Alprazolam.Pdf

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

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• 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

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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 the and duration of each drug to the minimum

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possible while still achieving therapeutic efficacy • Patients and their caregivers should Children and Adolescents be warned to seek medical attention • Safety and efficacy not established if unusual dizziness, lightheadedness, but often used, especially short-term sedation, slowed or difficulty breathing, or and at the lower end of the dosing unresponsiveness occur scale • Dosage changes should be made in • Long-term effects of alprazolam in collaboration with prescriber children/adolescents are unknown • Use with caution in patients with • Should generally receive lower doses and pulmonary disease; rare reports of death be more closely monitored after initiation of benzodiazepines in patients with severe pulmonary impairment • History of drug or alcohol abuse often creates greater risk for dependency Pregnancy • Hypomania and mania have occurred in • Effective June 30, 2015, the US FDA depressed patients taking alprazolam requires changes to the content and • Use only with extreme caution if patient has format of pregnancy and lactation obstructive sleep apnea information in prescription drug • Some depressed patients may experience a labels, including the elimination of the worsening of suicidal ideation pregnancy letter categories; the • Some patients may exhibit abnormal Pregnancy and Lactation Labeling Rule thinking or behavioral changes similar to (PLLR or final rule) applies only to those caused by other CNS depressants prescription drugs and will be phased in (i.e., either depressant actions or gradually for drugs approved on or after disinhibiting actions) June 30, 2001 Do Not Use • Possible increased risk of birth defects • If patient has angle-closure glaucoma when benzodiazepines are taken during • If patient is taking ketoconazole or pregnancy itraconazole (azole antifungal agents) • Because of the potential risks, • If there is a proven allergy to alprazolam or alprazolam is not generally recommended any benzodiazepine as treatment for anxiety during pregnancy, especially during first trimester • Drug should be tapered if discontinued SPECIAL POPULATIONS • Infants whose mothers received a benzodiazepine late in pregnancy may Renal Impairment experience withdrawal effects • Drug should be used with caution • Neonatal flaccidity has been reported in infants whose mothers took a Hepatic Impairment benzodiazepine during pregnancy • Should begin with lower starting dose • Seizures, even mild seizures, may cause (0.5–0.75 mg/day in 2 or 3 divided doses) harm to the embryo/fetus Cardiac Impairment • Benzodiazepines have been used to treat Breast Feeding anxiety associated with acute myocardial • Some drug is found in mother’s infarction breast milk ✽ Recommended either to discontinue drug Elderly or bottle feed • Should begin with lower starting dose • Effects on infant have been observed and (0.5–0.75 mg/day in 2 or 3 divided doses) include feeding difficulties, sedation, and and be monitored closely weight loss

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THE ART OF PSYCHOPHARMACOLOGY some patients, especially for immediate- Potential Advantages release alprazolam • Adding fluvoxamine, fluoxetine, or • Rapid onset of action nefazodone can increase alprazolam levels • Less sedation than some other and make the patient very sleepy unless the benzodiazepines alprazolam dose is lowered by half or more • Availability of an XR formulation with • When using to treat insomnia, remember longer duration of action that insomnia may be a symptom of some Potential Disadvantages other primary disorder itself, and thus warrant evaluation for comorbid psychiatric • Euphoria may lead to abuse and/or medical conditions • Abuse especially risky in past or present ✽ Alprazolam XR may be less sedating than substance abusers immediate-release alprazolam Primary Target Symptoms ✽ Alprazolam XR may be dosed less • Panic attacks frequently than immediate-release • Anxiety alprazolam, and lead to less interdose breakthrough symptoms and less “clock- watching” in anxious patients • Slower rises in plasma drug levels for Pearls alprazolam XR have the potential to reduce ✽ One of the most popular benzodiazepines euphoria/abuse liability, but this has not for anxiety, especially among primary care been proven physicians and psychiatrists • Slower falls in plasma drug levels for • Is a very useful adjunct to SSRIs and alprazolam XR have the potential to SNRIs in the treatment of numerous facilitate drug discontinuation by reducing anxiety disorders withdrawal symptoms, but this has not • Not effective for treating psychosis as been proven a monotherapy, but can be used as an ✽ Alprozolam XR generally has longer adjunct to antipsychotics biological duration of action than • Not effective for treating bipolar disorder clonazepam as a monotherapy, but can be used ✽ If clonazepam can be considered a as an adjunct to mood stabilizers and “long-acting alprazolam-like anxiolytic,” then antipsychotics alprazolam XR can be considered “an even • May both cause depression and treat longer-acting clonazepam-like anxiolytic” depression in different patients with the potential of improved tolerability • Risk of seizure is greatest during the first features in terms of less euphoria, abuse, 3 days after discontinuation of alprazolam, dependence, and withdrawal problems, but especially in those with prior seizures, head this has not been proven injuries, or withdrawal from drugs of abuse • Though not systematically studied, • Clinical duration of action may be shorter benzodiazepines have been used effectively than plasma half-life, leading to dosing to treat catatonia and are the initial more frequently than 2–3 times daily in recommended treatment

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