A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Xyrem Side Effects, and Drug Interactions - Sodium oxybate
Xyrem Side Effects, and Drug Interactions - Sodium oxybate
SIDE EFFECTS
A total of 448 narcoleptic patients were exposed to sodium
oxybate in clinical trials. The most commonly observed adverse events associated
with the use of sodium oxybate were:
Headache 25%, nausea 21%, dizziness 17%, pain 16%, somnolence
13%, pharyngitis 11%, infection 10%, viral infection 10%, flu syndrome 9%, accidental
injury 9%, diarrhea 8%, urinary incontinence 8%, vomiting 8%, rhinitis 8%, asthenia
8%, sinusitis 7%, nervousness 7%, back pain 7%, confusion 7%, sleepwalking 7%,
depression 6%, dyspepsia 6%, abdominal pain 6%, abnormal dreams 6%, insomnia
5%.
Two deaths occurred in these clinical trials, both from drug
overdoses. Both of these deaths resulted from ingestion of multiple drugs, including
sodium oxybate in one patient.
In these clinical trials, 13% of patients discontinued
because of adverse events.
The most frequent reasons for discontinuation (>1%) were
nausea 2% and headache 1%.
Approximately 6% of patients receiving sodium oxybate in 3
controlled clinical trials (n=147) withdrew due to an adverse event, compared
to 1% receiving placebo (n=79). The reasons for discontinuation that occurred
more frequently in sodium oxybate-treated patients than placebo-treated patients
were: nausea 3%, somnolence 2% and confusion 1%. Amnesia, asthenia, chest pain,
dizziness, dyspnea, fecal incontinence, hallucinations, headache, hyperkinesia,
paranoid reaction, thinking abnormal, vertigo, and vomiting, each caused discontinuation
in a single patient.
Incidence in Controlled Clinical Trials
Most Commonly Reported Adverse Events in Controlled Clinical
Trials
The most commonly reported adverse events associated with the
use of sodium oxybate and occurring with at least 5% greater frequency than
seen in placebo-treated patients were dizziness (23%), headache (20%), nausea
(16%), pain (12%), sleep disorder (9%), confusion (7%), infection (7%), vomiting
(6%), and urinary incontinence (5%). These incidences are based on combined
data from Trial 1 and two smaller randomized, double-blind, placebo-controlled,
cross-over trials (n=181).
Trial 1, the parallel-group, placebo-controlled trial, used
3 fixed doses of sodium oxybate (3 g, 6 g, and 9 g). In that trial, dizziness,
nausea, urinary incontinence, and vomiting were more common at higher doses,
with the majority of events occurring in the 6 g and 9 g dose groups.
Adverse Events With an Incidence of at Least 6% (two events)
in One or More Treatment Groups in Trial 1
Table 2 lists the incidence of treatment emergent adverse events
in Trial 1. Events have been included for which there are at least two episodes
in the considered drug group and for which the incidence in at least one dosage
group is greater on drug than placebo.
The prescriber should be aware that data provided below cannot
be used to predict the incidence of adverse experiences during the course of
usual medical practice where patient characteristics and other factors may differ
from those occurring during clinical trials. Similarly, the cited frequencies
cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. However, the cited
figures do provide the prescribing physician with some basis for estimating
the relative contribution of drug and non-drug factors to the adverse event
incidence rate in the population studied.
|
Table 2 Incidence (%) of Treatment-Emergent Adverse Events
in Trial 1
|
| |
|
Sodium Oxybate Dose
|
|
Body System
|
Placebo
|
3 g
|
6 g
|
9 g
|
|
Preferred Term
|
(n=34)
|
(n=34)
|
(n=33)
|
(n=35)
|
|
Body as a Whole
|
|
Asthenia
|
1 (3%)
|
0 (0%)
|
2 (6%)
|
0 (0%)
|
|
Flu Syndrome
|
0 (0%)
|
1 (3%)
|
0 (0%)
|
2 (6%)
|
|
Headache
|
7 (21%)
|
3 (9%)
|
5 (15%)
|
11 (31%)
|
|
Infection
|
1 (3%)
|
3 (9%)
|
5 (15%)
|
0 (0%)
|
|
Infection Viral
|
1 (3%)
|
1 (3%)
|
3 (9%)
|
0 (0%)
|
|
Pain
|
2 (6%)
|
3 (9%)
|
4 (12%)
|
7 (20%)
|
|
Digestive System
|
|
Diarrhea
|
0 (0%)
|
0 (0%)
|
2 (6%)
|
2 (6%)
|
|
Dyspepsia
|
2 (6%)
|
0 (0%)
|
3 (9%)
|
2 (6%)
|
|
Nausea
|
2 (6%)
|
2 (6%)
|
5 (15%)
|
12 (34%)
|
|
Nausea and Vomiting
|
0 (0%)
|
0 (0%)
|
2 (6%)
|
2 (6%)
|
|
Vomiting
|
0 (0%)
|
0 (0%)
|
2 (6%)
|
4 (11%)
|
|
Musculoskeletal System
|
|
Myasthenia
|
0 (0%)
|
2 (6%)
|
1 (3%)
|
0 (0%)
|
|
Nervous System
|
|
Amnesia
|
0 (0%)
|
1 (3%)
|
0 (0%)
|
2 (6%)
|
|
Anxiety
|
1 (3%)
|
1 (3%)
|
0 (0%)
|
2 (6%)
|
|
Confusion
|
1 (3%)
|
3 (9%)
|
1 (3%)
|
5 (14%)
|
|
Dizziness
|
2 (6%)
|
8 (24%)10 (30%)
|
12 (34%)
|
|
Dream Abnormal
|
0 (0%)
|
0 (0%)
|
3 (9%)
|
1 (3%)
|
|
Hypertension
|
1 (3%)
|
0 (0%)
|
2 (6%)
|
0 (0%)
|
|
Hypesthesia
|
0 (0%)
|
2 (6%)
|
0 (0%)
|
0 (0%)
|
|
Sleep Disorder
|
1 (3%)
|
2 (6%)
|
4 (12%)
|
5 (14%)
|
|
Somnolence
|
4 (12%)
|
5 (15%)
|
4 (12%)
|
5 (14%)
|
|
Thinking Abnormal
|
0 (0%)
|
1 (3%)
|
0 (0%)
|
2 (6%)
|
|
Skin
|
|
Increased Sweating
|
0 (0%)
|
1 (3%)
|
1 (3%)
|
4 (11%)
|
|
Special Senses
|
|
Amblyopia
|
1 (3%)
|
2 (6%)
|
0 (0%)
|
0 (0%)
|
|
Tinnitus
|
0 (0%)
|
2 (6%)
|
0 (0%)
|
0 (0%)
|
|
Urogenital System
|
|
Dysmenorrhea
|
1 (3%)
|
1 (3%)
|
0 (0%)
|
2 (6%)
|
|
Incontinence Urine
|
0 (0%)
|
0 (0%)
|
2 (6%)
|
5 (14%)
|
Other Adverse Events Observed During All Clinical Trials
During clinical trials sodium oxybate was administered to 448
patients with narcolepsy, and 125 healthy volunteers. A total of 150 patients
received 9 g/day, the maximum recommended dose. A total of 223 patients received
sodium oxybate for at least one year. To establish the rate of adverse events,
data from all subjects receiving any dose of sodium oxybate were pooled. All
adverse events reported by at least two people are included except for those
already listed elsewhere in the labeling, terms too general to be informative,
or events unlikely to be drug induced. Events are classified by body system
and listed under the following definitions: frequent adverse events (those occurring
in at least 1/100 people);infrequent events (those occurring in 1/100 to 1/1000
people). These events are not necessarily related to sodium oxybate treatment.
Body As A Whole
Frequent: Allergic reaction, chills; Infrequent:
Abdomen enlarged, hangover effect, neck rigidity.
Cardiovascular system
Infrequent: Syncope.
Digestive system
Frequent: Anorexia, constipation; Infrequent: Mouth
ulceration, stomatitis.
Hemic and lymphatic system
Infrequent: Anemia, ecchymosis, leukocytosis, lym-phadenopathy,
polycythemia.
Metabolic and nutritional
Frequent: Alkaline phosphatase increased, edema, hypercholesteremia,
hypocalcemia, weight gain;
Infrequent: Bilirubinemia, creatinine increased, dehydration,
hyperglycemia, hypernatremia, hyperuricemia, SGOT increased, SGPT increased,
thirst.
Musculoskeletal system
Frequent: Arthritis, leg cramps, myalgia.
Nervous system
Frequent: Agitation, ataxia, convulsion, stupor, tremor;
Infrequent: Akathisia, apathy, coma, depersonalization,
euphoria, hypertonia, libido decreased, myoclonus, neuralgia, paralysis.
Respiratory system
Frequent: Dyspnea; Infrequent: Apnea, epistaxis,
hiccup.
Skin and appendages
Frequent: Acne, alopecia, rash; Infrequent: Contact
dermatitis, urticaria.
Special senses
Infrequent: Taste loss.
Urogenital system
Frequent: Albuminuria, cystitis, hematuria, metrorrhagia,
urinary frequency; Infrequent: Urinary urgency.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Xyrem® is classified as a Schedule III controlled
substance by Federal law. The active ingredient, sodium oxy-bate or gamma-hydroxybutyrate
(GHB), is listed in the most restrictive schedule of the Controlled Substances
Act (Schedule I). Thus, non-medical uses of sodium oxybate (Xyrem®
or GHB) are classified under Schedule I.
Abuse, Dependence,and Tolerance
Abuse
See applicable directions for use under HANDLING
AND DISPOSAL below. Although sodium oxybate (also known as GHB) has
not been systematically studied in clinical trials for its potential for abuse,
illicit use and abuse have been reported. Sodium oxybate is a psychoactive drug
that produces a wide range of pharmacological effects. It is a sedative-hypnotic
that produces dose and concentration dependent central nervous system effects
in humans. The onset of effect is rapid, enhancing its desirability as a drug
of abuse or misuse.
The rapid onset of sedation, coupled with the amnestic features
of sodium oxybate, particularly when combined with alcohol, has proven to be
dangerous for the voluntary and involuntary (assault victim) user.
GHB is abused in social settings primarily by young adults.
GHB has some commonalties with ethanol over a limited dose range and some cross
tolerance with ethanol has been reported as well. Cases of severe dependence
and craving for GHB have been reported. Dependence is indicated by the use of
increasingly large doses, increased frequency of use, and continued use despite
adverse consequences. Some of the doses reported abused in the "rave" setting
have been similar to the dose range studied for therapeutic treatment of cataplexy.
Hospital emergency department reports increased 100-fold from
1992 to 1999 (source: Substance Abuse Mental Health Services Administration,
Drug Abuse Warning Network [DAWN]). Sixty percent of the ED reports involved
individuals 25 years and younger. Numerous deaths have been reported, typically
involving GHB in combination with alcohol and other drugs, including five in
the DAWN system in which GHB was the only drug that could be identified.
Dependence
There have been case reports of dependence after illicit use
of GHB at frequent repeated doses (18 to 250 g/day), in excess of the therapeutic
dose range. In these cases, the signs and symptoms of abrupt discontinuation
included an abstinence syndrome consisting of insomnia, restlessness, anxiety,
psychosis, lethargy, nausea, tremor, sweating, muscle cramps, and tachycardia.
These symptoms generally abated in 3 to 14 days. The discontinuation effects
of sodium oxybate have not been systematically evaluated in controlled clinical
trials. An abstinence syndrome has not been reported in clinical investigations.
Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy
patients at therapeutic doses does not show clear evidence of a withdrawal syndrome,
two patients reported anxiety and one reported insomnia following abrupt discontinuation
at the termination of the clinical trial;in the two patients with anxiety, the
frequency of cataplexy had increased markedly at the same time.
Tolerance
Tolerance to sodium oxybate has not been systematically studied
in controlled clinical trials. Open-label, long-term (³6
months) clinical trials did not demonstrate development of tolerance. There
have been some case reports of symptoms of tolerance developing after illicit
use at dosages far in excess of the recommended Xyrem® dosage
regimen. Clinical studies of sodium oxybate in the treatment of alcohol withdrawal
suggest a potential cross-tolerance with alcohol. 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). Physicians should document the diagnosis and indication
for Xyrem®, being alert to drug-seeking behavior and/or feigned
cataplexy.
DRUG INTERACTIONS
Interactions between sodium oxybate and three drugs commonly
used in patients with narcolepsy (zolpidem tartrate, protriptyline HCl, and
modafinil) have been evaluated in formal studies. Sodium oxybate, in combination
with these drugs, produced no significant pharmacokinetic changes for either
drug (see Pharmacokinetics).
However, pharmacodynamic interactions cannot be ruled out.
Nonetheless, sodium oxybate should not be used in combination with sedative
hypnotics or other CNS depressants.
In animal models, sodium oxybate and depressant drug combinations
generally gave greater central depressant effects than did either drug alone.
Concomitant administration to animals of sodium oxybate and benzodiazepines,
barbiturates, or ethanol increases sleep duration. In primates, sodium oxybate
blood levels were elevated with phenytoin pretreatment and reduced with L-Dopa,
ethosuximide, and trimethadione.
Carcinogenicity, Mutagenicity, Impairment of Fertility
Oral carcinogenicity studies have been conducted in rats and
mice with gamma-butyrolactone, 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.
Sodium oxybate was negative in the Ames microbial mutagen test,
an in vitro chromosomal aberration assay in CHO cells, and an in vivo rat micronucleus
assay.
Sodium oxybate did not impair fertility in rats at doses up
to 1000 mg/kg (approximately equal to the maximum recommended human daily dose
on a mg/m2 basis).
Pregnancy
Pregnancy Category B: Reproduction studies conducted in pregnant
rats at doses up to 1000 mg/kg (approximately equal to the maximum recommended
human daily dose on a mg/m2 basis) and in pregnant rabbits at doses
up to 1200 mg/kg (approximately 3 times the maximum recommended human daily
dose on a mg/m2 basis) revealed no evidence of teratogenicity. In
a study in which rats were given sodium oxybate from Day 6 of gestation through
Day 21 postpartum, slight decreases in pup and maternal weight gains were seen
at 1000 mg/kg;there were no drug effects on other developmental parameters.
There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response,
this drug should be used during pregnancy only if clearly needed.
Labor and Delivery
Sodium oxybate 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, but umbilical vein
levels of sodium oxybate were no more than 25% of the maternal concentration.
No sodium oxybate was detected in the infant's blood 30 minutes after delivery.
Elimination curves of sodium oxybate between a 2-day old infant and a 15-year
old patient were similar. Subsequent effects of sodium oxy-bate on later growth,
development and maturation in humans are unknown.
Nursing Mothers
It is not known whether sodium oxybate is excreted in human
milk. Because many drugs are excreted in human milk, caution should be exercised
when sodium oxybate is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in patients under 16 years of age
have not been established.
Race and Gender Effects
There were too few non-Caucasian patients to permit evaluation
of racial effects on safety or efficacy. More than 90% of the subjects in clinical
trials were Caucasian.
The database was 58% female. No important differences in safety
or efficacy of Xyrem® were noted between men and women. The overall
percentage of patients with at least one adverse event was slightly higher in
women (80%) than in men (69%). The incidence of serious adverse events and discontinuations
due to adverse events were similar in both men and women.
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