Texas Vendor Drug Program Drug Use Criteria: Benzodiazepines (Nonsedative/ Hypnotics*) Publication History 1. Developed October 1993. 2. Revised March 2020; March 2018; May 2017; December 2014; March 2013; June 2011; January 2009; April 2003; December 2001; December 2000; December 1999; November 1998; November 1997; December 1996. Notes: Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document. Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Vendor Drug Program formulary coverage. Prepared by: Drug Information Service, UT Health San Antonio. The College of Pharmacy, The University of Texas at Austin. (*Sedative/hypnotic benzodiazepines are included in Sedative/Hypnotics criteria.) 1 1 Dosage 1.1 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 [clobazam (Lennox-Gastaut syndrome), clonazepam, clorazepate, nasal, oral and rectal diazepam], and acute alcohol withdrawal (chlordiazepoxide, clorazepate, oral diazepam, oxazepam).[1-10] The FDA has approved a new dosage formulation for clobazam, an oral film (Sympazan®), for adjunctive seizure management in Lennox-Gastaut syndrome.[11] A new diazepam nasal formulation (Valtoco®) has been FDA-approved for use in adult patients to treat intermittent frequent seizure episodes that differ from a patient’s usual seizure pattern.[12] The chlordiazepoxide-amitriptyline combination is indicated for depression with associated anxiety symptoms, while chlordiazepoxide/clidinium is FDA-approved for emotional factor control in gastrointestinal disorders as well as adjunctive use in peptic ulcer disease and irritable bowel syndrome.[13, 14] Tables 1 and 2 summarize the adult maximum recommended dosages for non-sedative/hypnotic benzodiazepines as monotherapy and combination therapy. Table 1. Adult Benzodiazepine Maximum Recommended Daily Dosages: Monotherapy[1-12] Dosage Form/ Treatment Maximum Recommended Drug Name Strength Indication Dosage alprazolam 0.25 mg, 0.5 mg, 1 (Xanax®, generics) mg, 2 mg tablets, disintegrating tablets; 0.5 mg, 1 mg, 2 anxiety < and > 65 years: 4 mg daily mg, 3 mg extended-release tablets; 1 mg/ml oral solution alprazolam < and > 65 years: 10 mg panic daily 2 Dosage Form/ Treatment Maximum Recommended Drug Name Strength Indication Dosage chlordiazepoxide alcohol 5 mg , 10 mg, 25 < and > 65 years: 300 mg (generics) withdrawal mg capsule daily, in divided doses (AW) chlordiazepoxide < 65 years: mild, moderate: 40 mg daily anxiety severe: 100 mg daily > 65 years: 20 mg daily clobazam < 65 years: (Onfi®, 10 mg, 20 mg seizures 40 mg/day in two divided generics, tablets; associated doses Sympazan®) 2.5 mg/mL with > 65 years: suspension; 5 mg, Lennox- 20 mg/day in two divided 10 mg, 20 mg Gastaut doses (weights < 30 kg) oral soluble film syndrome 40 mg/day in two divided doses (weights > 30 kg) clonazepam 0.5 mg, 1 mg, 2 (Klonopin®, mg tablets; generics) 0.125 mg, 0.25 panic < and > 65 years: 4 mg daily mg, 0.5 mg, 1 mg, 2 mg disintegrating tablets clonazepam < and > 65 years: 20 mg seizures daily clorazepate 3.75 mg, 7.5 mg, < and > 65 years: 90 mg (Tranxene®, AW 15 mg tablets daily generics) clorazepate < and > 65 years: 60 mg anxiety daily clorazepate < and > 65 years: 90 mg seizures daily diazepam 28-50 kg^: 10 mg as one (nasal) spray in one nostril (Valtoco®) 5 mg as one 5 mg (equates to 0.2 mg/kg device, 10 mg as dose) one 10 mg 51-75 kg^: 15 mg as 2 x device, 15 mg as 7.5 mg devices with one 2 x 7.5 mg seizures spray in each nostril devices, 20 mg (equates to 0.2 mg/kg as 2 x 10 mg dose) devices nasal > 76 kg^: 20 mg as 2 x 10 liquid mg devices with one spray in each nostril (equates to 0.2 mg/kg dose) 3 Dosage Form/ Treatment Maximum Recommended Drug Name Strength Indication Dosage diazepam (oral) 2 mg, 5 mg, 10 mg (Valium®, oral tablets; < and > 65 years: 40 mg AW generics) 5 mg/mL, 5 mg/5 daily mL oral solution diazepam (oral) < and > 65 years: 40 mg anxiety daily diazepam (oral) musculoskeleta < and > 65 years: 40 mg l conditions daily diazepam (oral) < and > 65 years: 40 mg seizures daily diazepam < and > 65 years: (rectal) 2.5 mg, 10 mg, 20 0.2 mg/kg; may be repeated seizures (Valium®, mg rectal gel once 4-12 hours after initial generics) dose lorazepam 0.5 mg, 1 mg, 2 < and > 65 years: 10 mg (Ativan®, mg tablets; anxiety daily, in divided doses generics) 2 mg/mL solution oxazepam < 65 years: 120 mg daily in (Serax®, 10 mg, 15 mg, 30 divided doses AW generics) mg capsule > 65 years: 60 mg daily in divided doses# oxazepam < 65 years: mild, moderate: 60 mg daily in divided doses anxiety severe: 120 mg daily in divided doses > 65 years: 40 mg daily in divided doses *benzodiazepine doses should be reduced to lowest effective dose, if possible, in elderly (patients > 65 years of age), to minimize oversedation; these patients more sensitive to 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 #in elderly patients, doses up to 120 mg/day may be needed to treat AW ^may give second diazepam nasal dose at least 4 hours after first dose, if necessary; may not use more than 2 doses to treat single episode; may not treat more than 1 episode/5 days or more than 5 episodes/month 4 Table 2. Adult Benzodiazepine Maximum Recommended Dosages: Combination Therapy[1-7, 13, 14] Maximum Dosage Form/ Treatment Drug Name Recommended Strength Indication Dosage chlordiazepoxide/ 5 mg/12.5 mg 60 mg amitriptyline tablets depression with chlordiazepoxide (Limbitrol®, 10 mg/25 mg concurrent / 150 mg generics) double- anxiety amitriptyline strength symptoms daily in divided tablets doses chlordiazepoxide/ emotional/ clidinium somatic factors (Librax®, in gastro- generics) intestinal disorders; 40 mg/20 mg per 5 mg/ 2.5 mg adjunctive day (2 capsules 4 capsule therapy in times daily) peptic ulcer disease or irritable bowel syndrome 1.2 Pediatrics Safety and effectiveness of alprazolam and combination therapies, chlordiazepoxide/amitriptyline and chlordiazepoxide/clidinium, in children less than 18 years of age have not been established.[1-5, 9, 13, 14] Clobazam has recently been approved in children 2 years of age and older to manage seizures associated with Lennox-Gastaut syndrome.[1-5, 10] The FDA has approved a new dosage formulation for clobazam, an oral film (Sympazan®), for adjunctive seizure management in Lennox-Gastaut syndrome in patients 2 years and older.[11] A new diazepam nasal formulation (Valtoco®) has been FDA-approved for use in patients 6 years and older to treat intermittent frequent seizure episodes that differ from a patient’s usual seizure pattern.[12] With the exception of alprazolam, non-sedative/hypnotic benzodiazepines are indicated for use in pediatric patients to manage anxiety or seizures. Pediatric dosages and age limitations for benzodiazepines are summarized in Table 3. 5 Table 3. Pediatric Benzodiazepine Maximum Recommended Dosages[1-12] Treatment Drug Name Maximum Recommended Dosage Indication chlordiazepoxide alcohol adolescents > 12 years: 300 mg daily in divided withdrawal (AW) doses chlordiazepoxide anxiety > 6 years: 30 mg daily in divided doses clobazam seizures 2 years and older, adolescents < 30 kg: 20 associated with mg/day in two divided doses Lennox-Gastaut 2 years and older, adolescents > 30 kg: 40 syndrome mg/day in two divided doses clonazepam < 10 years or < 30 kg: 0.2 mg/kg daily in divided doses seizures > 10 years or > 30 kg: 20 mg daily in divided doses clorazepate 9-12 years: 60 mg daily in divided doses seizures > 12 years: 90 mg daily in divided doses diazepam 6-11 years of age: (nasal) 10-18 kg: 5 mg as one spray in one nostril (equates to 0.3 mg/kg dose) 19-37 kg^: 10 mg as one spray in one nostril (equates to 0.3 mg/kg dose) 38-55 kg^: 15 mg as 2 x 7.5 mg devices with one spray in each nostril (equates to 0.3 mg/kg dose) 56-74 kg^: 20 mg as 2 x 10 mg devices with one spray in each nostril (equates to 0.3 mg/kg dose) seizures > 12 years of age: 14-27 kg: 5 mg as one spray in one nostril (equates to 0.2 mg/kg dose) 28-50 kg^: 10 mg as one spray in one nostril (equates to 0.2 mg/kg dose) 51-75 kg^: 15 mg as 2 x 7.5 mg devices with one spray in each nostril (equates to 0.2 mg/kg dose) > 76 kg^: 20 mg as 2 x 10 mg devices with one spray in each nostril (equates to 0.2 mg/kg dose) diazepam (oral) > 6 months of age: 10 mg/day in divided doses musculoskeletal have been used; dose may be increased as needed conditions and tolerated – no maximum dose documented diazepam (oral) > 6 months of age: 10 mg/day in divided doses seizures have been used; dose may be increased as needed and tolerated – no maximum dose documented diazepam 2-5 years: 0.5 mg/kg/dose (rectal) seizures+ 6-11