4 Clinical Safety

    In clinical trials, adverse events were observed at therapeutic doses and were almost entirely related to the effects of the drug on the central nervous system. Effects observed included confusion, sleepwalking, somnolence, depressed respiration, and urinary and fecal incontinence. Incidence of adverse events was low and they were almost always reversible, however the margin of safety between clinically effective doses and those with serious or potentially serious adverse events is very narrow, and possibly even non-existent in some patients. Given the use of stimulant medications of the majority of patients enrolled in the clinical trials, there also exists the possibility that the CNS-related adverse events were made less evident by the co-administration of stimulants.
    Due to the high abuse potential and propensity for serious and possibly fatal adverse events, the use of Xyrem should be limited exclusively to cataplexy in patients with narcolepsy.
    3.4 Benefit/Risk Assessment and Recommendation

    3.4.1 Benefit/Risk Assessment

    Data from the well-controlled studies suggest that efficacy has been established for the dose of 9 g/day, whereas the dose of 6 g/day is somewhat equivocal. Published reports and long-term open studies suggest that doses as low as 4.5 g/day may be effective in some patients. It is noteworthy that the therapeutic doses required for treatment of cataplexy approach or exceed the dose required to induce general anesthesia. It is clear that, at doses required to treat cataplexy associated with narcolepsy, very serious side effects, including respiratory depression and coma may be expected. The FDA review of Xyrem had identified problems with the data generated at two clinical study sites, and concluded that they were unreliable. A re-analysis of the data, excluding patients from these sites suggested that the efficacy data was reliable, but that there may be too few patients for proper safety determination. Given that sodium oxybate will be used for an orphan indication, to treat a severely debilitating disorder, it is the opinion of Health Canada that the risk-benefit assessment is favourable, if and only if, the following conditions are met:
    • Sodium oxybate is to be indicated exclusively for the treatment of cataplexy in narcolepsy
    • To ensure that this is the case, a statement that sodium oxybate is not recommended for use in other conditions should be placed under the INDICATIONS section of the Product Monograph
    • The sponsor agrees to implement a comprehensive risk management program.
    3.4.2 Recommendation

    Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Xyrem is favourable only in the treatment of cataplexy in patients with narcolepsy. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
    To ensure the safe administration of Xyrem and limit the potential for drug diversion and abuse, the sponsor has agreed to implement a comprehensive risk management program, the Xyrem Success Program. The Xyrem Success Program is founded on the following core components:
    • Implementation of a program to educate physicians, pharmacists, and patients about the risks and benefits of Xyrem, including critical information necessary for the safe use, storage, and handling of the drug.
    • Implementation of a restricted distribution program for Xyrem through a single wholesale distribution company that will ship the drug directly to pharmacies on an as-needed basis after patients have presented with an initial legitimate prescription.
    • Filling of the initial prescription only after the prescribing physician, pharmacist, and patient have received and read the educational materials.
    • Maintenance of a registry of Xyrem Success Program trained physicians, pharmacies, and patients.
    The sponsor also committed to expanding their safety data collection system to Canada and providing the results of the analysis to Health Canada after data from 1000 patients has been received, working with the Colleges of Pharmacists and Physicians in Canada to provide a safe and efficient delivery and distribution system for use in Canada, and continuing the open-label clinical trial until product launch in Canada.

    http://www.hc-sc.gc.ca/dhp-mps/prod...ion/drug-med/sbd_smd_2005_xyrem_088659_e.html
     
    Last edited by a moderator: Sep 10, 2017
    1. 4/5,
      Very informative, thanks
      Jul 23, 2009
    2. 5/5,
      Very Helpful. Thanks for posting it
      Jan 2, 2007
    3. 5/5,
      nice work, thanks for the red too, helps for skim reading!
      Dec 22, 2006
  2. RunRedFox

    RunRedFox Gold Member

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    Re: Canadian SBD report on Xyrem

    9 grams a day seems like ALOT. Is this figure correct or advisable? Swirx takes about 2 grams and feels pretty inebriated, sleeps like a baby too.
     
  3. MrG

    MrG Platinum Member & Advisor

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    Re: Canadian SBD report on Xyrem

    It's the standard dosing pattern for Narcoleptics RX, 4.5g taken twice (the second dose taken after the "rebound" from the first one wakes them up) to induce slow wave sleep for about four hours each time this giving them a total of eight hours of *quality* sleep - something that Narco's have a hard time acheiving usually.

    Recreationally 9g would only be consumed, say, if a user was up all night on stimulants and repeatedly dosing the standard rec amount of 1 to 1.5g

    But that in itself can be a tad unwise given that it is a little too close to the beginnings of a 24/7 dosing habit. If it is done then it should not be allowed to continue through the next day.
     
  4. schiz0phren1c

    schiz0phren1c Silver Member

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    Excellent post as always MrG,very informative and interesting,the very high LD50 is particularly reassuring.
    (that is,High in comparison to recreational dosage)
     
  5. saline29

    saline29 Newbie

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    Heck, 9 grams is a joke to swim. He probably uses 2 to 3 times that a day in bd. But he also knows how to wean himself off of it when it comes time to not have any. Makes him feel like a fricken rock star and helps him to believe that something good will happen in his life still regardless of his situation. To swim, xyrem sucks... They only established what 30 years of study already came up with, but they did it to their advantage, to eventually make a killing off of something that was already known to be healthy, non toxic, etc., which was demonized previously by pure bs. GHB in swims opinion, is the closest thing to the fountain of youth, and it would be up to the greedy world government to take it away from the common man and give it the pharmaceutical companies to overcharge for the shit and regulate it, so that one can only use it to sleep, instead of as an all day long anti-aging compound, which it is, if one uses it correctly. It is addicting, just as the fountain of youth would be to someone who takes one drink; it invigorates and releases the life within. But thanks Mr. G for the info! I didn't know anything about g, before using, and learned initially, from swiy's posts.
     
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