What are the indications, dosing, side effects, contraindications, and precautions for Alprax (alprazolam)?

Alprax (Alprazolam): Uses and Side Effects

Primary Indications

Alprazolam is FDA-approved for the treatment of anxiety disorders and short-term relief of anxiety symptoms, including anxiety associated with depression. 1 The drug is also highly effective for panic disorder with or without agoraphobia, where it demonstrates comparable efficacy to antidepressants but with more rapid onset of action. 2, 3

Dosing for Anxiety Disorders

• Start with 0.25–0.5 mg three times daily, titrating gradually to a maximum of 4 mg/day divided into multiple doses. 1
• Most patients achieve therapeutic benefit at 0.5–4 mg/day, with steady-state plasma concentrations changing by approximately 10–12 mcg/L for each 1 mg/day dosage adjustment. 4

Dosing for Panic Disorder

• Begin with 0.5 mg three times daily, increasing by no more than 1 mg every 3–4 days as tolerated. 1
• Effective doses typically range from 2–6 mg/day, though many patients respond adequately to 2 mg/day without requiring higher doses. 3
• Optimal panic suppression occurs at steady-state plasma concentrations of 20–40 mcg/L, though higher concentrations may be needed for complete panic attack suppression. 4

Special Population Dosing

• For elderly or medically fragile patients, initiate therapy at 0.25 mg two or three times daily and titrate more gradually due to substantially increased risk of cognitive decline, falls, delirium, fractures, and motor vehicle accidents. 5
• Elderly patients exhibit a mean half-life of 16.3 hours (range 9.0–26.9 hours) compared to 11.0 hours in younger adults, necessitating dose reduction. 1
• The American Geriatrics Society explicitly recommends avoiding alprazolam in older adults whenever possible due to increased sensitivity and substantial safety risks. 5

Common Side Effects

Central Nervous System Effects (Most Frequent)

• Drowsiness occurs in 41% of patients (vs. 21.6% with placebo), making it the most common adverse effect. 1
• Light-headedness affects 20.8% of patients (vs. 19.3% placebo). 1
• Headache occurs in 12.9% (vs. 19.6% placebo), and confusion in 9.9% (vs. 10.0% placebo). 1
• Depression is reported in 13.9% of patients (vs. 18.1% placebo). 1

Panic Disorder-Specific Side Effects (Higher Doses)

• Drowsiness increases to 76.8% in panic disorder patients receiving higher doses (vs. 42.7% placebo). 1
• Fatigue and tiredness occur in 48.6% (vs. 42.3% placebo). 1
• Impaired coordination affects 40.1% of patients (vs. 17.9% placebo), representing a clinically significant safety concern. 1
• Memory impairment occurs in 33.1% (vs. 22.1% placebo). 1
• Cognitive disorder is reported in 28.8% (vs. 20.5% placebo). 1

Gastrointestinal Effects

• Dry mouth occurs in 14.7% of patients (vs. 13.3% placebo). 1
• Constipation affects 10.4% (vs. 11.4% placebo), and nausea/vomiting 9.6% (vs. 12.8% placebo). 1

Cardiovascular Effects

• Tachycardia or palpitations occur in 7.7% of patients (vs. 15.6% placebo). 1
• Hypotension is reported in 4.7% (vs. 2.2% placebo). 1

Additional Documented Adverse Effects

• Less common but clinically important effects include dystonia, irritability, concentration difficulties, transient amnesia, loss of coordination, seizures (upon abrupt discontinuation), slurred speech, musculoskeletal weakness, diplopia, changes in libido, menstrual irregularities, and urinary retention. 1

Absolute Contraindications

• Known hypersensitivity to alprazolam or other benzodiazepines. 1
• Acute narrow-angle glaucoma (open-angle glaucoma is acceptable with appropriate therapy). 1
• Concurrent use with ketoconazole or itraconazole, which increase alprazolam AUC by 3.98-fold and 2.70-fold respectively through CYP3A4 inhibition. 1

Critical Drug Interactions

Strong CYP3A4 Inhibitors (Contraindicated or Requiring Dose Reduction)

• Reduce alprazolam dose by 50% when coadministered with nefazodone (1.98-fold AUC increase) or fluvoxamine (1.96-fold increase). 6, 5
• Erythromycin increases alprazolam AUC by 1.61-fold. 1
• Cimetidine, fluoxetine, and propoxyphene significantly impair alprazolam clearance. 4

CYP3A4 Inducers

• Carbamazepine increases alprazolam oral clearance from 0.90 to 2.13 mL/min/kg and shortens elimination half-life from 17.1 to 7.7 hours, potentially requiring dose adjustment. 1

Concurrent CNS Depressants

• Avoid prescribing opioids and benzodiazepines simultaneously due to increased risk of respiratory depression and death. 5, 7
• If both medications are necessary, reduce benzodiazepines first during any tapering due to higher withdrawal risks. 5, 7
• Exercise caution with concurrent antipsychotics; fatalities have been reported with high-dose olanzapine and benzodiazepine combinations. 5

Pharmacokinetics

• Peak plasma concentrations of 12–22 mcg/L occur 0.7–1.8 hours after a single 1 mg oral dose. 4
• Absolute bioavailability averages 80–100%. 4
• Elimination half-life ranges from 9–16 hours in healthy adults, extending to 16.3 hours (range 9.0–26.9 hours) in elderly patients. 1, 4
• Volume of distribution is 0.8–1.3 L/kg, with 80% protein binding. 1, 4
• Alprazolam is extensively metabolized by CYP3A4 to 4-hydroxyalprazolam and α-hydroxyalprazolam, both of which have minimal pharmacological activity (<4% of parent drug concentrations). 1

Special Population Pharmacokinetics

• In patients with alcoholic liver disease, half-life ranges from 5.8–65.3 hours (mean 19.7 hours) compared to 6.3–26.9 hours in healthy subjects. 1
• In obese patients, half-life ranges from 9.9–40.4 hours (mean 21.8 hours) versus 6.3–15.8 hours in non-obese individuals. 1
• Maximal concentrations and half-life are approximately 15% and 25% higher in Asian populations compared to Caucasians. 1
• Cigarette smoking reduces alprazolam concentrations by up to 50%. 1

Critical Safety Warnings

Dependence and Withdrawal

• Alprazolam should never be used as monotherapy for long-term anxiety treatment due to high dependence risk; approximately 50% of patients prescribed benzodiazepines continuously for 12 months develop dependence. 5
• Do not prescribe PRN (as-needed) for chronic use, as this increases risk of dependence and misuse. 5
• Discontinuation must be gradual—reduce by no more than 0.5 mg every 3 days, though many patients require slower reductions of 0.25 mg every 1–2 weeks, particularly those on treatment for months. 5
• Abrupt discontinuation can cause seizures and death; alprazolam withdrawal is particularly difficult and associated with serious rebound and withdrawal symptoms. 5, 2

Monitoring Requirements

• Monitor for excessive sedation, dizziness, confusion, and respiratory depression at every clinical encounter. 5
• Screen for emerging depression, anxiety, and substance use disorders during treatment. 5
• Assess for cognitive impairment, falls, and functional decline, especially in elderly patients. 5

Safer Alternatives

• Buspirone 5 mg twice daily (titrating to 15–30 mg/day) offers anxiolytic effects without sedation, cognitive decline, fall risk, or dependence potential, though therapeutic effects require 2–4 weeks. 5
• SSRIs (particularly sertraline 25–200 mg/day or citalopram 10–40 mg/day) are first-line for chronic anxiety management. 6
• Cognitive-behavioral therapy (CBT) provides superior long-term outcomes without medication-related risks. 6, 5