XANAX XR- alprazolam tablet, extended release

Xanax by

Drug Labeling and Warnings

Xanax by is a Prescription medication manufactured, distributed, or labeled by Viatris Specialty LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS

    • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1), Drug Interactions (7.1)].
    • The use of benzodiazepines, including XANAX XR, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing XANAX XR and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].
    • The continued use of benzodiazepines, including XANAX XR, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of XANAX XR after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX XR or reduce the dosage [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].
  • 1 INDICATIONS AND USAGE

    XANAX XR is indicated for the treatment of panic disorder with or without agoraphobia, in adults.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage

    Administer XANAX XR orally once daily, preferably in the morning. Swallow tablets whole; do not divide, crush, or chew.

    The recommended starting oral dosage for XANAX XR is 0.5 mg to 1 mg once daily. Depending on the response, the dosage may be adjusted at intervals of every 3 to 4 days in increments of no more than 1 mg daily. The recommended dosage range is 3 mg to 6 mg once daily.

    Controlled trials of XANAX XR for the treatment of panic disorder included dosages in the range of 1 mg to 10 mg per day. Most patients showed a response in the dosage range of 3 mg to 6 mg per day. Occasional patients required as much as 10 mg per day.

    The longer term efficacy of XANAX XR has not been systematically evaluated. If XANAX XR is used for periods longer than 8 weeks, the healthcare provider should periodically reassess the usefulness of the drug for the individual patient.

    After a period of extended freedom from panic attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

    2.2 Discontinuation or Dosage Reduction of XANAX XR

    To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX XR or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].

    Reduce the dosage by no more than 0.5 mg every three days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

    In a controlled postmarketing discontinuation study of panic disorder patients which compared the 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.

    2.3 Dosage Recommendations in Geriatric Patients

    In geriatric patients, the recommended starting dosage of XANAX XR is 0.5 mg once daily. This may be gradually increased if needed and tolerated. Geriatric patients may be sensitive to the effects of benzodiazepines [see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)].

    2.4 Dosage Recommendations in Patients with Hepatic Impairment

    In patients with hepatic impairment, the recommended starting dosage of XANAX XR is 0.5 mg once daily. This may be gradually increased if needed and tolerated [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

    2.5 Dosage Modifications for Drug Interactions

    XANAX XR should be reduced to half of the recommended dosage when a patient is started on ritonavir and XANAX XR together, or when ritonavir is added to a patient treated with XANAX XR. Increase XANAX XR dosage to the target dose after 10 to 14 days of dosing ritonavir and XANAX XR together. It is not necessary to reduce XANAX XR dosage in patients who have been taking ritonavir for more than 10 to 14 days.

    XANAX XR is contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir [see Contraindications (4), Warnings and Precautions (5.5), Drug Interactions (7.1)].

    2.6 Switching Patients from XANAX Tablets to XANAX XR Tablets

    Patients who are currently being treated with divided doses of XANAX may be switched to XANAX XR at the same total daily dose taken once daily. If the clinical response after switching is inadequate, titrate the dosage as outlined above.

  • 3 DOSAGE FORMS AND STRENGTHS

    XANAX XR extended-release tablets are available as:

    • 0.5 mg: white, pentagonal shaped tablets debossed with an "X" on one side and "0.5" on the other side
    • 1 mg: yellow, square shaped tablets debossed with an "X" on one side and "1" on the other side
    • 2 mg: blue, round shaped tablets debossed with an "X" on one side and "2" on the other side
    • 3 mg: green, triangular shaped tablets debossed with an "X" on one side and "3" on the other side
  • 4 CONTRAINDICATIONS

    XANAX XR is contraindicated in patients:

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Risks from Concomitant Use with Opioids

    Concomitant use of benzodiazepines, including XANAX XR, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate.

    Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe XANAX XR concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of XANAX XR than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking XANAX XR, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

    Advise both patients and caregivers about the risks of respiratory depression and sedation when XANAX XR is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions (7.1)].

    5.2 Abuse, Misuse, and Addiction

    The use of benzodiazepines, including XANAX XR, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2)].

    Before prescribing XANAX XR and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of XANAX XR, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of XANAX XR along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

    5.3 Dependence and Withdrawal Reactions

    To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX XR or reduce the dosage (a patient-specific plan should be used to taper the dose) [see Dosage and Administration (2.3)].

    Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

    Acute Withdrawal Reactions

    The continued use of benzodiazepines, including XANAX XR, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of XANAX XR after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3)].

    Protracted Withdrawal Syndrome

    In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3)].

    Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to XANAX XR. These include a spectrum of withdrawal symptoms; the most important is seizure [see Drug Abuse and Dependence (9.3)]. Even after relatively short-term use at doses of ≤ 4 mg/day, there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients who received XANAX, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of XANAX greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.

    In a controlled clinical trial in which 63 patients were randomized to XANAX and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal.

    Interdose Symptoms

    Early morning anxiety and emergence of anxiety symptoms between doses of XANAX have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the interdosing interval.

    5.4 Effects on Driving and Operating Machinery

    Because of its CNS depressant effects, patients receiving XANAX XR should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with XANAX XR [see Drug Interactions (7.1)].

    5.5 Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A

    The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam.

    Strong CYP3A Inhibitors

    XANAX XR is contraindicated in patients receiving strong inhibitors of CYP3A such as azole antifungal agents [see Contraindications (4)]. Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively.

    Dosage adjustment is necessary when XANAX XR and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of XANAX XR [see Dosage and Administration (2.5), Drug Interactions (7.1)].

    Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction (7.1), Clinical Pharmacology (12.3)]. Use caution and consider dose reduction of XANAX XR, as appropriate, during co-administration with these drugs.

    5.6 Patients with Depression

    Benzodiazepines may worsen depression. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression.

    5.7 Mania

    Episodes of hypomania and mania have been reported in association with the use of XANAX XR in patients with depression [see Adverse Reactions (6.1)].

    5.8 Neonatal Sedation and Withdrawal Syndrome

    Use of XANAX XR 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 the neonate [see Use in Specific Populations (8.1)]. Monitor neonates exposed to XANAX XR during pregnancy or labor for signs of sedation and monitor neonates exposed to XANAX XR during pregnancy for signs of withdrawal; manage these neonates accordingly.

    5.9 Risks in Patients with Impaired Respiratory Function

    There have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue XANAX XR.

  • 6 ADVERSE REACTIONS

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

    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 information included in the section on Adverse Reactions Observed in Short-Term, Placebo-Controlled Trials with XANAX XR is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.

    Adverse Reactions Observed in Short-Term, Placebo-Controlled Trials of XANAX XR

    Adverse Reactions 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 1 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 drug-related (i.e., 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 Table 1.

    Table 1: Adverse Reactions Leading to Discontinuation in ≥1% of XANAX XR-Treated Patients and at Least Twice the Rate of Placebo-Treated Patients in Placebo-Controlled Trials
    n=number of patients

    Percentage of Patients Discontinuing Due to Adverse Reactions

    XANAX XR
    (n=531)

    Placebo
    (n=349)

    Nervous system disorders
         Sedation
         Somnolence
         Dysarthria
         Coordination abnormal
         Memory impairment

     
    7.5
    3.2
    2.1
    1.9
    1.5

     
    0.6
    0.3
    0
    0.3
    0.3

    General disorders/administration site
    conditions
         Fatigue

     

     
    1.7

     

     
    0.6

    Psychiatric disorders
         Depression

     
    2.5

     
    1.2

     

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

    Table 2 shows the incidence of adverse reactions that occurred during 6- and 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 reactions 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.

    Table 2: Adverse Reactions Occurring in ≥ 1% in XANAX-Treated Patients and Greater than Placebo-Treated Patients in 6- and 8-Week Placebo-Controlled Trials Panic Disorder

    XANAX XR
    (n=531)

    Placebo
    (n=349)

    Nervous system disorders
         Sedation
         Somnolence
         Memory impairment
         Dysarthria
         Coordination abnormal
         Mental impairment
         Ataxia
         Disturbance in attention
         Balance impaired
         Dyskinesia
         Hypoesthesia
         Hypersomnia

     
    45%
    23%
    15%
    11%
    9%
    7%
    7%
    3%
    3%
    2%
    1%
    1%

     
    23%
    6%
    7%
    3%
    1%
    6%
    3%
    1%
    1%
    1%
    <1%
    0%

    General disorders/administration site
    conditions
         Fatigue
         Lethargy

     

     
    14%
    2%

     

     
    9%
    1%

    Psychiatric disorders
         Depression
         Libido decreased
         Disorientation
         Confusion
         Depressed mood

     
    12%
    6%
    2%
    2%
    1%

     
    9%
    2%
    0%
    1%
    <1%

    Metabolism and nutrition disorders
         Appetite increased
         Anorexia

     
    7%
    2%

     
    6%
    0%

    Gastrointestinal disorders
         Constipation
         Nausea

     
    8%
    6%

     
    4%
    3%

    Investigations
         Weight increased

     
    5

     
    4

    Injury, poisoning, and procedural complications
         Road traffic accident

     
    2%

     
    0%

    Reproductive system and breast disorders
         Dysmenorrhea
         Sexual dysfunction

     
    4%
    2%

     
    3%
    1%

    Musculoskeletal and connective tissue disorder
         Arthralgia
         Myalgia
         Pain in limb

     
    2%
    2%
    1%

     
    1%
    1%
    0%

    Respiratory, thoracic, and mediastinal
    disorders
         Dyspnea

     

     
    2%

     

     
    0%

     

    Other Adverse Reactions Observed During the Premarketing Evaluation of XANAX XR

    Following is a list of other adverse reaction reported by 531 patients with panic disorder treated with XANAX XR. Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent); those occurring in less than 1/100 patients but at least 1/1000 patients (infrequent); those occurring in fewer than 1/1000 patients (rare).

    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

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

    Table 3 shows the incidence of discontinuation-emergent adverse reactions 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 2 times greater than the incidence in placebo-treated patients.

    Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of XANAX XR-Treated Patients and at Least Twice the Rate of Placebo-Treated Patients in Short-Term, Placebo-Controlled Trials

    XANAX XR
    n=422 (%)

    Placebo
    n=261(%)

    Nervous system disorders

         Tremor

         Headache

         Hypoesthesia

         Paresthesia

    28.2
    26.5
    7.8
    7.1

    10.7
    12.6
    2.3
    2.7

    Psychiatric disorders

         Insomnia

         Nervousness

         Depression

         Derealization

         Anxiety

         Depersonalization

     
    24.2
    21.8
    10.9
    8.0
    7.8
    5.7

     
    9.6
    8.8
    5.0
    3.8
    2.7
    1.9

    Gastrointestinal 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

    Musculoskeletal 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 XANAX [see Warning and Precautions (5.2), 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 post-approval use of XANAX and/or XANAX XR. 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, jaundice

    Investigations: Liver enzyme elevations

    Psychiatric disorders: Hypomania, mania

    Reproductive system and breast disorders: Gynecomastia, galactorrhea, menstruation irregular

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

  • 7 DRUG INTERACTIONS

    7.1 Drugs Having Clinically Important Interactions with XANAX XR

    Table 4 includes clinically significant drug interactions with XANAX XR [see Clinical Pharmacology (12.3)].

    Table 4: Clinically Significant Drug Interactions with XANAX XR

    Opioids

    Clinical implication

    The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid (GABAA) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

    Prevention or management

    Limit dosage and duration of concomitant use of XANAX XR and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1)].

    Examples

    Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorphanol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol.

    CNS Depressants

    Clinical implication

    The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants.

    Prevention or management

    Limit dosage and duration of XANAX XR during concomitant use with CNS depressants [see Warnings and Precautions (5.3)].

    Examples

    Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.

    Strong Inhibitors of CYP3A (except ritonavir)

    Clinical implication

    Concomitant use of XANAX XR with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology (12.3)].

    Prevention or management

    Concomitant use of XANAX XR with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)].

    Examples

    Ketoconazole, itraconazole, clarithromycin

    Moderate or Weak Inhibitors of CYP3A

    Clinical implication

    Concomitant use of XANAX XR with CYP3A inhibitors may increase the concentrations of XANAX XR, resulting in increased risk of adverse reactions [see Clinical Pharmacology (12.3)].

    Prevention or management

    Avoid use and consider appropriate dose reduction when XANAX XR is coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions (5.5)].

    Examples

    Nefazodone, fluvoxamine, cimetidine, erythromycin

    CYP3A Inducers

    Clinical implication

    Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3)].

    Prevention or management

    Caution is recommended during coadministration with alprazolam.

    Examples

    Carbamazepine, phenytoin

    Ritonavir

    Clinical implication

    Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (> 10-14 days), CYP3A4 induction offsets this inhibition.

     

    Alprazolam exposure was not meaningfully affected in the presence of ritonavir.

    Prevention or management

    Reduce XANAX XR dose when a patient is initiated with ritonavir and XANAX XR concomitantly, or when ritonavir is added to a regimen where XANAX XR is stabilized.

     

    Increase XANAX XR dosage to the target dosage after 10 to 14 days of dosing ritonavir and XANAX XR concomitantly. No dosage adjustment of XANXR XR is necessary in patients receiving ritonavir for more than 10 to 14 days [see Dosage and Administration (2.5)].

     

    Concomitant use of XANAX XR with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)].

    Digoxin

    Clinical implication

    Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age).

    Prevention or management

    In patients on digoxin therapy, measure serum digoxin concentrations before initiating XANAX XR. Continue monitoring digoxin serum concentration and toxicity frequently. Reduce the digoxin dose if necessary.

     

    7.2 Drug/Laboratory Test Interactions

    Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Exposure Registry

    There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including XANAX XR, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

    Risk Summary

    Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8), and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).

    The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

    Clinical Considerations

    Fetal/Neonatal Adverse Reactions

    Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to XANAX XR during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to XANAX XR during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8)].

    Data

    Human Data

    Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings.

    8.2 Lactation

    Risk Summary

    Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown.

    Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with XANAX XR.

    8.4 Pediatric Use

    Safety and effectiveness of XANAX XR have not been established in pediatric patients.

    8.5 Geriatric Use

    XANAX XR treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adults receiving the same doses. Therefore, dosage reduction of XANAX XR is recommended in geriatric patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

    8.6 Hepatic Impairment

    Patients with alcoholic liver disease exhibit a longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours). This may be caused by decreased clearance of alprazolam in patients with alcoholic liver disease. Dosage reduction of XANAX XR is recommended in patients with hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

  • 9 DRUG ABUSE AND DEPENDENCE

    9.1 Controlled Substance

    XANAX XR contains alprazolam, which is a Schedule IV controlled substance.

    9.2 Abuse

    XANAX XR is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

    Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].

    The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

    The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

    9.3 Dependence

    Physical Dependence

    XANAX XR may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)].

    To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX XR or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].

    Acute Withdrawal Signs and Symptoms

    Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

    Protracted Withdrawal Syndrome

    Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

    Tolerance

    Tolerance to XANAX XR may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of XANAX XR may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

  • 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 at (1-800-222-1222), or a medical toxicologist for additional overdosage management recommendations.

  • 11 DESCRIPTION

    XANAX XR contains alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.

    The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine. The molecular formula is C17H13ClN4 which corresponds to a molecular weight of 308.76.

    The structural formula is represented below:

    Alprazolam structural formula

    Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.

    Each XANAX XR extended-release tablet, for oral administration, contains 0.5 mg, 1 mg, 2 mg, or 3 mg of alprazolam. The inactive ingredients are colloidal silicon dioxide, hypromellose, lactose, and magnesium stearate. In addition, the 1 mg and 3 mg tablets contain D & C yellow No. 10 and the 2 mg and 3 mg tablets contain FD&C blue No. 2.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Alprazolam is a 1,4 benzodiazepine. Alprazolam exerts its effect for the treatment of panic disorder through binding to the benzodiazepine site of gamma aminobutyric acid-A (GABAA) receptors in the brain and enhances GABA-mediated synaptic inhibition.

    12.3 Pharmacokinetics

    The pharmacokinetics of alprazolam and two of its major active metabolites (4-hydroxyalprazolam and α-hydroxyalprazolam) are linear, and concentrations are proportional up to 10 mg XANAX XR given once daily.

    Absorption

    Following oral administration of XANAX XR in the morning, peak plasma concentration of alprazolam (Cmax) occurs in about 10 hours postdose. Compared to morning dosing, alprazolam Cmax increased by 30% and the Tmax decreased by an hour following dosing at night.

    The mean absolute bioavailability of alprazolam following administration of XANAX XR is approximately 90%, and the relative bioavailability compared to XANAX is about 100%. The bioavailability and pharmacokinetics of alprazolam following administration of XANAX XR are similar to that for XANAX, with the exception of a slower rate of absorption.

    Effect of Food

    A high-fat meal given up to 2 hours before dosing with XANAX XR 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 (t½) were not affected by eating.

    Distribution

    The apparent volume of distribution of alprazolam is similar for XANAX XR and XANAX. Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding.

    Elimination

    The mean plasma elimination half-life of alprazolam following administration of XANAX XR ranges from 10.7 to 15.8 hours in healthy adults.

    Metabolism

    Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. The plasma circulation levels of the two active metabolites after both XANAX XR and XANAX are less than 10% and 4% of the parent, 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. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. 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, indicating that the metabolism of alprazolam is not affected by absorption rate.

    Excretion

    Alprazolam and its metabolites are excreted primarily in the urine.

    Specific Populations

    Geriatric Patients

    The mean T1/2 of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects.

    Obese Patients

    The mean T1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects.

    Patients with Hepatic Impairment

    The mean T1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease.

    Racial or Ethnic Groups

    Maximal concentrations and T1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.

    Smoking

    Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.

    Drug Interaction Studies

    In Vivo Studies

    Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity.

    Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4), Warnings and Precautions (5.5), Drug Interactions (7.2)]. Other studied drugs include:

    Cimetidine: Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T1/2 by 16%.

    Fluoxetine: Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T1/2 by 17%, and decreased measured psychomotor performance.

    Oral Contraceptives: Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T1/2 by 29%.

    Carbamazepine: The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination T1/2 was shortened (from 17.1±4.9 to 7.7 ±1.7 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2)]. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 1200 mg per day); the effect at usual carbamazepine doses is unknown.

    Ritonavir: Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination T1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5)].

    Sertraline: A single dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam.

    Imipramine and Desipramine: The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of XANAX in doses up to 4 mg per day.

    Warfarin: Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.

    In Vitro Studies

    Data from in vitro studies of alprazolam suggest a possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not been determined.

  • 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/kg, 10 mg/kg, and 30 mg/kg per 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.

  • 14 CLINICAL STUDIES

    The efficacy of XANAX XR in the treatment of panic disorder in adults was established in two 6-week, flexible-dose, placebo-controlled studies in adult patients meeting DSM-III criteria for panic disorder. In these studies, patients were treated with XANAX XR in a dose range of 1 mg to 10 mg once per day. The effectiveness of XANAX XR was assessed on the basis of changes in various measures of panic attack frequency, on various measures of the Clinical Global Impression, and on the Overall Phobia Scale. In all, there were 7 primary efficacy measures in these studies, and XANAX XR was superior to placebo on all 7 outcomes in both studies. The mean dose of XANAX XR at the last treatment visit was 4.2 mg per day in the first study and 4.6 mg per day in the second.

    In addition, there were two 8-week, fixed-dose, placebo-controlled studies of XANAX XR in adult patients with panic disorder, involving fixed XANAX XR doses of 4 mg and 6 mg once per day that did not show a benefit for either dose of XANAX XR.

    Analyses of the relationship between treatment outcome and gender did not suggest any differential responsiveness on the basis of gender.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    XANAX XR is supplied in the following strengths and package configurations:

    XANAX XR Tablets

    Package
    Configuration

    Tablet
    Strength (mg)

    NDC

    Print

    Bottles of 60

    0.5 mg

    NDC: 58151-503-91

    white, pentagonal shaped tablets debossed with an "X" on one side and "0.5" on the other side

    Bottles of 60

    1 mg

    NDC: 58151-504-91

    yellow, square shaped tablets debossed with an "X" on one side and "1" on the other side

    Bottles of 60

    2 mg

    NDC: 58151-505-91

    blue, round shaped tablets debossed with an "X" on one side and "2" on the other side

    Bottles of 60

    3 mg

    NDC: 58151-506-91

    green, triangular shaped tablets debossed with an "X" on one side and "3" on the other side

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

  • 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 XR 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 XR, 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 XR may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of XANAX XR 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 XR 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 XR due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking XANAX XR [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 XR 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 XR during pregnancy [see Use in Specific Populations (8.1)].

    Lactation

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

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

    Made in Ireland

    © 2023 Viatris Inc.

    XANAX XR is a registered trademark of UPJOHN US 2 LLC, a Viatris Company.

    UPJ:XNXXRT:R1

  • Medication Guide

    XANAX XR (ZAN-aks XR)
    (alprazolam) extended-release tablets, C-IV

    What is the most important information I should know about XANAX XR?

    • XANAX XR is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens:
      • o shallow or slowed breathing
      • o breathing stops (which may lead to the heart stopping)
      • o excessive sleepiness (sedation)

        Do not drive or operate heavy machinery until you know how taking XANAX XR with opioids affects you.

    • Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines including XANAX XR which can lead to overdose and serious side effects including coma and death.
      • o Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including XANAX XR. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.
      • o You can develop an addiction even if you take XANAX XR as prescribed by your healthcare provider.
      • o Take XANAX XR exactly as your healthcare provider prescribed.
      • o Do not share your XANAX XR with other people.
      • o Keep XANAX XR in a safe place and away from children.
    • Physical dependence and withdrawal reactions. XANAX XR can cause physical dependence and withdrawal reactions.
      • o Do not suddenly stop taking XANAX XR. Stopping XANAX XR suddenly can cause serious and life-threatening side effects, including unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of the following symptoms.
      • o Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months, including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.
      • o Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.
      • o Do not take more XANAX XR than prescribed or take XANAX XR for longer than prescribed.

    What is XANAX XR?

    • XANAX XR is a prescription medicine used to treat panic disorder, with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia).
    • XANAX XR is a federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence. Keep XANAX XR in a safe place to prevent misuse and abuse. Selling or giving away XANAX XR may harm others and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.
    • It is not known if XANAX XR is safe and effective in children.
    • Elderly patients are especially susceptible to dose related adverse effects when taking XANAX XR.
    • It is not known if XANAX XR is safe and effective in the treatment of panic disorder for use longer than 8 weeks.

    Do not take XANAX XR if:

    • you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in XANAX XR. See the end of this Medication Guide for a complete list of ingredients in XANAX XR.
    • you are taking antifungal medicines including ketoconazole and itraconazole

    Before you take XANAX XR, tell your healthcare provider about all of your medical conditions, including if you:

    • have or have had depression, mood problems, or suicidal thoughts or behavior
    • have liver or kidney problems
    • have lung disease or breathing problems
    • are pregnant or plan to become pregnant.
      • o Taking XANAX XR late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).
      • o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with XANAX XR.
      • o There is a pregnancy registry for women who take XANAX XR during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with XANAX XR, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/research/pregnancyregistry/.
    • are breastfeeding or plan to breastfeed. XANAX XR passes into your breast milk.
      • o Talk to your healthcare provider about the best way to feed your baby if you take XANAX XR.
      • o Breastfeeding is not recommended during treatment with XANAX XR.

    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    Taking XANAX XR with certain other medicines can cause side effects or affect how well XANAX XR or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

    How should I take XANAX XR?

    • See “What is the most important information I should know about XANAX XR?”
    • Take XANAX XR exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much XANAX XR to take and when to take it.
    • If you take too much XANAX XR, call your healthcare provider or go to the nearest hospital emergency room right away.
    • Swallow XANAX XR tablets whole. Do not crush, chew or break XANAX XR.

    What are the possible side effects of XANAX XR?

    XANAX XR may cause serious side effects, including:

    • See “What is the most important information I should know about XANAX XR?”
    • Seizures. Stopping XANAX XR can cause seizures and seizures that will not stop (status epilepticus).
    • Mania. XANAX XR may cause an increase in activity and talking (hypomania and mania) in people who have depression.
    • XANAX XR can make you sleepy or dizzy and can slow your thinking and motor skills.
      • o Do not drive, operate heavy machinery, or do other dangerous activities until you know how XANAX XR affects you.
      • o Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking XANAX XR without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, XANAX XR may make your sleepiness or dizziness much worse.

    The most common side effects of XANAX XR include:

    • sleepiness
    • trouble saying words clearly (dysarthria)
    • problems with memory
    • problems with coordination
    • changes in sex drive (libido)
    • constipation
    • nausea

     

    These are not all the possible side effects of XANAX XR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store XANAX XR?

    • Store XANAX XR at room temperature between 68°F to 77°F (20°C to 25°C)
    • Keep XANAX XR and all medicines out of the reach of children.

    General information about the safe and effective use of XANAX XR.

    • Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
    • Do not use XANAX XR for a condition for which it was not prescribed.
    • Do not give XANAX XR to other people, even if they have the same symptoms that you have. It may harm them.
    • You can ask your pharmacist or healthcare provider for information about XANAX XR that is written for health professionals.

    What are the ingredients in XANAX XR?

    Active ingredient: alprazolam

    Inactive ingredients: lactose, magnesium stearate, colloidal silicon dioxide, and hypromellose. In addition, the 1 mg and 3 mg tablets contain D & C yellow No. 10 and the 2 mg and 3 mg tablets contain FD&C blue No. 2.

    For more information, call Viatris at 1-877-446-3679 (1-877-4-INFO-RX).

    Distributed by:

    Viatris Specialty LLC

    Morgantown, WV 26505  U.S.A.

    Made in Ireland

    © 2023 Viatris Inc.

    XANAX XR is a registered trademark of UPJOHN US 2 LLC, a Viatris Company.

    UPJ:MG:XNXXRT:R1

    This Medication Guide has been approved by the U.S. Food and Drug Administration.     Revised: 4/2023

  • PRINCIPAL DISPLAY PANEL – 0.5 mg

    ALWAYS DISPENSE WITH MEDICATION GUIDE

    NDC: 58151-503-91

    Xanax XR® CIV

    alprazolam
    extended-release tablets

    0.5 mg

    60 Tablets

    Rx only

    VIATRIS

    Store at 20°C to 25°C
    (68°F to 77°F);
    excursions permitted to
    15–30°C (59–86°F)
    [see USP Controlled Room
    Temperature].

    Dispense in tight (USP),
    child-resistant containers.

    DOSAGE AND USE
    See accompanying
    prescribing information.

    Each tablet contains
    0.5 mg alprazolam.

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

    Made in Ireland

    © 2023 Viatris Inc.

    RUPJ503D

    Carton Label 0.5 mg Xanax XR NDC: <a href=/NDC/58151-503-91>58151-503-91</a>
  • PRINCIPAL DISPLAY PANEL – 1 mg

    ALWAYS DISPENSE WITH MEDICATION GUIDE

    NDC: 58151-504-91

    Xanax XR® CIV

    alprazolam
    extended-release tablets

    1 mg

    60 Tablets

    Rx only

    VIATRIS

    Store at 20°C to 25°C
    (68°F to 77°F);
    excursions permitted to
    15–30°C (59–86°F)
    [see USP Controlled Room
    Temperature].

    Dispense in tight (USP),
    child-resistant containers.

    DOSAGE AND USE
    See accompanying
    prescribing information.

    Each tablet contains
    1 mg alprazolam.

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

    Made in Ireland

    © 2023 Viatris Inc.

    RUPJ504D

    Carton Label 1 mg Xanax XR NDC: <a href=/NDC/58151-504-91>58151-504-91</a>
  • PRINCIPAL DISPLAY PANEL – 2 mg

    ALWAYS DISPENSE WITH MEDICATION GUIDE

    NDC: 58151-505-91

    Xanax XR® CIV

    alprazolam
    extended-release tablets

    2 mg

    60 Tablets

    Rx only

    VIATRIS

    Store at 20°C to 25°C
    (68°F to 77°F);
    excursions permitted to
    15–30°C (59–86°F)
    [see USP Controlled Room
    Temperature].

    Dispense in tight (USP),
    child-resistant containers.

    DOSAGE AND USE
    See accompanying
    prescribing information.

    Each tablet contains
    2 mg alprazolam.

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

    Made in Ireland

    © 2023 Viatris Inc.

    RUPJ505D

    Carton Label 2 mg Xanax XR NDC: <a href=/NDC/58151-505-91>58151-505-91</a>
  • PRINCIPAL DISPLAY PANEL – 3 mg

    ALWAYS DISPENSE WITH MEDICATION GUIDE

    NDC: 58151-506-91

    Xanax XR® CIV

    alprazolam
    extended-release tablets

    3 mg

    60 Tablets

    Rx only

    VIATRIS

    Store at 20°C to 25°C
    (68°F to 77°F);
    excursions permitted to
    15–30°C (59–86°F)
    [see USP Controlled Room
    Temperature].

    Dispense in tight (USP),
    child-resistant containers.

    DOSAGE AND USE
    See accompanying
    prescribing information.

    Each tablet contains
    3 mg alprazolam.

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

    Made in Ireland

    © 2023 Viatris Inc.

    RUPJ506D

    Carton Label 3 mg Xanax XR NDC: <a href=/NDC/58151-506-91>58151-506-91</a>
  • INGREDIENTS AND APPEARANCE
    XANAX  XR
    alprazolam tablet, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 58151-503
    Route of AdministrationORALDEA ScheduleCIV    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM0.5 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapePENTAGON (5 SIDED) (pentagon) Size9mm
    FlavorImprint Code X;0;5
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 58151-503-9160 in 1 BOTTLE; Type 0: Not a Combination Product05/21/2024
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02143405/21/2024
    XANAX  XR
    alprazolam tablet, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 58151-504
    Route of AdministrationORALDEA ScheduleCIV    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM1 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
    Product Characteristics
    ColorYELLOWScoreno score
    ShapeSQUARESize8mm
    FlavorImprint Code X;1
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 58151-504-9160 in 1 BOTTLE; Type 0: Not a Combination Product06/20/2024
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02143406/20/2024
    XANAX  XR
    alprazolam tablet, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 58151-505
    Route of AdministrationORALDEA ScheduleCIV    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM2 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    Product Characteristics
    ColorBLUEScoreno score
    ShapeROUNDSize10mm
    FlavorImprint Code X;2
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 58151-505-9160 in 1 BOTTLE; Type 0: Not a Combination Product08/01/2024
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02143408/01/2024
    XANAX  XR
    alprazolam tablet, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 58151-506
    Route of AdministrationORALDEA ScheduleCIV    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM3 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    Product Characteristics
    ColorGREENScoreno score
    ShapeTRIANGLESize10mm
    FlavorImprint Code X;3
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 58151-506-9160 in 1 BOTTLE; Type 0: Not a Combination Product07/26/2024
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02143407/26/2024
    Labeler - Viatris Specialty LLC (117455616)

    • Trademark Results [Xanax]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    XANAX
    XANAX
    98640047 not registered Live/Pending
    Ghost Global LLC
    2024-07-09
    XANAX
    XANAX
    74527349 1911413 Live/Registered
    Kabushiki Kaisha Xanax
    1994-05-23
    XANAX
    XANAX
    74106690 1764575 Live/Registered
    Kabushiki Kaisha Xanax
    1990-10-17
    XANAX
    XANAX
    73832739 1596581 Dead/Cancelled
    KABUSHIKI KAISHA XANAX (XANAX CORPORATION)
    1989-10-20
    XANAX
    XANAX
    73832696 not registered Dead/Abandoned
    KABUSHIKI KAISHA XANAX (XANAX CORPORATION)
    1989-10-20
    XANAX
    XANAX
    73832693 1630811 Dead/Cancelled
    KABUSHIKI KAISHA XANAX (XANAX CORPORATION)
    1989-10-20
    XANAX
    XANAX
    73560909 not registered Dead/Abandoned
    NANIWA CORPORATION (NANIWA KABUSHIKI KAISHA)
    1985-09-30
    XANAX
    XANAX
    73172914 1137561 Live/Registered
    UPJOHN COMPANY, THE
    1978-06-02
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