1 INDICATIONS AND USAGE Alprazolam extended-release tablets are indicated for the treatment of panic disorder with or without agoraphobia, in adults.

Alprazolam extended-release tablets are a benzodiazepine indicated for the treatment of panic disorder with or without agoraphobia, in adults.

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2.1 Recommended Dosage Administer alprazolam extended-release tablets orally once daily, preferably in the morning.

Swallow tablets whole; do not divide, crush, or chew.

The recommended starting oral dosage for alprazolam extended-release tablets 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 alprazolam extended-release tablets 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 alprazolam extended-release tablets has not been systematically evaluated.

If alprazolam extended-release tablets 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 Alprazolam Extended-Release Tablets To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam extended-release tablets 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 alprazolam extended-release tablets 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 alprazolam extended-release tablets 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 Alprazolam extended-release tablets should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam extended-release tablets together, or when ritonavir is added to a patient treated with alprazolam extended-release tablets.

Increase alprazolam extended-release tablets dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam extended-release tablets together.

It is not necessary to reduce alprazolam extended-release tablets dosage in patients who have been taking ritonavir for more than 10 to 14 days.

Alprazolam extended-release tablets are 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 Alprazolam Tablets to Alprazolam Extended-Release Tablets Patients who are currently being treated with divided doses of alprazolam tablets may be switched to alprazolam extended-release tablets at the same total daily dose taken once daily.

If the clinical response after switching is inadequate, titrate the dosage as outlined above.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risks from Concomitant Use with Opioids [see Warnings and Precautions ( 5.1 )] Abuse, Misuse, and Addiction [see Warnings and Precautions ( 5.2 )] Dependence and Withdrawal Reactions [see Warnings and Precautions ( 5.3 )] Effects on Driving and Operating Machinery [see Warnings and Precautions ( 5.4 )] Patients with Depression [see Warnings and Precautions ( 5.6 )] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions ( 5.8 )] Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions ( 5.9 )] The most common adverse reactions in panic disorder patients treated with alprazolam extended-release tablets (incidence of ≥5% and at least twice that of placebo) include: somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased, constipation, and nausea.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 alprazolam extended-release tablets 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 Alprazolam Extended-Release Tablets Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Approximately 17% of the 531 patients who received alprazolam extended-release tablets 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 alprazolam extended-release tablets at a rate at least twice that of placebo) are shown in Table 1.

Table 1: Adverse Reactions Leading to Discontinuation in ≥1% of Alprazolam Extended-Release Tablets-treated Patients and at least twice the Rate of Placebo-treated Patients in Placebo-Controlled Trials Percentage of Patients Discontinuing Due to Adverse Reactions Alprazolam Extended-Release Tablets (n=531) Placebo (n=349) Nervous system disorders Sedation 7.5 0.6 Somnolence 3.2 0.3 Dysarthria 2.1 0 Coordination abnormal 1.9 0.3 Memory impairment 1.5 0.3 General disorders/administration site conditions Fatigue 1.7 0.6 Psychiatric disorders Depression 2.5 1.2 n=number of patients Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release Tablets 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 alprazolam extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was greater than the incidence in placebo-treated patients.

The most commonly observed adverse reactions in panic disorder patients treated with alprazolam extended-release tablets (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 Alprazolam Extended-Release Tablets-treated Patients and Greater than Placebo-treated Patients in 6- and 8-week Placebo-Controlled Trials Panic Disorder Alprazolam Extended-Release Tablets (n=531) Placebo (n=349) Nervous system disorders Sedation 45% 23% Somnolence 23% 6% Memory impairment 15% 7% Dysarthria 11% 3% Coordination abnormal 9% 1% Mental impairment 7% 6% Ataxia 7% 3% Disturbance in attention 3% 1% Balance impaired 3% 1% Dyskinesia 2% 1% Hypoesthesia 1% <1% Hypersomnia 1% 0% General disorders/administration site conditions Fatigue 14% 9% Lethargy 2% 1% Psychiatric disorders Depression 12% 9% Libido decreased 6% 2% Disorientation 2% 0% Confusion 2% 1% Depressed mood 1% <1% Metabolism and nutrition disorders Appetite increased 7% 6% Anorexia 2% 0% Gastrointestinal disorders Constipation 8% 4% Nausea 6% 3% Investigations Weight increased 5% 4% Injury, poisoning, and procedural complications Road traffic accident 2% 0% Reproductive system and breast disorders Dysmenorrhea 4% 3% Sexual dysfunction 2% 1% Musculoskeletal and connective tissue disorder Arthralgia 2% 1% Myalgia 2% 1% Pain in limb 1% 0% Respiratory, thoracic, and mediastinal disorders Dyspnea 2% 0% Other Adverse Reactions Observed During the Premarketing Evaluation of Alprazolam Extended-Release Tablets Following is a list of other adverse reaction reported by 531 patients with panic disorder treated with alprazolam extended-release tablets.

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 l/l00 patients (frequent); those occurring in less than l/100 patients but at least l/1,000 patients (infrequent); those occurring in fewer than l/1,000 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; Infrequen t: 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 Alprazolam Extended-Release Tablets 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 alprazolam extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was 2 times greater than the incidence in placebo-treated patients.

Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of Alprazolam Extended-Release Tablets-treated Patients and at least twice the Rate of Placebo-treated Patients in Short-Term, Placebo-Controlled Trials Alprazolam Extended-Release Tablets n=422 (%) Placebo n=261 (%) Nervous system disorders Tremor 28.2 10.7 Headache 26.5 12.6 Hypoesthesia 7.8 2.3 Paresthesia 7.1 2.7 Psychiatric disorders Insomnia 24.2 9.6 Nervousness 21.8 8.8 Depression 10.9 5.0 Derealization 8.0 3.8 Anxiety 7.8 2.7 Depersonalization 5.7 1.9 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 alprazolam [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 alprazolam tablets and/or alprazolam extended-release tablets.

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
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 alprazolam extended-release tablets 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 Alprazolam Extended-Release Tablets Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Approximately 17% of the 531 patients who received alprazolam extended-release tablets 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 alprazolam extended-release tablets at a rate at least twice that of placebo) are shown in Table 1.

Table 1: Adverse Reactions Leading to Discontinuation in ≥1% of Alprazolam Extended-Release Tablets-treated Patients and at least twice the Rate of Placebo-treated Patients in Placebo-Controlled Trials Percentage of Patients Discontinuing Due to Adverse Reactions Alprazolam Extended-Release Tablets (n=531) Placebo (n=349) Nervous system disorders Sedation 7.5 0.6 Somnolence 3.2 0.3 Dysarthria 2.1 0 Coordination abnormal 1.9 0.3 Memory impairment 1.5 0.3 General disorders/administration site conditions Fatigue 1.7 0.6 Psychiatric disorders Depression 2.5 1.2 n=number of patients Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release Tablets 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 alprazolam extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was greater than the incidence in placebo-treated patients.

The most commonly observed adverse reactions in panic disorder patients treated with alprazolam extended-release tablets (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 Alprazolam Extended-Release Tablets-treated Patients and Greater than Placebo-treated Patients in 6- and 8-week Placebo-Controlled Trials Panic Disorder Alprazolam Extended-Release Tablets (n=531) Placebo (n=349) Nervous system disorders Sedation 45% 23% Somnolence 23% 6% Memory impairment 15% 7% Dysarthria 11% 3% Coordination abnormal 9% 1% Mental impairment 7% 6% Ataxia 7% 3% Disturbance in attention 3% 1% Balance impaired 3% 1% Dyskinesia 2% 1% Hypoesthesia 1% <1% Hypersomnia 1% 0% General disorders/administration site conditions Fatigue 14% 9% Lethargy 2% 1% Psychiatric disorders Depression 12% 9% Libido decreased 6% 2% Disorientation 2% 0% Confusion 2% 1% Depressed mood 1% <1% Metabolism and nutrition disorders Appetite increased 7% 6% Anorexia 2% 0% Gastrointestinal disorders Constipation 8% 4% Nausea 6% 3% Investigations Weight increased 5% 4% Injury, poisoning, and procedural complications Road traffic accident 2% 0% Reproductive system and breast disorders Dysmenorrhea 4% 3% Sexual dysfunction 2% 1% Musculoskeletal and connective tissue disorder Arthralgia 2% 1% Myalgia 2% 1% Pain in limb 1% 0% Respiratory, thoracic, and mediastinal disorders Dyspnea 2% 0% Other Adverse Reactions Observed During the Premarketing Evaluation of Alprazolam Extended-Release Tablets Following is a list of other adverse reaction reported by 531 patients with panic disorder treated with alprazolam extended-release tablets.

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 l/l00 patients (frequent); those occurring in less than l/100 patients but at least l/1,000 patients (infrequent); those occurring in fewer than l/1,000 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; Infrequen t: 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 Alprazolam Extended-Release Tablets 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 alprazolam extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was 2 times greater than the incidence in placebo-treated patients.

Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of Alprazolam Extended-Release Tablets-treated Patients and at least twice the Rate of Placebo-treated Patients in Short-Term, Placebo-Controlled Trials Alprazolam Extended-Release Tablets n=422 (%) Placebo n=261 (%) Nervous system disorders Tremor 28.2 10.7 Headache 26.5 12.6 Hypoesthesia 7.8 2.3 Paresthesia 7.1 2.7 Psychiatric disorders Insomnia 24.2 9.6 Nervousness 21.8 8.8 Depression 10.9 5.0 Derealization 8.0 3.8 Anxiety 7.8 2.7 Depersonalization 5.7 1.9 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 alprazolam [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 alprazolam tablets and/or alprazolam extended-release tablets.

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