Alprazolam

Alprazolam XR is indicated for the treatment of panic disorder with or without agoraphobia, in adults. Alprazolam XR is a benzodiazepine indicated for the treatment of panic disorder with or without agoraphobia, in adults. ( 1 )

Alprazolam XR Extended-Release Tablets are available as:

• 0.5 mg: white, pentagonal shaped tablets debossed with an "G" on one side and "0.5" on the other side
• 1 mg: yellow, square shaped tablets debossed with an "G" on one side and "1" on the other side
• 2 mg: blue, round shaped tablets debossed with an "G" on one side and "2" on the other side
• 3 mg: green, triangular shaped tablets debossed with an "G" on one side and "3" on the other side Extended-Release Tablets: 0.5 mg, 1 mg, 2 mg, and 3 mg ( 3 )

Alprazolam XR is contraindicated in patients:

• with known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2) ] .
• taking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.5) , Warnings and Precautions (5.5) , Drug Interactions (7.1) ] .
• Known hypersensitivity to alprazolam or other benzodiazepines. ( 4 )
• Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. ( 4 , 5.5 , 7.1 )

• Effects on Driving and Operating Machinery: Patients receiving
• alprazolam XR should be cautioned against operating machinery or driving a motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. ( 5.4 )
• Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. ( 5.6 )
• Neonatal Sedation and Withdrawal Syndrome: Alprazolam XR use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.8 , 8.1 )

5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including alprazolam 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 alprazolam 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 alprazolam 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 alprazolam 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 alprazolam 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 alprazolam 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 alprazolam XR and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam XR, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam 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 alprazolam 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 alprazolam XR, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam 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 alprazolam 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 alprazolam, 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 alprazolam 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 alprazolam 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 alprazolam 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 alprazolam 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 alprazolam 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 Alprazolam 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 alprazolam XR and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam XR [see Dosage and Administration (2.5) , Drug Interactions (7.1) ]. […]

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 (5.7) ]
• 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 XR (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 Viatris at 1-877-446-3679 (1-877-4-INFO-RX) 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 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 Alprazolam XR Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Approximately 17% of the 531 patients who received alprazolam 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 alprazolam 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 Alprazolam 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 Alprazolam XR (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 Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam 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 alprazolam XR where the incidence in patients treated with alprazolam XR was greater than the incidence in placebo-treated patients. The most commonly observed adverse reactions in panic disorder patients treated with alprazolam 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 Alprazolam-Treated Patients and Greater than Placebo-Treated Patients in 6- and 8-Week Placebo-Controlled Trials Panic Disorder Alprazolam XR (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 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 Alprazolam XR Following is a list of other adverse reaction reported by 531 patients with panic disorder treated with alprazolam 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 Alprazolam 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 alprazolam XR where the incidence in patients treated with alprazolam XR was 2 times greater than the incidence in placebo-treated patients. […]

• Use with Opioids: Increase the risk of respiratory depression. ( 7.1 )
• Use with Other CNS Depressants: Produces additive CNS depressant effects. ( 7.1 )
• Use with Digoxin: Increase the risk of digoxin toxicity. ( 7.1 )
• Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. ( 4 , 5.5 , 7.1 )
• Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. ( 7.1 )

7.1 Drugs Having Clinically Important Interactions with Alprazolam XR Table 4 includes clinically significant drug interactions with alprazolam XR [see Clinical Pharmacology (12.3) ] . Table 4: Clinically Significant Drug Interactions with Alprazolam 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 (GABA A ) 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 alprazolam 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 alprazolam 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 alprazolam 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 alprazolam 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 alprazolam XR with CYP3A inhibitors may increase the concentrations of alprazolam XR, resulting in increased risk of adverse reactions [see Clinical Pharmacology (12.3) ] . Prevention or management Avoid use and consider appropriate dose reduction when alprazolam 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 alprazolam XR dose when a patient is initiated with ritonavir and alprazolam XR concomitantly, or when ritonavir is added to a regimen where alprazolam XR is stabilized. Increase alprazolam XR dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam XR concomitantly. No dosage adjustment of alprazolam XR is necessary in patients receiving ritonavir for more than 10 to 14 days [see Dosage and Administration (2.5) ] . Concomitant use of alprazolam 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 alprazolam 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.

Lactation: Breastfeeding not recommended. ( 8.2 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam 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 alprazolam XR during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam 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 alprazolam XR.

8.4 Pediatric Use Safety and effectiveness of alprazolam XR have not been established in pediatric patients.

8.5 Geriatric Use Alprazolam 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 alprazolam 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 alprazolam XR is recommended in patients with hepatic impairment [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] .

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 (GABA A ) receptors in the brain and enhances GABA-mediated synaptic inhibition.