Xanax xr

Overdose

Clinical Experience

Overdosage reports with XANAX Tablets are limited. Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes, and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.

Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.

General Treatment Of Overdose

As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescribers hould be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including

Undesirable effects

The information included in the subsection on Adverse Events Observed in Short-Term, Placebo- Controlled Trials with XANAX XR Tablets is based on pooled data of five 6- and 8-week placebocontrolled clinical studies in panic disorder.

Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology (version 4.0) was used to classify reported adverse events.

Adverse Events Observed In Short-Term, Placebo-Controlled Trials Of XANAX XR Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Approximately 17% of the 531 patients who received XANAX XR in placebo-controlled clinical trials for panic disorder had at least one adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drugrelated (ie, leading to discontinuation in at least 1% of the patients treated with XANAX XR at a rate at least twice that of placebo) are shown in the following table.

Common Advers e Events Leading to Dis continuation of Treatment in Placebo- Controlled Trials

System Organ Class / Adverse Event	Percentage of Patients Discontinuing Due to Adverse Events
	XANAX XR (n=531)	Placebo (n=349)
Nervous system disorders
Sedation	7.5	0.6
Somnolence	3.2	0.3
Dysarthria	2.1	0
Coordination abnormal	1.9	0.3
Memory impairment	1.5	0.3
General disorders /administration site conditions
Fatigue	1.7	0.6
Psychiatric disorders
Depression	2.5	1.2

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with XANAX XR

The prescriber should be aware that adverse event incidence cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators. The cited values, however, 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.

The following table shows the incidence of treatment-emergent adverse events that occurred during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with XANAX XR where the incidence in patients treated with XANAX XR was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with XANAX XR (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased (see table).

Treatment-Emergent Adverse Events : Incidence in Short-Term, PlaceboControlled Clinical Trials with XANAX XR

System Organ Class / Adverse Event	Percentage of Patients Reporting Adverse Event
	XANAX XR (n=531)	Placebo (n=349)
Nervous system disorders
Sedation	45.2	22.6
Somnolence	23.0	0.3
Memory impairment	15.4	6.9
Dysarthria	10.9	2.6
Coordination abnormal	9.4	0.9
Mental impairment	7.2	5.7
Ataxia	7.2	3.2
Disturbance in attention	3.2	0.6
Balance impaired	3.2	0.6
Paresthesia	2.4	1.7
Dyskinesia	1.7	1.4
Hypoesthesia	1.3	0.3
Hypersomnia	1.3	0
General disorders /administration site conditions
Fatigue	13.9	9.2
Lethargy	1.7	0.6
Infections and infestations
Influenza	2.4	2.3
Upper respiratory tract infections	1.9	1.7
Psychiatric disorders
Depression	12.1	9.2
Libido decreased	6.0	2.3
Disorientation	1.5	0
Confusion	1.5	0.9
Depressed mood	1.3	0.3
Anxiety	1.1	0.6
Metabolism and nutrition disorders
Appetite decreased	7.3	7.2
Appetite increased	7.0	6.0
Anorexia	1.5	0
Gastrointestinal disorders
Dry mouth	10.2	9.7
Constipation	8.1	4.3
Nausea	6.0	3.2
Pharyngolaryngeal pain	3.2	2.6
Investigations
Weight increased	5.1	4.3
Weight decreased	4.3	3.7
Injury, poisoning, and procedural complications
Road traffic accident	1.5	0
Reproductive system and breast disorders
Dysmenorrhea	3.6	2.9
Sexual dysfunction	2.4	1.1
Premenstrual syndrome	1.7	0.6
Musculoskeletal and connective tissue disorders
Arthralgia	2.4	0.6
Myalgia	1.5	1.1
Pain in limb	1.1	0.3
Vascular disorders
Hot flushes	1.5	1.4
Respiratory, thoracic, and mediastinal disorders
Dyspnea	1.5	0.3
Rhinitis allergic	1.1	0.6
Skin and subcutaneous tissue disorders
Pruritis	1.1	0.9

Other Adverse Events Observed During the Premarketing Evaluation of XANAX XR Tablets

Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531 patients with panic disorder treated with XANAX XR. All potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so general as to be uninformative, and those events that occurred at rates similar to background rates in the general population. It is important to emphasize that, although the events reported occurred during treatment with XANAX XR, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least l/l00 patients; infrequent adverse events are those occurring in less 16 than l/100 patients but at least l/1000 patients; rare events are those occurring in fewer than l/1000 patients.

Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia

Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain

Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia

Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent: dysphagia, salivary hypersecretion

General disorders and administration site conditions: Frequent: malaise, weakness, chest pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors

Musculoskeletal and connective tissue disorders: Frequent: back pain, muscle cramps, muscle twitching

Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor

Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation

Renal and urinary disorders: Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary incontinence

Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion, hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea

Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent: clamminess, rash, urticaria

Vascular disorders: Infrequent: hypotension

The categories of adverse events reported in the clinical development program for XANAX Tablets in the treatment of panic disorder differ somewhat from those reported for XANAX XR Tablets because the clinical trials with XANAX Tablets and XANAX XR Tablets used different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of adverse events reported in the clinical trials with XANAX Tablets were generally the same as those reported in the clinical trials with XANAX XR Tablets.

Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated with XANAX XR

The following table shows the incidence of discontinuation-emergent adverse events that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with XANAX XR where the incidence in patients treated with XANAX XR was two times greater than the incidence in placebotreated patients.

Discontinuation-Emergent Symptoms : Incidence in Short-Term, Placebo- Controlled Trials with XANAX XR

System Organ Class / Adverse Event	Percentage of Patients Reporting Advers e Event
	XANAX XR (n=422)	Placebo (n=261)
Nervous system disorders
Tremor	28.2	10.7
Headache	26.5	12.6
Hypoesthesia	7.8	2.3
Paraesthesia	7.1	2.7
Psychiatric disorders
Insomnia	24.2	9.6
Nervousness	21.8	8.8
Depression	10.9	5.0
Derealization	8.0	3.8
Anxiety	7.8	2.7
Depersonalization	5.7	1.9
Gastrointes tinal disorders
Diarrhea	12.1	3.1
Respiratory, thoracic and mediastinal disorders
Hyperventilation	8.5	2.7
Metabolism and nutrition disorders
Appetite decreased	9.5	3.8
Musculosketal and connective tissue disorders
Muscle twitching	7.4	2.7
Vascular disorders
Hot flushes	5.9	2.7

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam (see WARNINGS).

To discontinue treatment in patients taking XANAX XR Tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of XANAX XR Tablets be decreased by no more than 0.5 mg every three days (see DOSAGE AND ADMINISTRATION). Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.

As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving 18 other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder.

Post Introduction Reports

Various adverse drug reactions have been reported in association with the use of XANAX Tablets since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of XANAX Tablets cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, jaundice, hepatic failure, Stevens-Johnson syndrome, photosensitivity reaction, angioedema, peripheral edema, menstruation irregular, hyperprolactinemia, gynecomastia, and galactorrhea (see PRECAUTIONS).

Pharmacodynamic properties

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereospecific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.

Pharmacokinetic properties

Absorption

Following oral administration of XANAX (immediate-release) Tablets, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following 2 administration. Plasma levels are proportional to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3–26.9 hours) in healthy adults.

The mean absolute bioavailability of alprazolam from XANAX XR Tablets is approximately 90%, and the relative bioavailability compared to XANAX Tablets is 100%. The bioavailability and pharmacokinetics of alprazolam following administration of XANAX XR Tablets are similar to that for XANAX Tablets, with the exception of a slower rate of absorption. The slower absorption rate results in a relatively constant concentration that is maintained between 5 and 11 hours after the dosing. The pharmacokinetics of alprazolam and two of its major active metabolites (4-hydroxyalprazolam and α- hydroxyalprazolam) are linear, and concentrations are proportional up to the recommended maximum daily dose of 10 mg given once daily. Multiple dose studies indicate that the metabolism and elimination of alprazolam are similar for the immediate-release and the extended-release products.

Food has a significant influence on the bioavailability of XANAX XR Tablets. A high-fat meal given up to 2 hours before dosing with XANAX XR Tablets increased the mean Cmax by about 25%. The effect of this meal on Tmax depended on the timing of the meal, with a reduction in Tmax by about 1/3 for subjects eating immediately before dosing and an increase in Tmax by about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure (AUC) and elimination half-life (t ) were not affected by eating.

There were significant differences in absorption rate for the XANAX XR Tablet, depending on the time of day administered, with the Cmax increased by 30% and the Tmax decreased by an hour following dosing at night, compared to morning dosing.

Distribution

The apparent volume of distribution of alprazolam is similar for XANAX XR and XANAX Tablets. In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin accounts for the majority of the binding.

Metabolism

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and α-hydroxyalprazolam) were similar for XANAX and XANAX XR Tablets, indicating that the metabolism of alprazolam is not affected by absorption rate. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration after both XANAX XR and XANAX Tablets were always less than 10% and 4%, respectively. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations 3 and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

Elimination

Alprazolam and its metabolites are excreted primarily in the urine. The mean plasma elimination half-life of alprazolam following administration of XANAX XR Tablet ranges from 10.7–15.8 hours in healthy adults.

Date of revision of the text

Sep 2013

Fertility, pregnancy and lactation

Teratogenic Effects

Pregnancy Category D

(see WARNINGS section).

Nonteratogenic Effects

It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.