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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
XYWAV (NDA-212690)
(CALCIUM OXYBATE; MAGNESIUM OXYBATE; POTASSIUM OXYBATE; SODIUM OXYBATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
08/12/2021 (SUPPL-6)
5 Warnings and Precautions
5.4 Respiratory Depression and Sleep-Disordered Breathing(Additions and/or revisions underlined)
XYWAV may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses of oxybate and with illicit use of GHB, life-threatening respiratory depression has been reported [see Overdosage (10)].
Increased apnea and reduced oxygenation may occur with XYWAV administration in adult and pediatric patients. A significant increase in the number of central apneas and clinically significant oxygen desaturation may occur in patients with obstructive sleep apnea treated with XYWAV.
In a study assessing the respiratory-depressant effects of Xyrem (same active moiety as XYWAV) at doses up to 9 g per night in 21 adult 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 Xyrem 9 g per night in 50 adult patients with obstructive sleep apnea, Xyrem 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 Xyrem, and clinically significant oxygen desaturation (less than or equal to 55%) was measured in three patients (6%) after Xyrem administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation.
During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation were observed in pediatric patients with narcolepsy treated with Xyrem.
Prescribers should be aware that increased central apneas and clinically relevant oxygen desaturation events have been observed with sodium oxybate administration in adult and pediatric patients.
In clinical trials of Xyrem in 128 adult patients with narcolepsy, two patients 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 PSG measures in adult 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, in men, in postmenopausal women not on hormone replacement therapy, and among patients with narcolepsy.
(Additions and/or revisions underlined)
Depression, and suicidal ideation and behavior can occur in patients treated with XYWAV. In Study 1 [see Clinical Studies (14.1)], depression and depressed mood were reported in 3% and 4%, respectively, of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of depression, but in most cases, no change in XYWAV treatment was required.
In Study 2 [see Clinical Studies (14.3)], depression and depressed mood were reported in 1 patient (1%) and in 5 patients (3%), respectively, of patients treated with XYWAV, all of whom continued XYWAV treatment.
In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy (n=781), there were two suicides and two attempted suicides in patients treated with Xyrem, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Xyrem in conjunction with other drugs. Xyrem was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 patients treated with Xyrem, with four patients (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment was required. In a clinical trial with Xyrem in pediatric patients with narcolepsy (n=104), one patient experienced suicidal ideation and two patients reported depression while taking Xyrem.
The emergence of depression in patients treated with XYWAV 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 XYWAV.
(Additions and/or revisions underlined)
Other behavioral and psychiatric adverse reactions can occur in patients taking XYWAV.
In Study 1, confusion occurred in 1% of patients treated with XYWAV and anxiety occurred in 5% of patients treated with XYWAV. One patient experienced visual hallucinations and confusion after ingesting approximately 9 grams of XYWAV.
In Study 2, confusion occurred in 3% of patients treated with XYWAV, and anxiety occurred in 16% patients treated with XYWAV. One patient experienced visual hallucinations which led to discontinuation of XYWAV.
Other neuropsychiatric reactions reported in clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy and in the postmarketing setting included hallucinations, paranoia, psychosis, aggression, and agitation.
In a pediatric clinical trial with Xyrem in patients with narcolepsy, neuropsychiatric reactions, including acute psychosis, confusion, and anxiety, were reported while taking Xyrem.
The emergence or increase in the occurrence of behavioral or psychiatric events in patients taking XYWAV should be carefully monitored.
(Additions and/or revisions underlined)
Parasomnias can occur in patients taking XYWAV.
In Study 1, parasomnias, including sleepwalking, were reported in 6% of patients treated with XYWAV.
In Study 2, parasomnias, including sleepwalking, were reported in 5% of patients treated with XYWAV.
In a clinical trial of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy, five instances of sleepwalking with potential injury or significant injury were reported. Parasomnias, including sleepwalking, also have been reported in a pediatric clinical trial with sodium oxybate and in postmarketing experience with sodium oxybate.
Episodes of sleepwalking should be fully evaluated and appropriate interventions considered.
6 Adverse Reactions
6.1 Clinical Trials Experience(Extensive additions/revisions; please refer to label)
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions underlined)
Narcolepsy
The safety and effectiveness of XYWAV for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy have been established. XYWAV has not been studied in a pediatric clinical trial. Use of XYWAV in pediatric patients 7 years of age and older with narcolepsy is supported by evidence from an adequate and well-controlled study of sodium oxybate in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of XYWAV similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of XYWAV from healthy adult volunteers [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)].
In the pediatric clinical trial with sodium oxybate administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported [see Warnings and Precautions (5.4, 5.5, 5.6, 5.7) and Adverse Reactions (6.1)].
Safety and effectiveness of XYWAV for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients below the age of 7 years have not been established.
Idiopathic Hypersomnia
Safety and effectiveness of XYWAV for the treatment of idiopathic hypersomnia in pediatric patients have not been established.
Juvenile Animal Toxicity Data
In a study in which sodium oxybate (0, 100, 300, or 900 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 21 through 90), mortality was observed at the two highest doses tested. Deaths occurred during the first week of dosing and were associated with clinical signs (including decreased activity and respiratory rate) consistent with the pharmacological effects of the drug. Reduced body weight gain in males and females and delayed sexual maturation in males were observed at the highest dose tested. The no-effect dose for adverse effects in juvenile rats is associated with plasma exposures (AUC) less than that at the maximum recommended human dose (9 g/night).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Extensive additions/revisions; please refer to label)
(Additions and/or revisions underlined)
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Central Nervous System Depression
Inform patients and/or caregivers that XYWAV can cause central nervous system depression, including respiratory depression, hypotension, profound sedation, syncope, and death. Instruct patients not to engage in activities requiring mental alertness or motor coordination, including operating hazardous machinery, for at least 6 hours after taking XYWAV. Instruct patients and/or their caregivers to inform their healthcare providers of all the medications they take [see Warnings and Precautions (5.1)].
Abuse and Misuse
Inform patients and/or caregivers that the active ingredient of XYWAV is
gamma-hydroxybutyrate (GHB), which is associated with serious adverse reactions with illicit use and abuse [see Warnings and Precautions (5.2)].
XYWAV and XYREM REMS
XYWAV is available only through a restricted program called the XYWAV and XYREM REMS [see Warnings and Precautions (5.3)]. Inform the patient and/or caregiver of the following notable requirements:
XYWAV is dispensed only by the central pharmacy
- XYWAV will be dispensed and shipped only to patients enrolled in the XYWAV and XYREM REMS
- XYWAV is available only from the central pharmacy participating in the program. Therefore, provide patients and/or caregivers with the telephone number and website for information on how to obtain the product.
Alcohol or Sedative Hypnotics
Advise patients and/or caregivers that alcohol and other sedative hypnotics should not be taken with XYWAV [see Contraindications (4)].
Inform patients and/or caregivers that the patient is likely to fall asleep quickly after taking XYWAV (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 [see Adverse Reactions (6.2)]. Instruct patients and/or caregivers that the patient should remain in bed following ingestion of each dose. Instruct patients and/or caregivers that the patient should
not take a subsequent nightly dose until at least 2.5 to 4 hours after the previous dose [see Dosage and Administration (2.4)].
Administration Instructions
Inform patients to administer XYWAV at least 2 hours after eating. Inform patients and/or caregivers of patients taking XYWAV twice nightly, that the total nightly dosage of XYWAV is divided into two doses [see Dosage and Administration (2.4)].
Inform patients if their nightly dose requires multiple draws. Instruct patients on how to perform the draws from the bottle.
Respiratory Depression and Sleep-Disordered Breathing
Inform patients that XYWAV may impair respiratory drive, especially in patients with compromised respiratory function, and may cause apnea [see Warnings and Precautions (5.4)].
Depression and Suicidality
Instruct patients and/or caregivers 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 [see Warnings and Precautions (5.5)].
Other Behavioral or Psychiatric Adverse Reactions
Inform patients and/or caregivers that XYWAV can cause behavioral or psychiatric adverse reactions, including confusion, anxiety, and psychosis. Instruct them to notify their healthcare provider if any of these types of symptoms occur [see Warnings and Precautions (5.6)].
Sleepwalking
Instruct patients and/or caregivers that XYWAV has been associated with sleepwalking and other behaviors during sleep, and to contact their healthcare provider if this occurs [see Warnings and Precautions (5.7)].
02/11/2021 (SUPPL-1)
5 Warnings and Precautions
5.5 Depression and Suicidality
(Additions and/or revisions underlined)
Depression, and suicidal ideation and behavior can occur in patients treated with XYWAV.
In Study 1, depression and depressed mood were reported in 3% and 4%, respectively, of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of depression, but in most cases, no change in XYWAV treatment was required.
In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy (n=781), there were two suicides and two attempted suicides in patients treated with Xyrem, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Xyrem in conjunction with other drugs. Xyrem was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 patients treated with Xyrem, with four patients (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment was required. In a clinical trial with Xyrem in pediatric patients with narcolepsy (n=104), one patient experienced suicidal ideation and two patients reported depression while taking Xyrem.
6 Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
Pediatric Patients (7 Years of Age and Older)
In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), 104 patients aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received Xyrem for up to one year [see Clinical Studies (14.2)]. This study included an open-label safety continuation period in which eligible patients received Xyrem for up to an additional 2 years. The median and maximum exposure across the entire study were 371 and 987 days, respectively.
Adverse Reactions Leading to Treatment Discontinuation
In the pediatric clinical trial with Xyrem, 7 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and headache).
Adverse Reactions in the Xyrem Pediatric Clinical Trial
The most common adverse reactions (greater than or equal to 5%) were nausea (20%), enuresis (19%), vomiting (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and sleepwalking (6%).
8 Use in Specific Populations
8.4 Pediatric Use
(Additions and/or revisions underlined)
The safety and effectiveness of XYWAV for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy have been established. XYWAV has not been studied in a pediatric clinical trial. Use of XYWAV in pediatric patients 7 years of age and older with narcolepsy is supported by evidence from an adequate and well-controlled study of sodium oxybate in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of XYWAV similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of XYWAV from healthy adult volunteers [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)].
In the pediatric clinical trial with sodium oxybate administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported [see Warnings and Precautions (5.4, 5.5, 5.6, 5.7) and Adverse Reactions (6.1)].
02/11/2021 (SUPPL-2)
5 Warnings and Precautions
5.5 Depression and Suicidality
(Additions and/or revisions underlined)
Depression, and suicidal ideation and behavior can occur in patients treated with XYWAV.
In Study 1, depression and depressed mood were reported in 3% and 4%, respectively, of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of depression, but in most cases, no change in XYWAV treatment was required.
In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy (n=781), there were two suicides and two attempted suicides in patients treated with Xyrem, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used Xyrem in conjunction with other drugs. Xyrem was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 patients treated with Xyrem, with four patients (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment was required. In a clinical trial with Xyrem in pediatric patients with narcolepsy (n=104), one patient experienced suicidal ideation and two patients reported depression while taking Xyrem.
6 Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
Pediatric Patients (7 Years of Age and Older)
In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), 104 patients aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received Xyrem for up to one year [see Clinical Studies (14.2)]. This study included an open-label safety continuation period in which eligible patients received Xyrem for up to an additional 2 years. The median and maximum exposure across the entire study were 371 and 987 days, respectively.
Adverse Reactions Leading to Treatment Discontinuation
In the pediatric clinical trial with Xyrem, 7 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and headache).
Adverse Reactions in the Xyrem Pediatric Clinical Trial
The most common adverse reactions (greater than or equal to 5%) were nausea (20%), enuresis (19%), vomiting (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and sleepwalking (6%).
8 Use in Specific Populations
8.4 Pediatric Use
(Additions and/or revisions underlined)
The safety and effectiveness of XYWAV for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy have been established. XYWAV has not been studied in a pediatric clinical trial. Use of XYWAV in pediatric patients 7 years of age and older with narcolepsy is supported by evidence from an adequate and well-controlled study of sodium oxybate in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of XYWAV similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of XYWAV from healthy adult volunteers [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)].
In the pediatric clinical trial with sodium oxybate administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported [see Warnings and Precautions (5.4, 5.5, 5.6, 5.7) and Adverse Reactions (6.1)].