ADVERSE REACTIONS SECTION

Highlight: The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence >5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido. (6.1)

**To report SUSPECTED ADVERSE REACTIONS, contactViatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or **www.fda.gov/medwatch.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

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Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]

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Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]

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Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]

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Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4)]

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Patients with Depression [see Warnings and Precautions (5.6)]

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Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8)]

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Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]

6.1 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 practice.

The data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in:

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4-week placebo-controlled clinical studies with XANAX dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1)

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Short-term (up to 10 weeks) placebo-controlled clinical studies with XANAX dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).  

Table 1: Adverse Reactions Occurring in ≥1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety

In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

Table 2: Adverse Reactions Occurring in ≥1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder

In addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of XANAX: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.

Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials

In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received XANAX, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with XANAX and at a greater rate than the placebo-treated group are shown in Table 3.

Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of XANAX-treated Patients and > Placebo-treated Patients

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of XANAX [see Warning and Precautions (5.2) and Drug Abuse and Dependence (9.3)].

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 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of XANAX. 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.

Endocrine disorders: Hyperprolactinemia

General disorders and administration site conditions: Edema peripheral

Hepatobiliary disorders: Hepatitis, hepatic failure

Investigations: Liver enzyme elevations

Psychiatric disorders: Hypomania, mania

Reproductive system and breast disorders: Gynecomastia, galactorrhea

Skin and subcutaneous tissue disorders: Photosensitivity reaction, angioedema, Stevens-Johnson syndrome

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Generalized Anxiety Disorder

XANAX was compared to placebo in double-blind clinical studies (doses up to 4 mg per day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. XANAX was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s Global Impressions, and Self-Rating Symptom Scale.

14.2 Panic Disorder

The effectiveness of XANAX in the treatment of panic disorder was studied in 3 short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder.

The average dose of XANAX was 5 mg to 6 mg per day in 2 of the studies, and the doses of XANAX were fixed at 2 mg and 6 mg per day in the third study. In all 3 studies, XANAX was superior to placebo on a variable defined as “the number of patients with zero panic attacks” (range, 37% to 83% met this criterion), as well as on a global improvement score. In 2 of the 3 studies, XANAX was superior to placebo on a variable defined as “change from baseline on the number of panic attacks per week” (range, 3.3 to 5.2), and also on a phobia rating scale. A subgroup of patients who improved on XANAX during short-term treatment in 1 of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

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OVERDOSAGE SECTION

10 OVERDOSAGE

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

Consider contacting the Poison Help Line (1-800-222-1222), or a medical toxicologist for additional overdosage management recommendations.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2 years at doses up to 30 and 10 mg/kg day respectively. These doses are 29 times and 4.8 times the maximum recommended human dose of 10 mg/day based on mg/m2 body surface area, respectively.

Mutagenesis

Alprazolam was negative in the in vitro Ames bacterial reverse mutation assay and DNA Damage/Alkaline Elution Assay and in vivo rat micronucleus genetic toxicology assays.

Impairment of Fertility

Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg per day, which is approximately 5 times the maximum recommended human dose of 10 mg per day based on mg/m2 body surface area.

13.2 Animal Toxicology and/or Pharmacology

When rats were treated with alprazolam at oral doses of 3 mg, 10 mg, and 30 mg/kg day (3 to 29 times the maximum recommended human dose based on mg/m2 body surface area) for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Risks from Concomitant Use with Opioids

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when XANAX is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

Abuse, Misuse, and Addiction

Inform patients that the use of XANAX, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2), Drug Abuse and Dependence (9.2)].

Withdrawal Reactions

Inform patients that the continued use of XANAX may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of XANAX may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of XANAX may require a slow taper [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].

Effects on Driving and Operating Machinery

Advise patients not to drive a motor vehicle or operate heavy machinery while taking XANAX due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking XANAX [see Warnings and Precautions (5.3)].

Patients with Depression

Advise patients, their families, and caregivers to look for signs of suicidality or worsening depression, and to inform the patient’s healthcare provider immediately [see Warnings and Precautions (5.6)].

Concomitant Medications

Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see Drug Interactions (7)].

Pregnancy

Advise pregnant females that use of XANAX late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)]. Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XANAX during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with XANAX [see Use in Specific Populations (8.2)].

Distributed by:
Viatris Specialty LLC
Morgantown, WV 26505 U.S.A.

UPJ:XNXT:RX2

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

XANAX is supplied in the following strengths and package configurations:

XANAX Tablets

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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