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Benzodiazepines (not including sedative/hypnotics*) [Developed, October 1993; Revised, December 1996; November 1997; November 1998; December 1999; December 2000; December 2001; April 2003; January 2009; June 2011] MEDICAID DRUG USE REVIEW CRITERIA FOR OUTPATIENT USE (*Sedative/hypnotic benzodiazepines are included in Sedative/Hypnotics criteria.) Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*]. Dosage1-6 1.* Adults Non-sedative/hypnotic benzodiazepines are FDA-approved for use in the outpatient setting to manage anxiety (alprazolam, chlordiazepoxide, clorazepate, oral diazepam, lorazepam, oxazepam), panic disorder (alprazolam, clonazepam), acute musculoskeletal (MS) conditions including spasticity (oral diazepam), seizures (clonazepam, clorazepate, oral and rectal diazepam), and acute alcohol withdrawal (chlordiazepoxide, clorazepate, oral diazepam, oxazepam). The adult maximum recommended doses for non-sedative/hypnotic benzodiazepines are summarized in Table 1. Table 11-6 Adult Benzodiazepine Maximum Recommended Daily Doses DRUG NAME alprazolam (Xanax®, generics) chlordiazepoxide (Librium®, generics) clonazepam (Klonopin®, generics) clorazepate (Tranxene®, generics) diazepam (Valium®, generics) lorazepam (Ativan®, generics) oxazepam (Serax®, generics) MAXIMUM RECOMMENDED DOSE < 65 YEARS anxiety: 4 mg daily panic: 10 mg daily alcohol withdrawal (AW): 300 mg daily in divided doses mild, moderate anxiety: 40 mg daily severe anxiety: 100 mg daily seizures: 20 mg daily panic: 4 mg daily anxiety: 60 mg daily AW, seizures: 90 mg daily oral (AW, anxiety, MS conditions, seizures): 40 mg daily rectal gel (seizures):+ 0.2 mg/kg; may be repeated once 4-12 hours after initial dose anxiety: 10 mg daily, in divided doses mild, moderate anxiety: 60 mg daily AW, severe anxiety: 120 mg daily MAXIMUM RECOMMENDED DOSE > 65 YEARS* anxiety: 4 mg daily panic: 10 mg daily AW: 300 mg daily in divided doses anxiety: 20 mg daily seizures: 20 mg daily panic: 4 mg daily anxiety: 60 mg daily AW, seizures: 90 mg daily oral (AW, anxiety, MS conditions, seizures): 40 mg daily rectal gel (seizures):+ 0.2 mg/kg; may be repeated once 4-12 hours after initial dose anxiety: 10 mg daily, in divided doses AW, anxiety: 60 mg daily * In elderly patients (patients > 65 years of age), the benzodiazepine dose should be reduced to the lowest effective dose, if possible, to minimize oversedation, as these patients are more sensitive to the pharmacologic effects of these agents. + Dose rounded up to nearest commercially available dose (in multiples of 2.5 mg); should not be administered by caregivers outside the hospital more frequently than one course every 5 days with a maximum of 5 courses per month; not for chronic administration to minimize potential for development of tolerance Pediatrics7-11 Safety and effectiveness of alprazolam use in children less than 18 years of age have not been established. With the exception of alprazolam, non-sedative/hypnotic benzodiazepines are indicated for use in pediatric patients to provide sedation, or manage anxiety or seizures. Pediatric dosages and age limitations for benzodiazepines are summarized in Table 2. Table 21-7 Pediatric Benzodiazepine Maximum Recommended Dosages DRUG NAME chlordiazepoxide clonazepam clorazepate diazepam lorazepam oxazepam MAXIMUM RECOMMENDED DOSE AW (adolescents): > 12 years of age: 300 mg daily in divided doses anxiety: > 6 years of age: 30 mg daily in divided doses, or 0.5 mg/kg daily in divided doses seizures: < 10 years of age or < 30 kg: 0.2 mg/kg daily in divided doses > 10 years of age or > 30 kg: 20 mg daily in divided doses seizures: 9-12 years: 60 mg daily in divided doses > 12 years of age: 90 mg daily in divided doses oral (MS conditions, seizures): > 6 months of age: 0.8 mg/kg/day in divided doses; alternately, for seizures, 30 mg daily in divided doses rectal gel (seizures):+ 2-5 years of age: 0.5 mg/kg/dose 6-11 years of age: 0.3 mg/kg/dose > 12 years of age: 0.2 mg/kg/dose anxiety: > 12 years of age: 10 mg daily in divided doses (maximum, 2 mg/dose7) anxiety: 6-12 years of age: dose not established; 1 mg/kg/day in divided doses has been adequate > 12 years of age: 120 mg daily; 30-90 mg daily has also been used8-10 + Dose rounded up to nearest commercially available dose (in multiples of 2.5 mg); should not be administered by caregivers outside the hospital more frequently than one course every 5 days with a maximum of 5 courses per month; not for chronic administration to minimize potential for development of tolerance 2. Duration of Therapy12-18 Anxiety disorders are considered chronic disorders with low spontaneous remission rates and high rates of relapse. Pharmacotherapy for generalized anxiety disorder (GAD) in adults includes antidepressants, benzodiazepines, buspirone, hydroxyzine and pregabalin. Treatment duration for GAD ranges from 3 months to 12 months to accomplish treatment goals of symptom remission and improvement in quality of life. Although antidepressants are now considered drugs of choice for managing GAD, benzodiazepines are used frequently for short-term management of anxiety, as an adjunct to initiating antidepressant therapy, or improvement in sleep disturbances associated with GAD and/or antidepressant therapy. Benzodiazepines provide symptom improvement more rapidly than antidepressants and are more effective in managing somatic complaints rather than psychic symptoms. Although longer-term use is considered relatively safe and effective for benzodiazepines, the potential for abuse, dependence and withdrawal does exist. In pediatric patients, selective serotonin reuptake inhibitors (SSRIs) are agents of choice to manage childhood anxiety disorders, with benzodiazepines prescribed as alternatives either alone or concurrently with accepted antidepressant therapy. Panic disorder (PD) is a chronic, recurring condition requiring drug therapy suitable for prolonged use. The acute treatment phase for PD lasts approximately 12 weeks, and most patients require an additional 12to 18 months of therapy to optimize treatment response and prevent relapse. SSRIs are the agents of choice to manage PD, although benzodiazepines are frequently prescribed as well, usually in combination with antidepressant therapy. While benzodiazepines are effective in the short-term treatment of panic disorder due to rapid onset of action, long-term treatment may be less desirable due to the potential for dependence. Unlike anxiety disorder patients, patients with panic disorder are less successful at discontinuing benzodiazepine therapy. Additionally, there is a high prevalence of comorbid depression and/or bipolar disorder in patients with panic disorder. Benzodiazepines are less effective than other available agents when panic disorder coexists with other mood disorders. Therefore, patients with panic disorder and other psychiatric comorbidities may benefit from short-term therapy with a benzodiazepine, with chronic management incorporating mood stabilizing or antidepressant agents that are also effective in panic disorder. Alprazolam has been studied more than other available benzodiazepines for the treatment of panic disorder, although clonazepam, lorazepam, and diazepam have also been evaluated. Most studies evaluating benzodiazepine use in panic disorder have been short-term studies (< 8 weeks in duration). A few long-term panic disorder studies evaluating alprazolam have demonstrated sustained reductions in panic attack frequency when alprazolam has been administered for 6 to 8 months. Benzodiazepines should be tapered when discontinued, as patients may experience a withdrawal syndrome if therapy is discontinued abruptly. Benzodiazepine elimination half-life and seizure history for the patient also influence the taper duration. Patients receiving benzodiazepines in lower doses for shorter times periods (less than six months) may be effectively tapered over two to eight weeks, while patients receiving benzodiazepines with a short elimination half-life, in higher doses, and/or for a longer duration (six months or longer) may require a slow taper over two to four months. Benzodiazepines should be prescribed on a short-term basis to manage anxiety disorders. Benzodiazepine doses should be tapered rather than discontinued abruptly to avoid withdrawal symptoms. Patients receiving benzodiazepines for up to 6 months should be tapered over 2 to 8 weeks, while patients treated with benzodiazepines for up to 12 months should be tapered over 2 to 4 months. While concerns for benzodiazepine tolerance and withdrawal exist, patients may benefit from long-term use of benzodiazepines in panic disorder to minimize symptom recurrence. Additionally, significant problems with benzodiazepine dose escalation have not surfaced with chronic use for panic disorder. The use of benzodiazepines as an anti-epileptic is not limited in duration. 3.* Duplicative Therapy The combined use of two or more benzodiazepines is not supported in the literature and therefore is not recommended. The concurrent use of two or more benzodiazepines will be reviewed. 4.* Drug-Drug Interactions Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for nonsedative/hypnotic benzodiazepines are summarized in Table 3. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed: Table 31, 19, 20 Benzodiazepines (nonsedative/hypnotic) Drug-Drug Interactions TARGET DRUG INTERACTING DRUG INTERACTION RECOMMENDATIONS CLINICAL SIGNIFICANCE benzodiazepines (BZDs) CNS depressants oxidized BZDs (e.g., alprazolam, chlordiazepoxide, clonazepam, and diazepam) CYP3A4 inducers (e.g., carbamazepine, rifamycins) CYP3A4 inhibitors (e.g., azole antifungals, macrolides, NNRT inhibitors, protease inhibitors) monitor for respiratory depression; adjust doses as necessary monitor oxidized BZD clinical response and adjust dose as needed; may also consider substituting a BZD metabolized by glucuronidation (e.g., oxazepam) avoid combined therapy with most CYP3A4 inhibitors, if possible major (DrugReax) 3-moderate (CP*) 1 (DIF+) moderate (DrugReax) 2-major, 3-moderate (CP) 2 (DIF) alprazolam concurrent administration may potentiate respiratory depression, especially with overdosage combined use may result in increased oxidized BZD clearance, reduced oxidized BZD serum levels, and decreased pharmacologic effects; oxidized BZDs are metabolized by CYP3A4 adjunctive administration may result in enhanced oxidized BZD pharmacologic effects and/or toxicity, including significant sedation and/or respiratory depression, as alprazolam is metabolized by CYP3A4 other oxidized BZDs (chlordiazepoxide, clonazepam, diazepam) CYP3A4 inhibitors (e.g., azole antifungals, macrolides, NNRT inhibitors, protease inhibitors) adjunctive administration may result in enhanced oxidized BZD pharmacologic effects and/or toxicity, including significant sedation and/or respiratory depression, as oxidized BZDs are metabolized by CYP3A4 alprazolam phenytoin select BZDs (chlordiazepoxide, clonazepam, diazepam) phenytoin combined use may induce alprazolam metabolism and decrease alprazolam pharmacologic effects concomitant use may result in unpredictable effects on serum phenytoin levels (may increase, decrease, or not change) due to unknown effect on phenytoin metabolism; phenytoin may induce BZD metabolism, reduce BZD serum levels, and decrease BZD pharmacologic effects avoid combined therapy, if possible; if concurrent with BZD necessary, monitor for increased sedation, respiratory depression, or consider a BZD metabolized by glucuronidation (e.g., oxazepam) monitor for reduced alprazolam clinical effects and adjust doses as necessary closely monitor serum phenytoin levels and observed for altered pharmacologic effects (reduced efficacy, increased toxicity); monitor for reduced BZD clinical effects and adjust doses as necessary *CP = Clinical Pharmacology; +Drug Interaction Facts contraindicated -azole antifungals, NNRT inhibitors, protease inhibitors; moderate -macrolides (DrugReax) 1 – severe (azole antifungals, NNRT inhibitors, protease inhibitors); 3moderate (macrolides) (CP) 1-protease inhibitors; 2 - azoles, macrolides, NNRT inhibitors (DIF) moderate (DrugReax) 2-major (protease inhibitors); 3moderate (azoles, macrolides, NNRT inhibitors) (CP) 1-protease inhibitors; 2 - azoles, macrolides, NNRT inhibitors (DIF) 3-moderate (CP) alprazolam – 2 (DIF) moderate (DrugReax) 3-moderate (CP) 2 (DIF) REFERENCES 1. 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