Alprazolam

• •
  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 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 ]

  .

  ), Drug Interactions (

  7.1 Drugs Having Clinically Important Interactions with Alprazolam

  Table 4

  includes clinically significant drug interactions with alprazolam

  [see Clinical Pharmacology ]

  .

  Table 4: Clinically Significant Drug Interactions with Alprazolam

  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 gammaaminobutyric 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 alprazolam 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, butorpenol, 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 during concomitant use with CNS depressants [see Warnings and Precautions ] .
  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 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 ].
  Prevention or management	Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications , Warnings and Precautions ].
  Examples	Ketoconazole, itraconazole, clarithromycin
  Moderate or Weak Inhibitors of CYP3A
  Clinical implication	Concomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology ].
  Prevention or management	Avoid use and consider appropriate dose reduction when alprazolam is coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions ].
  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 ] .
  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 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir.
  Prevention or management	Reduce alprazolam dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam is stabilized. Increase alprazolam dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam concomitantly. No dosage adjustment of alprazolam is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration ] . Concomitant use of alprazolam with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications , Warnings and Precautions ].
  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. Continue monitoring digoxin serum concentration and toxicity frequently . Reduce the digoxin dose if necessary.

  )].
• •
  The use of benzodiazepines, including alprazolam tablets, 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 alprazolam tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction

  [see Warnings and Precautions (

  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 ].

  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.

  )].
• •
  The continued use of benzodiazepines, including alprazolam tablets, 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 alprazolam tablets 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 alprazolam tablets or reduce the dosage

  [see Dosage and Administration (

  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 ].

  ), Warnings and Precautions (

  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 ]

  .

  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, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam 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 ]

  .

  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 ]

  .

  Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure

  [see Drug Abuse and Dependence ]

  . 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.

  )].

Alprazolam tablets are indicated for the:

• •acute treatment of generalized anxiety disorder (GAD) in adults.
• •treatment of panic disorder (PD), with or without agoraphobia in adults.

• •
  Generalized Anxiety Disorder:
  (

  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 ]

  .

  )
• ○Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily.
• ○Dosage may be increased, at intervals of every 3 to 4 days, to a maximum recommended daily dose of 4 mg, given in divided doses.
• ○Use the lowest possible effective dose and frequently assess the need for continued treatment.
• •
  Panic Disorder:
  Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. (
  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 ].
  )
• •When tapering, decrease dosage by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. (
  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 , Drug Abuse and Dependence ]

  .

  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.
  , 5.2)
• •See the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. (
  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 , Clinical Pharmacology ]

  .
  ,
  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 , Clinical Pharmacology ]

  .
  ,
  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 , Warnings and Precautions ]

  .
  )

Alprazolam tablets are available as:

• •0.25 mg: white, oval, debossed “GG 256” on one side and scored on the reverse side
• •0.5 mg: peach, oval, debossed “GG 257” on one side and scored on the reverse side
• •1 mg: blue, oval, debossed “GG 258” on one side and scored on the reverse side
• •2 mg: white, rectangular, multi-scored, debossed “GG 249” on one side and plain on the reverse side

Breastfeeding not recommended. (