Utah Medicaid Dur Report June 2017 Benzodiazepines

UTAH MEDICAID DUR REPORT JUNE 2017

BENZODIAZEPINES Alprazolam Chlordiazepoxide Clobazam Clonazepam Clorazepate Diazepam Estazolam Flurazepam Lorazepam Midazolam Oxazepam Quazepam Temazepam Triazolam

Drug Regimen Review Center Joanita Lake B.Pharm, MSc EBHC (Oxon), Clinical Pharmacist Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Joanne LaFleur, PharmD, MSPH, Associate Professor

Acknowledgement Gary Oderda, PharmD, MPH, Emeritus Professor Melissa Archer, PharmD, Clinical Pharmacist Carin Steinvoort, PharmD, Clinical Pharmacist

Contents

Introduction ...... 4 Background ...... 5 Methodology ...... 8 Benzodiazepine Products & Indications ...... 8 Pharmacology ...... 8 Table 1. Duration of action ...... 9 Safety ...... 10 Risk factors that increase risk of adverse events ...... 11 Clinical Guidelines ...... 13 Table 2. Clinical Guidelines for the Treatment of Anxiety Disorders ...... 14 Table 3. Guidelines for the treatment of insomnia ...... 15 Table 4. Other Guidelines/Regulatory Safety updates ...... 16 Technology assessments/evidence‐based synopses ...... 18 Table 5. Technology Assessments/Evidence‐based synopses ...... 18 Efficacy ...... 20 Long‐term use ...... 21 Comparison of Xanax IR (alprazolam) to Xanax XR and other commonly used anxiolytics ...... 24 Place in therapy and potential criteria to be reviewed/What can be done to reduce the risk? ...... 26 Utah Medicaid Utilization Data ...... 31 Conclusions ...... 38 Appendix 1 – Drug information ...... 39 Table 6. Comparison of Benzodiazepine Agents ...... 39 Table 7. Warnings and Precautions for the Benzodiazepine Agents ...... 41 Table 8. Pharmacokinetics Properties of the Benzodiazepine Agents ...... 42 Appendix 2 ‐ Additional data ...... 45 Table 11. All claims ...... 45 Table 12. FFS claims ...... 46 Table 13. Pediatric claims ...... 47 Table 14. Number of pediatric patients by age and diagnosis codes ...... 49 Appendix 3 – Exceeding proposed limits and duration of use ...... 50 Table 15. Exceeding proposed limits and duration of use ...... 50 Table 16. Diagnosis codes submitted ...... 53 Table 17. Diagnosis codes submitted for those exceeding proposed/recommended duration of use . 55

Table 18. Diagnosis codes submitted for those exceeding proposed dose limits ...... 56 Table 19. Top prescribers and number of their claims and patients exceeding the proposed dose limits and duration of use ...... 58 References ...... 60

Introduction

The number of people receiving benzodiazepines, benzodiazepine prescriptions, doses prescribed, and overdose mortality have increased considerably.1,3 Benzodiazepine overprescribing, misuse, and abuse contribute to the alarming number of opioid overdoses in the United States. According to the national Treatment Episode Data Set (TEDS) report, between 2000 and 2010, substance abuse treatment admissions reporting both benzodiazepine and narcotic pain reliever abuse increased by more than 500% (5,032 admissions in 2000 to 33,701 admissions in 2010).4

Fourteen benzodiazepine agents are currently available for use in the United States: alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam and triazolam. Benzodiazepines (BZDs) are gamma‐ aminobutyric acid (GABA) receptor agonists and have anxiolytic, hypnotic, muscle relaxant, and anticonvulsant properties. Benzodiazepines are widely used to treat anxiety and insomnia. Other therapeutic uses of benzodiazepines include treatment of seizure disorders, alcohol withdrawal symptoms and conscious sedation or general anesthesia. In 2009, approximately 150 million prescriptions were issued in the United States for benzodiazepines–alprazolam (Xanax), clonazepam (Klonopin), and lorazepam were some of the most prescribed psychotropics. Benzodiazepine use has continued to increase.5‐7

20095 20117 #1 alprazolam: 44.5 million prescriptions 49.0 million #6 clonazepam: 23.1 million prescriptions 26.9 million #7: lorazepam: 22.4 million prescriptions 27.6 million #12 diazepam: 14.0 million prescriptions 15 million #17 temazepam: 9.0 million prescriptions 8.5 million

The Drug Enforcement Administration (DEA) also reports that these are the most frequently encountered benzodiazepines on the illicit market. Alprazolam is one of the top three diverted prescription drugs.7 Benzodiazepines are schedule IV controlled substances.7 In 2013, benzodiazepines were involved with approximately 31% of the estimated 22,767 fatal drug overdoses in the United States.3

Widespread and long‐term use of benzodiazepines is occurring despite recommended cautions and concerns (especially in the elderly). Very little evidence supports this practice and other agents remain first‐line recommended therapies (i.e. antidepressants for anxiety disorders).6,8,9 Olfson et al. conducted a retrospective descriptive analysis of benzodiazepine prescriptions to describe benzodiazepine prescription patterns in the United States focusing on patient age and duration of use.10 They used the 2008 LifeLink LRx Longitudinal Prescription database (IMS Health Inc), which included approximately 60% of all retail pharmacies in the United States (adjusting denominators to generalize estimates to the US population), and found that roughly one‐quarter of individuals in all age groups receiving benzodiazepines received long‐acting benzodiazepines, and that long‐term benzodiazepine use is common in the elderly.10

More vigorous clinical interventions supporting judicious benzodiazepine use may be needed to reduce the inappropriate use of benzodiazepines, rates of long‐term benzodiazepine use (especially in older adults), and improve safety outcomes. 1,3,10

The main focus of this review is on safety and appropriate use, including: a) Interactions with opioids/CDC recommendations to avoid concurrent use unless alternative treatment options are inadequate b) Abuse liability: To reduce inappropriate prescribing (e.g., excessive doses or quantities) Based on expert opinion (Susan L. Siegfreid, MD; Physician, Department of Health), few patients require immediate release (IR) Xanax instead of other products (e.g. use of 4‐5 tabs per month only). Is there any data available comparing Xanax IR (alprazolam) to Xanax extended release (XR) and other commonly used anxiolytics? c) Long‐term benefit versus risk: To assess whether long‐term use is appropriate d) To help identify and manage patients on long‐term benzodiazepines e) To assess drug‐drug interactions, including both pharmacokinetic and pharmacodynamic issues f) To ensure appropriate use (FDA‐labelled indications) based on the available evidence

The goals of this review are to: 1) Consider quantity limits; 2) Consider restricting concurrent use with opiates except by physician justification; and 3) Consider whether criteria are necessary to ensure appropriate use (per FDA indications)

This report will only focus on the benzodiazepines and does not include the non‐benzodiazepine agents (e.g. zolpidem and zaleplon, which are also benzodiazepine receptor agonists). Information from the University of Utah College of Pharmacy Drug Class Reviews for the P&T Committee, Benzodiazepines in the Treatment of Anxiety Disorder November 2016 AND Sedative Hypnotic Benzodiazepines in the Treatment of Sleep Disorders May 2012, have been included.

Background

A number of pharmacologic agents belong to the drug class referred to as sedative‐hypnotic agents. Sedative‐hypnotic agents work to induce a calming or sedating effect by depressing the central nervous system (CNS).11 Sedative‐hypnotic agents available in the United States include benzodiazepines, barbiturates and some newer anti‐insomnia agents with unique chemical structures. This review focuses on benzodiazepines.

Benzodiazepines have been used therapeutically since the early 1950s and were initially a part of a class of therapeutic agents referred to as tranquilizers.12 The “new” benzodiazepine agents were safer than the older barbiturate agents with far less addiction potential. Presently, benzodiazepines are referred to as sedative‐hypnotic agents and have a number of different therapeutic uses including treatment of anxiety disorders, insomnia, seizure disorders, alcohol withdrawal symptoms and conscious sedation or general anesthesia.11‐13 Darker et al., in a recent Cochrane systematic review, report that “While they [BZDs] can initially be helpful in relieving the symptoms of these problems, many people develop a tolerance to their effects, gain little therapeutic benefit from chronic consumption, become dependent on them and suffer a withdrawal syndrome when they stop taking them.”14

The most common indication for benzodiazepines is anxiety.1,3 According to a recently published study in which the investigators examined data from the Medical Expenditure Panel Survey and multiple‐ cause‐of‐death data from the Centers for Disease Control and Prevention, “In 2013, the most common indications for benzodiazepine prescription were anxiety disorders (56.1% [95% CI = 52.2%, 60.1%]),

5 mood disorders (12.1% [95% CI = 9.0%, 15.2%]), and codes in the unclassified category, which includes codes for insomnia (12.0% [95% CI = 9.4%, 14.6%]).”3

Disease Overview: Anxiety

The DSM (Diagnostic and Statistical Manual of Mental Disorders) classification is the 5‐axis diagnostic system developed and published by the American Psychiatric Association (APA). The DSM multi‐axial system provides a comprehensive and systematic evaluation of the patient to identify and diagnose mental health disorders.15,16 The axis I DSM psychiatric disorders include the depressive and anxiety disorders. Numerous anxiety disorders are included in this category including: acute stress disorder, agoraphobia, generalized anxiety disorder (GAD), obsessive‐compulsive disorder (OCD), panic disorder and posttraumatic stress disorder (PTSD).15,16 The anxiety disorders are the most common outpatient psychiatric illnesses and up to 75% of patients who have experienced a panic attack will meet the diagnosis for a major depressive disorder. Alcohol and/or substance abuse problems may also occur in patients with anxiety disorders, as a form of self‐medication.17‐22

The medical management of the anxiety disorders includes both pharmacotherapy and psychotherapy. With regard to psychological therapies, cognitive‐behavioral therapy (CBT) is considered the gold standard.23,24 A number of pharmacotherapy options exist for treatment of the anxiety disorders including: tricyclic antidepressants, monoamine oxidase inhibitors, second‐generation antidepressants, anticonvulsants, antipsychotic medications, buspirone and benzodiazepines. Historically, the benzodiazepines were the core of the medical management of anxiety disorders due to their tolerability and rapid onset of action.24 Current guidelines recommend other treatment options first before considering benzodiazepines. Current guideline information is summarized in the guideline section. A short course of a benzodiazepine, at the lowest dose and only on an as‐needed basis, is the usual recommendation for benzodiazepine therapy in the treatment of anxiety disorders. Buspirone, an anxiolytic that may be effective in the treatment of generalized anxiety disorders, is dosed multiple times a day and requires several weeks of therapy before a response is seen.17 The second‐generation antidepressants, including escitalopram, paroxetine, venlafaxine and duloxetine, are labeled for use in GAD and may be safer options for the long‐term treatment of chronic anxiety. Other agents used in the treatment of anxiety include the GABA‐nergic acting anticonvulsants, divalproex, gabapentin, oxcarbazepine, pregabalin and tiagabine.17 Overall, choice of therapy is based on presenting anxiety disorder, patient history and medical costs. The combination of both pharmacotherapy and psychotherapy is beneficial in the treatment of all anxiety disorders.23,24

Disease Overview: Insomnia

Insomnia is a disorder defined by difficulty with sleep initiation, duration, consolidation, or quality.25,26 Diagnostic criteria for chronic insomnia specify that “symptoms must cause clinically functional distress or impairment; be present for at least 3 nights per week for at least 3 months; and not be linked to other sleep, medical, or mental disorders.”27 General insomnia disorder occurs despite adequate opportunity for sleep, results in daytime impairment, and causes distress.25,26 Insomnia symptoms occur in up to half of the adult population in the United States.26 Risk factors for insomnia include increasing age, female sex, comorbid disorders, and shift work.25,26 There is also a difference reported between the type of insomnia experienced by younger and older people (difficulty falling asleep vs. waking up after sleep onset).28 Older adults are more likely to experience the latter.28

The medical management of insomnia includes both behavioral therapies, pharmacotherapy, or a combination of both.28 Behavioral therapies include: relaxation therapy, stimulus control therapy, and sleep restriction therapy.26 Cognitive Behavioral Therapy (CBT‐I) incorporates sleep restriction, stimulus control, sleep hygiene, and cognitive therapy such as relaxation techniques.29 The American College of Physicians (ACP) Guidelines recommend cognitive behavioral therapy for insomnia (CBT‐I) as the initial treatment for chronic insomnia disorder and that clinicians use a shared decision‐making approach regarding pharmacological therapy (if behavioral therapy fails).28 A number of pharmacotherapy options exist for the treatment of insomnia including: benzodiazepines (triazolam, estazolam, temazepam, flurazepam, and quazepam); benzodiazepine receptor agonists/nonbenzodiazepine hypnotics (zaleplon, zolpidem, and eszopiclone); melatonin receptor agonist (ramelteon); the orexin receptor antagonist (suvorexant); the antidepressant doxepin; and off‐label use of other drugs such as other sedating antidepressants, anticonvulsants, antipsychotic medications, melatonin, or other over‐the‐counter antihistamine and herbal drugs.26,28 According to Lexicomp information, “While experience to date in the management of insomnia principally has been with estazolam, flurazepam, quazepam, temazepam, and triazolam, other benzodiazepines also can be used for insomnia.”30 Before the introduction of the newer benzodiazepine receptor agonist insomnia medications (zolpidem, eszopiclone, zaleplon), drug therapy in the treatment of insomnia was dominated by benzodiazepine agents due to their tolerability and rapid onset of action.26,31 However, the newer agents may now be preferred because of relatively rapid onset of effect, short duration of action, a lower risk of abuse, tolerance, and dependence than the benzodiazepines.30,31 Pharmacotherapy should be considered second line treatment and should be used in conjunction with nonpharmacologic therapy. The pharmacological options were summarized in a recent continuing education by Bethany DiPaula (University of Maryland) as 1st: short‐intermediate acting BZD or benzodiazepine receptor agonist or ramelteon; 2nd: alternate of these as second; 3rd: sedating antidepressants (if concurrent depression/anxiety).29 Suvorexant is a new therapy without sufficient data so it is not currently recommended.29 This was based on the older 2008 guidelines. Guideline information is summarized in the guideline section.28 The recent ACP guidelines are for the management of chronic insomnia and the authors stated that evidence was insufficient to determine the benefits of pharmacologic therapy with benzodiazepines in the general population or in older adults, and that only a few trials met the inclusion criteria because many assessed short durations of treatment.28

Clinical Efficacy information from P&T reports

A brief summary of the University of Utah College of Pharmacy Drug Class Reviews for the P&T Committee (Benzodiazepines in the Treatment of Anxiety Disorder November 2016 and Sedative Hypnotic Benzodiazepines in the Treatment of Sleep Disorders May 2012) has been included below.

 How do the benzodiazepines compare with each other for reducing anxiety symptoms? In summary, the overall improvements in anxiety outcome measures between alprazolam, clorazepate, diazepam, lorazepam and oxazepam in current literature are similar. The majority of available evidence is captured in nine clinical trials comparing alprazolam to other benzodiazepines. Although some psychometric assessments were more improved for diazepam when compared to alprazolam and clorazepate, total scores for the outcome measures exhibited no differences between treatment groups. Overall, outcome measures were similar between each of the benzodiazepines evaluated in the treatment of anxiety disorders.32‐42

 How do the benzodiazepines compare with each other for reducing insomnia symptoms?

In summary, the majority of the data available comparing diazepam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, and triazolam suggest no major differences in efficacy between the agents in treating insomnia. According to clinical evidence comparing flurazepam to triazolam, flurazepam may be less effective in treating insomnia. Evidence also suggests quazepam is more effective than triazolam and midazolam may be more effective in improving sleep latency. With regard to safety from clinical trials, triazolam may be associated with an increased risk of withdrawal and rebound effects and lorazepam may be associated with an increased adverse event rate. Overall, the clinical data suggest patients should be treated with the lowest effective dose of a benzodiazepine for the shortest possible time in the treatment of insomnia to avoid adverse events.43‐68

Methodology

Relevant information from the University of Utah College of Pharmacy Drug Class Reviews (Benzodiazepines in the Treatment of Anxiety Disorder November 2016 AND Sedative Hypnotic Benzodiazepines in the Treatment of Sleep Disorders May 2012) was incorporated into this report.

Cochrane Library literature searches for systematic reviews were conducted. Medline (PubMed), Up to Date, the Agency for Healthcare Research and Quality (AHRQ), the U.S. Department of Health and Human Services website, the FDA website (including product labeling information), the Substance Abuse and Mental Health Services Administration (SAMHSA) website,69 University of Maryland Center for Substance Abuse Research (CESAR) website,70 Micromedex, Lexicomp, and the Trip database were searched for safety information, systematic reviews, clinical trials, and other guidelines. References of relevant search results were screened.

Benzodiazepine Products & Indications

Table 6 (Appendix 1) compares all of the benzodiazepine agents in terms of available doses, usual dosage ranges and maximum daily doses, route of administration, labeled and unlabeled uses, metabolites, and whether generics are available.

Pharmacology

All benzodiazepine agents enhance the binding of gamma‐aminobutyric acid (GABA), the major inhibitory neurotransmitter, to the GABA‐A subtype of GABA receptors, resulting in GABAnergic neurotransmission.71,72 All benzodiazepine agents exert similar clinical effects. However, differences in their pharmacokinetic profiles, such as rate of absorption, elimination half‐life and lipid solubility, contribute to varying patterns of therapeutic application by influencing onset and duration of action.71,72 Table 8 (Appendix 1) provides a summary of the pharmacokinetic properties for each of the benzodiazepine agents.

Table 1. Duration of action73,74 Short‐acting Intermediate‐ acting Long‐acting Midazolam Alprazolam Clorazepate Triazolam Estazolam Clonazepam Lorazepam Diazepam Oxazepam Flurazepam Temazepam Quazepam Chlordiazepoxide (alone or in combination with amitriptyline or clidinium)

 Short half‐life benzodiazepines (e.g. triazolam) “may be more likely to result in transient rebound insomnia after discontinuance and in pharmacodynamic tolerance and adaptation to the hypnotic effect after several weeks of therapy, with resultant diminished effectiveness during the end of each night’s use (early morning insomnia) and, possibly, increased daytime anxiety.”30  Long half‐life (e.g. flurazepam, quazepam) “may be more likely to result in residual daytime sedative effects and in impaired psychomotor and mental performance during continued therapy, although partial tolerance to these effects can occur.”30  Benzodiazepines with slow GI absorption (e.g., temazepam) “may be less effective in initial sleep induction” so may not be the best option for patients with difficulty in falling asleep (sleep‐ latency insomnia), or might have to take it longer before bedtime (e.g. 1‐2 hours before bedtime) to compensate for the delayed onset.30

 All benzodiazepine agents result in dependence or tolerance with long‐term use.75,76

ANXIOLYTICS

 Lorazepam, oxazepam and alprazolam have low hepatic metabolism and do not have active metabolites  Diazepam and chlorazepate are rapidly absorbed benzodiazepine agents and have the most rapid onset of action but also the greatest abuse/dependence potential.  Chlordiazepoxide, clonazepam, clorazepate and diazepam are considered long‐acting benzodiazepine agents and are associated with accumulation which may result in sedation, cognitive impairment and psychomotor retardation.  Alprazolam and lorazepam are considered short‐acting benzodiazepine agents and have been associated with increased anxiety, insomnia and rebound effects upon discontinuation.17,19,21,22,77,78

SEDATIVE/HYPNOTICS

 Benzodiazepines are not recommended for use in the elderly according to the American Geriatrics Society (AGS) Beers Criteria for potentially inappropriate medication use in older adults, but some are prescribed.29,73 Flurazepam and quazepam in particular have long half‐lives and are not recommended in the elderly by insomnia guidelines.29

Safety

Adverse reactions The most common drug‐related adverse reactions to benzodiazepines include blurred vision, confusion, drowsiness, dizziness, decreased alertness or concentration, euphoria, lack of coordination, nausea, nightmares and decreased libido. Additionally, hypotension and suppressed breathing have been reported with intravenous use.79,80

Evidence on differences in adverse event rates between benzodiazepine agents is limited. Benzodiazepines differ in their pharmacokinetic profiles which can contribute to differences in adverse event rates.79,80 For example, long‐acting benzodiazepines can accumulate and lead to an increased risk of dizziness, confusion, hypotension, or cognitive impairment.

According to the recently published (July 2016) American College of Physicians Guidelines on the management of chronic insomnia disorder in adults and the AHRQ review (which it is based on), observational studies suggest an association of hypnotics with infrequent but serious harms such as dementia, fractures, and major injury.28,81 Table 7 (Appendix 1) provides a summary of the warnings and precautions associated with benzodiazepine therapy.

Psychomotor impairment Benzodiazepine agents may cause psychomotor impairment and may increase risk for:

 Falls and hip fracture or other injuries, especially in the elderly.82,83 “Benzodiazepines increase the risk of hip fracture in older persons by at least 50%.”6,84

Benzodiazepine drug use is associated with increased risk for falls in older persons.85 Approximately 30% of community‐dwelling and 50% of nursing home adults older than 65 years of age fall every year.85‐87 Leipzig et al85, conducted a systematic analysis of trials evaluating sedative/hypnotic, antidepressant, or neuroleptic drug use with falling in adults aged >60. A total of 40 trials were included in the analysis. Benzodiazepines were found to be associated with increased risk for falls but no statistically significant differences were reported between specific benzodiazepine agents or between the short‐ and long‐acting benzodiazepine agents. Overall, the data suggest all benzodiazepines should be used with caution in geriatric patients.85‐87

 Impairment of driving skills; driving under benzodiazepine influence is reported to be about the same risk of driving with a blood alcohol level between 0.050 and 0.079%. Motor vehicle accidents are therefore of particular concern.88,89

Cognitive impairment Long‐term use of BZDs have been associated with:  Dementia14,90  Impaired cognitive attention14,91  Impaired verbal memory14,92

Potential cancer risk “Temazepam is associated with an increase in incident cancer cases.”28

Drug‐interactions: Most are substrates for CYP3A4 so could interact with any medications that are inhibitors or inducers (particularly an issue with inhibitors due to increased risk of toxicity).29

Misuse or abuse of benzodiazepines Misuse/abuse/inappropriate use is a problem with benzodiazepines and can be due to prescription sharing or intentional abuse through doctor shopping, fraudulent prescriptions, or drugs obtained through drug dealers (which could be prescription drugs that became street drugs).6,7,14 “According to the National Epidemiologic Survey on Alcohol and Related Conditions, which included 35,000 participants, benzodiazepine prescriptions were associated with nonmedical use (odds ratio = 1.9) and development of benzodiazepine abuse or dependence (odds ratio = 2.6).”6,93

Withdrawal Withdrawal symptoms may be precipitated with benzodiazepine discontinuation, and can occur after only one month of daily use, or according to the authors of a recent systematic review, “at any time up to three weeks after cessation of a long‐acting BZD, or a few hours after cessation of a short‐acting one”.6,14,94 Withdrawal symptoms include anxiety, insomnia, and may also include tinnitus, involuntary movements, nausea, perceptual changes, confusion and seizures.14 Long‐term use can result in a “protracted, uncomfortable withdrawal syndrome that can last for months.”6

Short‐acting benzodiazepines like alprazolam and lorazepam are associated with significant fluctuations between peak and trough levels between doses because these drugs are eliminated fairly rapidly. People often experience more intense withdrawal symptoms and may experience rebound anxiety between doses.95 When discontinuing treatment with these short‐acting benzodiazepines, patients are often switched to long‐acting benzodiazepines such as diazepam which can be reduced by 1 mg every 1‐ 4 weeks or more and low doses can therefore be achieved (which is difficult with other benzodiazepines).95

Risk factors that increase risk of adverse events

 Patients with a history of substance abuse: “Those with a history of a substance use disorder are at higher risk of misusing substances in their futures.”1

 High doses: High doses result in more CNS depression. Table 6 (Appendix 1) contains information on the Adult Oral Dosage Range & Maximum Oral doses (adults) for the different benzodiazepines.

Investigators of a recently presented study conducted at Mount Sinai Beth Israel in New York City (American Academy of Addiction Psychiatry (AAAP) 27th Annual meeting) involving 241 patients from a psychiatric outpatient clinic that were prescribed benzodiazepines by 18 different clinicians, found that "The average daily benzodiazepine dose was equivalent to about 2.8 mg/day of Ativan (lorazepam, Valeant), but 11% of the patients were getting what the literature has deemed a high dose, which is 6 mg/day of Ativan or more."1 More information on this study can also be found in the Factors to consider section under “As needed” prescribing.

Park et al. studied the association between benzodiazepine prescribing patterns including dose, type, and dosing schedule and the risk of fatal overdose among US veterans receiving opioid

analgesics in a case‐cohort study.96 They found that the risk of drug overdose was dose‐dependent. “Risk of death from drug overdose increased as daily benzodiazepine dose increased.”96

 Extended treatment periods/ Long‐term use: Refer to Long‐term use section

 Opioid and benzodiazepine combination: In 2016, the FDA issued a safety alert warning about “serious risks and death when combining opioid pain or cough medicines with benzodiazepines”, and stated that the prescribing of opioid pain medicines with benzodiazepines or other CNS depressants should be limited only to patients for whom alternative treatment options are inadequate.97 “If these medicines are prescribed together, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect.”97

 Elderly79,80,98,99: Active metabolite accumulation may occur more frequently in the elderly because of slowed hepatic and renal metabolic activity and may also result in increased adverse events. These patients are at increased risk of residual and cumulative CNS depressant effects.30 FDA labels advise lower doses for older/debilitated adults.81 Pomara et al. state that lorazepam is widely used in the treatment of anxiety and related conditions in the elderly and “negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses.”100 The authors also conducted a study evaluating its long‐term effect in this population. Pomara et al. (2015) conducted a double‐blind placebo‐ controlled cross‐over study assessing the effect of long‐term (at least three months) daily treatment with lorazepam in cognitively intact elderly individuals (n=37). They found that patients had “significantly poorer recall and slowed psychomotor performance following acute lorazepam administration” and “an absence of significant therapeutic benefits.”100

 Children: BZDs should generally avoided (due to long‐term risk of dependence)101

 Patients with kidney or liver failure (impaired elimination of drugs). It is important to consider appropriateness of a particular benzodiazepine and dosage adjustments in these patients. Diazepam and other long‐acting benzodiazepines may accumulate to toxic levels and may not be appropriate in these patients (e.g. when considering switching to diazepam when discontinuing a short‐acting benzodiazepine).95  Patients with liver disease: decrease dosage (except possibly lorazepam and oxazepam)  “Liver and kidney function tests and blood cell counts should be performed regularly during long‐term therapy, and benzodiazepines should be administered with caution to patients with hepatic or renal disease.”30 (“A few cases of hematological adverse effects have been reported with benzodiazepine use i.e. “leukopenia (including neutropenia and granulocytopenia), agranulocytosis, aplastic anemia, hemolytic anemia, decreased hematocrit, eosinophilia, and leukocytosis.”30)

 Patients whose job or lifestyle requires unimpaired intellectual or psychomotor function (increased risk with residual and cumulative CNS depressant effects)30

 All parties involved in the treatment process underestimating the degree of impairment caused by benzodiazepines

 Patients with certain disease states may be at increased risk/polydrug use e.g. patients using more than one sedative‐type drug such as opioids or alcohol.6,79,80,98,99

Patients may have complex psychiatric conditions and “Misuse of BZDs is most often found within a polydrug use pattern (the use of two or more psychoactive drugs in combination to achieve a particular effect) as an attempt to achieve a subjective euphoria or reduce anxiety symptoms or treat the side or withdrawal effects of other drugs of abuse.”14,102 People dependent on opioids may take benzodiazepines to augment the effects of the opiates which increase the risk for synergistic central nervous system and respiratory depression. Opiate dependence is also associated with other risk factors such as HIV and hepatitis C.14

Patients with bipolar disorder According to a psychiatrist from at Mayo Clinic (William V Bobo, M.D.), there is a high prevalence of alcohol and substance use disorder in patients with bipolar disorder.103 In acute settings benzodiazepines may be appropriate to use as adjuncts to core mood stabilizers (“for improving sleep and controlling mania and aggressive behavior”), but long‐term use is of particular concern in these patients because of safety issues related to other substance or alcohol abuse and because of the potential for benzodiazepine abuse.103

Clinical Guidelines

Anxiety Current guidelines from the World Federation of Societies of Biological Psychiatry (2012)104 recommend using a second generation antidepressant as first‐line therapy in the treatment of anxiety disorders because they are effective and well‐tolerated. According to the guidelines, benzodiazepines should only be used in treatment‐resistant patients without a history of substance abuse.104 The most current recommendations from the World Council of Anxiety (2003)105‐110 also support the use of second generation antidepressants as first‐line therapy in the treatment of anxiety disorders. According to the World Council of Anxiety, benzodiazepines may be beneficial in the short‐term treatment of anxiety disorders but their adverse‐effect profiles limit use in the long‐term treatment of anxiety disorders.105‐110 In general, short‐term is defined as ≤ 4 months. The APA has published individual practice guidelines with recommendations for each of the individual anxiety disorders.111‐113 Overall, the APA recommends using a second generation antidepressant as first‐line therapy for the treatment of PTSD, OCD or panic disorder. Benzodiazepines are recommended only as add‐on therapy for patients who are treatment‐ resistant to first‐line treatment.111‐113 Guidelines from the American Academy of Child and Adolescent Psychiatry recommend treatment with a second‐generation antidepressant if CBT is unsuccessful in the treatment of OCD in pediatric patients (2012).114 Two National Institute for Health and Care Excellence (NICE) guidelines are available: one addressing the management of general anxiety and panic disorders in adults19 and one developed by the National Collaborating Centre for Mental Health on behalf of NICE addressing social anxiety disorder.20 Both guidelines recommend the second‐generation antidepressant agents for first‐line pharmacologic treatment. According to the guidelines, benzodiazepines should only be used short‐term in general anxiety and panic disorders and should not be used in social anxiety disorder. Table 2 summarizes the current clinical practice guidelines available for the treatment of anxiety disorders.

Table 2. Clinical Guidelines for the Treatment of Anxiety Disorders Guideline Recommendations Guidelines for the First‐line pharmacological treatments pharmacological  selective serotonin reuptake inhibitors for all anxiety disorders treatment of anxiety  serotonin‐norepinephrine reuptake inhibitors in GAD, panic disorder, agoraphobia disorders, obsessive‐  pregabalin for generalized anxiety disorder only compulsive disorder and posttraumatic stress Combination of medication and cognitive behavior therapy is the clinically desired treatment disorder in primary care; strategy. World Federation of Societies of Biological Benzodiazepines should be used as needed and short‐term, in addition to a regular Psychiatry (2012)104 pharmacological treatment regimen. Of note, benzodiazepines were not found to be effective in acute stress disorder and in conditions with depression comorbidity or OCD. Practice parameter for the When possible, CBT is the first line treatment for mild to moderate cases of OCD in children. assessment and treatment of children and For moderate to severe OCD, medication is indicated in addition to CBT. adolescents with obsessive‐compulsive Serotonin reuptake inhibitors (SRIs) are the first‐line medications recommended for OCD in disorder; American children and should be monitored closely for response, tolerability and safety. Academy of Child and Adolescent Psychiatry (2012)114 NICE: Generalized anxiety First‐line: disorder and panic  Choice of high‐intensity psychological intervention (cognitive behavior therapy (CBT) or disorder in adults: applied relaxation or drug treatment management. [CG113],  Psychological Intervention: 12 to 15 1‐hour sessions of psychological intervention 201119  Pharmacological Treatment: Selective serotonin reuptake inhibitor (SSRI)

Second‐line:  A second SSRI or serotonin/norepinephrine reuptake inhibitor (SNRI)  If unable to tolerate SSRI/SNRI, consider pregabalin  ONLY use benzodiazepine short‐term  Do NOT use antipsychotics for GAD NICE: Social anxiety Interventions: disorder: recognition,  Cognitive behavioral therapy (CBT). Promote CBT before pharmacological therapy. assessment and treatment  For Partial Response to CBT, consider combination of drug therapy and CBT NICE guidelines [CG159], o Pharmacologic therapy: selective serotonin reuptake inhibitor (SSRI) such as 201320 escitalopram or sertraline.  For Partial Response to Drug Therapy (after 12 weeks) or Side Effects: o Alternative SSRI (fluvoxamine or paroxetine) or serotonin/norepinephrine reuptake inhibitor (SNRI), such as venlafaxine o Monoamine oxidase inhibitor (MAOI) such as phenylzine or moclobemide

NOT recommended: pharmacological interventions including anticonvulsants, tricyclic antidepressants, benzodiazepines, or antipsychotic medication, St. John’s wort or other over‐the‐counter preparations Treatment of Patients Treatment of ASD or PTSD symptoms includes three broad categories of intervention: With Acute Stress Disorder pharmacological treatment, psychotherapeutic intervention and education and supportive and Posttraumatic Stress measures. Disorder, APA (2004)111 SSRIs are recommended as first‐line medication treatment for PTSD.

Other antidepressants (Tricyclic antidepressants and MAOIs) and benzodiazepines may also be beneficial as second‐line or add‐on options.

Guideline Recommendations Practice guideline for the CBT and SSRIs are recommended on the basis of clinical trial results as safe and effective treatment of patients with first‐line treatments for OCD; “Clomipramine, fluoxetine, fluvoxamine, paroxetine, and obsessive‐compulsive sertraline, which are approved by the FDA for treatment of OCD, are recommended disorder, APA (2007)112 pharmacological agents.”

Strategies for Moderate Response: Augment with a second‐generation antipsychotic or with CBT, if not already provided.

Strategies for Little or No Response: Switch to a different SSRI (may try more than one trial), switch to clomipramine, augment with a second‐generation antipsychotic, switch to venlafaxine, switch to mirtazapine.

Benzodiazepines cannot be recommended as monotherapy for OCD. Practice guideline for the The use of an SSRI, SNRI, TCA, benzodiazepine (appropriate as a monotherapy only in the treatment of patients with absence of a co‐occurring mood disorder) or CBT as the initial treatment for panic disorder is panic disorder; APA (1998, strongly supported by demonstrated efficacy in numerous controlled trials. update 2009)113 Key: GAD=generalized anxiety disorder, SSRI=selective serotonin reuptake inhibitor, SNRI=selective serotonin/norepinephrine reuptake inhibitor, CBT=cognitive behavior therapy

Insomnia The recent American College of Physicians (ACP) Guidelines recommends cognitive behavioral therapy for insomnia (CBT‐I) as the initial treatment for chronic insomnia disorder and that clinicians use a shared decision‐making approach with regards to pharmacological therapy (if behavioral therapy fails).28 Pharmacologic treatment should be considered second line treatment and should be used in conjunction with nonpharmacologic therapy. The authors stated that evidence was insufficient to determine the benefits of chronic benzodiazepine therapy in the general population or in older adults, and that only a few trials met the inclusion criteria because many assessed only short durations of treatment.28

Table 3. Guidelines for the treatment of insomnia Guideline Recommendations Management of chronic 1. Initial treatment for chronic insomnia treatment: Cognitive behavioral therapy for all insomnia disorder in adult patients (Grade: strong recommendation, moderate‐quality evidence) adults: a clinical practice guideline from the “Cognitive behavioral therapy for insomnia consists of a combination of treatments that American College of include cognitive therapy around sleep, behavioral interventions (such as sleep restriction Physicians (2016)28 and stimulus control), and education (such as sleep hygiene). It can be performed in primary care. There are various delivery methods for CBT‐I, such as individual or group therapy, telephone‐ or Web‐based modules, or self‐help books. Most studies focused on in‐person CBT‐I; however, the data suggest that other delivery methods are also effective.”

2. Clinicians should use a shared decision‐making approach (“including a discussion of the benefits, harms, and costs of short‐term use of medications, to decide whether to add pharmacological therapy in adults with chronic insomnia disorder in whom cognitive behavioral therapy for insomnia (CBT‐I) alone was unsuccessful.”) (Grade: weak recommendation, low‐quality evidence)

Pharmacotherapy: The guidance state that evidence was insufficient for pharmacologic therapy or the choice of agent to treat patients if CBT‐I alone was unsuccessful. In the benefits/harms consideration, the American College of Physicians Guidelines state that evidence was insufficient to determine the benefits of pharmacologic therapy with benzodiazepines in the general population or in older adults, and that only a few trials met the inclusion criteria because many assessed short durations of treatment.

Guideline Recommendations Clinical Considerations:

 Medications not longer than 4 to 5 weeks (ideally). They state that the skills learned in CBT‐I can manage insomnia over the longer term.  It is recommended that clinicians consider treatable secondary causes of insomnia (e.g. restless leg syndrome, depression, pain, benign prostatic hypertrophy, substance use disorder, sleep apnea, etc.) before recommending to continue insomnia medications.  “If after a trial of CBT‐I, a shared decision is made to continue medications for longer than 4 to 5 weeks, clinicians should revisit the need for medication continuation at periodic intervals.”  “Chronic insomnia disorder itself may have deleterious health effects. However, whether medications decrease the harmful health effects of sleep deprivation is unknown, and evidence is insufficient to assess the balance of benefits and hams from long‐term use of medications.”  Older patients: more sensitive to adverse effects of medications and should be monitored closely.

American Academy of Recommend using pharmacotherapy in combination with behavioral therapy in the Sleep Medicine (2008)26 treatment of insomnia. 1. First‐line recommended pharmacotherapy: short to intermediate acting benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon, and temazepam) or ramelteon.26 2. Lowest effective maintenance dosage, accompanied by patient education, and followed on a regular basis to assess for safety and effectiveness.26

Obvious concerns regarding potential harms were noted in the American College of Physicians Guidelines: “Harms were insufficiently reported in many of the included randomized controlled trials (RCTs), which most often provided data only on study withdrawals. In addition to evidence from the systematic review on study withdrawals and adverse effects, specific adverse effects associated with the various pharmacologic treatments are summarized in Appendix Tables 4 and 5 of the original guideline document. Data from observational studies suggest that serious adverse effects, such as dementia and fractures, may be associated with hypnotic drugs. Product labels from the U.S. Food and Drug Administration (FDA) warn patients about cognitive and behavioral changes, such as possible driving impairment and motor vehicle accidents, as well as other adverse effects. The FDA also recommends lower doses of benzodiazepine and nonbenzodiazepine hypnotics in women and in older or debilitated adults. In addition, the FDA recommends short‐term use of these drugs, although many patients may continue their use for extended periods.”

Table 4. Other Guidelines/Regulatory Safety updates Guideline Recommendations CDC Guideline for  Avoid concurrent opioids and benzodiazepines whenever possible Prescribing Opioids for Chronic Pain ‐ United “Benzodiazepines and opioids both cause central nervous system depression and can States, 2016.115,116 decrease respiratory drive. Concurrent use is likely to put patients at greater risk for Note that this is a main potentially fatal overdose.”

Guideline Recommendations American Geriatrics  Avoid benzodiazepines in older adults Society 2015 Updated Beers Criteria for “Older adults have increased sensitivity to benzodiazepines and decreased metabolism of Potentially Inappropriate long‐acting agents; in general, all benzodiazepines increase risk of cognitive impairment, Medication Use in Older delirium, falls, fractures, and motor vehicle crashes in older adults.” Adults73 “May be appropriate for seizure disorders, rapid eye movement sleep disorders, benzodiazepine withdrawal, ethanol withdrawal, severe generalized anxiety disorder, and periprocedural anesthesia.”

Quality of evidence: Moderate Strength of recommendation: Strong 2015 AGS Beers Criteria for Delirium Potentially Inappropriate  Avoid benzodiazepines “in older adults with or at high risk of delirium because of the Medication Use in Older potential of inducing or worsening delirium” Adults Due to Drug‐ Dementia or cognitive impairment Disease or Drug‐Syndrome  Avoid benzodiazepines “because of adverse CNS effects” Interactions That May History of falls or fractures Exacerbate the Disease or  May cause ataxia, impaired psychomotor function, syncope, additional falls; shorter‐ Syndrome73 acting benzodiazepines are not safer than long‐acting ones => Avoid unless safer Only included information alternatives are not available regarding benzodazepines.  If one of the drugs must be used, consider reducing use of other CNS‐active medications Please refer to the that increase risk of falls and fractures (i.e., anticonvulsants, opioid‐receptor agonists, guidelines for complete antipsychotics, antidepressants, benzodiazepine receptor agonists, other sedatives and information. hypnotics) and implement other strategies to reduce fall risk

American Academy of STANDARD level of recommendation (for both medications: high body of evidence; benefit Sleep Medicine Clinical clearly outweighs harm; FDA indication) Practice Guideline: The pramipexole and ropinirole. treatment of restless legs syndrome and periodic GUIDELINE level of recommendation: limb movement disorder in levodopa with dopa decarboxylase inhibitor (high body of evidence; benefits closely adults—an update for balanced with harms; off‐label use) 2012: practice parameters opioids (low body of evidence; benefits clearly outweighs harms; off‐label use) with an evidence‐based gabapentin enacarbil (high body of evidence; uncertain benefits vs. harms; FDA indication) systematic review and cabergoline (only use if other recommended agents have been tried first due to side effects meta‐analyses.117 including heart valve; high body of evidence; benefits closely balanced with harms; off‐label)

OPTION level of recommendation (all low body of evidence or very low for ferritin; all off‐ label use) Carbamazepine (benefits closely balanced with harm) Gabapentin (unclear benefit vs harm) Pregabalin (benefits closely balanced with harm Clonidine (unclear benefit vs harm) Iron supplementation if low ferritin levels (unclear benefit vs harm)

Refer to guidelines for recommendations secondary to end stage renal disease (ESRD), neuropathy, and superficial venous insufficiency.

Benzodiazepines (clonazepam) “There is insufficient information on the effect of benzodiazepines on the treatment of RLS.” (few small studies with contradictory results)

“The committee strongly recommends that alternate and better studied RLS medications be considered in RLS therapy. The “no recommendation” status applies to the use of benzodiazepines as a first line agent. For example, clonazepam could still be considered as an adjunctive medication in treatment of RLS.”

Guideline Recommendations Medicines and Healthcare “Reminder for healthcare professionals: products Regulatory  given the risks associated with the use of benzodiazepines, patients should be prescribed Agency (MHRA) Drug the lowest effective dose for the shortest time possible. Maximum duration of Safety Update treatment should be 4 weeks, including the dose‐tapering phase” 6 July 2011 Addiction to benzodiazepines and codeine118 American Board of Internal “Recommends against the use of benzodiazepine drugs for adults 65 years and older.” Medicine Foundation Choosing Wisely Campaign (2012)119,120

Also, as part of this “advised physicians and patients to refrain from using benzodiazepines as first‐line campaign: treatment for insomnia in older adults.” Refer to 2015 AGS guidelines above. American Geriatrics Society (2013)119,121

NICE Guidance: Do Not Do Recommendation Depression in adults: The guidance include three strategies that should not be used routinely of which one recognition and involves benzodiazepines: management (CG90)  “augmentation of an antidepressant with a benzodiazepine for more than 2 weeks Published date: as there is a risk of dependence” June 2016122

Technology assessments/evidence‐based synopses

Table 5. Technology Assessments/Evidence‐based synopses Technology Assessment Findings Canadian Agency for Drugs KEY FINDINGS and Technologies in “The short‐term use of benzodiazepines for the treatment of generalized anxiety disorder is Health. Short‐ and long‐ recommended as adjunctive therapy to antidepressants until their effectiveness is apparent term use of or in times of acute crisis or increased anxiety. One guideline specified a daily dosage of benzodiazepines in alprazolam ranging between 1.5 mg and 6 mg when used to control the anxiety associated patients with generalized with first‐line use of antidepressants. Long‐term use of benzodiazepines is only anxiety disorder: a review recommended in patients who do not respond to or cannot tolerate numerous first‐line of guidelines. 28 July therapies. No recommendations were provided on the maximum daily doses for long‐term 2014123 BZD treatment for GAD. For special populations, the guidelines generally advise against the use of BZDs in the elderly (or to use at lower adult doses if required), to use them sparingly in children and adolescents, and to use them with caution during the first and third trimesters of pregnancy, during labour and delivery, and when breastfeeding.”

Canadian Agency for Drugs Published in 2011 and included guidelines published 2005‐2010 so it would be better to and Technologies in rather refer to the 2015 updated BEERS criteria.73 However, their review included below did Health. Benzodiazepines in not include BEERS criteria either. Older Adults: A Review of Clinical Effectiveness, Cost‐ Effectiveness, and Guidelines January 2011124

Technology Assessment Findings Canadian Agency for Drugs They did not identify any studies or guidelines on benzodiazepines in older adults based on and Technologies in their selection criteria. Health. Treatment of Older Adults with Insomnia, Agitation, or Delirium with Benzodiazepines: Clinical Effectiveness and Guidelines. 2016 Canadian Agency for Drugs “Three systematic reviews and meta‐analyses126‐128, two randomized controlled trials129,130*, and Technologies in and five non‐randomized studies131‐135 were identified regarding strategies to safely and Health. Discontinuation effectively discontinue adult patients from long‐term benzodiazepine use.” Strategies for Patients with Long‐Term Benzodiazepine Use: Clinical Evidence and Guidelines. 22 January 2015125

Canadian Agency for Drugs “Two systematic reviews and fourteen non‐randomized studies regarding the developmental and Technologies in harms in infants and young children associated with in utero exposure to prescription drug Health. Developmental abuse were identified.” The selection criteria included opioids, stimulants, benzodiazepines effects of in utero and gabapentins, but none of the evidence identified was regarding benzodiazepines. exposure to prescription drug abuse in infants and young children: harms. 5 November 2014136

Canadian Agency for Drugs “Research Questions: and Technologies in 1. What is the clinical effectiveness of long‐term versus short‐term use of benzodiazepines? Health. Long‐term Use of 2. What is the clinical evidence regarding the safety of long‐term use of benzodiazepines?” Benzodiazepines: Clinical Refer to Duration of use section. Effectiveness and Safety. 6 July 2015

*In 2015, Tannenbaum commented in BMJ on what is known about interventions for long‐term benzodiazepine use, what the Vicens et al. (2014)129 study added, limitations, future research, and whether these results would change her practice and why? Her response to the latter was: “Yes. Discussions about benzodiazepine discontinuation with chronic users were previously thought to be excessively time‐consuming and of little value. Knowing that one‐in‐two patients will successfully taper after a 20 min conversation and distribution of a tapering protocol— without the need for close follow‐up—is a strong motivator for introducing this routine into my practice. These results provide a way to personally contribute to the reduction of potentially harmful treatments as advocated by the Choosing Wisely campaign for physicians (http://www.choosingwisely.org/).”137

In 2016, Vicens et al. assessed whether the interventions that were shown to be successful at 1 year to promote cessation of long‐term benzodiazepine use (Vicens et al. 2014129), were also efficacious at 3 years.138 The authors found that they were successful after 3 years (“patients that discontinued at 12 months remained abstinent at 3 years”) and that “discontinuation of BZD use did not have a significant effect on anxiety, depression, or sleep quality.”138

Efficacy

The American College of Physicians 2016 Guideline for the management of chronic insomnia was based on a systematic review of randomized controlled trials published 2004 through September 2015; a full evidence report,81 and 2 background evidence review papers.139,140 The evidence review was sponsored by the Agency for Healthcare Research and Quality (AHRQ). The full evidence report included “181 unique studies (data from 128 unique RCTs and 3 systematic reviews that synthesize data from 42 unique RCTs) and 12 observational studies,” but most trials were short‐term studies.81 Sufficient evidence was identified for cognitive behavioral therapy for insomnia (CBT‐I) which “improved global outcomes and nearly all sleep parameters in the general adult population, older adults, and adults with pain”.81 Less evidence exist for other psychological interventions.81

“Low‐ to moderate‐strength evidence indicated that the nonbenzodiazepine hypnotics eszopiclone and zolpidem, and the orexin receptor antagonist suvorexant, improved short‐term global and sleep outcomes in general adult populations. Doxepin improved sleep outcomes. The absolute mean effect was small. Evidence for benzodiazepine hypnotics, melatonin agonists, and antidepressants in general populations and for most pharmacologic interventions in older adults was generally insufficient.”81 The full publication contains tables that summarize all the available evidence for the general population and for older adults.81

McCleery et al. (2016 Cochrane review) assessed treatments for sleep disorders in people with dementia and found no RCTs of benzodiazepines (and other drugs) that are widely prescribed for sleep problems in dementia.141 The authors also mention the uncertainties with regard to benefits vs. risks associated with these common treatments in their conclusion.141

Bighelli, I. et al. (2016 Cochrane review) assessed antidepressants and benzodiazepines for panic disorder in adults.142 They only found a few trials, low quality evidence of no difference between antidepressants and benzodiazepines in terms of response rate, and they did not “find clinically significant differences between individual benzodiazepines.”142 However, they report many limitations such as no information provided regarding random sequence generation and allocation concealment and blinding, and “the study protocol was not available for almost all studies so it is difficult to make a judgment on the possibility of outcome reporting bias. Information on adverse effects was very limited.”142 They therefore conclude that there is insufficient evidence. “…the possible role of antidepressants and benzodiazepines should be assessed by the clinician on an individual basis”, and choice should be based on overall evidence of efficacy and tolerability and by considering long‐term tolerability issues.142

Examples of off‐label uses with currently available evidence

Disturbed behavior / to reduce psychotic symptoms / schizophrenia Gillies et al. (2013 Cochrane review) assessed the effects of using benzodiazepines to control disturbed behavior and reduce psychotic symptoms either alone or in combination with antipsychotics and concluded that the evidence is not good/insufficient for using them alone or adding them to other drugs, and they have the potential for additional unnecessary adverse effects.143

Dold, et al. (2012 Cochrane review)144 found that “There is currently no convincing evidence to confirm or refute the practise of administering benzodiazepines as monotherapy or in combination with antipsychotics for the pharmacological treatment of schizophrenia and schizophrenia‐like psychosis.

Low‐quality evidence suggests that benzodiazepines are effective for very short‐term sedation and could be considered for calming acutely agitated people with schizophrenia.”144

Neuropathic pain and fibromyalgia Corrigan, R. et al. (2012 Cochrane review)145 assessed the efficacy and safety of clonazepam in the treatment of neuropathic pain and fibromyalgia (in adults) and found no evidence to support its use in these indications.

Relief of breathlessness Simon, S.T. et al. (2016)146 assessed the use of benzodiazepines for the relief of breathlessness in advanced malignant and non‐malignant diseases (in adults) and found no evidence for or against benzodiazepines for the relief of breathlessness in people with advanced cancer and COPD. However, most studies included were small and had an unclear risk of bias so there is a need for well‐conducted and adequately powered studies. The authors supposed that “benzodiazepines may be considered as a second‐ or third‐line treatment, when opioids and non‐pharmacological measures have failed to control breathlessness.”146

As a muscle relaxant in the treatment of rheumatoid arthritis (RA) Richards, B.L. et al. (2012)147 evaluated the efficacy and safety of muscle relaxants (which included benzodiazepines) in the treatment of RA pain. All included trials were rated by the authors at high risk of bias. There were concerns about the associated adverse effects of muscle relaxants (predominantly drowsiness and dizziness), even short‐term, and the authors concluded that “Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.”147

Long‐term use

Short‐term treatment was initially recommended based on the duration of trials (e.g. 2‐3 weeks) and since due to insufficient evidence (most trials are of short duration)28 and the potential adverse effects28 and misuse/abuse sequela. However, in clinical practice benzodiazepines are often used for much longer.29 Some have reported that duration of treatment is somewhat controversial,29,148 but guidelines, recommendations by regulatory bodies and product information recommend that benzodiazepine treatment be limited to short‐term use. However, despite repeated recommendations and warnings, prescribers are still prescribing them for months or years.149 Investigators of the study mentioned under ‘Increased risk factors: High doses’ (presented at the American Academy of Addiction Psychiatry (AAAP) 27th Annual meeting), noted that it was interesting to see that “the majority of patients in the sample (60%) had been receiving benzodiazepines for 5 years or longer” even though it is indicated for “short‐ term, limited duration of use because there aren’t many illnesses that necessitate long‐term use of benzos.”1 It is not only opioid dependence and abuse that has become a major problem. Benzodiazepine dependence and misuse/abuse is recognized as a major clinical problem and in the UK for example, “the National Performance Assessment Framework for the NHS makes it a national priority to reduce this within each health board area. Junior doctors who have recently graduated from medical school are commonly placed in rotations where they have to manage patients on benzodiazepine prescriptions. It is necessary for doctors in general to be aware of the essentials of benzodiazepines not only for the

21 adequate management of patients on chronic benzodiazepine prescriptions, but also for responsible prescription of this drug when it is appropriate.”

Authors of the recently published (July 2016) American College of Physicians Guidelines on the Management of chronic insomnia disorder found that most studies were short‐term. Long‐term adverse effects are unknown with some observational studies indicating rare, but serious harms.28,81 The authors therefore state that “as indicated on FDA labeling, pharmacological treatments for insomnia are intended for short‐term use, and patients should be discouraged from using these drugs for extended periods.”28 The effectiveness of benzodiazepines for long‐term use as anxiolytics (i.e., Lexicomp states > 4 months as anxiolytics and >4‐10 weeks for panic disorder) has not been established either and continued therapy with benzodiazepines should be reassessed periodically.30 Dosages may require frequent adjustments due to the episodic nature of anxiety.30 Even though we are not focusing on epilepsy/seizure disorders, it is worth mentioning that usefulness in the long‐term management of seizure disorders is limited by the fact that tolerance often develops to anticonvulsant effects of benzodiazepines.30

Regulatory authorities (FDA and MHRA) recommend that the duration of use of benzodiazepines be limited to 2 to 4 weeks. There has been concerns about the risk of dependence and withdrawal reactions after long‐term use of benzodiazepines since the 1980s.118 In fact, the MHRA safety alert (July 2011) reminded healthcare professionals that “patients should be prescribed the lowest effective dose for the shortest time possible. Maximum duration of treatment should be 4 weeks, including the dose‐ tapering phase.”118

CADTH prepared a report/reference list on the long‐term use of benzodiazepines in terms of clinical effectiveness and safety.150 The report states that they identified two systematic reviews (Billioti et al. (2015)151 and Sim et al. (2015)152, one meta‐analysis (Zhong et al. (2015)148, and three randomized controlled trials.100,153,154 However the latter (of the 3 RCTs) was a preliminary explorative study in which the effects of temazepam was assessed for a week in patients with COPD to determine the feasibility to perform a larger study.154

Billioti et al.151 found that nine out of ten studies reported an increased risk of dementia in benzodiazepine users, and that the “risk increased with cumulative dose and treatment duration and when long‐acting molecules were used.” They therefore conclude that “the body of evidence seems sufficient for avoiding prescriptions or renewals that are not fully justified and indiscriminate long‐term use.”151

Sim et al.152 examined the clinical outcomes for benzodiazepines in schizophrenia. This included two long‐term studies that compared benzodiazepines with first‐generation antipsychotics (FGAs) in which greater global improvements were reported for antipsychotics. The authors concluded that “Benzodiazepine superiority over placebo was found for global, psychiatric and behavioural outcomes, but inferiority to antipsychotics on longer‐term global outcomes. Conflicting evidence exists regarding the addition of benzodiazepines to antipsychotics; thus the use of benzodiazepines in clinical practice and antipsychotic trials should be limited.”152

Zhong et al. included six studies (11,891 dementia cases and 45,391 participants) in their review and found that “long‐term benzodiazepine users have an increased risk of dementia compared with never users” and that the “risk of dementia increased by 22% for every additional 20 defined daily dose per year (RR, 1.22, 95%CI 1.18‐1.25).”148 These investigators included “nested case‐control or prospective

22 cohort studies that provided risk estimates on the association of benzodiazepine use with risk of dementia, and a clear definition of status of benzodiazepine use.”148 The authors state that the findings should be treated with caution until more evidence is available from large prospective cohort studies with long follow‐up duration.148

As is the case with any medication with abuse potential, prescribing excessive quantities of benzodiazepines may lead to misuse and abuse and its associated adverse sequela (not just by the patient, but also other people). It is important to note that dependence does not mean addiction. Patients may need higher doses because of tolerance and strategies to prevent this include considering alternating agents, or not taking the benzodiazepine every night.29 It is recommended to “implement periodic tapers for consecutive administration to determine continued need” and to “consider supplementing with Cognitive Behavioral Therapy (CBT) during taper.”29

Darker et al. in a Cochrane review reported that “long term use of BZDs is not generally recommended and can lead to physical and psychological dependence and withdrawal symptoms when patients reduce or stop using them.” In this Cochrane review, the authors aimed ‘to measure the effectiveness of psychosocial interventions for treating people who harmfully use, abuse or are dependent on benzodiazepines (BZDs).’ Others have also evaluated interventions for benzodiazepine harmful use.137,155

There is conflicting evidence regarding long‐term benzodiazepine use and cognitive decline. Chung, Jun Ku et al. (2016)156 in a small pilot study found that long‐term benzodiazepine use (6 months or longer) was not associated with cognitive decline, but according to Dr Cheong (Professor of psychiatry, University of Florida College of Medicine) "Just because it does not 'prove' that there is a direct link between benzodiazepine use and the development of cognitive decline or dementia, it does not necessarily disprove that there is a link between benzodiazepines and cognitive decline." Dr Maust (University of Michigan) noted that the sample size is small and Alzheimer's Disease Neuroimaging Initiative (ADNI) patients are not at all representative of the general population (average years of education in the benzodiazepine group was more than 16 years). These clinicians stated that benzodiazepines should be used with caution in the elderly because of the link between benzodiazepines and falls, fractions, car accidents, confusion, amnesic effects, and cognitive impairment.157 Gray et al. in a recently published population based cohort (mean follow‐up of 7.3 years) found that “The risk of dementia is slightly higher in people with minimal exposure to benzodiazepines but not with the highest level of exposure. These results do not support a causal association between benzodiazepine use and dementia.”158

As mentioned earlier, in acute settings benzodiazepines may be appropriate to use as adjuncts to core mood stabilizers (“for improving sleep and controlling mania and aggressive behavior”103) in patients with bipolar disorder, but long‐term use is of particular concern in these patients because of safety issues related to other substance or alcohol abuse issues and because of the potential for benzodiazepine misuse or abuse.103 Currently there is limited evidence available and there is a need for additional studies. Based on limited evidence (and trial limitations), it appears that long‐term benzodiazepine use in these patients may not significantly affect outcomes and there is a potential for abuse and an association with recurrences.159 Another study by the same research team using data from the same study explored the characteristics of patients that received benzodiazepines and it appears that these patients had more complex psychiatric symptoms and received more psychotropic medications in an attempt to achieve better control of symptoms.160 Overall, there is insufficient evidence to make specific recommendations or to give a complete understanding of scenarios when long‐term benzodiazepine use would be beneficial or detrimental, but these results provide some

23 insight into factors to consider. A cautious approach assessing the potential improvement (or not) weighed against the potential risks should be considered individually for every patient and should be reviewed regularly.

In general, there is agreement that apart from exceptional circumstances (e.g. terminally ill patients), there is no evidence to support long‐term use of BZDs and major safety concerns exist.74 Some patients report enhanced sleep with long‐term use, but it is reported that the effect wears off in a few weeks and rebound insomnia is experienced upon cessation, thus there is no objective evidence to support long‐ term use.6 According to a recent editorial by BRIAN JOHNSON, MD, State University of New York Upstate Medical University, New York, it is unclear where long‐term benzodiazepine use fits into current medical practice. However, he discusses the associated risks and factors that would increase the risks (which has been incorporated into the report).

Comparison of Xanax IR (alprazolam) to Xanax XR and other commonly used anxiolytics

According to the recently published (July 2016) American College of Physicians Guidelines on the Management of chronic insomnia disorder in adults and the AHRQ review, there was insufficient evidence overall on the comparative effectiveness and safety of the various pharmacologic treatments (within or across classes).28,81 Evidence was also insufficient to compare medications with CBT‐I.28,81

Bighelli et al. (2016 Cochrane review) did not find clinically significant differences between benzodiazepines when they assessed benzodiazepines and antidepressants for effects in panic disorder.142

In general, it was noted in the literature that the risk of abuse might be higher with fast‐acting benzodiazepines such as lorazepam and alprazolam (Xanax) compared to clonazepam which is believed to have a lower risk of abuse because of the “slow‐on and slow‐off action.”101 The Drug Enforcement Administration (DEA) also reports that it is particularly the rapid onset benzodiazepines that are abused to produce euphoric effects.7

 FDA approved (labeled) indications for alprazolam formulations are as follows: “Anxiety disorders (immediate release tablet, oral concentrate, orally‐disintegrating tablets): Treatment of generalized anxiety disorder (GAD), short‐term anxiety and anxiety association with depression Panic disorder (extended‐release tablets, oral solution, orally‐disintegrating tablets, immediate‐release tablets): Treatment of panic disorder, with or without agoraphobia”30

Comparison of pharmacokinetics of alprazolam IR and XR161 Similarities Differences IR & XR IR XR Bioavailability Narrow/short therapeutic window* Wider therapeutic window* resulting in: Distribution  Blood drug levels rapidly climb into toxic  Fewer side effects Metabolism range (greater side effects), followed by  Less breakthrough anxiety before next Elimination  Rapid descent of blood drug levels dose Extent of accumulation below the minimum effective concentration

Similarities Differences IR & XR IR XR “Clock‐watching effect”=> therapeutic effects disappear rapidly (well before time for the next dose) Duration of action: 4‐6 hours Duration of action: ≥12 hours *Therapeutic window: below toxicity range and above the minimum effective concentration

No Cochrane or other reviews were identified in the Cochrane Library comparing alprazolam IR to XR, only some clinical trials that are discussed below.

In 1995, Klein in a review, based on 3 small studies, reported that benzodiazepines with short half‐lives were associated with a higher risk of discontinuation difficulties compared to those with long half‐ lives.162 “The nature of the anxiety disorder for which treatment is prescribed might also have a bearing on successful medication discontinuation.”162 The author concluded that alprazolam XR and IR are equally effective, but that alprazolam XR may offer advantages during drug tapering and withdrawal.162

In 1995, Mumford et al. evaluated “the behavioral, subjective, and reinforcing effects of immediate‐ release (IR) alprazolam and extended‐release (XR) alprazolam to assess the effect of release rate on laboratory measures of abuse liability.”163 This was a small study (n=14), but it had some interesting results. The authors found that immediate‐release alprazolam had a higher potential for abuse than extended‐release alprazolam.163

In 2007, Leufkens et al. reported that the delayed absorption of alprazolam XR is expected to produce fewer and less severe side effects than alprazolam IR, and therefore should have less effect on potentially dangerous daily activities, such as driving.164 A small study was conducted to explore the effects of alprazolam XR (1 mg) and alprazolam IR (1 mg) on driving ability and cognitive function. The authors concluded that “The acute impairing effects of alprazolam XR 1 mg on driving and psychomotor functions were generally less, as compared to its immediate‐release equivalent, but still of sufficient magnitude to increase the risk of becoming involved in traffic accidents.”164

Poisoning/overdose considerations

Buckley et al. (1995) assessed “the sedative effects in overdose of temazepam and oxazepam compared with other benzodiazepines” through a cohort study of patients admitted with benzodiazepine poisoning “to determine if this explains reported differences in fatal toxicity,” and found that “oxazepam produced less sedation and temazepam more when compared to other benzodiazepines.”165 They concluded that their findings “were in accordance with fatal toxicity indices derived from coroners' data on mortality and rates of prescription” and that “the relative safety of benzodiazepines in overdose should be a consideration when they are prescribed.”165

Isbister et al. (2004) studied consecutive deliberate self‐poisonings by searching the database of poisoning admissions to a regional toxicology service in order to describe alprazolam poisoning and the relative toxicity compared to other benzodiazepines.166 “There were 2063 single benzodiazepine overdose admissions: 131 alprazolam overdoses, 823 diazepam overdoses and 1109 other benzodiazepine overdoses.”166 The authors found that alprazolam was significantly more toxic than other benzodiazepines. When comparing overdoses of alprazolam vs. benzodiazepines, the median length of stay was 1.27 times longer, patients were 2.06 times more likely to be admitted to intensive care unit (ICU), flumazenil was administered to 14% vs. 8% and 16% vs. 11% were ventilated, and 12%

25 vs. 10% had a GCS(Glasgow coma scale) <9 indicating coma.166 They conclude that “the increased prescription of alprazolam to groups with an increased risk of deliberate self poisoning is concerning and needs review.”166

Park et al. (2015) studied the association between benzodiazepine prescribing patterns and the risk of death from drug overdose among US veterans receiving opioid analgesics.96 The authors found that in these patients temazepam was associated with a decreased risk of death from drug overdose compared to clonazepam.96 “Benzodiazepine dosing schedule was not associated with risk of death from drug overdose.”96

There are major differences in potency between benzodiazepines. UK Medicines Information (UKMi) pharmacists have prepared a document regarding equivalent doses of benzodiazepines (for UK NHS healthcare professionals) that states there is broad agreement in the literature about equivalent doses, although clonazepam has a wide variety of reported equivalences so particular care is advised.95 Also, inter‐patient variability and differing half‐lives make it difficult to determine exact equivalents.95

Place in therapy and potential criteria to be reviewed/What can be done to reduce the risk?

Factors and limitations to consider:

 CDC recommends avoiding concurrent opioid and benzodiazepine use. We have reviewed opioids and implemented criteria/strategies to help reduce the opioid misuse/abuse and adverse sequela (i.e. overdose), but many opioid overdose cases involve benzodiazepine use which is an additional risk factor. It is important to also review benzodiazepine use.

 ‘Holy Trinity’: According to Horsfall & Sprague, current guidelines do not recognize an additional potential risk factor: skeletal muscle relaxants. Opioids, benzodiazepines, and skeletal muscle relaxants are all respiratory depressants. These agents are reportedly combined ('The Holy Trinity') in misuse to potentiate a 'high'.167

 Set realistic expectations for insomnia management: Natural changes in sleep occur with age (less sleep when older) and it is important to set realistic expectations.29 Educate about CBT‐I, because most patients that want drugs do not know or trust CBT‐I.

 Encourage use of effective alternatives (i.e. education or prior authorization):  Anxiety: CBT and antidepressants are the treatments of choice.  Insomnia: CBT‐I; refer to guideline and evidence section for options and quality of evidence.

 Evaluate appropriateness for indication:  Muscle relaxant: There may be some situations when use may be appropriate e.g. diazepam is indicated a “an adjunct for the relief of acute, painful musculoskeletal conditions”, but may also be used as “short‐ and long‐term management of skeletal muscle spasticity such as reflex spasm secondary to local pathology (e.g., trauma, inflammation), spasticity caused by upper motor neuron disorders (e.g., cerebral palsy, paraplegia), athetosis, stiff‐man syndrome, strychnine poisoning, and tetanus.”30

 Other short‐term indications: as part of a protocol for treating alcohol withdrawal, urgent treatment of acute psychosis with agitation or acute mania, single‐dose treatment of phobias (e.g. flying phobia), seizures (and a few neurologic disorders), sedation for office procedures.74  Off‐label use: Table 6 includes off‐label uses. Use in bipolar disorder is discussed below (Special populations: patients with complex psychiatric symptoms). Use in the treatment of restless leg syndrome is covered in table 4 (other guidelines). This is an off‐label use and alternatives should be considered e.g. ropinirole (refer to guideline recommendations).74 Burning mouth syndrome: Additional evidence is needed. Limited data suggests that clonazepam may help to reduce pain, but its dependence and abuse potential needs to be considered.30,168‐170 Tardive dyskinesia: Additional evidence is needed. Limited data suggests that clonazepam may be beneficial for the treatment of tardive dyskinesia.30,171 “Based on the American Academy of Neurology guideline for the treatment of tardive syndromes, clonazepam given for tardive dyskinesia is probably effective in decreasing tardive dyskinesia symptoms in the short‐term (approximately 3 months) and is suggested for the short‐term treatment of tardive dyskinesia.”30,172 Tic disorders: Additional evidence is needed. Limited data suggests that “clonazepam may be beneficial for multifocal tic disorder or Tourette disorder.”30,173

 Misuse or abuse/inappropriate use of benzodiazepines; Withdrawal symptoms: This can be reduced by prescribing/using the smallest dose for the shortest duration possible; “generally should not be prescribed continuously for more than a month”6; and by tapering the dose gradually.6,94 Use of longer acting agents also decrease withdrawal.

 Long‐term use: Basically, there is general agreement that apart from exceptional circumstances (e.g. terminally ill patients, ongoing on‐hand supply for epilepsy, muscle spasm due to conditions such as cerebral palsy and paraplegia), there is no evidence to support long‐term use and there are major safety concerns.74

 Pro re nata (PRN) or “as needed” benzodiazepines:

“New research suggests that while prescribing benzodiazepines "as needed" may be aimed at deterring patients from taking them unless absolutely necessary, the wording may actually foster misuse.”1,2

Results of a study conducted at Mount Sinai Beth Israel in New York City was recently presented at the American Academy of Addiction Psychiatry (AAAP) 27th Annual meeting. Researchers found that patients may actually be taking their medications more often when prescribed “as needed” than what the prescribers’ think they should.1,174 In this study, data was gathered on benzodiazepine prescribing from residents and fellows at their psychiatric outpatient clinic in April and May 2015.1,2 The residents and addiction and geriatric fellows in the clinic entered information into a spreadsheet of “who they were prescribing benzodiazepines for, what other medications they were prescribing, what the doses were, and other aspects of their prescribing practices.”1 The most commonly prescribed benzodiazepine was clonazepam (71% of these patients).1 “Based on 241 patients taking benzodiazepines as prescribed by 18 different clinicians, investigators found that those with a pro re nata recommendation were much more likely to exhibit markers of misuse—including requesting early refills, violating the clinic's prescription drug monitoring program, and engaging in a conflict

with their health care provider.”2

“because the prescriber is saying to take them only when needed, and the patient may be thinking, 'I can take them as much as I need.'"1

(lead author Amy Swift, MD.)

 Educating all parties involved to reduce risks: Explicitly advise the patient regarding the duration of treatment and that long‐term use is not recommended, and review the risks and side‐effects with the patient (including risk of dependence).74 Discontinuing benzodiazepines has been associated with fewer patient falls and improved cognitive and psychomotor function.174 Several references have been identified regarding strategies to safely and effectively discontinue benzodiazepine use.125 As mentioned by Tannenbaum based on the Vicens et al. (2014)129 study, this may just be a matter of making prescribers aware that even something as simple as “a 20 min conversation and distribution of a tapering protocol—without the need for close follow‐up” will result in one‐in‐two patients successfully tapering, and Vicens et al. (2016) found that “patients that discontinued at 12 months remained abstinent at 3 years”, and that “discontinuation of BZD use did not have a significant effect on anxiety, depression, or sleep quality.”138

 Special Populations: Are there patient subgroups based on demographics (e.g., age, racial groups, gender) or comorbidities for which one of the benzodiazepines is more effective or associated with fewer adverse effects? Benzodiazepines were evaluated in two special populations: geriatric patients (refer to BEERS criteria73) and patients with a history of substance abuse. Evidence is limited and inconsistent regarding benzodiazepine use in these populations. It is recommended benzodiazepine use be limited in these populations and used only when necessary.

Patients with a History of Drug/Alcohol Abuse It is generally accepted that a history of alcohol or drug abuse suggests a high potential for benzodiazepine abuse.173 Prescribing benzodiazepines in patients with a substance abuse history is controversial.175 There is limited evidence available comparing the benzodiazepines in patients with a history of drug/alcohol abuse.176,177 In two prospective studies, evidence was inconclusive regarding increased risk for abuse in this population.178,179 One longitudinal study found former alcoholics may reduce benzodiazepine use over time.180 Sokolow et al180, followed a cohort of 1,340 patients with a history of alcohol abuse over 8 months. The authors concluded that patients with a history of alcohol abuse are not at higher risk for benzodiazepine abuse. A second study found no differences in benzodiazepine use between patients with a history of substance abuse and patients without a history of substance abuse.181 Romach et al181, evaluated 123 patients taking a benzodiazepine, of which 40% (n = 49) had a history of prior history of alcohol abuse or dependence. Overall, in these studies, the patterns of benzodiazepine use by patients with a history of substance abuse did not indicate abuse, addiction, or drug dependence for any of the patients. Although there is limited evidence for benzodiazepine use in patients with a history of substance abuse, data suggest benzodiazepines may still be used in this population with a comprehensive treatment plan and careful follow‐up.176,177 It is important to remember that benzodiazepines are not first‐line recommended therapies for anxiety or insomnia. If used to treat anxiety or insomnia,

benzodiazepines should be used at the lowest effective dose and on a short‐term basis (≤ 4 months) only. It is a perplexing situation for prescribers to decide which patients with substance abuse histories may be good candidates for not abusing a prescribed benzodiazepine.175 Prescribers have to determine whether they are in fact dealing with a person who has a comorbid condition or a person trying to get them to think they have a comorbid condition.175 Drug seeking behavior include a history of antisocial behavior and dishonesty, multiple prescribers i.e. doctor shopping, patients reciting list of symptoms like it “comes straight out of DSM‐IV” (vs. a patient suffering from anxiety may not even mention “anxiety”), and requests for dose increases or early refills.175 Given that prescribers have to rely on their “clinical feel”175 on a case by case basis, it remains a better option to consider a trial of non‐abusive treatment options first. If benzodiazepines are prescribed, limiting quantities and follow‐ up visits would help prevent abuse. One prescriber states that he typically says to his patients, “Let’s not pay for a pound of this stuff until we know it works. I’ll write you enough for ten days and let me see you back in a week and we will look at what we want to prescribe from there. Call me if you have any problems.”175 He says that he does “the same sort of thing with refills.”175

Patients with complex psychiatric symptoms According to Dr. William Bobo, M.D. (Mayo Clinic psychiatrist), managing patients with bipolar‐ and coexisting anxiety disorders over the long term is a dilemma for clinicians, and it is controversial.103 "Higher illness complexity appeared to be the major driver of benzodiazepine use in patients with bipolar I and II disorder, and using benzodiazepines with more established treatments may represent clinicians' best efforts to bring complex psychiatric symptoms under better control, but that has to be weighed against the risks and limited evidence supporting long‐term benzodiazepine treatment. My recommendation would be to exercise caution. Not every patient is guaranteed a worse or no outcome with these drugs, but we need to better understand for which patients they may be safe and effective." NOTE: Use of benzodiazepines in bipolar is an off‐label use. Lexicomp summarizes guideline recommendations for this use as follows: “APA guidelines182 for the treatment of patients with bipolar disorder suggest that the use of benzodiazepines, such as clonazepam, in sedative doses may be useful short‐term as adjunctive therapy when used with traditional mood‐stabilizing agents. CANMAT guidelines183 for the management of patients with bipolar disorder recommend against the use of benzodiazepines as monotherapy, but suggest they may be useful adjunctive therapy for the sedation of acutely agitated patients. Similarly, WFSBP guidelines184 for the treatment of acute mania in bipolar disorder recommend benzodiazepines as adjunctive therapy to target anxiety and insomnia in patients taking mood‐stabilizing agents.”30

 Adverse effects & abuse/dependence potential: The most common drug‐related adverse reactions relate to the sedative effects of the medication class. Evidence available for differences in adverse event rates between the benzodiazepine agents is limited. The benzodiazepines have varying pharmacokinetic profiles which may contribute to differences in adverse event rates. Rapidly absorbed benzodiazepine agents have the most rapid onset of action but also the greatest abuse/dependence potential. Long‐acting benzodiazepine agents are associated with accumulation which may result in sedation, cognitive impairment and psychomotor retardation. Short‐acting benzodiazepine agents are associated with increased anxiety, insomnia and rebound effects upon discontinuation. All benzodiazepine agents are associated with dependence or tolerance with long‐ term use. Benzodiazepine therapy should be discontinued by a slow taper to avoid withdrawal effects. Adverse events may be reduced by using the smallest dose and shortest duration possible and by titrating the dose gradually. Refer to safety section for additional information.

 Duplication of therapy: Generally, use of two or more benzodiazepines at the same time is not indicated. In rare situations, differences in pharmacokinetic parameters may make use of two agents for different situations in the same patient a reasonable therapeutic choice (e.g. epilepsy and insomnia).

 Challenges/Food for thought:  Patients already receiving both benzodiazepines and opioids (should be avoided; CDC recommendations). It is the responsibility of physicians to communicate the risks of overdose with each patient and discuss with other providers to determine whether both medications are indicated.185  According to Dr. William Bobo, M.D. (Mayo Clinic psychiatrist), “outpatient doctors often inherit patients discharged from the hospital on benzodiazepines, and there is no clear evidence to guide decisions about continuing or stopping these drugs.”103 Given that benzodiazepines should only be used short‐term and that alternatives are available, continued benzodiazepine use should rather be the exception than the norm, considering alternatives if appropriate.  “The individuals who intentionally abuse BZDs and those who inadvertently become dependent on them may differ substantially in clinical and demographic characteristics and possibly in response to treatment.”14

 Consider consultation with behavioral health service experts/referring patients with complex conditions e.g. current or history of alcohol or drug use disorder, or concurrent severe psychiatric disorder.74

 Prior authorization criteria of another plan186:  Diagnosis/diagnosis code (e.g. anxiety disorder, acute muscle spasms, chronic muscle spasms, epilepsy, seizure disorder, panic disorder, insomnia, or other) Specifically regarding insomnia: Have other insomnia related disorders been ruled out? (e.g., movement, breathing or psychiatric disorders and medication) For all diagnoses apart from epilepsy: What non‐pharmacological therapies has the recipient tried? (e.g. Applied Relaxation, Cognitive Behavioral, Mindfulness‐based Therapy, Muscle Relaxation, Worry Exposure, Short‐term Psychodynamic Psychotherapy, Stimulus Control, Sleep Hygiene Measures, Sleep restriction, or Other) AND for how long?  Whether the Controlled Substance Database (PMP) was checked on date of request and to list information (e.g. Date of Fill, Drug, Quantity, Day Supply, and Prescriber) for the most recent five (5) entries found on the PMP.  Whether the patient has a history of alcohol or drug abuse or dependence and whether the patient is in acute alcohol withdrawal.  Whether the patient is pregnant, because the use of benzodiazepines is contraindicated during pregnancy. Also, whether the patient has been counseled regarding risks to the fetus if becoming pregnant while receiving this medication.

Utah Medicaid Utilization Data

Overall total utilization of benzodiazepines (Please refer to Appendix 2 for additional information)

Year Claims Patients 2014 102,134 20,501 2015 98,867 18,825 2016 93,798 17,783 2017 to date 22,326 9,383 TOTAL for this period 317,125 37,186

2014‐2017 Most commonly prescribed benzodiazepines 120,000 100,000 80,000 60,000 40,000 20,000 0 Alprazolam Clonazepam Diazepam Lorazepam Temazepam Tablet Tablet Tablet Tablet Capsule Number of claims 90,880 107,465 37,980 50,796 11,086 Number of patients 11,441 11,800 9,344 9,767 1,634

2014‐2017 Benzodiazepines claims (only showing those exceeding 1000 claims for this period) 120,000

100,000

80,000

60,000

40,000

20,000

Ratio of total claims/patients Estazolam Tablet Diazepam Oral Concentrate Onfi (clobazam) Oral Suspension Midazolam Injection Clonazepam Tablet Dispersible Lorazepam Oral Concentrate Oxazepam Capsule Onfi (clobazam)Tablet Diazepam Oral Solution Clorazepate Tablet Chlordiazepoxide Capsule Tranxene (clorazepate) Tablet Alprazolam Tablet Dispersible Triazolam Tablet Lorazepam Tablet Clonazepam Tablet Temazepam Capsule Diazepam Tablet Alprazolam Tablet Lorazepam Injection Alprazolam Tablet Extended Release Diazepam Injection Flurazepam Capsule Klonopin (clonazepam)Tablet Midazolam Syrup Ativan (lorazepam)Tablet 0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00

This provides an indication of which products are potentially used for longer periods or in excessive quantities based on number of claims/patient. However, it does not provide details to draw accurate conclusions.

Age & Sex 7,500 6,000 patients

4,500 of 3,000 M 1,500

Number F 0 <18 18‐24 25‐34 35‐44 45‐54 55‐64 >64 Age

 649 (185 male; 464 female) patients >64 years old received benzodiazepine prescriptions  A considerable number of patients are pediatric patients (5,580). Additional information on prescribers and diagnosis codes submitted in these patients have been included in appendix 2.

Prescribers (by credentials)

Physician Nurse Practioner Physician Assistant Osteopath Dentist Nurse Midwife Optometrist

0 25,000 50,000 75,000 100,000 125,000 150,000 175,000 200,000 Number of claims

BENZODIAZEPINES ‐ ALL PATIENTS PRESCRIBER TYPE TOTAL CLAIMS 2014‐17 Optometrist 4 0.00% Nurse Midwife 220 0.07% Dentist 2,284 0.72% Osteopath 29,866 9.42% Physician Assistant 32,996 10.40% Nurse Practitioner 63,217 19.93% Physician 188,538 59.45% TOTAL CLAIMS 317,125

Prescribers by specialty

Family Medicine Psychiatry Internal Medicine Pediatrics Neurology Emergency Medicine Obstetrics‐Gynecology Geriatric Medicine Physical Medicine & Rehab Orthopedics Nephrology Oncology Pain Management Pulmonology General Surgery Hospitalist Endocrinology Anesthesiology Hematology Infectious Disease Cardiology Gastroenterology Otorhinolaryngology Rheumatology Urology Radiology Ophthalmology Sleep Medicine Dermatology Gerontology Immunology Proctology Hepatology 0 30,000 60,000 90,000 120,000 150,000 180,000 210,000 Number of claims

BENZODIAZEPINES ‐ ALL PATIENTS PRESCRIBER SPECIALTY TOTAL CLAIMS 2014‐17 Hepatology 1 0.00% Proctology 4 0.00% Immunology 8 0.00% Gerontology 14 0.00% Dermatology 37 0.01% Sleep Medicine 68 0.02% Ophthalmology 70 0.02% Radiology 82 0.03% Urology 180 0.06% Rheumatology 186 0.06% Otorhinolaryngology 252 0.08% Gastroenterology 268 0.08% Cardiology 280 0.09% Infectious Disease 311 0.10% Hematology 334 0.11% Anesthesiology 342 0.11% Endocrinology 369 0.12% Hospitalist 471 0.15% General Surgery 499 0.16% Pulmonology 640 0.20% Pain Management 649 0.20% Oncology 936 0.30% Nephrology 1,081 0.34% Orthopedics 1,332 0.42% Physical Medicine & Rehab 2,066 0.65% Geriatric Medicine 2,492 0.79% Obstetrics‐Gynecology 2,759 0.87% Emergency Medicine 4,868 1.54% Neurology 7,612 2.40% Pediatrics 10,373 3.27% Internal Medicine 23,566 7.43% Psychiatry 52,433 16.53% Family Medicine 202,542 63.87% TOTAL CLAIMS 317,125

Appendix 3 contains information on: (Table number as listed in appendix listed first e.g. T15)

T15. The number of patients exceeding proposed dose and duration limits for each product. It is important to review the data in the table as it varies by product and benzodiazepine.

Overall, out of 37,186 patients,  about 7% exceeded the proposed dose limits, and  about 50% exceeded duration of use limits  12,791 (34%) received benzodiazepines for >4 months. Additional information can be found in appendix 3 for the number of patients exceeding longer durations.

 About 5.5% of claims exceeded the proposed dose limits.

T16. How many patients had diagnosis codes submitted for the following? However, it is important to consider that there are several limitations when reviewing data based on diagnosis codes.

Diagnosis grouping Number of patients A EPILEPSY/SEIZURES 5,570 (15%) B ALCOHOL MISUSE 3,742 (10%) C DRUG DEPENDENCE 11,657 (31%) D DRUG ABUSE 5,289 (14%) E BENZODIAZAPINE POISONING 820 (2%) F OTHER POISONING 2,837 (8%) G BENZODIAZAPINE ACCIDENTAL POISONING 213 (1%) H OTHER ACCIDENTAL POISONING 1,445 (4%)

Information on these diagnoses were gathered to further explore benzodiazepine use:  because abuse of benzodiazepines is often associated with multiple‐substance abuse  to separate out patients with alcohol dependence related diagnoses that could have received higher doses. However, according to Susan Siegfried, “the higher maximum doses listed for alcohol withdrawal are almost exclusively prescribed on an inpatient basis, due to inherent risks.” Doses in critical illness/emergency care may also be different from usual practice.  to explore the number of patients who had experienced poisoning (including accidental)

T17. The number of patients that exceeded duration of use limits who had diagnosis codes submitted as described above and to compare whether these patients were at increased risk compared to the overall patient group (T16) in terms of the number of diagnosis codes submitted for poisoning and whether more of these patients had diagnosis codes submitted for any of the other categories. It is important to consider that excessive quantities also put other people at risk for overdose if shared etc. which would not be shown in this data.  Increased risk => higher percentages for dependence, abuse, and poisoning (double and more for abuse and poisoning compared to all patients which is very concerning; refer to table on next page)

T18. The number of patients that exceeded proposed dose limits that had diagnosis codes submitted as described above to compare whether these patients were at increased risk compared to the overall patient group (T16) in terms of the number of diagnosis codes submitted for poisoning and whether more of these patients had diagnosis codes submitted for any of the other categories. “The doses of benzodiazepines taken by abusers are usually in excess of the recommended therapeutic dose.”7  Increased risk => higher percentages for dependence, abuse, and poisoning (also clearly much higher for abuse and poisoning compared to all patients; refer to table on next page).

T19. The top prescribers and how many of their patients and associated claims exceeded the proposed quantity limits and duration of use.  Exceeding dose limit ‐ Claims: Some higher percentages (as high as 50% vs 5.5% ALL) Patients: Higher percentage of about 20‐40% for some (vs. 7% ALL)  Exceeding duration: Higher percentage of about 60‐80% (as high as 87% vs 50% ALL)

The table below is a comparison of overall percentages for diagnosis codes submitted for all patients, those exceeding recommended doses and those exceeding duration of use recommendations.

Accidental Accidental Epilepsy/ Alcohol Drug Drug Benzo Other Benzo Other Seizures dependence dependence abuse poisoning poisoning poisoning poisoning

DX A DX B DX C DX D DX E DX F DX G DX H

All 14.98% 10.06% 31.35% 14.22% 2.21% 7.63% 0.57% 3.89%

Exceeding Dose ALL 25.49% 23.28% 55.54% 30.36% 5.70% 16.59% 2.10% 9.46%

Exceeding Dose FFS 24.72% 22.68% 54.39% 28.99% 5.29% 15.86% 2.30% 9.04%

Exceeding Duration

4 Months 18.07% 12.26% 43.25% 19.62% 3.84% 10.86% 1.13% 6.25%

6 Months 19.68% 12.34% 44.67% 19.79% 3.95% 11.07% 1.22% 6.64%

9 Months 21.13% 12.15% 45.86% 19.51% 3.92% 11.16% 1.20% 6.75%

1 Year 22.60% 11.63% 46.54% 18.86% 3.65% 10.81% 1.17% 6.86%

18 Months 24.61% 11.30% 45.29% 17.55% 3.27% 10.16% 1.16% 6.87%

2 Years 26.60% 10.16% 43.57% 16.35% 3.27% 9.77% 1.22% 6.59%

3 Years 26.93% 8.40% 39.58% 14.58% 2.99% 9.27% 1.25% 5.79%

4 Years 36.88% 7.50% 36.88% 16.25% 3.13% 7.50% 1.25% 6.25%

When comparing percentages of diagnosis codes by product, it is also clear that patients who exceeded recommended doses and duration, also had a higher percentage of diagnosis codes submitted for abuse and poisoning.

Duplicative therapy

As mentioned before, use of two or more benzodiazepines at the same time is likely inappropriate and filling prescriptions for benzodiazepines on the same day or within the same month indicates potential misuse/abuse. This occurred on thousands of occasions and the tables below contains additional information on this issue.

SAME DAY THERAPY Same Day Fill: Total Occurrences 6,602 Same Day Fill: Total Unique Patients 1,658 Same Day and Same Prescriber: Total Occurrences 5,700 Same Day and Same Prescriber: Total Unique Patients 1,441 Patients: Same Prescriber, Different Agent 1,197 Patients: Same Prescriber, Different Agent and >1 Pharmacy 190 Patients: Same Prescriber, Same Agent, Different Dose 395 Patients: Same Prescriber, Same Agent, Different Dose and >1 Pharmacy 52 Same Day and Different Prescriber: Total Occurrences 902 Same Day and Different Prescriber: Total Unique Patients 337 Patients: Different Prescriber, Different Agent 282 Patients: Different Prescriber, Different Agent and >1 Pharmacy 11 Patients: Different Prescriber, Same Agent, Different Dose 67 Patients: Different Prescriber, Same Agent, Different Dose and >1 Pharmacy 7

SAME MONTH THERAPY Same Month Fill: Total Occurrences 20,959 Same Month Fill: Total Unique Patients 7,334 Same Month and Same Prescriber: Total Occurrences 15,095 Same Month and Same Prescriber: Total Unique Patients 6,174 Patients: Same Prescriber, Different Agent 4,812 Patients: Same Prescriber, Different Agent and >1 Pharmacy 637 Patients: Same Prescriber, Same Agent, Different Dose 1,962 Patients: Same Prescriber, Same Agent, Different Dose and >1 Pharmacy 158 Same Month and Different Prescriber: Total Occurrences 5,864 Same Month and Different Prescriber: Total Unique Patients 1,390 Patients: Different Prescriber, Different Agent 963 Patients: Different Prescriber, Different Agent and >1 Pharmacy 56 Patients: Different Prescriber, Same Agent, Different Dose 376 Patients: Different Prescriber, Same Agent, Different Dose and >1 Pharmacy 29

Conclusions

Benzodiazepines are overprescribed (excessive quantities and long‐term use) and this overuse is not supported by the evidence. Clinical guidelines do not recommend benzodiazepines as first line treatment in anxiety or insomnia. According to the guidelines for treating anxiety disorders and insomnia disorders, very little evidence supports the use of benzodiazepine agents, even as second line agents. If used to treat anxiety or insomnia, benzodiazepines should be used at the lowest effective dose and on a short‐term basis (≤ 4 months) only. Inappropriate prescribing has led to excessive long‐term use and clinicians and patient resistance to treatment discontinuation.

Due to limited evidence and safety concerns, it is recommended to limit benzodiazepine use in the elderly, in children, and in patients with a history of substance abuse.

In general, all benzodiazepines have similar adverse events but the rates of these events may differ depending on their individual pharmacokinetic profiles. Overall, benzodiazepines should be used at the lowest effective dose for the shortest time possible with a comprehensive treatment plan and careful follow‐up.

Review of the Utah Medicaid Utilization data raised many concerns regarding benzodiazepine use. Thousands of patients are receiving benzodiazepines in doses and durations that exceed recommendations. Many patients receiving benzodiazepines had diagnosis codes submitted for abuse and poisoning/overdoses (a much higher percentages of those that exceeded limits/duration had these diagnosis codes submitted). Duplicative therapy is also of particular concern. We therefore have a long way to go on educating prescribers about evidence‐based prescribing, implementing measures to ensure safe doses and durations are employed, and to help channel people with problematic drug use to get the help they need. A lot of emphasis has been put on opioid misuse and abuse. Adverse consequences of inappropriate benzodiazepine use and abuse are major problems that need to be addressed.

Appendix 1 – Drug information

Table 6. Comparison of Benzodiazepine Agents11,13,30,71,72,187 Product Route of Available Doses Labeled Uses Unlabeled Uses Active Generic Adult Oral Dosage Range & Administration Metabolite Available Maximum Oral dose (adults) Alprazolam Oral Oral tablets: 0.25 mg, 0.5 Treatment of anxiety Treatment of anxiety No Yes 0.75 to 6 mg daily (Xanax® and mg, 1 mg, 2 mg disorders, panic disorder and in children. Xanax XR®) 0.5 mg XR, 1 mg XR, 2 mg anxiety associated with Prescribing Limits/Maximum: XR, 3 mg XR depression. Anxiety Disorders: 4 mg daily Oral solution: 1mg/mL (30 Panic Disorder: 10 mg daily. mL) Chlordiazepoxide Oral, IM, IV Oral tablets: 5 mg, 10 mg, Treatment of anxiety N/A Yes Yes 15 to 300 mg daily (Librium®, others) 25 mg disorders, withdrawal Mild to moderate anxiety: 5–10 mg symptoms of acute 3 or 4 times daily alcoholism and preoperative Severe anxiety, 20–25 mg 3 or 4 apprehension/anxiety. times daily. Maximum: Acute alcohol withdrawal: 300 mg daily Chlordiazepoxide/ Oral 5/12.5 mg, 10/25 mg Treatment of anxiety, N/A Yes Yes 2 to 6 tablets daily in one or more Amitriptyline agitation and depression. divided doses. (Limbitrol®) Maximum daily dose: amitriptyline 150 mg/ chlordiazepoxide 60 mg. Clidinium/ Oral 2.5/5 mg Treatment of irritable bowel N/A Yes Yes 1 to 2 capsules 3 to 4 times daily Chlordiazepoxide syndrome and adjunct (Librax®) treatment of peptic ulcer. Clobazam (Onfi™) Oral 5 mg, 10 mg, 20 mg Adjunctive treatment of Catamenial epilepsy; Yes No 5 to 40 mg daily seizures associated with epilepsy Maximum: Lennox‐Gastaut syndrome (monotherapy) Adjunctive Therapy in Lennox‐ Gastaut Syndrome: 20 mg daily in those weighing ≤30 kg and 40 mg daily in those weighing >30 kg Clonazepam Oral 0.125 mg, 0.25 mg, 0.5 Treatment of petit mal Treatment of restless No Yes 1 to 20 mg daily (Klonopin®) mg, 1 mg, 2 mg variant (Lennox‐Gastaut), leg syndrome, akinetic and myoclonic neuralgia, multifocal Maximum: seizures; petit mal (absence) tic disorder, Seizure Disorders: 20 mg daily seizures unresponsive to parkinsonian Panic Disorder: 4 mg daily succimides; and panic dysarthria, bipolar disorder. disorder, burning mouth syndrome and adjunct therapy for schizophrenia. 39

Product Route of Available Doses Labeled Uses Unlabeled Uses Active Generic Adult Oral Dosage Range & Administration Metabolite Available Maximum Oral dose (adults) Clorazepate Oral 3.75 mg, 7.5 mg, 15 mg Treatment of anxiety N/A Yes Yes 15 to 90 mg daily (Traxene®, others) disorders, ethanol withdrawal Maximum: and adjunct in management Alcohol Withdrawal: 90 mg daily of partial seizures. Adjunctive Therapy for Partial Seizures: 90 mg daily Diazepam Oral, IM, IV, Oral tablets: 2 mg, 5 mg, Oral and injection: Treatment Treatment of panic Yes Yes 4 to 40 mg daily (Valium®, others) Rectal 10 mg of anxiety disorders, ethanol disorders and Maximum: Oral solution: 1mg/mL (5 withdrawal, skeletal muscle spasticity in children Rectal: Maximum recommended mL, 500 mL), 5mg/mL (30 relaxant, convulsive disorders with cerebral palsy. frequency for administration by mL) and sedation/amnesia. caregivers outside hospital is 1 Injection solution: Rectal gel: Treatment of treatment course every 5 days and 5mg/mL (2 mL, 10 mL) refractory epilepsy patients. 5 treatment courses per month. Rectal Gel: 5 mg, 10 mg, 20 mg Estazolam Oral 1 mg, 2 mg Short‐term treatment of N/A No Yes 1 to 2 mg (Prosom®) insomnia. Flurazepam Oral 15 mg, 30 mg Short‐term treatment of N/A Yes Yes 15 to 30 mg (Dalmane®) insomnia. Lorazepam Oral, IM, IV Oral tablets: 0.5 mg, 1 mg, Oral: Treatment of anxiety Treatment of ethanol No Yes 2 to 6 mg daily (Ativan®) 2 mg disorders and short‐term withdrawal, insomnia, Oral solution: 2mg/mL (30 management of anxiety psychogenic catatonia, mL) associated with depressive partial complex Injection solution: symptoms. seizures, agitation and 2mg/mL (1 mL, 10 mL), I.V.: Status epilepticus, as antiemetic adjunct. 4mg/mL (1mL, 10 mL) amnesia and sedation. Midazolam Oral, IV, IM Oral solution: 2mg/mL For preoperative, Treatment of anxiety Yes Yes N/A (Versed®) (118 mL) preprocedural, or ICU and status epilepticus. Injection solution: sedation and 1mg/mL (2 mL, 5 mL, 10 induction/maintenance of mL), 5mg/mL (1 mL, 2 mL, general anesthesia. 5 mL, 10 mL) Oxazepam Oral 10 mg, 15 mg, 30 mg Treatment of anxiety and Management of No Yes 30 to 120 mg daily (Serax®) ethanol withdrawal. simple partial seizures and as a hypnotic. Quazepam Oral 15 mg Treatment of insomnia. N/A Yes No 7.5 to 15 mg (Doral®) Temazepam Oral 7.5 mg, 15 mg, 22.5 mg, Short‐term treatment of Treatment of anxiety, No Yes; 7.5 to 30 mg (Restoril®) 30 mg insomnia. panic attacks and as excluding an adjunct in the 7.5 mg treatment of and 22.5 depression. mg doses Triazolam Oral 0.125 mg, 0.25 mg Short‐term treatment of N/A No Yes 0.125 to 0.25 mg (Halcion®) insomnia. Maximum: 0.5 mg daily Key: IM = intramuscular, IV = intravenous 40

Table 7. Warnings and Precautions for the Benzodiazepine Agents188,189 Warnings Precautions Other Considerations ALERT: US Boxed Warning Appropriate use: Does not have analgesic, antidepressant, or Alprazolam: Contraindicated in acute narrow‐angle glaucoma; concurrent use with Risks from concomitant use with opioids: antipsychotic properties. ketoconazole, itraconazole, or other potent CYP3A4 inhibitors. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory Breakthrough anxiety: At the end of dosing interval, breakthrough anxiety Chlordiazepoxide: Use with caution in patients with an impaired gag reflex. depression, coma, and death. Reserve concomitant may occur. prescribing of these drugs for use in patients for Clonazepam: Contraindicated in significant liver disease and acute narrow‐angle whom alternative treatment options are Tolerance: Alprazolam has a short half‐life for a benzodiazepine and the glaucoma; Monitor all patients for notable changes in behavior that might indicate inadequate. Limit dosages and durations to the duration of action after a single dose is determined by redistribution suicidal thoughts or depression; Use with caution in patients with porphyria, may minimum required. Follow patients for signs and rather than metabolism. Tolerance does not develop to the anxiolytic have a porphyrogenic effect. symptoms of respiratory depression and sedation. effects. Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect. Clorazepate: Contraindicated in acute narrow‐angle glaucoma and Myasthenia Contraindications: Hypersensitivity to agent or any gravis; Use with caution in the elderly, dosage adjustment recommended. component of the formulation (cross‐sensitivity Withdrawal: Rebound or withdrawal symptoms, including seizures, may with other benzodiazepines may exist). occur following abrupt discontinuation or large decreases in dose (more Diazepam: The FDA is alerting health care providers and emergency responders that common in adult patients receiving >4 mg/day or prolonged treatment); certain lots of CANA (diazepam) autoinjectors manufactured by Meridian Medical the risk of seizures appears to be greatest 24 to 72 hours following Technologies can be used beyond the labeled expiration date, which should help discontinuation of therapy. Use caution when reducing dose or mitigate potential shortages of these drugs; acute narrow‐angle glaucoma; withdrawing therapy; decrease slowly (eg, ≤0.5 mg every 3 days in adults) Contraindicated in untreated open‐angle glaucoma, infants <6 months of age (oral), and monitor for withdrawal symptoms. Flumazenil may cause withdrawal myasthenia gravis, severe respiratory impairment, severe hepatic impairment, sleep in patients receiving long‐term benzodiazepine therapy. apnea syndrome; When used as an adjunct in treating convulsive disorders, an increase in frequency/severity of tonic‐clonic seizures may occur and require dose Use with caution: in patients with depression, particularly if suicidal risk adjustment of anticonvulsant, abrupt withdrawal may result in a temporary increase may be present; in patients with a history of drug abuse or acute in the frequency and/or severity of seizures; Use with caution in patients with an alcoholism; in patients with hepatic impairment; in patients with impaired gag reflex and in obese patients as diazepam may have prolonged action porphyria; in patients with renal impairment; in patients with respiratory when discontinued in obese patients; Psychotic patients: Use of diazepam is not disease; in debilitated patients; active metabolites with extended half‐ recommended in place of appropriate therapy. lives may lead to delayed accumulation and adverse effects; in patients who are at risk of falls; in children. Lorazepam: Contraindicated in acute narrow‐angle glaucoma, sleep apnea (parenteral), intra‐arterial injection of parenteral formulation, severe respiratory Drug‐drug interactions: Potentially significant interactions may exist, insufficiency (except during mechanical ventilation); Psychiatric disorders: requiring dose or frequency adjustment, additional monitoring, and/or Preexisting depression may emerge or worsen during therapy, not recommended for selection of alternative therapy. use in primary depressive or psychotic disorders, should not be used in patients at risk for suicide without adequate antidepressant treatment; Use with caution in Benzodiazepines have been associated with anterograde amnesia. patients with an impaired gag reflex; Appropriate use: as a hypnotic, should be used only after evaluation of potential causes of sleep disturbance, failure of sleep Benzodiazepines may cause CNS depression, which may impair physical or disturbance to resolve after 7 to 10 days may indicate psychiatric or medical illness, a mental abilities; patients must be cautioned about performing tasks worsening of insomnia or the emergence of new abnormalities of thought or which require mental alertness (eg, operating machinery or driving); Use behavior may represent unrecognized psychiatric or medical illness and requires with caution in patients receiving other CNS depressants or psychoactive immediate and careful evaluation. medication; effects with other sedative drugs or ethanol may be potentiated. Oxazepam: May cause hypotension (rare), use with caution in patients with cardiovascular or cerebrovascular disease, or in patients who would not tolerate Paradoxical reactions, including hyperactive or aggressive behavior, have transient decreases in blood pressure; Use with caution in patients with an impaired been reported with benzodiazepines, particularly in adolescent/pediatric gag reflex; Relative to other benzodiazepines, oxazepam possesses a short half‐life or psychiatric patients and lacks an active metabolite which may be preferable in the elderly if benzodiazepine use is required for anxiety.

Table 8. Pharmacokinetics Properties of the Benzodiazepine Agents11,13,30,71,72 Product Route of Absorption Distribution t½, hours Metabolism Active Elimination Administration Metabolite ANXIOLYTIC Alprazolam Oral Readily absorbed; Extended Immediate 6.3‐26.9 Hepatic via CYP3A4; forms two active No Urine (as release: Slower relative to release: Vd: 0.84 metabolites (4‐hydroxyalprazolam and α‐ unchanged drug immediate release to 1.42 L/kg hydroxyalprazolam [about half as active as and metabolites) formulation resulting in a alprazolam]) and an inactive metabolite concentration that is Protein binding: benzophenone metabolite, however, the maintained 5 to 11 hours 80%; primarily to active metabolites are unlikely to contribute after dosing; rate increased albumin to much of the pharmacologic effects because following night time dosing of their low concentrations and lesser (versus morning dosing) potencies.

Bioavailability: Immediate release: 84% to 92%; Extended release: 90% Chlordiazepoxide Oral, IM, IV Well absorbed: peak Vd: 3.3 L/kg 18‐96 Extensively hepatic to desmethyldiazepam Yes Urine (minimal as concentrations 1‐2 hours (active and long‐acting), unchanged drug) after administration; rate of Protein binding: desmethylchlordiazepoxide, and demoxepam absorption is age‐related 96% and tends to be delayed in the elderly. Clonazepam Oral Rapidly and completely Children: Vd: 1.5 18‐50 Extensively hepatic via glucuronide and sulfate No Urine (<2% as absorbed to 3 L/kg; Adults: conjugation; undergoes nitroreduction to 7‐ unchanged drug); Vd: 1.5 to 64.4 aminoclonazepam, followed by acetylation to metabolites Onset of action: ~20 to 40 L/kg 7‐acetamidoclonazepam; nitroreduction and excreted as minutes acetylation are via cytochrome P450 enzyme glucuronide or Protein binding: system; metabolites undergo glucuronide and sulfate conjugates Bioavailability: ~90% ~85% sulfate conjugation Clorazepate Oral Rapidly absorbed following Nordiazepam: Vd: 40‐120 Rapidly decarboxylated to nordiazepam Yes Urine (62% to 67%; oral administration 0.7 to 2.2 L/kg (active) in acidic stomach prior to absorption; primarily nordiazepam is hepatically hydroxylated by metabolites of Bioavailability: 91% Protein binding: CYP 2C19 and CYP3A4 to oxazepam (active) conjugated Nordiazepam: and undergoes glucuronidation to form a oxazepam); feces 97% to 98% glucuronide conjugate (15% to 19%)

Product Route of Absorption Distribution t½, hours Metabolism Active Elimination Administration Metabolite Diazepam Oral, IM, IV, Oral: Well absorbed (>90%); IV: 1.2 L/kg 40‐120a Hepatic; diazepam is N‐demethylated by Yes Urine Rectal delayed and decreased (range: 0.6 to 2 CYP3A4 and 2C19 to the active metabolite N‐ (predominantly as when administered with a L/kg) desmethyldiazepam, and is hydroxylated by glucuronide moderate fat meal Oral: 1.1 L/kg CYP3A4 to the active metabolite temazepam. conjugates) Rectal: Well absorbed (range: 0.6 to 1.8 N‐desmethyldiazepam and temazepam are L/kg both further metabolized to oxazepam. Bioavailability: Rectal: 1 L/kg Temazepam and oxazepam are largely IM: >90% eliminated by glucuronidation. Oral: >90% Protein binding: Rectal: 90% Oral: Neonates: 84% to 86% Adults: 98% Rectal: 95% to 98% Lorazepam Oral, IM, IV IM: Rapid and complete IV: Vd: 10‐20 Hepatic; rapidly conjugated to lorazepam No Urine (~88%; absorption Neonates: 0.76 ± glucuronide (inactive) predominantly as Oral: Readily absorbed 0.37 L/kg (range: inactive 0.14 to 1.3 L/kg) metabolites); feces Onset of action: Pediatric (~7%) Anticonvulsant: IV: Within patients: Crosses 10 minutes the blood brain Hypnosis: IM: 20 to 30 barrier minutes 5 months to < 3 Sedation: IV: Within 2 to 3 years: 1.62 L/kg minutes (range: 0.67 to 3.4 L/kg) Bioavailability: Oral: 90% 3 to <13 years: 1.5 L/kg (range: 0.49 to 3 L/kg) 13 to <18 years: 1.27 L/kg (range: 1 to 1.54 L/kg) Adults: 1.3 L/kg

Protein binding: ~85% to 93%; free fraction may be significantly higher in elderly Oxazepam Oral Slowly absorbed from the Vd: 0.6 to 2 L/kg 5‐20 Hepatic glucuronide conjugation to produce a No Urine (as inactive GI tract single, major inactive metabolite glucuronide Protein binding: (benzophenone) conjugate) 96% to 98%

Product Route of Absorption Distribution t½, hours Metabolism Active Elimination Administration Metabolite SEDATIVE/HYPNOTIC Triazolam Oral Onset (oral): intermediate Vd: 0.6 to 1.7 1.5‐5.5 Hepatic via CYP3A4 and glucuronide No Urine (as L/kg (Short) conjugation unchanged drug and metabolites) Protein binding: 89% Temazepam Oral Onset: intermediate Vd: 1.4 L/kg 3.5‐18.4 Hepatic No Urine (as inactive to slow (Intermediate) metabolites) Protein binding: 96% Estazolam Oral N/A Vd: N/A 10‐24 Hepatic via CYP3A4 No Urine (as (Intermediate) unchanged drug Protein binding: and inactive 93% metabolites) and feces (minimal)

Flurazepam Oral Onset: rapid to Vd: 3.4 L/kg Parent: 2.3 Hepatic Yes Urine (as active and intermediate Metabolite: inactive Protein binding: 74‐158 metabolites) 97% (long) Quazepam Oral N/A Vd: 5‐8.6 L/kg Parent: 39 Hepatic via CYP3A4, 2C9, 2C19 Yes Urine (primarily Metabolite: metabolites) and Protein binding: 39‐73 feces >95% (long) MISCELLANEOUS (used in seizure disorders/Lennox‐Gastaut syndrome) Clobazam Oral N/A Vd: 100 L/kg Parent: 36‐42 Hepatic via CYP3A4, 2C19, 2B6 Yes Urine (primarily as Metabolite: active and inactive Protein binding: 71‐82 metabolites) 80‐90% Clonazepam See under anxiolytics Clorazepate See under anxiolytics aHalf‐life of active metabolite, to which effects can be attributed. IM = intramuscular, IV = intravenous

Appendix 2 ‐ Additional data

Table 11. All claims BENZODIAZEPINES - ALL CLAIMS 2014 2015 2016 2017* ALL AGENT PRODUCT CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Alprazolam Alprazolam Oral Concentrate 0 0 0 0 1 1 0 0 1 1 Alprazolam Alprazolam Tablet 29,974 6,410 27,895 5,777 26,718 5,362 6,293 2,904 90,880 11,441 Alprazolam Alprazolam Tablet Dispersible 23 10 31 7 23 7 3 3 80 18 Alprazolam Alprazolam Tablet XR 447 113 406 104 358 79 84 37 1,295 227 Alprazolam Xanax Tablet 0 0 0 0 3 1 0 0 3 1 Chlordiazepoxide Chlordiazepoxide Capsule 572 293 564 310 616 323 157 107 1,909 814 Clobazam Onfi Oral Suspension 120 25 215 31 242 39 78 29 655 62 Clobazam Onfi Tablet 1,029 119 1,081 119 1,210 131 316 110 3,636 204 Clonazepam Clonazepam Tablet 34,436 6,729 33,642 6,160 31,697 5,639 7,690 3,150 107,465 11,800 Clonazepam Clonazepam Tablet Dispersible 384 116 497 136 575 150 158 72 1,614 315 Clonazepam Klonopin Tablet 30 5 12 2 11 1 2 1 55 5 Clorazepate Clorazepate Tablet 1,114 168 1,251 155 1,215 145 275 89 3,855 242 Clorazepate Tranxene Tablet 12 1 12 1 12 1 3 1 39 1 Diazepam Diazepam Injection 33 12 13 11 21 14 8 6 75 28 Diazepam Diazepam Oral Concentrate 8 8 7 5 18 15 8 8 41 29 Diazepam Diazepam Oral Solution 383 255 454 254 429 211 107 68 1,373 675 Diazepam Diazepam Tablet 12,278 4,090 12,177 3,866 10,966 3,508 2,559 1,375 37,980 9,344 Estazolam Estazolam Tablet 9 3 19 4 22 5 6 4 56 11 Flurazepam Flurazepam Capsule 128 26 89 18 60 14 15 7 292 41 Lorazepam Ativan Tablet 4 1 0 0 0 0 0 0 4 1 Lorazepam Lorazepam Injection 107 41 137 37 95 28 21 9 360 98 Lorazepam Lorazepam Oral Concentrate 174 87 176 87 226 111 71 40 647 253 Lorazepam Lorazepam Tablet 16,292 4,634 15,813 4,241 15,060 4,085 3,631 1,795 50,796 9,767 Midazolam Midazolam Injection 272 139 344 171 444 227 74 52 1,134 395 Midazolam Midazolam Syrup 235 192 151 125 84 72 15 13 485 382 Oxazepam Oxazepam Capsule 14 3 18 6 17 5 3 1 52 12 Temazepam Temazepam Capsule 3,669 819 3,437 720 3,304 688 676 318 11,086 1,634 Triazolam Triazolam Tablet 387 127 426 141 371 150 73 46 1,257 375 TOTAL 102,134 20,501 98,867 18,825 93,798 17,783 22,326 9,383 317,125 37,186 (Only products with claims/utilization are shown)

Table 12. FFS claims BENZODIAZEPINES - FFS CLAIMS 2014 2015 2016 2017* ALL AGENT PRODUCT CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Alprazolam Alprazolam Tablet 11,917 3,098 9,711 2,486 8,235 1,945 1,748 855 31,611 5,488 Alprazolam Alprazolam Tablet Dispersible 3 2 4 2 0 0 0 0 7 3 Alprazolam Alprazolam Tablet Extended Release 153 43 125 38 89 27 20 9 387 92 Chlordiazepoxide Chlordiazepoxide Capsule 241 131 208 132 188 118 41 27 678 355 Clobazam Onfi Oral Suspension 32 6 46 10 58 11 28 10 164 21 Clobazam Onfi Tablet 270 36 255 30 228 21 41 16 794 61 Clonazepam Clonazepam Tablet 13,007 3,066 11,332 2,542 9,573 1,965 2,124 901 36,036 5,509 Clonazepam Clonazepam Tablet Dispersible 114 27 119 34 149 40 41 17 423 82 Clorazepate Clorazepate Tablet 457 65 572 53 535 39 107 25 1,671 95 Clorazepate Tranxene Tablet 12 1 12 1 12 1 3 1 39 1 Diazepam Diazepam Injection 29 10 6 6 16 11 8 6 59 22 Diazepam Diazepam Oral Concentrate 3 3 5 3 7 7 3 3 18 12 Diazepam Diazepam Oral Solution 90 67 116 63 83 36 21 15 310 158 Diazepam Diazepam Tablet 4,498 1,584 3,711 1,264 2,720 927 592 337 11,521 3,136 Flurazepam Flurazepam Capsule 68 14 55 11 35 6 10 5 168 20 Lorazepam Lorazepam Injection 49 34 45 32 36 23 10 7 140 85 Lorazepam Lorazepam Oral Concentrate 65 32 67 33 74 43 25 15 231 102 Lorazepam Lorazepam Tablet 7,018 2,168 6,011 1,788 5,248 1,480 1,287 603 19,564 4,400 Midazolam Midazolam Injection 27 8 21 5 70 46 12 10 130 60 Midazolam Midazolam Syrup 0 0 29 27 32 27 2 2 63 54 Oxazepam Oxazepam Capsule 10 1 7 2 0 0 0 0 17 2 Temazepam Temazepam Capsule 1,279 374 1,082 281 831 211 162 78 3,354 695 Triazolam Triazolam Tablet 19 5 18 4 18 2 3 2 58 8 TOTAL 39,361 9,337 33,557 7,663 28,237 6,067 6,288 2,728 107,443 16,733

Table 13. Pediatric claims BENZODIAZEPINES - PEDIATRIC CLAIMS 2014 2015 2016 2017* ALL AGENT PRODUCT CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Alprazolam Alprazolam Oral Concentrate 0 0 0 0 1 1 0 0 1 1 Alprazolam Alprazolam Tablet 295 158 272 157 312 146 68 45 947 416 Alprazolam Alprazolam Tablet Dispersible 3 3 3 2 0 0 1 1 7 4 Alprazolam Alprazolam Tablet Extended Release 1 1 11 4 4 4 0 0 16 8 Chlordiazepoxide Chlordiazepoxide Capsule 12 1 0 0 0 0 0 0 12 1 Clobazam Onfi Oral Suspension 104 23 200 29 230 38 66 23 600 56 Clobazam Onfi Tablet 401 52 372 46 397 51 108 43 1,278 89 Clonazepam Clonazepam Tablet 1290 291 1246 271 1089 265 261 121 3,886 626 Clonazepam Clonazepam Tablet Dispersible 238 57 296 67 372 82 92 39 998 145 Clorazepate Clorazepate Tablet 302 64 278 47 228 50 55 25 863 91 Diazepam Diazepam Injection 3 1 1 1 4 1 1 1 9 3 Diazepam Diazepam Oral Concentrate 4 4 4 4 13 12 4 4 25 21 Diazepam Diazepam Oral Solution 341 240 396 238 337 195 76 54 1,150 636 Diazepam Diazepam Tablet 1297 851 1129 776 944 690 194 163 3,564 2,235 Flurazepam Flurazepam Capsule 13 1 3 1 0 0 0 0 16 1 Lorazepam Lorazepam Injection 3 2 3 3 2 1 2 2 10 8 Lorazepam Lorazepam Oral Concentrate 103 56 117 58 138 68 36 21 394 165 Lorazepam Lorazepam Tablet 578 266 560 240 611 242 145 98 1,894 675 Midazolam Midazolam Injection 231 118 280 148 334 180 46 34 891 324 Midazolam Midazolam Syrup 235 192 150 124 80 68 13 11 478 375 Temazepam Temazepam Capsule 42 15 51 18 62 15 10 5 165 42 Triazolam Triazolam Tablet 32 26 30 29 34 30 8 6 104 88 TOTAL 5,528 2,216 5,402 2,079 5,192 1,920 1,186 631 17,308 5,580

BENZODIAZEPINES - PEDIATRIC PATIENTS TOTAL CLAIMS Prescribers (pediatric claims) PRESCRIBER TYPE 2014-17 Nurse Midwife 5 0.03% Physician Osteopath 744 4.30% Nurse Practitioner Physician Assistant 1,196 6.91% Dentist Dentist 1,723 9.95% Physician Assistant Nurse Practitioner 1,763 10.19% Osteopath Physician 11,877 68.62% Nurse Midwife TOTAL CLAIMS 17,308 0 2,000 4,000 6,000 8,000 10,000 12,000

Number of claims BENZODIAZEPINES - PEDIATRIC PATIENTS TOTAL CLAIMS PRESCRIBER SPECIALTY 2014-17 Prescriber specialty (pediatric claims) Radiology 1 0.01% Hospitalist 1 0.01% Pain Management 1 0.01% Family Medicine Immunology 1 0.01% Pediatrics Oncology 1 0.01% Cardiology 2 0.01% Psychiatry Urology 3 0.02% Physical Medicine & Rehab Sleep Medicine 4 0.02% Infectious Disease 4 0.02% Internal Medicine Dermatology 9 0.05% Emergency Medicine Gastroenterology 16 0.09% General Surgery 21 0.12% Neurology Obstetrics-Gynecology 22 0.13% Orthopedics Pulmonology 30 0.17% Endocrinology Ophthalmology 33 0.19% Otorhinolaryngology 35 0.20% Hematology Hematology 63 0.36% Otorhinolaryngology Endocrinology 75 0.43% Orthopedics 137 0.79% Ophthalmology Neurology 145 0.84% Pulmonology Emergency Medicine 159 0.92% Internal Medicine 192 1.11% Obstetrics‐Gynecology Physical Medicine & Rehab 264 1.53% General Surgery Psychiatry 1,792 10.35% Gastroenterology Pediatrics 6,778 39.16% Family Medicine 7,519 43.44% Dermatology TOTAL CLAIMS 17,308 Infectious Disease

Sleep Medicine Urology Cardiology Oncology Immunology Pain Management Hospitalist Radiology 0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000

Table 14. Number of pediatric patients by age and diagnosis codes

BENZODIAZEPINES - PEDIATRIC PATIENTS

TOTAL PATIENTS 2014-2017

AGE* M F Total DX A PERCENT DX B PERCENT DX C PERCENT DX D PERCENT DX E PERCENT DX F PERCENT DX G PERCENT DX H PERCENT

0 27 15 42 16 38.10% 0 0.00% 5 11.90% 1 2.38% 1 2.38% 2 4.76% 1 2.38% 1 2.38%

1 67 43 110 57 51.82% 1 0.91% 15 13.64% 4 3.64% 0 0.00% 6 5.45% 1 0.91% 3 2.73%

2 74 63 137 80 58.39% 1 0.73% 3 2.19% 2 1.46% 0 0.00% 1 0.73% 0 0.00% 1 0.73%

3 80 79 159 76 47.80% 0 0.00% 4 2.52% 0 0.00% 1 0.63% 5 3.14% 0 0.00% 3 1.89%

4 122 142 264 64 24.24% 1 0.38% 2 0.76% 1 0.38% 0 0.00% 5 1.89% 1 0.38% 1 0.38%

5 188 195 383 66 17.23% 0 0.00% 4 1.04% 0 0.00% 0 0.00% 3 0.78% 1 0.26% 2 0.52%

6 252 218 470 70 14.89% 0 0.00% 4 0.85% 1 0.21% 0 0.00% 2 0.43% 0 0.00% 2 0.43%

7 206 177 383 74 19.32% 0 0.00% 1 0.26% 0 0.00% 0 0.00% 4 1.04% 0 0.00% 1 0.26%

8 173 159 332 59 17.77% 0 0.00% 3 0.90% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 1 0.30%

9 156 165 321 74 23.05% 0 0.00% 1 0.31% 0 0.00% 0 0.00% 9 2.80% 0 0.00% 9 2.80%

10 145 147 292 61 20.89% 0 0.00% 6 2.05% 0 0.00% 1 0.34% 3 1.03% 0 0.00% 2 0.68%

11 152 107 259 70 27.03% 0 0.00% 4 1.54% 1 0.39% 0 0.00% 3 1.16% 0 0.00% 2 0.77%

12 142 129 271 73 26.94% 1 0.37% 4 1.48% 4 1.48% 0 0.00% 6 2.21% 0 0.00% 1 0.37%

13 147 154 301 79 26.25% 0 0.00% 8 2.66% 6 1.99% 3 1.00% 12 3.99% 0 0.00% 5 1.66%

14 163 165 328 67 20.43% 3 0.91% 10 3.05% 14 4.27% 5 1.52% 20 6.10% 1 0.30% 8 2.44%

15 179 230 409 65 15.89% 10 2.44% 31 7.58% 37 9.05% 3 0.73% 26 6.36% 1 0.24% 12 2.93%

16 232 283 515 74 14.37% 23 4.47% 53 10.29% 56 10.87% 9 1.75% 49 9.51% 2 0.39% 13 2.52%

17 264 340 604 89 14.74% 29 4.80% 83 13.74% 84 13.91% 14 2.32% 46 7.62% 3 0.50% 18 2.98%

TOTAL 2,769 2,811

* Age at first claim.

Appendix 3 – Exceeding proposed limits and duration of use

Table 15. Exceeding proposed limits and duration of use BENZODIAZEPINES - ALL CLAIMS PROPOSED TOTAL EXCEED TOTAL EXCEED PROPOSED TOTAL EXCEED AGENT PRODUCT LIMIT CLAIMS PROPOSED PERCENT PATIENTS PROPOSED PERCENT LIMIT PATIENTS PROPOSED PERCENT

Alprazolam ALPRAZOLAM CON 1 MG/ML >4 MG / DAY 1 0 0.00% 1 0 0.00% >12 WEEKS 1

Alprazolam ALPRAZOLAM TAB 0.25 ODT >4 MG / DAY 18 0 0.00% 4 0 0.00% >12 WEEKS 4

Alprazolam ALPRAZOLAM TAB 0.25MG >4 MG / DAY 6,915 1 0.01% 1,863 1 0.05% >12 WEEKS 1,863

Alprazolam ALPRAZOLAM TAB 0.5MG >4 MG / DAY 28,495 73 0.26% 5,588 33 0.59% >12 WEEKS 5,588

Alprazolam ALPRAZOLAM TAB 0.5MG ER >4 MG / DAY 173 0 0.00% 54 0 0.00% >12 WEEKS 54

Alprazolam ALPRAZOLAM TAB 0.5MG OD >4 MG / DAY 50 0 0.00% 11 0 0.00% >12 WEEKS 11

Alprazolam ALPRAZOLAM TAB 0.5MG XR >4 MG / DAY 30 0 0.00% 13 0 0.00% >12 WEEKS 13

Alprazolam ALPRAZOLAM TAB 1MG >4 MG / DAY 40,441 916 2.27% 4,948 275 5.56% >12 WEEKS 4,948

Alprazolam ALPRAZOLAM TAB 1MG ER >4 MG / DAY 404 3 0.74% 87 1 1.15% >12 WEEKS 87

Alprazolam ALPRAZOLAM TAB 1MG ODT >4 MG / DAY 4 3 75.00% 2 1 50.00% >12 WEEKS 2

Alprazolam ALPRAZOLAM TAB 1MG XR >4 MG / DAY 143 4 2.80% 43 2 4.65% >12 WEEKS 43

Alprazolam ALPRAZOLAM TAB 2MG >4 MG / DAY 15,029 8,116 54.00% 1,422 802 56.40% >12 WEEKS 1,422

Alprazolam ALPRAZOLAM TAB 2MG ER >4 MG / DAY 311 24 7.72% 56 5 8.93% >12 WEEKS 56

Alprazolam ALPRAZOLAM TAB 2MG ODT >4 MG / DAY 8 8 100.00% 1 1 100.00% >12 WEEKS 1

Alprazolam ALPRAZOLAM TAB 2MG XR >4 MG / DAY 123 56 45.53% 13 4 30.77% >12 WEEKS 13

Alprazolam ALPRAZOLAM TAB 3MG ER >4 MG / DAY 94 19 20.21% 27 5 18.52% >12 WEEKS 27

Alprazolam ALPRAZOLAM TAB 3MG XR >4 MG / DAY 17 0 0.00% 7 0 0.00% >12 WEEKS 7

Alprazolam XANAX TAB 2MG >4 MG / DAY 3 0 0.00% 1 0 0.00% >12 WEEKS 1

TOTAL ALL 92,259 9,223 10.00% 11,525 1,076 9.34% 11,525 5,983 51.91%

TOTAL FFS 32,005 3,008 9.40% 5,534 506 9.14% 5,534 2,891 52.24% >4 Chlordiazepoxide CHLORDIAZEP CAP 10MG >100 MG / DAY 387 7 1.81% 218 4 1.83% MONTHS 218 >4 Chlordiazepoxide CHLORDIAZEP CAP 25MG >100 MG / DAY 1,367 369 26.99% 664 251 37.80% MONTHS 664 >4 Chlordiazepoxide CHLORDIAZEP CAP 5MG >100 MG / DAY 155 0 0.00% 49 0 0.00% MONTHS 49

TOTAL ALL 1,909 376 19.70% 814 254 31.20% 814 240 29.48%

TOTAL FFS 678 141 20.80% 355 102 28.73% 355 101 28.45% Clonazepam CLONAZEP ODT TAB 0.125MG >4 MG / DAY 452 0 0.00% 75 0 0.00% >12 WEEKS 75

Clonazepam CLONAZEP ODT TAB 0.25MG >4 MG / DAY 624 0 0.00% 149 0 0.00% >12 WEEKS 149 50

BENZODIAZEPINES - ALL CLAIMS PROPOSED TOTAL EXCEED TOTAL EXCEED PROPOSED TOTAL EXCEED AGENT PRODUCT LIMIT CLAIMS PROPOSED PERCENT PATIENTS PROPOSED PERCENT LIMIT PATIENTS PROPOSED PERCENT

Clonazepam CLONAZEP ODT TAB 0.5MG >4 MG / DAY 293 0 0.00% 79 0 0.00% >12 WEEKS 79

Clonazepam CLONAZEP ODT TAB 1MG >4 MG / DAY 232 20 8.62% 37 1 2.70% >12 WEEKS 37

Clonazepam CLONAZEP ODT TAB 2MG >4 MG / DAY 13 6 46.15% 8 2 25.00% >12 WEEKS 8

Clonazepam CLONAZEPAM TAB 0.5MG >4 MG / DAY 36,702 21 0.06% 6,370 11 0.17% >12 WEEKS 6,370

Clonazepam CLONAZEPAM TAB 1MG >4 MG / DAY 56,869 661 1.16% 6,540 179 2.74% >12 WEEKS 6,540

Clonazepam CLONAZEPAM TAB 2MG >4 MG / DAY 13,894 4,941 35.56% 1,348 543 40.28% >12 WEEKS 1,348

Clonazepam KLONOPIN TAB 0.5MG >4 MG / DAY 28 0 0.00% 3 0 0.00% >12 WEEKS 3

Clonazepam KLONOPIN TAB 1MG >4 MG / DAY 27 0 0.00% 2 0 0.00% >12 WEEKS 2

TOTAL ALL 109,134 5,649 5.18% 11,970 710 5.93% 11,970 6,961 58.15%

TOTAL FFS 36,459 1,987 5.45% 5,550 338 6.09% 5,550 3,170 57.12% >4 Clorazepate CLORAZ DIPOT TAB 15MG >90 MG / DAY 604 12 1.99% 31 6 19.35% MONTHS 31 >4 Clorazepate CLORAZ DIPOT TAB 3.75MG >90 MG / DAY 1,937 0 0.00% 174 0 0.00% MONTHS 174 >4 Clorazepate CLORAZ DIPOT TAB 7.5MG >90 MG / DAY 1,314 2 0.15% 77 1 1.30% MONTHS 77 >4 Clorazepate TRANXENE T TAB 3.75MG >90 MG / DAY 29 0 0.00% 1 0 0.00% MONTHS 1 >4 Clorazepate TRANXENE T TAB 7.5MG >90 MG / DAY 10 0 0.00% 1 0 0.00% MONTHS 1

TOTAL ALL 3,894 14 0.36% 243 6 2.47% 243 125 51.44%

TOTAL FFS 1,710 6 0.35% 96 3 3.13% 96 47 48.96% Diazepam DIAZEPAM CON 5MG/ML >40 MG / DAY 41 1 2.44% 29 1 3.45% >16 WEEKS 29

Diazepam DIAZEPAM INJ 5MG/ML >40 MG / DAY 75 2 2.67% 28 2 7.14% >16 WEEKS 28

Diazepam DIAZEPAM SOL 1MG/ML >40 MG / DAY 1,358 1 0.07% 670 1 0.15% >16 WEEKS 670

Diazepam DIAZEPAM SOL 5MG/5ML >40 MG / DAY 15 0 0.00% 8 0 0.00% >16 WEEKS 8

Diazepam DIAZEPAM TAB 10MG >40 MG / DAY 14,534 256 1.76% 2,751 75 2.73% >16 WEEKS 2,751

Diazepam DIAZEPAM TAB 2MG >40 MG / DAY 3,492 0 0.00% 1,284 0 0.00% >16 WEEKS 1,284

Diazepam DIAZEPAM TAB 5MG >40 MG / DAY 19,954 39 0.20% 6,349 31 0.49% >16 WEEKS 6,349

TOTAL ALL 39,469 299 0.76% 10,018 110 1.10% 10,018 2,695 26.90%

TOTAL FFS 11,908 109 0.92% 3,308 47 1.42% 3,308 1,120 33.86% Estazolam ESTAZOLAM TAB 1MG >2 MG / DAY 5 0 0.00% 4 0 0.00% >12 WEEKS 4

Estazolam ESTAZOLAM TAB 2MG >2 MG / DAY 51 1 1.96% 7 1 14.29% >12 WEEKS 7

TOTAL ALL 56 1 1.79% 11 1 9.09% 11 7 63.64% 51

BENZODIAZEPINES - ALL CLAIMS PROPOSED TOTAL EXCEED TOTAL EXCEED PROPOSED TOTAL EXCEED AGENT PRODUCT LIMIT CLAIMS PROPOSED PERCENT PATIENTS PROPOSED PERCENT LIMIT PATIENTS PROPOSED PERCENT

TOTAL FFS 0 0 0.00% 0 0 0.00% 0 0 0.00% Flurazepam FLURAZEPAM CAP 15MG >30 MG / DAY 50 0 0.00% 13 0 0.00% >1 MONTH 13

Flurazepam FLURAZEPAM CAP 30MG >30 MG / DAY 242 1 0.41% 30 1 3.33% >1 MONTH 30

TOTAL ALL 292 1 0.34% 41 1 2.44% 41 31 75.61%

TOTAL FFS 168 1 0.60% 20 1 5.00% 20 13 65.00% Lorazepam ATIVAN TAB 2MG >6 MG / DAY 4 0 0.00% 1 0 0.00% >12 WEEKS 1

Lorazepam LORAZEPAM CON 2MG/ML >6 MG / DAY 647 109 16.85% 253 54 21.34% >12 WEEKS 253

Lorazepam LORAZEPAM INJ 2MG/ML >6 MG / DAY 360 80 22.22% 98 35 35.71% >12 WEEKS 98

Lorazepam LORAZEPAM TAB 0.5MG >6 MG / DAY 15,499 45 0.29% 4,018 29 0.72% >12 WEEKS 4,018

Lorazepam LORAZEPAM TAB 1MG >6 MG / DAY 28,318 240 0.85% 6,178 107 1.73% >12 WEEKS 6,178

Lorazepam LORAZEPAM TAB 2MG >6 MG / DAY 6,979 915 13.11% 1,115 210 18.83% >12 WEEKS 1,115

TOTAL ALL 51,807 1,389 2.68% 9,993 415 4.15% 9,993 4,026 40.29%

TOTAL FFS 19,935 504 2.53% 4,506 207 4.59% 4,506 1,847 40.99% Oxazepam OXAZEPAM CAP 10MG >60 MG / DAY 7 1 14.29% 5 1 20.00% >12 WEEKS 5

Oxazepam OXAZEPAM CAP 15MG >60 MG / DAY 42 2 4.76% 5 2 40.00% >12 WEEKS 5

Oxazepam OXAZEPAM CAP 30MG >60 MG / DAY 3 3 100.00% 2 2 100.00% >12 WEEKS 2

TOTAL ALL 52 6 11.54% 12 5 41.67% 12 6 50.00%

TOTAL FFS 17 0 0.00% 2 0 0.00% 2 2 100.00% Temazepam TEMAZEPAM CAP 15MG >30 MG / DAY 4,239 48 1.13% 958 12 1.25% >1 MONTH 958

Temazepam TEMAZEPAM CAP 22.5MG >30 MG / DAY 35 0 0.00% 8 0 0.00% >1 MONTH 8

Temazepam TEMAZEPAM CAP 30MG >30 MG / DAY 6,694 136 2.03% 867 31 3.58% >1 MONTH 867

Temazepam TEMAZEPAM CAP 7.5MG >30 MG / DAY 118 0 0.00% 31 0 0.00% >1 MONTH 31

TOTAL ALL 11,086 184 1.66% 1,634 42 2.57% 1,634 1,243 76.07%

TOTAL FFS 3,354 36 1.07% 695 15 2.16% 695 546 78.56% Triazolam TRIAZOLAM TAB 0.125MG >0.5 MG / DAY 42 1 2.38% 20 1 5.00% >7 DAYS 20

Triazolam TRIAZOLAM TAB 0.25MG >0.5 MG / DAY 1,215 56 4.61% 361 43 11.91% >7 DAYS 361

TOTAL ALL 1,257 57 4.53% 375 44 11.73% 375 174 46.40%

TOTAL FFS 58 3 5.17% 8 1 12.50% 8 4 50.00% TOTAL ALL BENZOS ALL PTS 311,215 17,199 5.53% 37,186 2,526 6.79% 37,186 18,756 50.44%

TOTAL ALL BENZOS FFS PTS 106,292 5,795 5.45% 16,733 1,173 7.01% 16,733 7,850 46.91% 52

Table 16. Diagnosis codes submitted

A EPILEPSY/SEIZURES B ALCOHOL MISUSE C DRUG DEPENDENCE D DRUG ABUSE E BENZODIAZAPINE POISONING F OTHER POISONING G BENZODIAZAPINE ACCIDENTAL POISONING H OTHER ACCIDENTAL POISONING (definitions/list of diagnosis codes included in each category available on request)

BENZODIAZEPINES - ALL CLAIMS 2014 - 2017

AGENT PRODUCT CLAIMS PATIENTS DX A DX B DX C DX D DX E DX F DX G DX H

Alprazolam Oral Alprazolam Concentrate 1 1 1 100.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00%

Alprazolam Alprazolam Tablet 90,880 11,441 1,307 11.42% 1,183 10.34% 4,432 38.74% 2,000 17.48% 384 3.36% 1,044 9.13% 105 0.92% 571 4.99%

Alprazolam Tablet Alprazolam Dispersible 80 18 5 27.78% 2 11.11% 5 27.78% 2 11.11% 1 5.56% 4 22.22% 2 11.11% 2 11.11%

Alprazolam Tablet Alprazolam Extended Release 1,295 227 34 14.98% 31 13.66% 106 46.70% 50 22.03% 12 5.29% 29 12.78% 5 2.20% 14 6.17%

Alprazolam Xanax Tablet 3 1 1 100.00% 0 0.00% 1 100.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00%

Chlordiazepoxide Chlordiazepoxide Capsule 1,909 814 279 34.28% 651 79.98% 563 69.16% 348 42.75% 55 6.76% 220 27.03% 17 2.09% 90 11.06%

Onfi Oral Clobazam Suspension 655 62 62 100.00% 0 0.00% 2 3.23% 0 0.00% 1 1.61% 3 4.84% 0 0.00% 0 0.00%

Clobazam Onfi Tablet 3,636 204 199 97.55% 3 1.47% 13 6.37% 4 1.96% 1 0.49% 7 3.43% 0 0.00% 3 1.47%

Clonazepam Clonazepam Tablet 107,465 11,800 1,878 15.92% 1,493 12.65% 4,679 39.65% 2,339 19.82% 443 3.75% 1,305 11.06% 109 0.92% 634 5.37%

Clonazepam Tablet Clonazepam Dispersible 1,614 315 138 43.81% 28 8.89% 68 21.59% 40 12.70% 8 2.54% 28 8.89% 3 0.95% 18 5.71%

Clonazepam Klonopin Tablet 55 5 3 60.00% 0 0.00% 1 20.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00%

Clorazepate Clorazepate Tablet 3,855 242 168 69.42% 6 2.48% 33 13.64% 12 4.96% 0 0.00% 10 4.13% 0 0.00% 4 1.65%

Clorazepate Tranxene Tablet 39 1 1 100.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 53

BENZODIAZEPINES - ALL CLAIMS 2014 - 2017

AGENT PRODUCT CLAIMS PATIENTS DX A DX B DX C DX D DX E DX F DX G DX H

Diazepam Diazepam Injection 75 28 21 75.00% 3 10.71% 3 10.71% 3 10.71% 0 0.00% 3 10.71% 0 0.00% 1 3.57%

Diazepam Oral Diazepam Concentrate 41 29 16 55.17% 0 0.00% 2 6.90% 3 10.34% 0 0.00% 1 3.45% 1 3.45% 0 0.00%

Diazepam Oral Diazepam Solution 1,373 675 168 24.89% 1 0.15% 12 1.78% 6 0.89% 3 0.44% 17 2.52% 3 0.44% 13 1.93%

Diazepam Diazepam Tablet 37,980 9,344 1,203 12.87% 828 8.86% 2,995 32.05% 1,271 13.60% 206 2.20% 647 6.92% 54 0.58% 388 4.15%

Estazolam Estazolam Tablet 56 11 2 18.18% 1 9.09% 5 45.45% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 1 9.09%

Flurazepam Flurazepam Capsule 292 41 8 19.51% 7 17.07% 21 51.22% 5 12.20% 2 4.88% 8 19.51% 0 0.00% 3 7.32%

Lorazepam Ativan Tablet 4 1 1 100.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00%

Lorazepam Lorazepam Injection 360 98 60 61.22% 15 15.31% 30 30.61% 11 11.22% 1 1.02% 10 10.20% 0 0.00% 3 3.06%

Lorazepam Oral Lorazepam Concentrate 647 253 119 47.04% 15 5.93% 50 19.76% 13 5.14% 4 1.58% 19 7.51% 1 0.40% 12 4.74%

Lorazepam Lorazepam Tablet 50,796 9,767 1,840 18.84% 1,352 13.84% 3,562 36.47% 1,724 17.65% 280 2.87% 988 10.12% 68 0.70% 511 5.23%

Midazolam Midazolam Injection 1,134 395 374 94.68% 4 1.01% 20 5.06% 10 2.53% 1 0.25% 18 4.56% 0 0.00% 10 2.53%

Midazolam Midazolam Syrup 485 382 14 3.66% 1 0.26% 2 0.52% 2 0.52% 0 0.00% 3 0.79% 0 0.00% 1 0.26%

Oxazepam Oxazepam Capsule 52 12 3 25.00% 5 41.67% 6 50.00% 4 33.33% 1 8.33% 3 25.00% 0 0.00% 2 16.67%

Temazepam Temazepam Capsule 11,086 1,634 263 16.10% 190 11.63% 633 38.74% 272 16.65% 64 3.92% 191 11.69% 18 1.10% 109 6.67%

Triazolam Triazolam Tablet 1,257 375 49 13.07% 28 7.47% 90 24.00% 57 15.20% 8 2.13% 27 7.20% 1 0.27% 17 4.53%

TOTALS 317,125 37,186 5,570 14.98% 3,742 10.06% 11,657 31.35% 5,289 14.22% 820 2.21% 2,837 7.63% 213 0.57% 1,445 3.89%

Table 17. Diagnosis codes submitted for those exceeding proposed/recommended duration of use (as defined above)

Percent Any Percent DX A Percent DX B Percent DX C Percent DX D Percent DX E Percent DX F Percent DX G Percent DX H Percent Duration (>) Patients of Total DX of PTS (Seiz) of PTS (Alc) of PTS (DEP) of PTS (ABU) of PTS (BNZ) of PTS (OTH) of PTS (BNZ) of PTS (OTH) of PTS

4 Months 12,791 34.40% 7554 59.06% 2311 18.07% 1568 12.26% 5532 43.25% 2509 19.62% 491 3.84% 1389 10.86% 145 1.13% 799 6.25%

6 Months 10,122 27.22% 6185 61.10% 1992 19.68% 1249 12.34% 4522 44.67% 2003 19.79% 400 3.95% 1120 11.07% 123 1.22% 672 6.64%

9 Months 7,571 20.36% 4754 62.79% 1600 21.13% 920 12.15% 3472 45.86% 1477 19.51% 297 3.92% 845 11.16% 91 1.20% 511 6.75%

1 Year 5,726 15.40% 3653 63.80% 1294 22.60% 666 11.63% 2665 46.54% 1080 18.86% 209 3.65% 619 10.81% 67 1.17% 393 6.86%

18 Months 3,612 9.71% 2319 64.20% 889 24.61% 408 11.30% 1636 45.29% 634 17.55% 118 3.27% 367 10.16% 42 1.16% 248 6.87%

2 Years 2,293 6.17% 1471 64.15% 610 26.60% 233 10.16% 999 43.57% 375 16.35% 75 3.27% 224 9.77% 28 1.22% 151 6.59%

3 Years 1,036 2.79% 645 62.26% 279 26.93% 87 8.40% 410 39.58% 151 14.58% 31 2.99% 96 9.27% 13 1.25% 60 5.79%

4 Years 160 0.43% 111 69.38% 59 36.88% 12 7.50% 59 36.88% 26 16.25% 5 3.13% 12 7.50% 2 1.25% 10 6.25%

TOTAL 37,186

Table 18. Diagnosis codes submitted for those exceeding proposed dose limits (as defined above)

TOTAL EXCEED Percent DX A Percent DX B Percent DX C Percent DX D Percent PATIENTS MAX ADD Any DX of PTS (All) of PTS (All) of PTS (DEP) of PTS (ABU) of PTS Alprazolam ALL 11,525 1,076 759 70.54% 230 21.38% 163 15.15% 654 60.78% 354 32.90%

FFS 5,534 506 351 69.37% 100 19.76% 67 13.24% 300 59.29% 156 30.83% Chlordiazepoxide ALL 814 254 247 97.24% 97 38.19% 227 89.37% 181 71.26% 110 43.31%

FFS 355 102 98 96.08% 41 40.20% 93 91.18% 71 69.61% 35 34.31% Clonazepam ALL 11,970 710 522 73.52% 180 25.35% 126 17.75% 425 59.86% 241 33.94%

FFS 5,550 338 249 73.67% 85 25.15% 64 18.93% 193 57.10% 116 34.32% Clorazepate ALL 243 6 6 100.00% 6 100.00% 0 0.00% 0 0.00% 0 0.00%

FFS 96 3 3 100.00% 3 100.00% 0 0.00% 0 0.00% 0 0.00% Diazepam ALL 10,018 110 66 60.00% 31 28.18% 13 11.82% 46 41.82% 22 20.00%

FFS 3,308 47 28 59.57% 13 27.66% 6 12.77% 19 40.43% 8 17.02% Estazolam ALL 11 1 1 100.00% 0 0.00% 0 0.00% 1 100.00% 0 0.00%

FFS 0 0 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% Flurazepam ALL 41 1 1 100.00% 0 0.00% 0 0.00% 1 100.00% 0 0.00%

FFS 20 1 1 100.00% 0 0.00% 0 0.00% 1 100.00% 0 0.00% Lorazepam ALL 9,993 415 294 70.84% 148 35.66% 95 22.89% 180 43.37% 99 23.86%

FFS 4,506 207 139 67.15% 66 31.88% 47 22.71% 85 41.06% 47 22.71% Oxazepam ALL 12 5 4 80.00% 1 20.00% 4 80.00% 3 60.00% 2 40.00%

FFS 2 0 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% Temazepam ALL 1,634 42 20 47.62% 5 11.90% 3 7.14% 19 45.24% 9 21.43%

FFS 695 15 4 26.67% 1 6.67% 1 6.67% 3 20.00% 2 13.33% Triazolam ALL 375 44 11 25.00% 3 6.82% 1 2.27% 6 13.64% 3 6.82%

FFS 8 1 0 0.00% 0 0.00% 0 0.00% 0 0.00% 0 0.00% TOTAL ALL 37,186 2,526 1,811 71.69% 644 25.49% 588 23.28% 1,403 55.54% 767 30.36%

FFS 16,733 1,173 835 71.18% 290 24.72% 266 22.68% 638 54.39% 340 28.99%

TOTAL EXCEED DX E Percent DX F Percent DX G Percent DX H Percent PATIENTS MAX ADD (BNZ) of PTS (OTH) of PTS (BNZ) of PTS (OTH) of PTS Alprazolam ALL 11,525 1,076 71 6.60% 172 15.99% 30 2.79% 118 10.97%

FFS 5,534 506 35 6.92% 74 14.62% 15 2.96% 50 9.88% Chlordiazepoxide ALL 814 254 22 8.66% 78 30.71% 7 2.76% 26 10.24%

FFS 355 102 7 6.86% 23 22.55% 4 3.92% 12 11.76% Clonazepam ALL 11,970 710 54 7.61% 129 18.17% 15 2.11% 73 10.28%

FFS 5,550 338 21 6.21% 65 19.23% 8 2.37% 35 10.36% Clorazepate ALL 243 6 0 0.00% 0 0.00% 0 0.00% 0 0.00%

FFS 96 3 0 0.00% 0 0.00% 0 0.00% 0 0.00% Diazepam ALL 10,018 110 3 2.73% 11 10.00% 3 2.73% 8 7.27%

FFS 3,308 47 2 4.26% 3 6.38% 1 2.13% 3 6.38% Estazolam ALL 11 1 0 0.00% 0 0.00% 0 0.00% 0 0.00%

FFS 0 0 0 0.00% 0 0.00% 0 0.00% 0 0.00% Flurazepam ALL 41 1 0 0.00% 0 0.00% 0 0.00% 0 0.00%

FFS 20 1 0 0.00% 0 0.00% 0 0.00% 0 0.00% Lorazepam ALL 9,993 415 10 2.41% 60 14.46% 4 0.96% 31 7.47%

FFS 4,506 207 5 2.42% 30 14.49% 2 0.97% 12 5.80% Oxazepam ALL 12 5 1 20.00% 2 40.00% 0 0.00% 2 40.00%

FFS 2 0 0 0.00% 0 0.00% 0 0.00% 0 0.00% Temazepam ALL 1,634 42 3 7.14% 6 14.29% 10 23.81% 2 4.76%

FFS 695 15 0 0.00% 1 6.67% 0 0.00% 0 0.00% Triazolam ALL 375 44 1 2.27% 2 4.55% 0 0.00% 0 0.00%

FFS 8 1 0 0.00% 0 0.00% 0 0.00% 0 0.00% TOTAL ALL 37,186 2,526 144 5.70% 419 16.59% 53 2.10% 239 9.46%

FFS 16,733 1,173 62 5.29% 186 15.86% 27 2.30% 106 9.04%

Table 19. Top prescribers and number of their claims and patients exceeding the proposed dose limits and duration of use

Type Specialty Claims Exceed ADD Percent Patients Exceed ADD Percent Exceed DUR Percent

Nurse Practitioner Psychiatry 5743 1015 17.67% 465 94 20.22% 360 77.42%

Physician Psychiatry 2431 431 17.73% 221 37 16.74% 170 76.92%

Nurse Practitioner Psychiatry 2392 121 5.06% 224 14 6.25% 156 69.64%

Physician Psychiatry 2333 185 7.93% 211 22 10.43% 157 74.41%

Osteopath Family Medicine 2247 85 3.78% 314 17 5.41% 229 72.93%

Nurse Practitioner Psychiatry 2246 17 0.76% 85 2 2.35% 68 80.00%

Physician Family Medicine 2004 20 1.00% 194 5 2.58% 129 66.49%

Physician Family Medicine 1984 2 0.10% 59 2 3.39% 40 67.80%

Nurse Practitioner Psychiatry 1893 11 0.58% 151 2 1.32% 121 80.13%

Nurse Practitioner Family Medicine 1702 10 0.59% 180 4 2.22% 125 69.44%

Physician Family Medicine 1605 142 8.85% 168 21 12.50% 121 72.02%

Nurse Practitioner Family Medicine 1556 0 0.00% 137 0 0.00% 103 75.18%

Nurse Practitioner Psychiatry 1537 4 0.26% 170 1 0.59% 129 75.88%

Physician Family Medicine 1526 16 1.05% 219 5 2.28% 140 63.93%

Nurse Practitioner Psychiatry 1496 10 0.67% 134 2 1.49% 101 75.37%

Physician Geriatric Medicine 1447 43 2.97% 247 13 5.26% 136 55.06%

Physician Psychiatry 1258 67 5.33% 178 8 4.49% 146 82.02%

Nurse Practitioner Family Medicine 1246 218 17.50% 134 22 16.42% 79 58.96%

Physician Psychiatry 1240 81 6.53% 139 14 10.07% 101 72.66%

Physician Family Medicine 1234 14 1.13% 77 4 5.19% 62 80.52%

Physician Psychiatry 1229 52 4.23% 135 6 4.44% 97 71.85%

Nurse Practitioner Psychiatry 1185 29 2.45% 197 8 4.06% 119 60.41%

Physician Internal Medicine 1165 97 8.33% 112 4 3.57% 78 69.64%

Osteopath Family Medicine 1104 262 23.73% 101 26 25.74% 65 64.36%

Physician Family Medicine 1096 93 8.49% 117 16 13.68% 96 82.05%

Osteopath Psychiatry 1095 2 0.18% 100 2 2.00% 77 77.00%

Nurse Practitioner Family Medicine 1087 66 6.07% 117 10 8.55% 84 71.79%

Nurse Practitioner Psychiatry 1073 43 4.01% 156 4 2.56% 130 83.33%

Physician Family Medicine 1056 169 16.00% 94 17 18.09% 63 67.02%

Physician Neurology 1044 0 0.00% 15 0 0.00% 13 86.67%

Physician Neurology 1005 0 0.00% 65 0 0.00% 51 78.46%

Physician Pediatrics 1003 39 3.89% 97 6 6.19% 33 34.02%

Physician Family Medicine 988 1 0.10% 56 1 1.79% 35 62.50%

Nurse Practitioner Family Medicine 986 81 8.22% 205 25 12.20% 172 83.90%

Physician Family Medicine 971 147 15.14% 190 29 15.26% 145 76.32%

Physician Psychiatry 966 1 0.10% 81 1 1.23% 59 72.84%

Osteopath Family Medicine 927 47 5.07% 143 8 5.59% 89 62.24%

Physician Assistant Family Medicine 920 86 9.35% 172 25 14.53% 115 66.86%

Nurse Practitioner Nephrology 877 107 12.20% 170 17 10.00% 147 86.47%

Physician Family Medicine 877 23 2.62% 184 14 7.61% 118 64.13%

Type Specialty Claims Exceed ADD Percent Patients Exceed ADD Percent Exceed DUR Percent

Nurse Practitioner Psychiatry 874 11 1.26% 168 3 1.79% 130 77.38%

Physician Family Medicine 869 0 0.00% 115 0 0.00% 53 46.09%

Nurse Practitioner Psychiatry 865 16 1.85% 150 3 2.00% 129 86.00%

Physician Assistant Neurology 856 1 0.12% 66 1 1.52% 19 28.79%

Nurse Practitioner Psychiatry 855 11 1.29% 185 3 1.62% 149 80.54%

Physician Assistant Family Medicine 785 109 13.89% 180 35 19.44% 134 74.44%

Osteopath Family Medicine 778 21 2.70% 85 6 7.06% 52 61.18%

Physician Psychiatry 776 199 25.64% 55 11 20.00% 48 87.27%

Physician Pediatrics 773 2 0.26% 73 2 2.74% 24 32.88%

Physician Family Medicine 770 44 5.71% 96 6 6.25% 62 64.58%

Nurse Practitioner Psychiatry 745 0 0.00% 88 0 0.00% 61 69.32%

Osteopath Family Medicine 737 30 4.07% 99 8 8.08% 54 54.55%

Physician Psychiatry 734 47 6.40% 92 3 3.26% 69 75.00%

Physician Assistant Family Medicine 733 39 5.32% 72 3 4.17% 55 76.39%

Dentist Family Medicine 716 0 0.00% 570 0 0.00% 0 0.00%

Physician Assistant Family Medicine 714 90 12.61% 74 9 12.16% 49 66.22%

Physician Psychiatry 712 142 19.94% 128 29 22.66% 108 84.38%

Nurse Practitioner Family Medicine 701 12 1.71% 105 5 4.76% 62 59.05%

Physician Family Medicine 697 133 19.08% 140 29 20.71% 97 69.29%

Physician Psychiatry 693 20 2.89% 87 6 6.90% 60 68.97%

Physician Assistant Family Medicine 692 4 0.58% 88 1 1.14% 60 68.18%

Nurse Practitioner Family Medicine 690 5 0.72% 74 3 4.05% 56 75.68%

Osteopath Family Medicine 690 81 11.74% 67 6 8.96% 47 70.15%

Osteopath Family Medicine 685 55 8.03% 65 4 6.15% 31 47.69%

Physician Psychiatry 671 4 0.60% 52 1 1.92% 35 67.31%

Physician Family Medicine 665 156 23.46% 67 16 23.88% 56 83.58%

Physician Family Medicine 659 20 3.03% 111 8 7.21% 69 62.16%

Physician Psychiatry 658 7 1.06% 84 2 2.38% 68 80.95%

Physician Psychiatry 655 7 1.07% 76 3 3.95% 55 72.37%

Nurse Practitioner Family Medicine 655 5 0.76% 109 1 0.92% 85 77.98%

Osteopath Family Medicine 651 153 23.50% 76 17 22.37% 45 59.21%

Physician Family Medicine 650 329 50.62% 84 34 40.48% 56 66.67%

Physician Family Medicine 648 39 6.02% 64 2 3.13% 31 48.44%

Physician Geriatric Medicine 638 39 6.11% 127 19 14.96% 84 66.14%

Physician Internal Medicine 620 84 13.55% 44 6 13.64% 32 72.73%

Physician Assistant Family Medicine 619 33 5.33% 95 5 5.26% 58 61.05%

Osteopath Family Medicine 612 97 15.85% 141 17 12.06% 108 76.60%

Physician Family Medicine 609 2 0.33% 156 2 1.28% 111 71.15%

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