ALPRAZOLAM THERAPEUTICS • For long-term symptoms of anxiety, consider switching to an SSRI or SNRI for • Xanax Brands long-term maintenance • Xanax XR • If long-term maintenance with a see index for additional brand names benzodiazepine is necessary, continue treatment for 6 months after symptoms Generic? Yes resolve, and then taper dose slowly • If symptoms reemerge, consider treatment with an SSRI or SNRI, or consider Class restarting the benzodiazepine; sometimes • Neuroscience-based Nomenclature: GABA benzodiazepines have to be used in combi­ positive allosteric modulator (GABA-PAM) nation with SSRIs or SNRIs for best results • Benzodiazepine (anxiolytic) If It Doesn’t Work Commonly Prescribed for • Consider switching to another agent or (bold for FDA approved) adding an appropriate augmenting agent • Generalized anxiety disorder (IR) • Consider psychotherapy, especially • Panic disorder (IR and XR) cognitive behavioral psychotherapy • Other anxiety disorders • Consider presence of concomitant • Anxiety associated with depression substance abuse • Premenstrual dysphoric disorder • Consider presence of alprazolam abuse • Irritable bowel syndrome and other somatic • Consider another diagnosis, such as a symptoms associated with anxiety disorders comorbid medical condition • Insomnia • Acute mania (adjunctive) Best Augmenting Combos • Acute psychosis (adjunctive) for Partial Response or • Catatonia Treatment Resistance • Benzodiazepines are frequently used as augmenting agents for antipsychotics How the Drug Works and mood stabilizers in the treatment of • Binds to benzodiazepine receptors at the psychotic and bipolar disorders GABA-A ligand-gated chloride channel complex • Benzodiazepines are frequently used as • Enhances the inhibitory effects of GABA augmenting agents for SSRIs and SNRIs in • Boosts chloride conductance through the treatment of anxiety disorders GABA-regulated channels • Not generally rational to combine with • Inhibits neuronal activity presumably in other benzodiazepines amygdala-centered fear circuits to provide • Caution if using as an anxiolytic concom­ therapeutic benefits in anxiety disorders itantly with other sedative hypnotics for sleep • Could consider augmenting alprazolam How Long Until It Works with either gabapentin or pregabalin for • Some immediate relief with first dosing is treatment of anxiety disorders common; can take several weeks with daily dosing for maximal therapeutic benefit Tests • In patients with seizure disorders, If It Works concomitant medical illness, and/or those • For short-term symptoms of anxiety – after with multiple concomitant long-term a few weeks, discontinue use or use on an medications, periodic liver tests and blood “as-needed” basis counts may be prudent • For chronic anxiety disorders, the goal of treatment is complete remission of symptoms as well as prevention of future relapses SIDE EFFECTS • For chronic anxiety disorders, treatment How Drug Causes Side Effects most often reduces or even eliminates symptoms, but not a cure since symptoms • Same mechanism for side effects as for can recur after medicine stopped therapeutic effects – namely due to excessive actions at benzodiazepine receptors 11 ALPRAZOLAM (continued) • Long-term adaptations in benzodiazepine DOSING AND USE receptors may explain the development of Usual Dosage Range dependence, tolerance, and withdrawal • Side effects are generally immediate, but • Anxiety: alprazolam IR: 1–4 mg/day immediate side effects often disappear in • Panic: alprazolam IR: 5–6 mg/day t i m e • Panic: alprazolam XR: 3–6 mg/day Notable Side Effects Dosage Forms ✽ Sedation, fatigue, depression • Alprazolam IR tablet 0.25 mg scored, ✽ Dizziness, ataxia, slurred speech, 0.4 mg (Japan), 0.5 mg scored, 0.8 mg weakness (Japan), 1 mg scored, 2 mg multiscored ✽ Forgetfulness, confusion • Alprazolam IR solution, concentrate ✽ Hyperexcitability, nervousness 1 mg/mL • Rare hallucinations, mania • Alprazolam XR (extended-release) tablet • Rare hypotension 0.5 mg, 1 mg, 2 mg, 3 mg • Hypersalivation, dry mouth How to Dose • For anxiety, alprazolam IR should be Life-Threatening or started at 0.75–1.5 mg/day divided into 3 Dangerous Side Effects doses; increase dose every 3–4 days until • Respiratory depression, especially when desired efficacy is reached; maximum dose taken with CNS depressants in overdose generally 4 mg/day • Rare hepatic dysfunction, renal • For panic, alprazolam IR should be started dysfunction, blood dyscrasias at 1.5 mg/day divided into 3 doses; increase 1 mg or less every 3–4 days until Weight Gain desired efficacy is reached, increasing by smaller amounts for dosage over 4 mg/ day; may require as much as 10 mg/day for • Reported but not expected desired efficacy in difficult cases • For panic, alprazolam XR should be Sedation started at 0.5–1 mg/day once daily in the morning; dose may be increased by 1 mg/day every 3–4 days until desired • Occurs in significant minority efficacy is reached; maximum dose • Especially at initiation of treatment or when generally 10 mg/day dose increases • Tolerance often develops over time Dosing Tips What to Do About Side Effects • Use lowest possible effective dose for • W a i t the shortest possible period of time (a • W a i t benzodiazepine-sparing strategy) • W a i t • Assess need for continued treatment • Lower the dose regularly • Switch to alprazolam XR • Risk of dependence may increase with dose • Take largest dose at bedtime to avoid and duration of treatment sedative effects during the day • For interdose symptoms of anxiety, can • Switch to another agent either increase dose or maintain same • Administer flumazenil if side effects are total daily dose but divide into more severe or life-threatening frequent doses, or give as extended-release formulation Best Augmenting Agents for Side • Can also use an as-needed occasional Effects “top-up” dose for interdose anxiety • Many side effects cannot be improved with • Because panic disorder can require an augmenting agent doses higher than 4 mg/day, the risk 12 (continued) ALPRAZOLAM of dependence may be greater in these rest; 3–7 days later, dispose of 2 mL, and patients so on). This is both a form of very slow • Some severely ill patients may require 8 biological tapering and a form of behavioral mg/day or more desensitization. Not for XR • Extended-release formulation only needs to • Be sure to differentiate reemergence be taken once or twice daily of symptoms requiring reinstitution of • Do not break or chew XR tablets as this will treatment from withdrawal symptoms alter controlled-release properties • Benzodiazepine-dependent anxiety patients • Frequency of dosing in practice is often and insulin-dependent diabetics are not greater than predicted from half-life, as addicted to their medications. When duration of biological activity is often shorter benzodiazepine-dependent patients stop than pharmacokinetic terminal half-life their medication, disease symptoms can • Alprazolam and alprazolam XR generally reemerge, disease symptoms can worsen dosed about one-tenth the dosage of (rebound), and/or withdrawal symptoms diazepam can emerge ✽ Alprazolam and alprazolam XR generally dosed about twice the dosage of Pharmacokinetics clonazepam • Metabolized by CYP450 3A4 • Inactive metabolites Overdose • Elimination half-life 12–15 hours • Fatalities have been reported both in • Food does not affect absorption monotherapy and in conjunction with alcohol; sedation, confusion, poor coordination, diminished reflexes, coma Drug Interactions Long-Term Use • Increased depressive effects when taken with other CNS depressants (see Warnings • Risk of dependence, particularly for below) treatment periods longer than 12 weeks • Inhibitors of CYP450 3A, such as and especially in patients with past or nefazodone, fluvoxamine, fluoxetine, current polysubstance abuse and even grapefruit juice, may decrease Habit Forming clearance of alprazolam and thereby raise • Alprazolam is a Schedule IV drug alprazolam plasma levels and enhance • Patients may develop dependence and/or sedative side effects; alprazolam dose may tolerance with long-term use need to be lowered • Thus, azole antifungal agents (such as How to Stop ketoconazole and itraconazole), macrolide • Seizures may rarely occur on withdrawal, antibiotics, and protease inhibitors may especially if withdrawal is abrupt; greater also raise alprazolam plasma levels risk for doses above 4 mg and in those • Inducers of CYP450 3A, such as with additional risks for seizures, including carbamazepine, may increase clearance of those with a history of seizures alprazolam and lower alprazolam plasma • Taper by 0.5 mg every 3 days to reduce levels and possibly reduce therapeutic effects chances of withdrawal effects • For difficult-to-taper cases, consider Other Warnings/ reducing dose much more slowly after Precautions reaching 3 mg/day, perhaps by as little as • Boxed warning regarding the increased 0.25 mg per week or less (not for XR) risk of CNS depressant effects when • For other patients with severe problems benzodiazepines and opioid medications are discontinuing a benzodiazepine, dosing used together, including specifically the risk may need to be tapered over many months of slowed or difficulty breathing and death (i.e., reduce dose by 1% every 3 days • If alternatives to the combined use of by crushing tablet and suspending or benzodiazepines and opioids are not dissolving in 100 mL of fruit juice and available, clinicians should limit the dosage then disposing of 1 mL and drinking