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.
The use of benzodiazepines, including alprazolam, 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 and throughout treatment, assess each patient's risk for abuse, misuse, and addiction.
The continued use of benzodiazepines, including alprazolam, 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 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 or reduce the dosage.
Note: Reduce dose or avoid use in patients receiving opioids, with significant chronic disease (eg, respiratory compromise), or at increased risk for accumulation (eg, advanced cirrhosis). Use is contraindicated in severe respiratory disease or severe hepatic impairment. Avoid use in patients with a history of substance use, misuse of medications, or depression (Craske 2022).
Anxiety:
Anxiety disorders (adjunctive therapy or monotherapy) (alternative agent):
Note: Generally used short term for symptom relief until preferred therapy (eg, serotonin reuptake inhibitor) is effective (eg, 4 to 6 weeks, followed by tapering). Long-term, low-dose therapy (eg, 2 mg/day) may be considered in select patients when other treatments are ineffective or poorly tolerated (Craske 2022; Katzman 2014; WFSBP [Bandelow 2012]). Use with caution in patients with posttraumatic stress disorder; benzodiazepines may worsen symptoms (VA/DoD 2017).
Immediate release: Oral: Initial: 0.25 mg 3 to 4 times daily; may increase dose based on response and tolerability in increments ≤1 mg/day at intervals ≥3 days up to a usual dose of 2 to 6 mg/day in 3 to 4 divided doses. Some patients may require up to 8 mg/day for optimal response; manufacturer's labeling maximum: 10 mg/day. With doses >4 mg/day, increase more gradually to minimize adverse effects; periodically reassess and consider dosage reduction (APA [Stein 2009]; WFSBP [Bandelow 2012]; manufacturer's labeling).
Extended release (panic disorder labeled use): Oral: Initial: 0.5 to 1 mg once daily; may increase dose based on response and tolerability in increments ≤1 mg/day at intervals ≥3 days up to a usual dose of 2 to 6 mg/day. Some patients may require up to 8 mg/day for optimal response; manufacturer's labeling maximum: 10 mg/day. With doses >4 mg/day, increase more gradually to minimize adverse effects; periodically reassess and consider dosage reduction. Administration in 2 divided doses may be considered to maximize efficacy (APA [Stein 2009]; WFSBP [Bandelow 2012]; manufacturer's labeling).
Procedural anxiety (premedication) (off-label use):
Immediate release: Oral, Sublingual: 0.5 mg 30 to 90 minutes before procedure; if needed due to incomplete response and/or duration of procedure, may repeat the dose (usually at 50% of the initial dose) after 30 to 60 minutes (Choy 2020; De Witte 2002; Shavakhi 2014).
Vertigo, acute episodes (alternative agent) (off-label use):
Note: Reserve use for symptomatic relief of episodes lasting several hours to days (maximum duration: 3 days); chronic use may impede adaptation and recovery (Furman 2022).
Immediate release: Oral: Initial: 0.5 mg every 8 hours as needed for up to 48 to 72 hours (Furman 2022).
Dosing conversions: Immediate release to extended release: ER tablet may be substituted for the IR tablet on a mg-per-mg basis, administering the ER tablet once daily. Administration of the ER formulation in 2 divided doses may be considered to maximize efficacy (APA [Stein 2009]).
Discontinuation of therapy: Unless safety concerns require a more rapid withdrawal, gradually taper to detect reemerging symptoms and minimize rebound and withdrawal symptoms in patients receiving therapy ≥4 weeks or as appropriate based on patient-specific factors (Lader 2011; VA/DoD 2021).
Low or moderate dose, no concerns for benzodiazepine use disorder : Taper total daily dose by 20% to 25% every week based on response and tolerability (taper increments will be limited by available dosage forms) (Craske 2022; VA/DoD 2021).
Extended or high-dose therapy, or suspected benzodiazepine use disorder: Taper total daily dose by approximately 25% every 1 to 2 weeks based on response, tolerability, and individual patient factors (taper increments will be limited by available dosage forms) (Park 2022; VA/DoD 2021). Reduce dose more rapidly in the beginning and slow the dose reduction as the taper progresses because earlier stages of withdrawal are easier to tolerate (Lader 2011; VA/DoD 2021). The optimal duration and taper increment will vary; up to 6 months may be necessary for some patients on higher doses, and a taper rate of 50% every week may be tolerated in some patients (Park 2022; VA/DoD 2021). For benzodiazepines with half-lives significantly <24 hours, including alprazolam, consider substituting an equivalent dose of a long-acting benzodiazepine to allow for a more gradual reduction in drug serum concentrations (Lader 2011; VA/DoD 2021).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; use caution.
Advanced liver disease:
IR tablet, oral concentrate, orally disintegrating tablet: 0.25 mg 2 to 3 times daily.
Extended release: 0.5 mg once daily
(For additional information see "Alprazolam: Pediatric drug information")
Note: Titrate dose to effect; use lowest effective dose. The usefulness of this medication should be periodically reassessed.
Anxiety:
Children ≥7 years and Adolescents <18 years: Limited data available: Oral: Immediate release: Initial: 0.005 to 0.02 mg/kg/dose 3 times daily (Gal 2007); dosing based on a trial in patients 7 to 16 years of age (n=13), initial doses of 0.005 mg/kg or 0.125 mg/dose were given 3 times/day for situational anxiety and increments of 0.125 to 0.25 mg/dose were used to increase doses to maximum of 0.02 mg/kg/dose or 0.06 mg/kg/day; a range of 0.375 to 3 mg/day was needed (Pfefferbaum 1987). Another study in 17 children (8 to 17 years of age) with overanxious disorder or avoidant disorders used initial daily doses of 0.25 mg for children <40 kg and 0.5 mg for those >40 kg. The dose was titrated at 2-day intervals to a maximum of 0.04 mg/kg/day. Required doses ranged from 0.5 to 3.5 mg/day with a mean of 1.6 mg/day. Based on clinical global ratings, alprazolam appeared to be better than placebo; however, this difference was not statistically significant (Simeon 1992).
Adolescents ≥18 years: Oral: Immediate release: Initial: 0.25 to 0.5 mg 3 times daily; titrate dose upward as needed every 3 to 4 days; usual maximum daily dose: 4 mg/day. Patients requiring doses >4 mg/day should be increased cautiously. Periodic reassessment and consideration of dosage reduction is recommended.
Panic disorder: Adolescents ≥18 years: Oral:
Immediate release: Initial: 0.5 mg 3 times daily; titrate dose upward as needed every 3 to 4 days in increments ≤1 mg/day; mean dose used in controlled trials: 5 to 6 mg/day; maximum daily dose: 10 mg/day (rarely required).
Extended release: Initial: 0.5 to 1 mg once daily; titrate dose upward as needed every 3 to 4 days in increments ≤1 mg/day; usual dose: 3 to 6 mg/day; maximum daily dose: 10 mg/day (rarely required).
Switching from immediate release to extended release: Administer the same total daily dose, but give once daily; if effect is not adequate, titrate dose as above.
Premenstrual dysphoric disorder: Limited data available: Adolescents: Oral: Initial dose: 0.25 mg 3 times daily; titrate as needed. Usual daily dose: 1.25 to 2.25 mg/day (Kliegman 2011).
Discontinuation of therapy: Abrupt discontinuation should be avoided. Daily dose must be gradually decreased no more frequently than every 3 days; however, some patients may require a slower reduction. If withdrawal symptoms occur, resume previous dose and discontinue on a less rapid schedule.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
Immediate release: Oral: Use lower initial doses of 0.25 mg 2 to 3 times daily and titrate slowly; refer to adult dosing.
Extended release: Oral: Use lower initial doses of 0.5 mg once daily and titrate slowly; refer to adult dosing.
Dosing conversions: Refer to adult dosing.
Discontinuation of therapy: Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Concentrate, Oral:
ALPRAZolam Intensol: 1 mg/mL (30 mL) [unflavored flavor]
Tablet, Oral:
Xanax: 0.25 mg [scored]
Xanax: 0.5 mg [scored; contains fd&c yellow #6 (sunset yellow)]
Xanax: 1 mg [scored; contains fd&c blue #2 (indigotine)]
Xanax: 2 mg [scored]
Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Tablet Disintegrating, Oral:
Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Tablet Extended Release 24 Hour, Oral:
ALPRAZolam XR: 0.5 mg
ALPRAZolam XR: 1 mg [contains quinoline yellow (d&c yellow #10)]
ALPRAZolam XR: 2 mg [contains fd&c blue #2 (indigotine)]
ALPRAZolam XR: 3 mg [contains fd&c blue #2 (indigotine), quinoline yellow (d&c yellow #10)]
Xanax XR: 0.5 mg
Xanax XR: 1 mg [contains quinoline yellow (d&c yellow #10)]
Xanax XR: 2 mg [contains fd&c blue #2 (indigotine)]
Xanax XR: 3 mg [contains fd&c blue #2 (indigotine), quinoline yellow (d&c yellow #10)]
Generic: 0.5 mg, 1 mg, 2 mg, 3 mg
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Xanax: 0.25 mg
Xanax: 0.5 mg [contains corn starch, docusate sodium/sodium benzoate, fd&c yellow #5 (tartrazine)aluminum lake, fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]
Xanax: 1 mg [contains corn starch, docusate sodium/sodium benzoate, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigo carm) aluminum lake]
Xanax TS: 2 mg
Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg
C-IV
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Xanax: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018276s058lbl.pdf#page=27
Xanax XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021434s021lbl.pdf#page=26
Oral:
IR preparations: May be administered sublingually if oral administration is not possible; absorption and onset of effect are comparable to oral administration (Scavone 1987; Scavone 1992)
ER tablet: Should be taken once daily in the morning; do not crush, break, or chew.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Switch to IR formulation.
Oral concentrate: Use only the provided calibrated dropper to withdraw the prescribed dose. Mix the dose with ≥30 mL of juice or other liquid or semi-solid foods (eg, applesauce, pudding). The prepared mixture should be administered immediately.
Orally disintegrating tablets: Using dry hands, place tablet on top of tongue and allow to disintegrate. Administration with water is not necessary.
Oral:
Immediate-release tablet: Adults: May be administered sublingually if oral administration is not possible; absorption and onset of effect is comparable to oral administration (Scavone 1987; Scavone 1992)
Extended-release tablet: Administer once daily, preferably in the morning; do not crush, chew, or break; swallow whole
Oral concentrate: Use only the provided calibrated dropper to withdraw the prescribed dose. Mix the dose with ≥30 mL of juice or other liquid or semi-solid foods (eg, applesauce, pudding). The prepared mixture should be administered immediately.
Orally-disintegrating tablet: Do not remove tablets from bottle until right before dose; using dry hands, place tablet on top of tongue. If using one-half of tablet, immediately discard remaining half (half tablet may not remain stable). Administration with water is not necessary.
Anxiety disorders: Treatment of generalized anxiety disorder, short-term anxiety, and anxiety associated with depression (IR tablet, oral concentrate, orally disintegrating tablets); treatment of panic disorder with or without agoraphobia (IR tablet, ER tablet, oral concentrate, orally disintegrating tablets).
Vertigo, acute episodes
ALPRAZolam may be confused with alprostadil, clonazePAM, LORazepam, triazolam
Xanax may be confused with Fanapt, Lanoxin, Tenex, Tylox, Xopenex, Zantac, ZyrTEC
Beers Criteria: Alprazolam is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use. However, use may be appropriate in the elderly when used for seizure disorders, rapid eye movement sleep behavior disorder, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2019]).
Anterograde amnesia: Benzodiazepines can impair explicit memory and produce short-term anterograde amnesia (ie, memory of information or events after drug administration). Retrograde amnesia (ie, events or information prior to drug administration) is unaffected. However, the magnitude of the amnesic effect from benzodiazepines differs among the various agents, depending on their pharmacokinetic/pharmacodynamic properties, route of administration, and dose. Anterograde amnesia is associated with higher doses, IV administration, and benzodiazepines with faster absorption and higher potency (Ref).
Mechanism: Dose-related. Benzodiazepines, including alprazolam, bind to the gamma-aminobutyric acid (GABA)-A receptor, subsequently increasing the frequency of chloride channel opening and producing GABA’s inhibitory effect throughout the CNS. The GABA-A receptor complex is composed of 5 subunits, each with multiple isoforms. Each receptor complex contains a benzodiazepine-binding site, which is classified into several types, based on the alpha subunit isoforms and clinical effects related to each type. The BZ1 receptor type, containing the alfa 1 subunit isoform, is highly concentrated in the cortex, thalamus, and cerebellum, and is responsible for benzodiazepine-associated anterograde amnesia (Ref).
Onset: Rapid; during chronic benzodiazepine administration, tolerance appears to develop, and memory impairment is limited to a window of 90 minutes following each dose (Ref).
Risk factors:
• Specific benzodiazepine: Benzodiazepines, such as alprazolam, with a high affinity for the benzodiazepine-receptor site, are associated with a higher propensity for amnesic effects (Ref)
• Higher doses (Ref)
CNS effects: Alprazolam can cause drowsiness, fatigue, decreased alertness, and confusion. In addition, alprazolam has been shown to cause ataxia and psychomotor impairment. Tolerance usually develops to its sedative and psychomotor effects (Ref). Benzodiazepines, in general, are associated with an increased risk of motor vehicle accidents and falls (particularly in older adults) (Ref).
Mechanism: Dose-related (Ref); benzodiazepines, including alprazolam, bind to the gamma-aminobutyric acid (GABA)-A receptor, subsequently increasing the frequency of chloride channel opening and producing GABA’s inhibitory effect throughout the CNS. Benzodiazepine-associated sedation are mediated by the alpha 1-containing GABA-A receptors (Ref).
Onset: Sedation (mean onset): 40 minutes following a single 1 mg oral dose of immediate release alprazolam (Ref).
Risk factors:
Sedating effects:
• Older adults (benzodiazepines in general) (Ref). Note: Conflicting data exists for alprazolam specifically (Ref)
• Higher doses (Ref)
• Titrating the initial dose too rapidly (gradual titration and dividing the dosing frequently, if using the immediate release formulation, is preferred) (Ref)
• Immediate release formulation is associated with a higher risk for sedation compared to extended release (due to lower absorption rate of the extended release resulting in peak plasma concentrations that are half those of immediate release) (Ref)
• Concomitant use of other CNS depressants (Ref)
Paradoxical reactions, sometimes referred to as disinhibitory reactions or behavioral disinhibition, have been reported in children, adults, and older adults with benzodiazepine use, particularly in those with risk factors. Reactions are relatively uncommon and have been characterized in a number of ways, including increased talkativeness, excitement, restlessness, hyperactivity, sleep disturbances, hostility, rage, agitation, and/or aggressive behavior (Ref). In children, paradoxical reactions to benzodiazepines, particularly midazolam, have been most commonly described as agitation, restlessness, inconsolable crying, screaming, disorientation, and/or excitement (Ref). Of note, alprazolam has been frequently associated with behavioral aggression in adults (Ref).
Mechanism: Dose-related (potentially, although may also be idiosyncratic); exact mechanism is unclear due to limited evidence (Ref). One hypothesis has suggested that increased GABAergic activity in the brain from benzodiazepines causes a decrease in the restraining influence of the frontal cortex, thereby causing excitement, hostility, and rage. An additional proposed mechanism is that benzodiazepines can reduce serotonergic neurotransmission, subsequently causing aggressive behavior. Another mechanism is that in select patients with genetic variations in GABA-A receptors, there is decreased GABA transmission with benzodiazepines which results in neuronal overexcitation manifested clinically as a paradoxical reaction (Ref).
Risk factors:
Benzodiazepines in general:
Age-related (extremes of age):
• Children (Ref)
• Older adults (Ref)
Disease- or condition-related:
• Past history of aggressive behavior or violence (Ref)
• Alcoholism or history of alcohol use (Ref) or social use of alcohol (on risk of aggressive behavior with alprazolam, specifically) (Ref)
• Psychiatric or personality disorders, including affective disorder (Ref)
• Dementia (Ref).
Patient-related:
• Genetic predisposition (potential risk factor) (ie, variability in the density of the GABA-benzodiazepine receptors throughout the brain, a persistence of a juvenile pattern of benzodiazepine response in adulthood, or multiple allelic forms of the receptors with varying affinities for benzodiazepines have all been suggested as potentially playing a role) (Ref)
Other potential risk factors: Note: No established risk factors since evidence is limited (Ref)
• Higher doses (likely a risk, but not firmly established) (Ref)
• Parenteral benzodiazepine administration (potential risk) (Ref).
• Specific benzodiazepines (potential risk): Benzodiazepines with a higher potency (eg, alprazolam, clonazepam) and/or a short half-life (eg, alprazolam) are believed to carry an increased risk; however, it has also been suggested that there is no difference in risk among the various benzodiazepines (Ref)
Withdrawal syndrome: Therapeutic use of benzodiazepines, including alprazolam, is associated with a withdrawal syndrome in children and adults, particularly following abrupt or overly rapid discontinuation following regular use. Benzodiazepine-associated withdrawal symptoms can include new withdrawal symptoms or rebound symptoms, both of which are typically transient, short-lasting, and reversible. A persistent post-withdrawal disorder, which can be long-lasting, severe, and potentially irreversible, has also been described. In general, withdrawal symptoms are typically mild and characterized as anxiety, panic attacks, restlessness, insomnia and other sleep disturbances, irritability, poor concentration, confusion, nausea/vomiting, weight loss, tremor, diaphoresis, tachycardia, and muscle pain/stiffness. Severe symptoms such as seizure and psychosis may also rarely occur following abrupt discontinuation. Severe withdrawal may be fatal. Data are limited on persistent post-withdrawal disorders, but cognitive impairment; depression; anxiety; sensory disturbances (eg, tinnitus, paresthesia, skin sensations); motor disturbances (eg, muscle pain, weakness, spasms); and GI disturbances have been described (Ref). For alprazolam specifically, there are also rare case reports of new-onset withdrawal catatonia occurring after abrupt withdrawal of chronic therapy (Ref). Severity, onset, and duration of any benzodiazepine withdrawal syndrome varies based on several factors, such as specific benzodiazepine administered (and its half-life), dose, and duration of use. However, in general, new withdrawal symptoms typically resolve within 2 to 4 weeks and rebound symptoms may last 3 weeks, but persistent post-withdrawal symptoms may last >6 weeks and take 6 to 12 months to completely resolve, and in some cases, persist for years (Ref).
Mechanism: Withdrawal; exact mechanisms are complex and unclear, but chronic exposure to benzodiazepines alters GABAergic neurotransmission (up/down regulation of gamma-aminobutyric acid [GABA]-A receptor subunits) and rapid or abrupt withdrawal results in underactivity of inhibitory GABA functions subsequently increasing excitatory nervous activity and likely contributing to symptoms associated with withdrawal (Ref). A role of glutamate receptors, including N-methyl-D aspartate (NMDA)-, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-receptors, and metabotropic glutamate (mGlu) receptors, has also been suggested. In mice and rat studies, antagonists for glutamate receptors have shown the ability to potently suppress the withdrawal signs caused by chronic benzodiazepine administration (Ref).
Onset: Varied; onset of symptoms usually occurs within the first day following abrupt withdrawal of short- acting or intermediate-acting benzodiazepines (such as alprazolam and lorazepam, respectively). Long-acting benzodiazepines (eg, diazepam, flurazepam) are usually associated with an initial onset of withdrawal symptoms 5 days following abrupt discontinuation (Ref). Alprazolam may produce physical dependence after durations of only a few weeks and in doses as small as 0.75 to 1 mg/day (Ref). In general, persistent post-withdrawal disorder associated with psychotropic medications (eg, benzodiazepines) have an onset ranging from 24 hours to 6 weeks following a decrease, discontinuation, or switch (Ref).
Risk factors:
Benzodiazepines in general:
• Abrupt discontinuation (rather than gradual dosage reduction) of a benzodiazepine used long-term (Ref)
• Higher doses (Ref)
• Chronic dosing (ie, intermittent dosing may reduce the risk of withdrawal symptoms) (Ref)
• Long treatment durations (Ref)
• Withdrawal-associated seizure: Predisposed patients (eg, brain damage, alcohol abuse, history of seizure, or those taking medications that lower the seizure threshold) (Ref)
Alprazolam specifically:
• History of substance use disorder, including alcohol use disorder (Ref)
• Specific benzodiazepine: High-potency benzodiazepines with short and intermediate half-lives generally have a higher risk for rebound, withdrawal reactions, and dependence compared to long-acting agents. Alprazolam is a high potency benzodiazepine with a short half-life and may produce more dependency and withdrawal than many other benzodiazepines. Benzodiazepines with a relatively longer half-life (usually reported at >24 hours in adults), such as clonazepam, are usually associated with fewer (and potentially less severe) rebound and withdrawal symptoms, particularly if tapered appropriately (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults. [IR = Immediate release, ER = Extended release]
>10%:
Dermatologic: Skin rash (IR: 11%; ER: <1%)
Endocrine & metabolic: Decreased libido (6% to 14%), weight gain (IR: 27%; ER: 5%), weight loss (IR: 23%)
Gastrointestinal: Constipation (IR: 26%; ER: 8%), decreased appetite (IR: 28%), increased appetite (IR: 33%; ER: 7%), xerostomia (IR: 15%)
Genitourinary: Difficulty in micturition (IR: 12%; ER: ≥1%)
Nervous system: Ataxia (IR: 40%; ER: 7% to 9%) (table 1), cognitive dysfunction (IR: 29%; ER: Bradyphrenia: <1%), depression (ER: 12%; depressed mood: 1%), dizziness (IR: 2% to 21%; ER: ≥1%), drowsiness (IR: 41% to 77%; ER: 23%) (table 2), dysarthria (IR: 23%; ER: 11%), fatigue (IR: 49%; ER: 14%) (table 3), irritability (IR: 33%; ER: ≥1%), memory impairment (IR: 33%; ER: 15%), sedated state (ER: 45%)
|
Drug (Alprazolam) |
Placebo |
Dosage Form |
Indication |
Number of Patients (Alprazolam) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|---|
|
40% |
18% |
Immediate-release tablets |
Panic disorder |
1,388 |
1,231 |
Described as "impaired coordination" |
|
9% |
1% |
Extended-release tablets |
Panic disorder |
531 |
349 |
Described as "coordination abnormal" |
|
7% |
3% |
Extended-release tablets |
Panic disorder |
531 |
349 |
N/A |
|
Drug (Alprazolam) |
Placebo |
Dosage Form |
Indication |
Number of Patients (Alprazolam) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
41% |
22% |
Immediate-release tablets |
Generalized anxiety |
565 |
505 |
|
77% |
43% |
Immediate-release tablets |
Panic disorder |
1,388 |
1,231 |
|
23% |
6% |
Extended-release tablets |
Panic disorder |
531 |
349 |
|
Drug (Alprazolam) |
Placebo |
Dosage Form |
Indication |
Number of Patients (Alprazolam) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
49% |
42% |
Immediate-release tablets |
Panic disorder |
1,388 |
1,231 |
|
14% |
9% |
Extended-release tablets |
Panic disorder |
531 |
349 |
1% to 10%:
Cardiovascular: Chest pain (ER: ≥1%), hypotension (IR: 5%; ER: <1%), palpitations (ER: ≥1%)
Dermatologic: Allergic skin reaction (IR: ≤4%), dermatitis (IR: ≤4%), diaphoresis (ER: ≥1%)
Endocrine & metabolic: Change in libido (IR: 7%), increased libido (IR: 8%; ER: ≥1%), menstrual disease (IR: 10%)
Gastrointestinal: Abdominal pain (ER: ≥1%), anorexia (ER: 2%), diarrhea (ER: ≥1%), dyspepsia (ER: ≥1%), nausea (ER: 6%), sialorrhea (IR: 4% to 6%; ER: ≥1%), vomiting (ER: ≥1%)
Genitourinary: Dysmenorrhea (ER: 4%), sexual disorder (IR: 7%; ER: 2%), urinary incontinence (≤2%)
Nervous system: Agitation (ER: ≥1%), akathisia (IR: 2%), asthenia (ER: ≥1%), balance impairment (ER: 3%), confusion (IR: 10%; ER: 2%) (table 4), decreased mental acuity (ER: 7%), depersonalization (ER: ≥1%), derealization (≥1%), disinhibition (IR: 3%), disorientation (ER: 2%), disturbance in attention (ER: 3%), feeling hot (≤1%), headache (ER: ≥1%), hypersomnia (ER: 1%), hypoesthesia (ER: 1%), insomnia (ER: ≥1%), lethargy (ER: 2%), malaise (ER: ≥1%), nervousness (ER: ≥1%), nightmares (ER: ≥1%), restlessness (ER: ≥1%), talkativeness (≤2%), tremor (ER: ≥1%), vertigo (ER: ≥1%)
|
Drug (Alprazolam) |
Placebo |
Dosage Form |
Indication |
Number of Patients (Alprazolam) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
10% |
8% |
Immediate-release tablets |
Panic disorder |
1,388 |
1,231 |
|
2% |
1% |
Extended-release tablets |
Panic disorder |
531 |
349 |
Neuromuscular & skeletal: Arthralgia (ER: 2%), back pain (ER: ≥1%), dyskinesia (ER: 2%), limb pain (ER: 1%), muscle cramps (ER: ≥1%), muscle twitching (ER: ≥1%), myalgia (ER: 2%)
Ophthalmic: Blurred vision (ER: ≥1%)
Respiratory: Dyspnea (ER: 2%), hyperventilation (ER: ≥1%), nasal congestion (ER: ≥1%)
<1%:
Cardiovascular: Chest tightness (ER), edema (ER), sinus tachycardia (ER), syncope (ER)
Dermatologic: Cold and clammy skin (ER), urticaria (ER)
Endocrine & metabolic: Increased thirst (ER)
Gastrointestinal: Dysgeusia (IR), dysphagia (ER)
Genitourinary: Urinary frequency (ER)
Hepatic: Increased serum bilirubin (IR)
Nervous system: Abnormal dreams (ER), aggressive behavior (ER), amnesia (ER), apathy (ER), choking sensation (ER), clumsiness (ER), emotional lability (ER), euphoria (ER), falling (ER), hallucination, hangover effect (ER), homicidal ideation (ER), hypomania, hypotonia (ER), impaired consciousness (ER), impulse control disorder (ER), increased energy (ER), intoxicated feeling (ER), jitteriness (ER), mania, outbursts of anger (ER), paraplegia (ER), psychomotor impairment (ER), relaxation (ER), rigors (ER), seizure, sensation of cold (ER), sleep talking (ER), stupor (ER), suicidal ideation (ER), voice disorder (ER)
Ophthalmic: Diplopia (IR), mydriasis (ER), photophobia (ER)
Otic: Otalgia (ER), tinnitus (ER)
Respiratory: Epistaxis (ER), rhinorrhea (ER), sleep apnea (ER)
Miscellaneous: Fever (ER)
Frequency not defined: Nervous system: Paresthesia
Postmarketing:
Cardiovascular: Peripheral edema
Dermatologic: Skin photosensitivity (Kanwar 1990), Stevens-Johnson syndrome
Endocrine & metabolic: Amenorrhea (Petrić 2011; Shioiri 1996), galactorrhea not associated with childbirth (Petrić 2011; Shioiri 1996), gynecomastia, hyperprolactinemia (Shioiri 1996)
Hepatic: Hepatic failure, hepatitis (Judd 1986), increased liver enzymes (Judd 1986), jaundice (Judd 1986)
Hypersensitivity: Angioedema
Nervous system: Anterograde amnesia (Curran 1994), drug abuse (Juergens 1988; Sheehan 1991), drug dependence (Juergens 1988), hostility (Rapaport 1985), withdrawal syndrome (including catatonia, rebound anxiety, and status epilepticus) (Mellman 1986; Oldham 2016; Vicente Ferreira Naves 2018)
Miscellaneous: Paradoxical reaction (including muscle spasticity, paradoxical central nervous system stimulation, and sleep disturbance) (Kirkpatrick 2016)
Hypersensitivity to alprazolam, any component of the formulation, or other benzodiazepines (cross-sensitivity with other benzodiazepines may exist); concurrent therapy with strong cytochrome P-450 3A (CYP3A) inhibitors (eg, itraconazole, ketoconazole), except ritonavir; acute narrow angle glaucoma.
Canadian labeling: Additional contraindications (not in US labeling): Myasthenia gravis; severe hepatic insufficiency; severe respiratory insufficiency; sleep apnea.
Concerns related to adverse effects:
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines; risk may be increased in adolescent/pediatric patients, geriatric patients, or patients with a history of alcohol use disorder or psychiatric/personality disorders (Mancuso 2004).
• Sleep-related activities: Hazardous sleep-related activities such as sleep-driving, cooking and eating food, and making phone calls while asleep have been noted with benzodiazepines (Dolder 2008).
Disease-related concerns:
• Depression: Avoid use in patients with depression because of concerns about worsening mood symptoms, particularly if suicidal risk may be present, except for acute or emergency situations (eg, acute agitation, status epilepticus) (Craske 2022).
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment or predisposition to urate nephropathy; has weak uricosuric properties.
• Respiratory disease: Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression.
Special populations:
• Debilitated patients: Use with caution in debilitated patients; use lower starting dose.
• Older adult patients: Older adults may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in elderly dementia patients (Jennum 2015; Saarelainen 2018).
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury (Nelson 1999).
• Obese patients: Use with caution in obese patients; may have prolonged action when discontinued.
• Smokers: Cigarette smoking may decrease alprazolam concentrations up to 50%.
Other warnings/precautions:
• Abuse, misuse, and addiction: Counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and addiction. Institute early treatment or refer patients in whom substance use disorder is suspected. Limit dosages and durations to the minimum required.
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties.
• Breakthrough anxiety: At the end of dosing interval, breakthrough anxiety may occur.
• Dependence and withdrawal reactions: Some patients may develop a protracted withdrawal syndrome lasting >12 months; may be difficult to differentiate withdrawal symptoms from reemergence or continuation of symptoms for which benzodiazepines were prescribed. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
• Tolerance: Alprazolam has a short half-life for a benzodiazepine and the duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance does not develop to the anxiolytic effects (Vinkers 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
CarBAMazepine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CycloSPORINE (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of ALPRAZolam. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of ALPRAZolam. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of ALPRAZolam. Management: Consider alternatives to this combination when possible. If combined, consider an alprazolam dose reduction and monitor for increased alprazolam effects and toxicities (eg, sedation, lethargy). Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of ALPRAZolam. Risk X: Avoid combination
CYP3A4 Inhibitors (Weak): May increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Delavirdine: May increase the serum concentration of ALPRAZolam. Risk X: Avoid combination
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Finerenone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Finerenone. Risk C: Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Ixabepilone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ixabepilone. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Risk D: Consider therapy modification
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Risk D: Consider therapy modification
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: Monitor therapy
Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Midazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Midazolam. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Nefazodone: May increase the serum concentration of ALPRAZolam. Management: Consider alternatives to this combination when possible. If combined, consider an alprazolam dose reduction and monitor for increased alprazolam effects and toxicities (eg, sedation, lethargy). Risk D: Consider therapy modification
NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Risk C: Monitor therapy
Nirmatrelvir and Ritonavir: May increase the serum concentration of ALPRAZolam. Management: Reduce the alprazolam dose by 50% when a patient is started on nirmatrelvir/ritonavir and alprazolam together, or when nirmatrelvir/ritonavir is initiated in a patient already treated with alprazolam. Risk D: Consider therapy modification
OLANZapine: Benzodiazepines may enhance the adverse/toxic effect of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of ALPRAZolam. Risk C: Monitor therapy
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Pacritinib: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ritonavir: May increase the serum concentration of ALPRAZolam. Specifically, this occurs with ritonavir initiation/short-term use. Management: Reduce alprazolam dose by 50% when ritonavir and alprazolam are initiated together, or when ritonavir is initiated in a patient already treated with alprazolam. No alprazolam dose reduction required in patients taking ritonavir for more than 10 to 14 days Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Simvastatin: CYP3A4 Inhibitors (Weak) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Weak) may increase the serum concentration of Simvastatin. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Sirolimus (Protein Bound). Management: Reduce the dose of protein bound sirolimus to 56 mg/m2 when used concomitantly with a weak CYP3A4 inhibitor. Risk D: Consider therapy modification
Spironolactone: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Tacrolimus (Systemic): CYP3A4 Inhibitors (Weak) may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy
Treosulfan: May increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Risk D: Consider therapy modification
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
The Cmax of the extended release formulation is increased by 25% when a high-fat meal is given 2 hours before dosing. Tmax is decreased 33% when food is given immediately prior to dose and increased by 33% when food is given ≥1 hour after dose. Management: Administer without regard to food.
Amenorrhea and galactorrhea were observed in a patient following self-medication with high doses of alprazolam. Following a tapered withdrawal of alprazolam, prolactin levels returned to normal, regular menstrual cycles resumed, and galactorrhea resolved (Petric 2011).
Alprazolam and its metabolites cross the human placenta (García-Algar 2007).
Benzodiazepines have the potential to cause harm to the fetus. Teratogenic effects have been observed with some benzodiazepines; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) has been reported with some benzodiazepines (Bergman 1992; Iqbal 2002; Shyken 2019; Tinker 2019; Wikner 2007). Newborns exposed to alprazolam in utero should be monitored for feeding problems, respiratory depression, sedation, and withdrawal.
When treating pregnant patients with panic disorder, psychosocial interventions should be considered prior to pharmacotherapy (APA [Stein 2009]). If a benzodiazepine is needed in pregnancy, agents other than alprazolam are preferred (Larsen 2015).
Data collection to monitor pregnancy and infant outcomes following exposure to alprazolam is ongoing. Health care providers are encouraged to enroll patients exposed to alprazolam during pregnancy in the National Pregnancy Registry for Other Psychiatric Medications (866-961-2388).
Alprazolam is present in breast milk.
Following administration of a single oral dose of alprazolam 0.5 mg to eight postpartum females, peak breast milk concentrations of alprazolam occurred at ~1 hour and the half-life was ~14 hours; metabolites were not detected (Oo 1995).
Case reports have noted drowsiness (Ito 1993) or CNS depression (Kelly 2012) in infants exposed to alprazolam while breastfeeding. Symptoms of withdrawal were described in an infant following alprazolam exposure in utero and via breast milk (Anderson 1989).
Breastfeeding is not recommended by the manufacturer. If a benzodiazepine is needed in breastfeeding patients, use of shorter acting agents is preferred (Larsen 2015; WHO 2002).
Orally-disintegrating tablets may contain phenylalanine.
Respiratory and cardiovascular status; assess risk for abuse, misuse, and addiction.
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors.
Absorption: Readily absorbed; Extended release: Slower relative to immediate release formulation resulting in a concentration that is maintained 5 to 11 hours after dosing; rate increased following night time dosing (versus morning dosing)
Distribution: Immediate release: Vd: 0.84 to 1.42 L/kg (Greenblatt 1993)
Protein binding: 80%; primarily to albumin
Metabolism: Hepatic via CYP3A4; forms two active metabolites (4-hydroxyalprazolam and α-hydroxyalprazolam [about half as active as alprazolam]) and an inactive metabolite benzophenone metabolite, however, the active metabolites are unlikely to contribute to much of the pharmacologic effects because of their low concentrations and lesser potencies.
Bioavailability: Immediate release: 84% to 92% (Greenblatt 1993); Extended release: 90%
Half-life elimination:
Adults: 11.2 hours (Immediate release range: 6.3 to 26.9 hours; Extended release range: 10.7 to 15.8 hours); Orally-disintegrating tablet: Mean: 12.5 hours (range: 7.9 to 19.2 hours)
Alcoholic liver disease: 19.7 hours (range: 5.8 to 65.3 hours)
Obesity: 21.8 hours (range: 9.9 to 40.4 hours)
Elderly: 16.3 hours (range: 9 to 26.9 hours)
Time to peak, serum:
Immediate release: 1 to 2 hours
Extended release: Adolescents and Adults: ~9 hours, relatively steady from 4 to 12 hours (Glue 2006); decreased by 1 hour when administered at bedtime (as compared to morning administration); decreased by 33% when administered with a high-fat meal; increased by 33% when administered ≥1 hour after a high-fat meal
Orally-disintegrating tablet: 1.5 to 2 hours; occurs ~15 minutes earlier when administered with water; increased to ~4 hours when administered with a high-fat meal
Excretion: Urine (as unchanged drug and metabolites)
Race/ethnicity: Maximal concentrations and half-life are approximately 15% and 25% higher in Asians.
Cigarette smoking: Concentrations may be reduced by up to 50% in smokers.
Concentrate (ALPRAZolam Intensol Oral)
1 mg/mL (per mL): $3.66
Tablet, 24-hour (ALPRAZolam ER Oral)
0.5 mg (per each): $2.15 - $2.26
1 mg (per each): $2.67 - $2.81
2 mg (per each): $3.55 - $3.73
3 mg (per each): $5.32 - $5.59
Tablet, 24-hour (Xanax XR Oral)
0.5 mg (per each): $11.21
1 mg (per each): $13.95
2 mg (per each): $18.52
3 mg (per each): $27.78
Tablet, orally-disintegrating (ALPRAZolam Oral)
0.25 mg (per each): $1.52 - $2.18
0.5 mg (per each): $1.89 - $2.72
1 mg (per each): $2.52 - $3.63
2 mg (per each): $4.29 - $6.17
Tablets (ALPRAZolam Oral)
0.25 mg (per each): $0.60 - $0.70
0.5 mg (per each): $0.76 - $0.93
1 mg (per each): $0.96 - $1.16
2 mg (per each): $1.69 - $1.96
Tablets (Xanax Oral)
0.25 mg (per each): $5.82
0.5 mg (per each): $7.25
1 mg (per each): $9.67
2 mg (per each): $16.45
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
