2.1 Dosage in Generalized Anxiety Disorder

The recommended starting oral dosage of alprazolam for the acute treatment of patients with GAD is 0.25 mg to 0.5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every 3 to 4 days. The maximum recommended dosage is 4 mg daily (in divided doses).

Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5.2)].

2.2 Dosage in Panic Disorder

The recommended starting oral dosage of alprazolam for the treatment of PD is 0.5 mg three times daily. Depending on the response, the dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day.

Controlled trials of alprazolam in the treatment of panic disorder included dosages in the range of 1 mg to 10 mg daily. The mean dosage was approximately 5 mg to 6 mg daily. Occasional patients required as much as 10 mg per day.

For patients receiving doses greater than 4 mg per day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg per day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit.

The necessary duration of treatment for PD in patients responding to alprazolam is unknown. 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 (2.3)].

2.3 Discontinuation or Dosage Reduction of Alprazolam

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Alprazolam 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)].

Reduced the dosage by no more than 0.5 mg every 3 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.

2.4 Dosage Recommendations in Geriatric Patients

In geriatric patients, the recommended starting oral dosage of Alprazolam is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. Geriatric patients may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dosage, the dosage may be reduced [see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)].

2.5 Dosage Recommendations in Patients with Hepatic Impairment

In patients with hepatic impairment, the recommended starting oral dosage of Alprazolam is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. If adverse reactions occur at the recommended starting dose, the dosage may be reduced [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.6 Dosage Modifications for Drug Interactions

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

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

5.1 Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including alprazolam, 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 alprazolam 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 alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam, 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 alprazolam 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 alprazolam, 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 Alprazolam and throughout treatment, assess each patient's risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Alprazolam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Alprazolam 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 Alprazolam 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 Alprazolam 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 Alprazolam [see Drug Interactions (7.1)].

5.5 Neonatal Sedation and Withdrawal Syndrome

Use of Alprazolam during later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Observe newborns for signs of sedation and neonatal withdrawal syndrome and manage accordingly [see Use in Specific Populations (8.1)].

5.6 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.

5.7 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.

5.8 Mania

Episodes of hypomania and mania have been reported in association with the use of Alprazolam in patients with depression [see Adverse Reactions (6.2)].

5.9 Risk 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 alprazolam.

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:

•

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

•

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

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.

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 alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.

6.2 Postmarketing Experience

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

7.1 Drugs Having Clinically Important Interactions with Alprazolam

Table 4 includes clinically significant drug interactions with alprazolam [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 alprazolam have not been established in pediatric patients.

8.5 Geriatric Use

Alprazolam-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of alprazolam is recommended in geriatric patients [see Dosage and Administration (2.4) 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 alprazolam is recommended in patients with hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

9.1 Controlled Substance

Alprazolam contains alprazolam, which is a Schedule IV controlled substance.

9.2 Abuse

Alprazolam 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

Alprazolam 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 Alprazolam or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].

10.1 Clinical Experience

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

10.2 Management of Overdose

In case of an overdosage, consult a Certified Poison Control Center at 1-800-222-1222 for latest recommendations.

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

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

12.1 Mechanism of Action

Alprazolam is a 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and 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

Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3.0 mg.

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, 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.

14.1 Generalized Anxiety Disorder

Aplrazolam 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. Alprazolam 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 Alprazolam 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 alprazolam was 5 mg to 6 mg per day in 2 of the studies, and the doses of alprazolam were fixed at 2 mg and 6 mg per day in the third study. In all 3 studies, alprazolam 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, alprazolam 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 alprazolam during short-term treatment in 1 of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

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

Risks from Concomitant Use with Opioids

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam 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 alprazolam, 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 alprazolam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam 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 alprazolam 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 alprazolam due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking alprazolam [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

Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Advise mothers using alprazolam to monitor neonates for signs of sedation, respiratory depression, withdrawal symptoms, and feeding problems. Instruct patients to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with alprazolam [see Warnings and Precautions (5.4). Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed during treatment with alprazolam [see Use in Specific Populations (8.2)].