Version July 2025
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.
Dosage guidance:
Dosing: All pediatric dosing for immediate-release formulations unless otherwise specified. Titrate dose to effect; use lowest effective dose.
Anxiety:
Children ≥7 years and Adolescents <18 years: Limited data available: Oral: Initial: 0.005 to 0.02 mg/kg/dose 3 times daily; in trials, doses were rounded to nearest available tablet size (lowest available dose is 0.125 mg [1/2 of 0.25 mg tablet]). May titrate at 2- to 3-day intervals in 0.125 to 0.25 mg/dose increments up to a maximum 0.06 mg/kg/day or 4 mg/day, whichever is less (Ref).
Dosing based on 2 small open-label trials (n=13, n=17) in patients diagnosed with situational anxiety, overanxious disorder, or avoidant disorder; the reported ranges were 0.375 to 3 mg/day in one trial (Ref) and in the other trial, 0.5 to 3.5 mg/day with a mean of 1.6 mg/day was reported and based on clinical global ratings, alprazolam appeared to be better than placebo; however, this difference was not statistically significant (Ref).
Discontinuation of therapy: Abrupt discontinuation should be avoided. 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 (Ref). 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.
Pediatric-specific recommendations are not available; in adults, lower doses are suggested if advanced liver disease present.
(For additional information see "Alprazolam: Drug information")
Dosage guidance:
Safety: Reduce dose or avoid use in patients receiving opioids or with significant chronic disease (eg, respiratory compromise). Avoid use in patients with a history of substance use, misuse of medications, or depression (Ref).
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 (Ref). Use with caution in patients with posttraumatic stress disorder; benzodiazepines may cause cognitive changes (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
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 (Ref).
Immediate release: Oral: Initial: 0.5 mg every 8 hours as needed for up to 48 to 72 hours (Ref).
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 (Ref).
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 (Ref).
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) (Ref).
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) (Ref). 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 (Ref). 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 (Ref). 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 (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function:
CrCl ≥10 mL/minute: No dosage adjustment necessary (Ref).
CrCl <10 mL/minute: No dosage adjustment necessary; use with caution as enhanced pharmacodynamic effects (eg, psychomotor and memory impairment) may be observed in patients with end-stage kidney disease (Ref).
Hemodialysis, intermittent (thrice weekly): Significant removal by hemodialysis is unlikely (moderately protein bound; moderate Vd) (Ref):
No dosage adjustment necessary (Ref). Use with caution as enhanced pharmacodynamic effects (eg, psychomotor and memory impairment) may be observed (Ref).
Peritoneal dialysis: Significant removal by hemodialysis is unlikely (moderately protein bound; moderate Vd) (Ref):
Initial: Consider administering 50% to 75% of the usual indication-specific recommended dose; in one pharmacokinetic study patients on peritoneal dialysis exhibited a higher free fraction and AUC compared to patients with normal kidney function and hemodialysis patients (Ref). Additionally, enhanced pharmacodynamic effects (eg, psychomotor and memory impairment) may be observed (Ref).
CRRT: Drug clearance may be dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) and minimal residual kidney function unless otherwise noted. Close monitoring of response and adverse reactions (eg, sedation, respiratory depression) due to drug accumulation is important.
No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance may be dependent on the effluent flow rate, filter type, and method of renal replacement. Close monitoring of response and adverse reactions (eg, sedation, respiratory depression) due to drug accumulation is important.
No dosage adjustment necessary (Ref).
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
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.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Canadian labeling: Additional contraindications (not in US labeling): Myasthenia gravis; severe hepatic insufficiency; severe respiratory insufficiency; sleep apnea.
Concerns related to adverse effects:
• 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.
Concurrent drug therapy issues:
• Flumazenil: Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
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 substance use disorder: Counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and substance use disorder. 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.
• 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.
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,indigo carmine)]
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,indigo carmine)]
ALPRAZolam XR: 3 mg [contains fd&c blue #2 (indigotine,indigo carmine), 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,indigo carmine)]
Xanax XR: 3 mg [contains fd&c blue #2 (indigotine,indigo carmine), quinoline yellow (d&c yellow #10)]
Generic: 0.5 mg, 1 mg, 2 mg, 3 mg
May be product dependent
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): $12.60
1 mg (per each): $15.68
2 mg (per each): $20.81
3 mg (per each): $31.21
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): $6.73
0.5 mg (per each): $8.39
1 mg (per each): $11.19
2 mg (per each): $19.03
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Xanax: 0.25 mg [contains corn starch, sodium benzoate]
Xanax: 0.5 mg [contains corn starch, fd&c yellow #6(sunset yellow)alumin lake, sodium benzoate]
Xanax: 1 mg [contains corn starch, fd&c blue #2 (indigo carm) aluminum lake, sodium benzoate]
Xanax TS: 2 mg [contains corn starch, sodium benzoate]
Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Note: Commercial oral solution is available (Alprazolam Intensol™: 1 mg/mL [dye free, ethanol free, sugar free; contains propylene glycol])
A 1 mg/mL oral suspension may be made with tablets and one of three different vehicles (a 1:1 mixture of Ora-Sweet® and Ora-Plus®, a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®, or a 1:4 mixture of cherry syrup with Simple Syrup, NF). Crush sixty 2 mg tablets in a mortar and reduce to a fine powder. Add 40 mL of vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add a quantity of vehicle sufficient to make 120 mL. Label "shake well" and "refrigerate". Stable for 60 days.
C-IV
Oral:
Immediate-release tablet: In adults, may be administered sublingually if oral administration is not possible; absorption and onset of effect is comparable to oral administration (Ref).
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.
Oral:
IR preparations: May be administered sublingually if oral administration is not possible; absorption and onset of effect are comparable to oral administration (Ref)
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.
Immediate release tablets: Store at 20°C to 25°C (68°F to 77°F).
Extended release tablets: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Oral concentrate: Store at 20°C to 25°C (68°F to 77°F). Protect from moisture. Discard opened bottle after 90 days.
Orally disintegrating tablet: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.
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/2023/018276s059lbl.pdf#page=22
Xanax XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021434s022lbl.pdf#page=23
Immediate-release tablets and oral solution: Treatment of generalized anxiety disorder (GAD); anxiety associated with depression; short-term relief of symptoms of anxiety; treatment of panic disorder, with or without agoraphobia (All indications: FDA approved in adults).
Extended-release tablets: Treatment of panic disorder, with or without agoraphobia (FDA approved in adults).
Orally disintegrating tablets: Treatment of GAD and treatment of panic disorder, with or without agoraphobia (All indications: FDA approved in adults).
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 due to risk of abuse, misuse, physical dependence, and addiction. In addition, older adults have increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use. However, benzodiazepines 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 2023]).
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 drug interactions program by clicking on the “Launch drug interactions program” link above.
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 drug interactions program
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Aldesleukin: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
ARIPiprazole Lauroxil: May increase CNS depressant effects of Benzodiazepines. ARIPiprazole Lauroxil may increase hypotensive effects of Benzodiazepines. Specifically, the risk of orthostatic hypotension may be increased. Risk C: Monitor
ARIPiprazole: May increase CNS depressant effects of Benzodiazepines. ARIPiprazole may increase hypotensive effects of Benzodiazepines. Specifically, orthostatic hypotension may be increased. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Atazanavir: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Beta-Acetyldigoxin: Benzodiazepines may increase serum concentration of Beta-Acetyldigoxin. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects 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 increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bulevirtide: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects 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
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
CarBAMazepine: CYP3A4 Inhibitors (Weak) may increase serum concentration of CarBAMazepine. Risk C: Monitor
Certoparin: May increase serum concentration of Benzodiazepines. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects 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 increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
CloZAPine: Benzodiazepines may increase adverse/toxic effects 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 increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Corticosteroids (Orally Inhaled): Benzodiazepines may increase adverse/toxic effects of Corticosteroids (Orally Inhaled). Specifically, the risk of pneumonia may be increased. Risk C: Monitor
CycloSPORINE (Systemic): CYP3A4 Inhibitors (Weak) may increase serum concentration of CycloSPORINE (Systemic). Risk C: Monitor
CYP3A4 Inducers (Moderate): May decrease serum concentration of ALPRAZolam. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of ALPRAZolam. Risk C: Monitor
CYP3A4 Inhibitors (Moderate): May increase 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 serum concentration of ALPRAZolam. Risk X: Avoid
CYP3A4 Inhibitors (Weak): May increase serum concentration of ALPRAZolam. Risk C: Monitor
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Daridorexant: May increase CNS depressant effects 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
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dinutuximab Beta: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Dofetilide: CYP3A4 Inhibitors (Weak) may increase serum concentration of Dofetilide. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroPERidol: May increase CNS depressant effects 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
Elranatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Epcoritamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Finerenone: CYP3A4 Inhibitors (Weak) may increase serum concentration of Finerenone. Risk C: Monitor
Flibanserin: CYP3A4 Inhibitors (Weak) may increase serum concentration of Flibanserin. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects 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 serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification
Gepotidacin: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid
Givinostat: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Glofitamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects 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
Ilaprazole: May increase serum concentration of Benzodiazepines. Risk C: Monitor
Ixabepilone: CYP3A4 Inhibitors (Weak) may increase serum concentration of Ixabepilone. Risk C: Monitor
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: CYP3A4 Inhibitors (Weak) may increase 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 increase CNS depressant effects 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
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lomitapide: CYP3A4 Inhibitors (Weak) may increase 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
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melatonin: May increase sedative effects of Benzodiazepines. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methadone: Benzodiazepines may increase CNS depressant effects 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 increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects 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
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Midazolam: CYP3A4 Inhibitors (Weak) may increase serum concentration of Midazolam. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mosunetuzumab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nefazodone: May increase 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 serum concentration of NiMODipine. Risk C: Monitor
Nirmatrelvir and Ritonavir: May increase 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
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
OLANZapine: Benzodiazepines may increase adverse/toxic effects 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
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Ombitasvir, Paritaprevir, and Ritonavir: May increase serum concentration of ALPRAZolam. Risk C: Monitor
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase serum concentration of ALPRAZolam. Risk C: Monitor
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects 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
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: Benzodiazepines may increase CNS depressant effects of Oxybate Salt Products. Risk X: Avoid
OxyCODONE: CNS Depressants may increase CNS depressant effects 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
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pimozide: CYP3A4 Inhibitors (Weak) may increase serum concentration of Pimozide. Risk X: Avoid
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ritlecitinib: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Ritonavir: May increase 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 increase adverse/toxic effects 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 increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Simvastatin: CYP3A4 Inhibitors (Weak) may increase serum concentration of Simvastatin. CYP3A4 Inhibitors (Weak) may increase active metabolite exposure of Simvastatin. Risk C: Monitor
Sirolimus (Conventional): CYP3A4 Inhibitors (Weak) may increase serum concentration of Sirolimus (Conventional). Risk C: Monitor
Sirolimus (Protein Bound): CYP3A4 Inhibitors (Weak) may increase 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 serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects 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 serum concentration of Tacrolimus (Systemic). Risk C: Monitor
Talquetamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Tarlatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Teclistamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Teduglutide: May increase serum concentration of Benzodiazepines. Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Theophylline Derivatives: May decrease therapeutic effects of Benzodiazepines. Risk C: Monitor
Treosulfan: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Triazolam: CYP3A4 Inhibitors (Weak) may increase serum concentration of Triazolam. Risk C: Monitor
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Trofinetide: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Ubrogepant: CYP3A4 Inhibitors (Weak) may increase 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Xanomeline: May increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Yohimbine: May decrease therapeutic effects of Antianxiety Agents. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects 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
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. 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.
Orally-disintegrating tablets may contain phenylalanine.
Amenorrhea and galactorrhea were observed in a patient following self-medication with high doses of alprazolam (alprazolam extended release 3 mg and alprazolam 5 to 6 mg daily for several months). Following a tapered withdrawal of alprazolam, prolactin levels returned to normal, regular menstrual cycles resumed, and galactorrhea resolved (Petric 2011).
Alprazolam is not a first-line medication to treat anxiety disorders prior to conception in patients who are treatment naive or who do not have a history of effective treatment with a specific medication. Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist. Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]).
Alprazolam can be detected in seminal fluid; however, alterations of the seminal profile (eg, sperm concentration, motility) were not observed in 4 patients evaluated (Mazzilli 2021).
Alprazolam and its metabolites cross the human placenta (García-Algar 2007).
In utero exposure to benzodiazepines has the potential to cause harm to the fetus. Teratogenic effects have been observed in some studies; however, a clear association has not been reported and additional data are needed (Bellantuono 2013; Chuang 2024; Freeman 2018; Grigoriadis 2019; Tinker 2019; Wu 2024). Exposure to a benzodiazepine late in pregnancy may cause neonatal sedation (hypotonia, lethargy, and respiratory depression) and/or symptoms of neonatal withdrawal (feeding difficulties, hyperreflexia, inconsolable crying, irritability, restlessness, and tremors). Monitor newborns exposed to alprazolam in utero for adverse events. Data related to long-term effects on neurodevelopment following maternal use of benzodiazepines are inconclusive (Andrade 2024; Radojčić 2017; Sundbakk 2025; Wang 2022).
Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Anxiety disorders during pregnancy are associated with low birth weight, preterm birth, and adverse behavioral outcomes in the offspring. Discontinuing effective medications during pregnancy increases the risk of relapse. Management should be made as part of a shared decision-making process. Alprazolam use should be avoided during pregnancy due to its addictive potential and risk of acute withdrawal. The use of benzodiazepines for the treatment of perinatal anxiety should be avoided or used sparingly until preferred therapy is initiated and effective, or when preferred therapy is not effective. When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Monthly monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).
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 Psychiatric Medications (1-866-961-2388).
CNS and cardiovascular status, respiratory rate.
Short-acting benzodiazepine (Griffin 2013). 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).
Duration of action: Adults: Classified as a short-acting benzodiazepine; classification based on benzodiazepines with half-life between 1 and 12 hours (Griffin 2013).
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.
