Dosing Tips

• Use lowest possible effective dose for the shortest possible period of time (a benzodiazepine-sparing strategy)

• Assess need for continued treatment regularly

• Risk of dependence may increase with dose and duration of treatment

• For interdose symptoms of anxiety, can either increase dose or maintain same total daily dose but divide into more frequent doses, or give as extended-release formulation

• Can also use an as-needed occasional “top up” dose for interdose anxiety

• Because panic disorder can require doses higher than 4 mg/day, the risk of dependence may be greater in these patients

• Some severely ill patients may require 8 mg/day or more

• Extended release formulation only needs to be taken once or twice daily

• Do not break or chew XR tablets as this will alter controlled release properties

• Frequency of dosing in practice is often greater than predicted from half-life, as duration of biological activity is often shorter than pharmacokinetic terminal half-life

• Alprazolam and alprazolam XR generally dosed about one tenth the dosage of diazepam

✽ Alprazolam and alprazolam XR generally dosed about twice the dosage of clonazepam

Overdose

• Fatalities have been reported both in monotherapy and in conjunction with alcohol; sedation, confusion, poor coordination, diminished reflexes, coma

Long-Term Use

• Risk of dependence, particularly for treatment periods longer than 12 weeks and especially in patients with past or current polysubstance abuse

Habit Forming

• Alprazolam is a Schedule IV drug

• Patients may develop dependence and/or tolerance with long-term use

How to Stop

• Seizures may rarely occur on withdrawal, especially if withdrawal is abrupt; greater risk for doses above 4 mg and in those with additional risks for seizures, including those with a history of seizures

• Taper by 0.5 mg every 3 days to reduce chances of withdrawal effects

• For difficult to taper cases, consider reducing dose much more slowly after reaching 3 mg/day, perhaps by as little as 0.25 mg per week or less (not for XR)

• For other patients with severe problems discontinuing a benzodiazepine, dosing may need to be tapered over many months (i.e., reduce dose by 1% every 3 days by crushing tablet and suspending or dissolving in 100 mL of fruit juice and then disposing of 1 mL while drinking the rest; 3–7 days later, dispose of 2 mL, and so on). This is both a form of very slow biological tapering and a form of behavioral desensitization. Not for XR

• Be sure to differentiate reemergence of symptoms requiring reinstitution of treatment from withdrawal symptoms

• Benzodiazepine-dependent anxiety patients and insulin-dependent diabetics are not addicted to their medications. When benzodiazepine-dependent patients stop their medication, disease symptoms can reemerge, disease symptoms can worsen (rebound), and/or withdrawal symptoms can emerge

Pharmacokinetics

• Metabolized by CYP450 3A4

• Inactive metabolites

• Elimination half-life 12–15 hours

Drug Interactions

• Increased depressive effects when taken with other CNS depressants

• Inhibitors of CYP450 3A, such as nefazodone, fluvoxamine, fluoxetine, and even grapefruit juice, may decrease clearance of alprazolam and thereby raise alprazolam plasma levels and enhance sedative side effects; alprazolam dose may need to be lowered

• Thus, azole antifungal agents (such as ketoconazole and itraconazole), macrolide antibiotics, and protease inhibitors may also raise alprazolam plasma levels

• Inducers of CYP450 3A, such as carbamazepine, may increase clearance of alprazolam and lower alprazolam plasma levels and possibly reduce therapeutic effects