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.

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.

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.

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.

6.1 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.

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

7.1 Drugs Having Clinically Important Interactions with XANAX XR

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

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.

8.1 Pregnancy

8.2 Lactation

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)].

9.1 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

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.