Natrii oxybutyras Kalceks

Limitations Of Use

Natrii oxybutyras Kalceks may only be dispensed to patients enrolled in the Natrii oxybutyras Kalceks REMS Program.

Cataplexy In Narcolepsy

Natrii oxybutyras Kalceks (sodium oxybate) oral solution is indicated for the treatment of cataplexy in narcolepsy.

Excessive Daytime Sleepiness In Narcolepsy

Natrii oxybutyras Kalceks (sodium oxybate) oral solution is indicated for the treatment of excessive daytime sleepiness (EDS) in narcolepsy.

Healthcare professionals who prescribe Natrii oxybutyras Kalceks must enroll in the Natrii oxybutyras Kalceks REMS Program and must comply with the requirements to ensure safe use of Natrii oxybutyras Kalceks.

Dosing Information

The recommended starting dose is 4.5 grams (g) per night administered orally in two equal, divided doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dose by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dose range of 6 g to 9 g per night orally. Doses higher than 9 g per night have not been studied and should not ordinarily be administered.

Table 1: Natrii oxybutyras Kalceks Dose Regimen (g = grams)

Important Administration Instructions

Take the first dose of Natrii oxybutyras Kalceks at least 2 hours after eating because food significantly reduces the bioavailability of sodium oxybate.

Prepare both doses of Natrii oxybutyras Kalceks prior to bedtime. Prior to ingestion, each dose of Natrii oxybutyras Kalceks should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy vials provided. Patients should take both doses of Natrii oxybutyras Kalceks while in bed and lie down immediately after dosing as Natrii oxybutyras Kalceks may cause them to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 minutes of taking Natrii oxybutyras Kalceks, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. Patients should remain in bed following ingestion of the first and second doses, and should not take the second dose until 2.5 to 4 hours after the first dose. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep.

Dose Modification In Patients With Hepatic Impairment

The recommended starting dose in patients with hepatic impairment is 2.25 g per night administered orally in two equal, divided doses: approximately 1.13 g at bedtime and approximately 1.13 g taken 2.5 to 4 hours later.

Dose Adjustment With Co-Administration Of Divalproex Sodium

Pharmacokinetic and pharmacodynamic interactions have been observed when Natrii oxybutyras Kalceks is co-administered with divalproex sodium. For patients already stabilized on Natrii oxybutyras Kalceks, it is recommended that addition of divalproex sodium should be accompanied by an initial reduction in the nightly dose of Natrii oxybutyras Kalceks by at least 20%. For patients already taking divalproex sodium, it is recommended that prescribers use a lower starting Natrii oxybutyras Kalceks dose when introducing Natrii oxybutyras Kalceks. Prescribers should monitor patient response and adjust dose accordingly.

• Natrii oxybutyras Kalceks is contraindicated in patients being treated with sedative hypnotic agents.
• Patients should not drink alcohol when using Natrii oxybutyras Kalceks.
• Natrii oxybutyras Kalceks is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. This is a rare disorder of inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Central Nervous System Depression

Natrii oxybutyras Kalceks is a central nervous system (CNS) depressant. Alcohol and sedative hypnotics are contraindicated in patients who are using Natrii oxybutyras Kalceks. The concurrent use of Natrii oxybutyras Kalceks with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with Natrii oxybutyras Kalceks is required, dose reduction or discontinuation of one or more CNS depressants (including Natrii oxybutyras Kalceks) should be considered. In addition, if short-term use of an opioid (e.g. post-or perioperative) is required, interruption of treatment with Natrii oxybutyras Kalceks should be considered.

Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that Natrii oxybutyras Kalceks does not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery or a motor vehicle or flying an airplane, for at least 6 hours after taking the second nightly dose of Natrii oxybutyras Kalceks. Patients should be queried about CNS depression-related events upon initiation of Natrii oxybutyras Kalceks therapy and periodically thereafter.

Abuse And Misuse

Natrii oxybutyras Kalceks is a Schedule III controlled substance. The active ingredient of Natrii oxybutyras Kalceks, sodium oxybate or gamma-hydroxybutyrate (GHB), is a Schedule I controlled substance. Abuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death. The rapid onset of sedation, coupled with the amnestic features of Natrii oxybutyras Kalceks, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim). Because illicit use and abuse of GHB have been reported, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of GHB (e.g. increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy).

Natrii oxybutyras Kalceks REMS Program

Because of the risks of central nervous system depression and abuse/misuse, Natrii oxybutyras Kalceks is available only through a restricted distribution program called the Natrii oxybutyras Kalceks REMS Program.

Required components of the Natrii oxybutyras Kalceks REMS Program include:

• Healthcare Providers who prescribe Natrii oxybutyras Kalceks are specially certified
• Natrii oxybutyras Kalceks will be dispensed only by the central pharmacy that is specially certified
• Natrii oxybutyras Kalceks will be dispensed and shipped only to patients who are enrolled in the Natrii oxybutyras Kalceks REMS Program with documentation of safe use

Further information is available at www.Natrii oxybutyras KalceksREMS.com or 1-866-Natrii oxybutyras Kalceks88^® (1-866-9973688).

Respiratory Depression And Sleep-Disordered Breathing

Natrii oxybutyras Kalceks may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported.

In a study assessing the respiratory-depressant effects of Natrii oxybutyras Kalceks at doses up to 9 g per night in 21 patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four patients with preexisting, moderate-to-severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment.

In a study assessing the effects of Natrii oxybutyras Kalceks 9 g per night in 50 patients with obstructive sleep apnea, Natrii oxybutyras Kalceks did not increase the severity of sleep-disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central apneas in patients taking Natrii oxybutyras Kalceks, and clinically significant oxygen desaturation (≤ 55%) was measured in three patients (6%) after Natrii oxybutyras Kalceks administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation. Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with Natrii oxybutyras Kalceks administration.

In clinical trials in 128 patients with narcolepsy, two subjects had profound CNS depression, which resolved after supportive respiratory intervention. Two other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea. In two controlled trials assessing polysomnographic (PSG) measures in patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered breathing. None of the 40 patients had a clinically significant worsening of respiratory function as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 g per night.

Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients and in postmenopausal women not on hormone replacement therapy as well as among patients with narcolepsy.

Depression And Suicidality

In clinical trials in patients with narcolepsy (n=781), there were two suicides and two attempted suicides in Natrii oxybutyras Kalceks-treated patients, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Natrii oxybutyras Kalceks in conjunction with other drugs. Natrii oxybutyras Kalceks was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 Natrii oxybutyras Kalceks-treated patients, with four patients (< 1%) discontinuing because of depression. In most cases, no change in Natrii oxybutyras Kalceks treatment was required.

In a controlled trial, with patients randomized to fixed doses of 3 g, 6 g, or 9 g per night Natrii oxybutyras Kalceks or placebo, there was a single event of depression at the 3 g per night dose. In another controlled trial, with patients titrated from an initial 4.5 g per night starting dose, the incidences of depression were 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo, 4.5 g, 6 g, and 9 g per night doses, respectively.

The emergence of depression in patients treated with Natrii oxybutyras Kalceks requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored carefully for the emergence of depressive symptoms while taking Natrii oxybutyras Kalceks.

Other Behavioral Or Psychiatric Adverse Reactions

During clinical trials in narcolepsy, 3% of 781 patients treated with Natrii oxybutyras Kalceks experienced confusion, with incidence generally increasing with dose.

Less than 1% of patients discontinued the drug because of confusion. Confusion was reported at all recommended doses from 6 g to 9 g per night. In a controlled trial where patients were randomized to fixed total daily doses of 3 g, 6 g, or 9 g per night or placebo, a dose-response relationship for confusion was demonstrated, with 17% of patients at 9 g per night experiencing confusion. In all cases in that controlled trial, the confusion resolved soon after termination of treatment. In Trial 3 where sodium oxybate was titrated from an initial 4.5 g per night dose, there was a single event of confusion in one patient at the 9 g per night dose. In the majority of cases in all clinical trials in narcolepsy, confusion resolved either soon after termination of dosing or with continued treatment. However, patients treated with Natrii oxybutyras Kalceks who become confused should be evaluated fully, and appropriate intervention considered on an individual basis.

Anxiety occurred in 5.8% of the 874 patients receiving Natrii oxybutyras Kalceks in clinical trials in another population. The emergence of or increase in anxiety in patients taking Natrii oxybutyras Kalceks should be carefully monitored.

Other neuropsychiatric reactions reported in Natrii oxybutyras Kalceks clinical trials and the post-marketing setting included hallucinations, paranoia, psychosis, aggression, and agitation. The emergence of thought disorders and/or behavior abnormalities requires careful and immediate evaluation.

Parasomnias

Sleepwalking, defined as confused behavior occurring at night and at times associated with wandering, was reported in 6% of 781 patients with narcolepsy treated with Natrii oxybutyras Kalceks in controlled and long-term open-label studies, with < 1% of patients discontinuing due to sleepwalking. Rates of sleepwalking were similar for patients taking placebo and patients taking Natrii oxybutyras Kalceks in controlled trials. It is unclear if some or all of the reported sleepwalking episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Five instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of Natrii oxybutyras Kalceks in patients with narcolepsy.

Parasomnias including sleepwalking have been reported in postmarketing experience with Natrii oxybutyras Kalceks. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

Use In Patients Sensitive To High Sodium Intake

Natrii oxybutyras Kalceks has a high salt content. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment) consider the amount of daily sodium intake in each dose of Natrii oxybutyras Kalceks. Table 2 provides the approximate sodium content per Natrii oxybutyras Kalceks dose.

Table 2 Approximate Sodium Content per Total Nightly Dose of Natrii oxybutyras Kalceks (g = grams)

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Natrii oxybutyras Kalceks REMS Program

Inform patients that Natrii oxybutyras Kalceks is available only through a restricted distribution program called the Natrii oxybutyras Kalceks REMS Program.

The contents of the Natrii oxybutyras Kalceks Medication Guide and educational materials are reviewed with every patient before initiating treatment with Natrii oxybutyras Kalceks.

Patients must read and understand the materials in the Natrii oxybutyras Kalceks REMS Program prior to initiating treatment. Inform the patient that they should be seen by the prescriber frequently to review dose titration, symptom response, and adverse reactions; a follow-up of every three months is recommended.

Discuss safe and proper use of Natrii oxybutyras Kalceks and dosing information with patients prior to the initiation of treatment. Instruct patients to store Natrii oxybutyras Kalceks bottles and Natrii oxybutyras Kalceks doses in a secure place, out of the reach of children and pets.

Alcohol Or Sedative Hypnotics

Advise patients not to drink alcohol or take other sedative hypnotics if they are taking Natrii oxybutyras Kalceks.

Sedation

Inform patients that after taking Natrii oxybutyras Kalceks they are likely to fall asleep quickly (often within 5 and usually within 15 minutes), but the time it takes to fall asleep can vary from night to night. The sudden onset of sleep, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization. Instruct patients to remain in bed following ingestion of the first and second doses. Instruct patients not to take their second dose until 2.5 to 4 hours after the first dose.

Food Effects On Natrii oxybutyras Kalceks

Inform patients to take the first dose at least 2 hours after eating.

Respiratory Depression

Inform patients that Natrii oxybutyras Kalceks can be associated with respiratory depression.

Operating Hazardous Machinery

Inform patients that until they are reasonably certain that Natrii oxybutyras Kalceks does not affect them adversely (e.g., impair judgment, thinking, or motor skills) they should not operate hazardous machinery, including automobiles or airplanes.

Suicidality

Instruct patients or families to contact a healthcare provider immediately if the patient develops depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or suicidal ideation.

Sleepwalking

Instruct patients and their families that Natrii oxybutyras Kalceks has been associated with sleepwalking and to contact their healthcare provider if this occurs.

Sodium Intake

Instruct patients who are sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment) that Natrii oxybutyras Kalceks contains a significant amount of sodium and they should limit their sodium intake.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Administration of sodium oxybate to rats at oral doses of up to 1,000 mg/kg/day for 83 (males) or 104 (females) weeks resulted in no increase in tumors. Plasma exposure (AUC) at the highest dose tested was 2 times that in humans at the maximum recommended human dose (MRHD) of 9 g per night.

The results of 2-year carcinogenicity studies in mouse and rat with gamma-butyrolactone, a compound that is metabolized to sodium oxybate in vivo, showed no clear evidence of carcinogenic activity. The plasma AUCs of sodium oxybate achieved at the highest doses tested in these studies were less than that in humans at the MRHD.

Mutagenesis

Sodium oxybate was negative in the in vitro bacterial gene mutation assay, an in vitro chromosomal aberration assay in mammalian cells, and in an in vivo rat micronucleus assay.

Impairment Of Fertility

Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females through early gestation resulted in no adverse effects on fertility. The highest dose tested is approximately equal to the MRHD on a mg/m² basis.

Use In Specific Populations

Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of sodium oxybate in pregnant women. Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity; however, oral administration to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and growth, at a clinically relevant dose.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations

Labor or Delivery

Natrii oxybutyras Kalceks has not been studied in labor or delivery. In obstetric anesthesia using an injectable formulation of sodium oxybate, newborns had stable cardiovascular and respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. There was a fall in the rate of uterine contractions 20 minutes after injection. Placental transfer is rapid and gamma hydroxybutyrate (GHB) has been detected in newborns at delivery after intravenous administration of GHB to mothers. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown.

Data

Animal Data

Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m²) basis.

Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested. The no-effect dose for pre-and postnatal developmental toxicity in rats is less than the MRHD on a mg/m² basis.

Lactation

Risk Summary

GHB is excreted in human milk after oral administration of sodium oxybate. There is insufficient information on the risk to a breastfed infant, and there is insufficient information on milk production in nursing mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Natrii oxybutyras Kalceks and any potential adverse effects on the breastfed infant from Natrii oxybutyras Kalceks or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Natrii oxybutyras Kalceks in patients with narcolepsy did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects. In controlled trials in another population, 39 (5%) of 874 patients were 65 years or older. Discontinuations of treatment due to adverse reactions were increased in the elderly compared to younger adults (20.5% v. 18.9%). Frequency of headaches was markedly increased in the elderly (38.5% v. 18.9%). The most common adverse reactions were similar in both age categories. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

The starting dose of Natrii oxybutyras Kalceks should be reduced by one-half in patients with liver impairment.

The following adverse reactions appear in other sections of the labeling:

• CNS depression
• Abuse and Misuse
• Respiratory Depression and Sleep-disordered Breathing
• Depression and Suicidality
• Other Behavioral or Psychiatric Adverse Reactions
• Parasomnias
• Use in Patients Sensitive to High Sodium Intake

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Natrii oxybutyras Kalceks was studied in three placebo-controlled clinical trials (Trials N1, N3, and N4, described in Sections 14.1 and 14.2) in 611 patients with narcolepsy (398 subjects treated with Natrii oxybutyras Kalceks, and 213 with placebo). A total of 781 patients with narcolepsy were treated with Natrii oxybutyras Kalceks in controlled and uncontrolled clinical trials.

Section 6.1 and Table 3 presents adverse reactions from three pooled, controlled trials (N1, N3, N4) in patients with narcolepsy.

Adverse Reactions Leading To Treatment Discontinuation:

Of the 398 Natrii oxybutyras Kalceks-treated patients with narcolepsy, 10.3% of patients discontinued because of adverse reactions compared with 2.8% of patients receiving placebo. The most common adverse reaction leading to discontinuation was nausea (2.8%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.

Commonly Observed Adverse Reactions In Controlled Clinical Trials:

The most common adverse reactions (incidence ≥ 5% and twice the rate seen with placebo) in Natrii oxybutyras Kalceks-treated patients were nausea, dizziness, vomiting, somnolence, enuresis, and tremor.

Adverse Reactions Occurring At An Incidence Of 2% Or Greater:

Table 3 lists adverse reactions that occurred at a frequency of 2% or more in any treatment group for three controlled trials and were more frequent in any Natrii oxybutyras Kalceks treatment group than with placebo. Adverse reactions are summarized by dose at onset. Nearly all patients in these studies initiated treatment at 4.5 g per night. In patients who remained on treatment, adverse reactions tended to occur early and to diminish over time.

Table 3: Adverse Reactions Occurring in ≥2% of Patients and More Frequently with Natrii oxybutyras Kalceks than Placebo in Three Controlled Trials (N1, N3, N4) by Body System and Dose at Onset

Dose-Response Information

In clinical trials in narcolepsy, a dose-response relationship was observed for nausea, vomiting, paresthesia, disorientation, irritability, disturbance in attention, feeling drunk, sleepwalking, and enuresis. The incidence of all these reactions was notably higher at 9 g per night.

In controlled trials in narcolepsy, discontinuations of treatment due to adverse reactions were greater at higher doses of Natrii oxybutyras Kalceks.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Natrii oxybutyras Kalceks. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

arthralgia, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity, hypertension, memory impairment, nocturia, panic attack, vision blurred, and weight decreased

Human Experience

Information regarding overdose with Natrii oxybutyras Kalceks is derived largely from reports in the medical literature that describe symptoms and signs in individuals who have ingested GHB illicitly. In these circumstances the co-ingestion of other drugs and alcohol was common, and may have influenced the presentation and severity of clinical manifestations of overdose.

In clinical trials two cases of overdose with Natrii oxybutyras Kalceks were reported. In the first case, an estimated dose of 150 g, more than 15 times the maximum recommended dose, caused a patient to be unresponsive with brief periods of apnea and to be incontinent of urine and feces. This individual recovered without sequelae. In the second case, death was reported following a multiple drug overdose consisting of Natrii oxybutyras Kalceks and numerous other drugs.

Signs And Symptoms

Information about signs and symptoms associated with overdosage with Natrii oxybutyras Kalceks derives from reports of its illicit use. Patient presentation following overdose is influenced by the dose ingested, the time since ingestion, the co-ingestion of other drugs and alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma. Emesis (even when obtunded), diaphoresis, headache, and impaired psychomotor skills have been observed. No typical pupillary changes have been described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision has been reported. An increasing depth of coma has been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact.

Recommended Treatment Of Overdose

General symptomatic and supportive care should be instituted immediately, and gastric decontamination may be considered if co-ingestants are suspected. Because emesis may occur in the presence of obtundation, appropriate posture (left lateral recumbent position) and protection of the airway by intubation may be warranted. Although the gag reflex may be absent in deeply comatose patients, even unconscious patients may become combative to intubation, and rapid-sequence induction (without the use of sedative) should be considered. Vital signs and consciousness should be closely monitored. The bradycardia reported with GHB overdose has been responsive to atropine intravenous administration. No reversal of the central depressant effects of Natrii oxybutyras Kalceks can be expected from naloxone or flumazenil administration. The use of hemodialysis and other forms of extracorporeal drug removal have not been studied in GHB overdose. However, due to the rapid metabolism of sodium oxybate, these measures are not warranted.

Poison Control Center

As with the management of all cases of drug overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider is encouraged to collect urine and blood samples for routine toxicologic screening, and to consult with a regional poison control center (1-800-222-1222) for current treatment recommendations.

Pharmacokinetics of GHB are nonlinear and are similar following single or repeat dosing of Natrii oxybutyras Kalceks.

Absorption

Following oral administration of Natrii oxybutyras Kalceks, GHB is absorbed rapidly across the clinical dose range, with an absolute bioavailability of about 88%. The average peak plasma concentrations (Cmax) following administration of each of the two 2.25 g doses given under fasting conditions 4 hours apart were similar. The average time to peak plasma concentration (Tmax) ranged from 0.5 to 1.25 hours. Following oral administration of Natrii oxybutyras Kalceks, the plasma levels of GHB increased more than dose-proportionally, with blood levels increasing 3.7-fold as total daily dose is doubled from 4.5 g to 9 g. Single doses greater than 4.5 g have not been studied. Administration of Natrii oxybutyras Kalceks immediately after a high-fat meal resulted in delayed absorption (average Tmax increased from 0.75 hr to 2 hr) and a reduction in Cmax of GHB by a mean of 59% and of systemic exposure (AUC) by 37%.

Distribution

GHB is a hydrophilic compound with an apparent volume of distribution averaging 190 mL/kg to 384 mL/kg. At GHB concentrations ranging from 3 mcg/mL to 300 mcg/mL, less than 1% is bound to plasma proteins.

Metabolism

Animal studies indicate that metabolism is the major elimination pathway for GHB, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. The primary pathway involves a cytosolic NADP⁺-linked enzyme, GHB dehydrogenase, that catalyzes the conversion of GHB to succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyzes the conversion to succinic semialdehyde in the presence of α-ketoglutarate. An alternate pathway of biotransformation involves β-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified.

Elimination

The clearance of GHB is almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration. On average, less than 5% of unchanged drug appears in human urine within 6 to 8 hours after dosing. Fecal excretion is negligible. GHB has an elimination half-life of 0.5 to 1 hour.