STATE OPERATED FACILITIES EXECUTIVE FORMULARY COMMITTEE MINUTES February 2, 2018

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1 STATE OPERATED FACILITIES EXECUTIVE FORMULARY COMMITTEE MINUTES February 2, 2018 The Executive Formulary Committee convened on Friday, February 2, 2018 in Room ASH Building 552. The meeting was called to order by Dr. Messer, Chair at 9:35 a.m. John Bennett, M.D. E. Ross Taylor, M.D. Barbara Carroll, R.N. Connie Horton, RNP (non-voting) Absent Cleveland Chip Dunlap, MSN, MHA Nina Muse, M.D. (non-voting) Absent Catherine Hall, Pharm.D. Tim Bray (non-voting) Absent Jeanna Heidel, Pharm.D. Scott Schalchlin (non-voting) Absent Marla Knight, Pharm.D., CGP, FASCP (phone) Mike Maples (non-voting) Absent Jeff Matthews, M.D. Absent Raul Luna, RN, MSN (non-voting) Absent Mark Messer, D.O. Rachel Samsel, (non-voting) Absent Scott Murry, M.D. Absent Vacant Center Position Kenda Pittman, Pharm.D. Vacant Center Position Ann L. Richards, Pharm.D. Vacant SH Physician Position Glenn Shipley, D.O., MPH Vacant SSLC Physician Position Guests Present: Brad Fitzwater, M.D.; Evita Lopez, pharmacy student, ASH; Simone Mack, pharmacy student, ASH; Melody Martinez, pharmacy student, SASH; Lisa Mican, Pharm.D., ASH Introduction and Other Information The guests attending the meeting were introduced. It was noted that Ms. Millhollon, Dr. Smith and Dr. Wright have resigned from the Committee. Dr. Messer has been appointed as Chair. New members of the Committee include: Dr. Taylor, Psychiatry Services Coordinator, State Supported Living Centers and Ms. Carroll, registered nurse at Austin State Hospital. The vacant physician positions from the state hospital and state supported living center are pending. Approval of Minutes of October 27, 2017 On a motion of Dr. Hall, seconded by Dr. Pittman, the minutes of the October 27 th meeting were approved as previously distributed. Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

2 Conflict of Interest The Executive Formulary Committee Conflict of Interest Policy was distributed to the Committee members prior to the meeting. Committee members are required to submit annual disclosures. The following individuals have submitted their statements and indicated no conflicts of interest: John Bennett Barbara Carroll Cleveland Chip Dunlap Catherine Hall Jeanna Heidel Marla Knight Jeff Matthews Mark Messer Kenda Pittman Ann Richards Glenn Shipley Eulon Ross Taylor Dr. Murry s disclosure statement is pending. Adverse Drug Reaction Reports The Executive Formulary Committee discussed several adverse drug reaction reports that were received from the field. On 9/13/17, a 64 year old female was transferred from a community hospital in another city to the local psychiatric hospital because of worsening psychotic and mood symptoms. Her medications upon transfer were as follows: quetiapine 400 mg bedtime, clonazepam 0.5 mg bedtime, trazodone 150 mg bedtime, amlodipine 10 mg bedtime, losartan 25 mg every 12 hours, and atorvastatin 20 mg bedtime. The following is a summary of her lab findings during the hospitalization: Date Platelets (K/mm 3) LDL (mg/dl) 9/14/ /3/ /24/ /27/ /7/ /27/ /8/ Due to the persistent psychosis, on 9/18/17 paliperidone was added to the regimen with the plan to taper and discontinue the quetiapine once she was stabilized on the paliperidone. By 9/29/17, she was on paliperidone 9 mg daily in addition to all medications listed above. On 10/4/17, clonazepam 0.5 mg bedtime and trazodone 150 mg bedtime were stopped and eszopiclone 1 mg bedtime was started. On 10/24/17, atorvastatin 20 mg bedtime was discontinued. She was off statin therapy from 10/24/17 11/28/17. On 11/28/17, pravastatin 20 mg was started. CBC and lipids were checked every four weeks. Her current medications include quetiapine 600 mg, sertraline 150 mg daily (started early November 2017), temazepam 30 mg bedtime (started early January 2018), amlodipine 10 mg bedtime, losartan 50 mg daily, pravastatin 20 mg bedtime, ibuprofen 600 mg TID (through 2/5/18 for ear/dental pain), pantoprazole 40 mg daily (started early January 2018 for reflux), penicillin 500 mg every 6 hours (through 1/26/18 for dental infection). Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

3 A 45 year old African American female with schizoaffective disorder, bipolar type, hypertension and alcohol use disorder was admitted to the psychiatric hospital in August, Medications prescribed with unknown adherence prior to admission were: docusate calcium, losartan, psyllium fiber, divalproex DR 500 mg twice a day, quetiapine 200 mg in the morning and 400 mg at bedtime, and buspirone 10 mg twice a day. All medications were initially continued with the exception of divalproex and losartan (substituted with valsartan). Baseline LFTs were alkaline phosphatase of 76 U/L, ALT 25 U/L, and AST 25 U/L and a valproic acid level 38.3 mcg/ml. Buspirone was discontinued. Two weeks after admission, divalproex DR 500 mg twice a day was restarted and prescribed along with quetiapine 400 mg twice a day and lorazepam 1 mg three times a day. Diphenhydramine 50 mg was also added at bedtime for insomnia. Repeat LFTs one week after reinitiating divalproex indicated a stable alkaline phosphatase of 74 U/L, and increased ALT 51 U/L and AST 37 U/L. Her valproic acid level was 87.3 mcg/ml; the dose of divalproex DR was increased to 500 mg in the morning and 1,000 mg at bedtime due to continued mood instability and decreased sleep. The following day, trazodone 100 mg at bedtime was added for sleep and her quetiapine dose was adjusted to 200 mg in the morning and 600 mg at bedtime. A week after the last divalproex DR dose increase, the follow-up valproic acid level was mcg/ml. Sertraline was added and increased to 100 mg daily. She had a negative acute hepatitis panel and ammonia level of 27 µmol/l. At this time, the patient was believed to be at her baseline functioning level. After being prescribed divalproex for a 1½ months, it was found that the order had expired for a week resulting in acute decompensation. Quetiapine was discontinued and chlorpromazine 100 mg BID was initiated. Divalproex DR was restarted at the previous dose with a level of 94.7 mcg/ml the following week. In addition, tolterodine ER 2 mg daily was prescribed for incontinence. A week and a half after restarting divalproex, she appeared markedly more confused compared to baseline and struggled with words and names. A Montreal Cognitive Assessment (MoCA) was conducted and she scored an 11/30. Diphenhydramine was discontinued, lorazepam was reduced to 0.5 mg three times a day. Labs revealed a stable alkaline phosphatase of 70 U/L, and improved ALT 35 U/L and AST 27 U/L. Her ammonia level was rechecked and was increased to 69 µmol/l. She received lactulose for the elevated ammonia with possible encephalopathy and the divalproex DR dose was decreased. Repeat labs three days after the onset of altered mental status revealed an alkaline phosphatase of 58 U/L, and improved ALT 39 U/L and AST 29 U/L. Her ammonia level was improved at 39 µmol/l. Divalproex was discontinued and chlorpromazine was changed to haloperidol. Four days after the onset of altered mental status, she was noted to be less confused, fully oriented, and able to remember names. Repeat LFTs and ammonia were within normal limits. A 58 year old female was admitted to the psychiatric hospital in May 2017 with severe major depressive disorder with psychosis, a history of alcohol use disorder and leukoencephalopathy (possibly due to small vessel disease per neurologist). The admission electrolytes were within normal limits including magnesium (2.1 meq/l) and a slightly low potassium of 3.4 meq/l (normal ). She was treated for a UTI with nitrofurantoin 100 mg twice daily. Psychiatric medications were sertraline 50 mg in the morning, aripiprazole 5 mg in the morning and melatonin 5 mg at bedtime. She had a QTc 461 msec at two weeks after admission. The dose of sertraline was reduced to 25 mg in the morning and aripiprazole was increased to 20 mg in the morning with a follow-up QTc of 440 msec with normal electrolytes on CMP approximately 2 months after admission. Neurology was consulted due to cognitive impairment which resulted in the addition of donepezil 5 mg. Aripiprazole was switched to quetiapine due to tremor and titrated to 400 mg at bedtime. In addition, the antidepressant was switched to duloxetine 40 mg in the morning. Four months after admission, she had a normal EKG with QTc 433 msec and electrolytes were within normal limits on CMP. The only changes made to the possible QT prolonging medications was an increase in quetiapine by 150 mg to a daily dose of 550 mg per day and a dose increase of Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

4 donepezil from 5 to 10 mg daily. Zolpidem 5 mg at bedtime, propranolol 10 mg twice daily, vitamin B1, omega 3-fatty acids and folic acid were also added to the medication regimen. Approximately 6 months after admission while on these medications, the QTc was found to be severely prolonged at 516 msec. No other cardiac symptoms were noted or reported during that time. Six days later on the same regimen except a reduced dose of quetiapine of 100 mg at bedtime, the QTc was found to be normal by the consulting cardiologist at 411 msec. An ECHO was refused by the patient. A repeat EKG the following day at the psychiatric hospital showed moderate QTc prolongation of 481 msec on the same medication regimen. Quetiapine 100 mg at bedtime was discontinued and mirtazapine 15 mg at bedtime was then added to the medication regimen. After being on mirtazapine for 20 days along with donepezil 10 mg at bedtime severe QTc prolongation was again noted with QTc of 513 msec. Mirtazapine was discontinued and a follow-up EKG one week later still on donepezil 10 mg at bedtime was within normal limits with QTc of 446 msec. Atypical Antipsychotics Psychotropic Audit Criteria & Guidelines At the last meeting, it was recommended to update the Atypical Antipsychotics Psychotropic Audit Criteria & Guidelines to reflect the common components found in the revised clozapine psychotropic audit criteria and to include Invega Trinza and cariprazine (Vraylar ). The following summary are changes that were made: Added Invega Trinza and cariprazine (Vraylar ) Changed Pregnancy and Breast-Feeding to: See relative contraindications. Review productspecific labeling. Consider risks/benefits in reviewing medication-specific labeling. Added Cariprazine: CYP3A4 and lesser extent 2D6 for the major metabolic pathways Changed the lipid screening to If no lipid screening has been done within the last year, then a lipid profile should be obtained within 30 days of initiation of the drug under patient monitoring parameters. Added CBC (for patients on cariprazine) baseline and as clinically indicated to the monitoring parameters. On a motion of Dr. Heidel, seconded by Dr. Bennett, the revised Atypical Antipsychotics Psychotropic Audit Criteria & Guidelines were approved as modified. See Attachment A. The Committee recommended to review the Typical Antipsychotic Psychotropic Audit Criteria & Guidelines at the next meeting to address the changes made in the glucose and lipid monitoring. Midazolam Use in Status Epilepticus and Acute Agitation in those with Psychiatric Disorders presented by Evita Lopez At the last meeting, it was suggested that midazolam use in status epilepticus and in acute agitation in those with psychiatric disorders be reviewed. The use of midazolam in status epilepticus and for acute agitation is off-label. See Attachment B for this review. Midazolam is FDA approved for: Anesthesia Sedation/anxiolytic/amnesia (preoperative/procedural) Sedation for mechanically-ventilated patients Midazolam s off label use includes the following: Seizures in both children and adolescents Status epilepticus in children, adolescents, and adults Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

5 Refractory status epilepticus in children, adolescents, and adults Palliative sedation Acute agitation The dosing of midazolam is tailored to each patient, depending on different factors including: Underlying disease state Patient s age Concurrent medications Dose reductions of 20% to 50% should be considered for patients that are debilitated, chronically ill, or elderly, as well as patients concurrently taking opioids or other CNS depressants. In status epilepticus in children and adolescents, the IM route is preferred in patients without IV access. For pediatric patients < 13 kg, the dose has not been established For pediatric patients between 13 to 40 kg, give 5 mg IM once For pediatric patients > 40 kg, give 10 mg IM once The intranasal and buccal midazolam use in status epilepticus in pediatric patients has limited data. Intranasal dose 0.2 mg/kg o Use a 5 mg/ml injectable concentrated solution via atomizer o Burning upon administration is likely due to low ph Buccal dose 0.5 mg/kg o Injectable solution generally used For adults, the IM route is preferred in patients without IV access. There are limited data for the use of intranasal and buccal midazolam in adult patients. Dose 10 mg IM once or 0.2 mg/kg once with a maximum dose of 10 mg Intranasal dose 0.2 mg/kg Use 5 mg/ml injectable concentrated solution via atomizer Burning upon administration is likely due to low ph Buccal dose 0.5 mg/kg Injection solution generally used According to the American Epilepsy Society Convulsive Status Epilepticus Guideline in children and adults, if a seizure lasts between 5 and 20 minutes, patients are to be treated with a benzodiazepine as the initial therapy of choice using one of the following first line options: intramuscular midazolam, intravenous lorazepam, or intravenous diazepam. If the first line options are unavailable, one of the following options is recommended: intravenous phenobarbital, rectal diazepam, or intranasal/buccal midazolam. Midazolam requires monitoring of respiration, oxygenation, and vital signs. The approved FDA labeling states that midazolam should only be used in settings that can provide for continuous monitoring for respiratory and cardiac function and immediate availability of resuscitative drugs for ventilation and intubation and personnel trained in their use and skilled in airway management. If an overdose is known or suspected, flumazenil is indicated for the partial or complete reversal of midazolam s sedative effects. Flumazenil is a specific benzodiazepine-receptor antagonist. For acute agitation, the off-label midazolam dose in pediatric patients (6-12 years) is mg/kg/dose IM. For adults, the dose is 2.5 to 5 mg IM. In severely agitated patients, the Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

6 dose may be repeated every 3 to 5 minutes. Higher doses have been studied although they may result in increased risk for respiratory depression/oxygen desaturation and CNS depression. In renal impairment as well as hepatic impairment, no dosage adjustments necessary, but midazolam should be used with caution in these patients. For IM administration, midazolam should be administered undiluted deep into the large muscle. For intranasal administration, an atomizer is recommended for use to reduce the burning sensation. In order to minimize volume, the use of higher concentration of the injectable solution is recommended. The maximum recommended dose volume per nares is generally 1 ml. For buccal dosing for prolonged seizures the injectable solution rather than the syrup is generally used. According to, Issues in the Management of Acute Agitation: How Much Current Guidelines Consider Safety? Diazepam and midazolam administration bear a strong respiratory function depression risk, especially in patients with conditions limiting respiratory functions or benzodiazepine metabolism (hepatic impairment or alcohol abuse). Some of the guidelines (e.g., Rationale and Guidelines for Inpatient Treatment of Acute Psychosis; Expert Consensus Guideline on Assessment and Management of Agitation in Psychiatry) either do not mention respiratory depression with benzodiazepine or fail to address safety concerns. Protocol for the Management of Psychiatric Patients with Psychomotor Agitation states that benzodiazepines are a treatment option in nonpsychotic agitation, but are not an option for agitation due to psychotic symptoms. Midazolam 5 mg IM or other benzodiazepines could be a treatment option for patients with psychomotor agitation from alcohol abstinence, anxiety disorder, affective disorder, or personality and adjustment disorder. Cariprazine (Vraylar ) Drug Purchases The following is a summary of cariprazine drug purchases from October 1, 2017 through December 31, Facility Type Cariprazine Purchases Percent of Antipsychotic Purchases State Hospitals $17, % State Supported Living Centers $59, % New Drug Applications (Please refer to Attachment C for the monographs and applications that were considered when determining action by the committee.) Cariprazine (Vraylar ) - presented by Catherine Hall, Pharm.D. Cariprazine is a second generation (atypical) antipsychotic indicated for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Cariprazine is a dopamine D3 and D2 receptor partial agonist. It differs from other antipsychotics in that it has almost 10-fold greater affinity for D3 than D2 receptors in vitro and high and balanced in vivo occupancy of both D2 and D3 in rats and humans. It is thought that the D3 receptor modulates mood and cognition and may play a role in treating the negative symptoms of schizophrenia. In addition, cariprazine is a serotonin 5-HT1A receptor partial agonist and a serotonin 5-HT2A receptor antagonist. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR) that have in vitro receptor binding profiles similar to the parent drug. The starting dose of cariprazine is 1.5 mg/day for both schizophrenia and bipolar mania. For Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

7 schizophrenia, the dose maybe increased to 3 mg on Day 2. For bipolar mania, the dose should be increased to 3 mg on Day 2. The recommended dose for schizophrenia is 1.5 mg to 6 mg/day and for bipolar mania it is 3 mg to 6 mg/day. Cariprazine can be administered with or without food. Due to the long half-life of cariprazine and its metabolites, changes in dose will not be fully reflected in the plasma for several weeks. For patients with mild to moderate hepatic impairment, no dosage adjustments are needed. It is not recommended for use in patients with severe hepatic impairment. No dosage adjustments are recommended for patients with mild to moderate renal impairment. Usage in patients with severe renal impairment is not recommended. The follow table identifies action needed for patients receiving strong CYP3A4 inhibitors: Current Medication Drug Regimen Change Action to be Taken Stable dose cariprazine Initiating - Strong CYP3A4 Inhibitor Reduce current dose of cariprazine by half: On 4.5 mg daily reduce to 1.5 mg or 3 mg daily On 1.5 mg daily, adjust dose to every other day Strong CYP3A4 Inhibitor Initiating cariprazine Administer cariprazine 1.5 mg on Day 1 and Day 3. No drug on Day 2. Day 4 onward, administer 1.5 mg daily. Then, increase to a maximum dose of 3 mg. Stable dose of cariprazine and Strong CYP3A4 Inhibitor Withdrawing - CYP3A4 Inhibitor May need to increase dose of cariprazine Concomitant use of cariprazine and CYP3A4 inducers has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear. On a motion of Dr. Heidel, seconded by Dr. Taylor, it was recommended to add cariprazine to the Formulary. The Formulary Check List was completed and no issues were detected. Zoster vaccine Recombinant, Adjuvanted (Shingrix ) - presented by Melody Martinez, pharmacy student Shingrix is indicated for the prevention of herpes zoster (shingles) in adults aged 50 years and older. It is not indicated for the prevention of primary varicella infection (chickenpox). Shingrix must be reconstituted according to the manufacturer s direction prior to administration. The lyophilized varicella-zoster vaccine virus glycoprotein E (ge) antigen component is reconstituted with AS01B adjuvant suspension component. After reconstitution, Shingrix should be administered immediately or stored refrigerated between 2 o and 8 o C (30 o and 46 o F) and used within 6 hours. If the reconstituted vaccine is not used within 6 hours, it should be discarded. Two doses are required for immunization with the first dose of 0.5 ml being administered at Month 0, followed by a second dose that can be administered anytime between 2 and 6 months later. The preferred site for the injection is the deltoid region of the upper arm. Shingrix is contraindicated in patients that have a history of severe allergic reactions (e.g., anaphylaxis) to any component of Shingrix or after a previous dose. Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

8 The Advisory Committee on Immunization Practices (ACIP) has endorsed Shingrix as the recommended vaccine in preventing herpes zoster. Individuals aged 50 years and older who have been previously vaccinated with Zostavax, or who have never received a vaccine for herpes zoster should consider the two-dose Shingrix vaccine. An advantage of Shingrix is that it requires refrigeration unlike Zostavax which requires storage in a freezer. On a motion of Dr. Pittman, seconded by Dr. Shipley, it was recommended to add zoster vaccine recombinant, adjuvanted (Shingrix ) to the Formulary. The Formulary Check List was completed and no issues were detected. Since Shingrix is new to the market, it will be reviewed in a year for reported adverse drug reactions and medication errors associated with its use within the facilities. Drug Formulary Sectional Review- Nasal/Mouth/Throat Agents Otic Agents Ophthalmic Agents Dr. Hall presented the review of the Nasal/Mouth/Throat Agents. The following recommendations were made: Mouth and Throat Change carbamide peroxide glycerin- propylene glycol- sodium stannate (Gly-Oxide ) to carbamide peroxide o Change oral, solution to solution, mouth/throat o Delete gel product Sodium fluoride and stannous fluoride o Combine sodium fluoride and stannous fluoride products into one main listing as Fluoride There were no recommended changes to the Nasal Agents. Dr. Hall presented the review of the Otic Agents. The following recommendations were made: Otics Delete antipyrine-benzocaine as it is no longer available Change carbamide peroxide glycerin- propylene glycol- sodium stannate (Debrox ) to carbamide peroxide It was recommended to consider the addition of ciprofloxacin-dexamethasone otic at the next meeting. Dr. Hall presented the review of the Ophthalmic Agents. The following recommendations were made: Ophthalmics Travoprost delete brand name Travatan as it is no longer available Sulfacetamide sodium delete brand name Sulamyd as it is no longer available and add brand name Bleph-10 Add fluorescein/benoxinate drops On a motion of Dr. Heidel, seconded by Dr. Bennett, the recommended changes to the Nasal/Mouth/Throat Agents, Otic Agents and Ophthalmic Agents were approved. Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

9 Rosuvastatin Formulary Status Rosuvastatin (Crestor ) was added to the Drug Formulary in July 2015 as a reserve drug with the following criteria: For those patients needing high intensity statin therapy with nonresponse or significant drug-drug interactions with atorvastatin (Lipitor ). Since rosuvastatin is now available generically, on a motion of Dr. Taylor, seconded by Mr. Dunlap, it was recommended to move rosuvastatin from the reserve status into the regular formulary. State Operated Facilities Drug Formulary 2018 Website The State-Operated Facilities Drug Formulary 2018 is available on the following website: Psychotropic Consent List The Psychotropic Consent List was reviewed. The following changes were recommended: Remove Nonformulary status from cariprazine Delete molindone as it is no longer available on the market For Vivitrol - Change Nonformulary reference to Reserve Alphabetize the Mood Stabilizers section On a motion of Dr. Heidel, seconded by Dr. Pittman, the Psychotropic Consent List was approved as modified. Hepatitis C Drug Purchases From October through December, the following purchases for drugs to treat hepatitis C were made: State Hospitals $71, State Supported Living Centers $94, It was noted that individuals in the State Supported Living Centers that have Medicare Part D have their drug treatment for hepatitis C obtained from an outside pharmacy. Otherwise, the facility will purchase the drug. Drug Deletion The Committee did not consider deleting any products. New Dosage Strengths The Committee did not add any new dosage strengths to the Formulary. TAC Title 25, Part 1, Chapter 415, Subchapter C The work group of Mr. Dunlap, Dr. Heidel, Dr. Pittman and Dr. Richards have not met to work on Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

10 the Texas Administrative Code Use and Maintenance of Department of State Health Services/Department of Aging and Disability Services Drug Formulary. Psychotropic Audit Criteria & Guidelines - Antidepressants The Antidepressant Audit Criteria and Guidelines have not been reviewed. Psychotropic Audit Criteria & Guidelines Chemical Dependence Adjunct The Chemical Dependence Adjunct Audit Criteria and Guidelines have not been developed. However, a small work group has been appointed to revise the naltrexone audit criteria. Issues from the Medical Director, State Hospital System Dr. Muse did not have any information to report. Issues from the Medical Director, State Supported Living Centers Dr. Taylor noted that the definition of polypharmacy in the State Supported Living Centers (SSLCs) is different than the definition used by the State Hospitals. For the SSLCs, polypharmacy is defined as two or more psychotropic medications from the same therapeutic class, or three or more psychotropic medications regardless of the class. The SSLCs are trying to develop reports that will identify patients on polypharmacy through their electronic medical record system. Currently, manual reviews are being used to identify these patients. FDA Drug Safety Communications The FDA has issued the following communications that may impact our facilities. The FDA's most prominent warning, the Boxed Warning, about asthma-related death has been removed from the drug labels of medicines that contain both an ICS and LABA. A FDA review of four large clinical safety trials shows that treating asthma with long-acting beta agonists (LABAs) in combination with inhaled corticosteroids (ICS) does not result in significantly more serious asthma-related side effects than treatment with ICS alone. A description of the four trials is now also included in the Warnings and Precautions section of the drug labels. These trials showed that LABAs, when used with ICS, did not significantly increase the risk of asthma-related hospitalizations, the need to insert a breathing tube known as intubation, or asthma-related deaths, compared to ICS alone. To foster safe use of the over-the counter (OTC) anti-diarrhea drug loperamide, the FDA is working with manufacturers to use blister packs or other single dose packaging and to limit the number of doses in a package. The FDA continues to receive reports of serious heart problems and deaths with much higher than the recommended doses of loperamide, primarily among people who are intentionally misusing or abusing the product, despite the addition of a warning to the medicine label and a previous communication. Loperamide is a safe drug when used as directed. Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

11 Quarterly Non-Formulary Drug Justification Report For the first quarter of fiscal year 2018, only the State Hospitals reported use of non-formulary agents. The DADS facilities still do not have the reporting capabilities to obtain the non-formulary drugs from their computer system. The following were the top non-formulary agents that were prescribed in the State Hospitals: Sitagliptin Losartan Insulin detemir (Levemir ) Magnesium oxide Sectional Review for Next Meeting The following section will be reviewed at the next meeting: Psychotropic Agents Other Issues The following information was shared with the Committee members: Endocrinology Advisor (11/3, Broder) reported, The use of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) was associated with an increased risk for type 2 diabetes [T2D], researchers concluded after studying a large cohort of young people insured by Medicaid. The findings were published online Oct. 16 in JAMA Pediatrics. HealthDay (11/4, Preidt) reports a preliminary study found a link between proton pump inhibitors (PPIs) and kidney disease. Reviewing data from five trials including over 500,000 patients, the researchers found that people who took a PPI were a third more likely to develop chronic kidney disease or kidney failure than those who didn t take the drugs. STAT (11/8, Silverman) reports that a study shows that at least 74 percent of medicines associated with new patents were already on the market, reflecting the practice of pharmaceutical companies making minor changes in order to thwart generic competition. The research also found that the number of drugs adding three or more patents in a single year more than doubled from 37 drugs in 2005 to 76 drugs in The study has not yet been peer-reviewed in an academic journal. Reuters (11/9, Mathias) reports that the postpartum depression drug brexanolone succeeded in two late-stage studies. The article mentions that earlier this year, the drug failed in a trial testing it as a treatment for a life-threatening seizure disorder. STAT (11/15, Silverman) reports that on Wednesday, consumer group Public Citizen filed a petition with the FDA to ban the sale of a widely prescribed blood pressure medication as well as several generic versions over concerns the drug can cause a gastrointestinal disorder that leads to severe and chronic diarrhea, vomiting, abdominal pain, and weight loss. The drug, olmesartan medoxomil, is marketed as Azor, Benicar, Benicar HCT, and Tribenzor. Pointing to case studies published in 2012 in Mayo Clinic Proceedings, Public Citizen cited overwhelming evidence that treatment with the medication causes severe sprue-like enteropathy, which is similar to celiac disease but does not improve with a gluten- Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

12 free diet. The group argued the risk of life-threatening complication is far greater for this medication than for seven similar medications used to treat hypertension. The AP (12/1, Perrone) reports the Food and Drug Administration on Thursday approved the first injectable form of the leading medication to treat patients recovering from addiction to heroin, prescription painkillers and other opioids. Once-a-month Sublocade was approved for adults with opioid use disorder who are already stabilized on addiction medication. The AP notes the hefty price of the drug at $1,580 per monthly dose compared to Suboxone, which costs $100 a month. The AP notes FDA Commissioner Scott Gottlieb has pledged to promote all available forms of medication-based addiction treatments. He has stressed that some patients may need to take the medications for life. The Charleston (WV) Gazett (12/5, Eyre) reports the West Virginia Board of Pharmacy has designated the nerve-pain medication Neurontin (gabapentin) a drug of concern amid a surge of overdoses. Gabapentin-related overdose deaths have increased from 36 in 2012 to 106 last year. Dr. Brad Henry, president of the West Virginia State Medical Association said gabapentin has a market value on the streets. It s being abused and meets the definition of a scheduled drug. The article notes that the Food and Drug Administration approved gabapentin to treat seizures and pain caused by shingles, but a study released earlier this year found one out of five people taking the drug are using it illegally. The Centers for Disease Control and Prevention has promoted the drug as a safer alternative to prescription opioids. The Beckley (WV) Register-Herald (12/14, Holdren) reports that Sen. Joe Manchin (D-WV) is calling on the Food and Drug Administration and the Drug Enforcement Administration to consider rescheduling a type of medication connected to overdose deaths in West Virginia. In a letter to acting DEA Administrator Robert Patterson and FDA Commissioner Scott Gottlieb, Manchin asked the officials to consider rescheduling and requiring additional risk mitigation for gabapentin, a nerve-pain medication labeled as a drug of concern by the West Virginia Board of Pharmacy. While our focus is appropriately on the devastating impact of prescription opioids, there are other prescription drugs that are also contributing to this crisis, Manchin wrote. In fact, the West Virginia Board of Pharmacy recently designated the nerve-pain medication gabapentin as a drug of concern after the number of overdose deaths related to the drug increased from 36 in 2012 to 106 in Reuters (12/12, Varghese) reports that the US Food and Drug Administration has accepted British drug maker Indivior s application for its new schizophrenia treatment, RBP-7000, an investigational once-a-month injectable. Indivior announced the news Tuesday. Reuters adds that the company s experimental drug to help fight America s growing opioid addiction crisis was approved by the FDA earlier this month. Newsweek (1/25, Sheridan) reports the combination of GW Pharmaceuticals Epidiolex (cannabidiol), which is derived from cannabis, and other anti-seizure drugs reduced seizures in patients with Lennox-Gastaut syndrome by 41%, according to a study published in The Lancet. The article reports that GW applied for FDA approval last year, and the agency may approve the drug this summer. Drug Shortages Many drug shortages are occurring throughout health care. The facilities were asked to submit a list of drug shortages that are impacting care. Dr. Pittman noted that the Supported Living Centers are experiencing shortages in unit dose packaged medications which means that the facilities have to repackage from bulk bottles. The repackaging process takes time and staff. In addition, facilities Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

13 are being forced to buy larger quantity bottles as smaller quantity bottles are not available. It was recommended that the lists be distributed to the facilities. Next Meeting Date The next meeting was scheduled for April 20, Adjourn There being no further business, the meeting was adjourned at 1:10 p.m. Approved: Mark Messer D.O. Mark Messer, D.O., Chairman Minutes Prepared by: Ann L. Richards, Pharm.D., BCPP Attachments Attachment A Atypical Antipsychotic Audit Criteria & Guidelines Attachment B Midazolam Use in Status Epilepticus and Acute Agitation in those with Psychiatric Disorders Attachment C New Drug Monographs Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

14 Attachment A1 ATYPICAL ANTIPSYCHOTICS risperidone (Risperdal, Risperdal Consta ), olanzapine (Zyprexa, Zyprexa Relprevv ), paliperidone (Invega, Invega Sustenna, Invega Trinza ), quetiapine (Seroquel ), ziprasidone (Geodon ), aripiprazole (Abilify, Abilify Maintena, Aristada ), asenapine (Saphris ), iloperidone (Fanapt ), lurasidone (Latuda ), brexpiprazole (Rexulti ), cariprazine (Vraylar ) INDICATIONS 1) Disorders with psychotic symptoms (schizophrenia, schizoaffective disorder, manic disorders, depression with psychotic features, drug-induced psychosis, psychosis associated with other medical conditions) 2) Schizophrenia adolescents risperidone (13 to 17 years old), olanzapine (13 to 17 years old), paliperidone (12 to 17 years old), quetiapine (13 to 17 years old), aripiprazole (13 to 17 years old), lurasidone (13 to 17 years old) 3) Severe aggression secondary to a psychiatric disorder 4) Self Injurious Behavior secondary to a psychiatric disorder 5) Bipolar disorder (not paliperidone, iloperidone, or brexpiprazole) 6) Bipolar disorder, adolescents risperidone (10 to 17 years old, monotherapy), quetiapine (10 to 17 years old, adjunct & monotherapy), olanzapine (13 to 17 years old, acute & maintenance), aripiprazole (10 to 17 years old, adjunct & monotherapy), asenapine (10 to 17 years old, monotherapy) 7) Irritability associated with autistic disorders in children and adolescent risperidone (5 to 17 years old) and aripiprazole (6 to 17 years old) 8) Adjunct for patients on antidepressants for major depressive disorder (aripiprazole, quetiapine, brexpiprazole) PRECAUTIONS TO CONSIDER Contraindications Absolute: 1) History of anaphylactic reaction and similarly severe significant hypersensitivity to medication prescribed 2) For ziprasidone - Recent myocardial infarction, uncompensated congestive heart failure or when other drugs are being used that also prolong the QT interval such as (not complete list) quinidine, dofetilide, pimozide, sotalol, thioridazine, moxifloxacin, and sparfloxacin 3) For lurasidone use of ketoconazole (3A4 inhibitor) or rifampin (3A4 inducer) Relative: 1) Pregnancy/nursing mothers 2) History of drug induced agranulocytosis or leukopenia 3) Breast cancer 4) History of neuroleptic malignant syndrome 5) Impaired hepatic function 6) Parkinson s disease 7) Severe cardiovascular diseases 8) Known clinically significant QTc prolongation Medication Audit Criteria and Guidelines-Criteria Form 23 EFC Approval 2/2/18

15 ATYPICAL ANTIPSYCHOTICS (continued) risperidone (Risperdal, Risperdal Consta ), olanzapine (Zyprexa, Zyprexa Relprevv ), paliperidone (Invega, Invega Sustenna, Invega Trinza ), quetiapine (Seroquel ), ziprasidone (Geodon ), aripiprazole (Abilify, Abilify Maintena, Aristada ), asenapine (Saphris ), iloperidone (Fanapt ), lurasidone (Latuda ), brexpiprazole (Rexulti ), cariprazine (Vraylar ) PRECAUTIONS TO CONSIDER (continued) Precautions Alcoholism (active), cataracts (quetiapine), recent or current blood dyscrasias, diabetes mellitus, angina, hypotension, congestive heart failure, arrhythmias, obesity, poorly controlled seizure disorder, severe tardive dyskinesia, dementia-related psychosis, renal impairment (paliperidone and ziprasidone injection) Pregnancy and Breast-Feeding See relative contraindications. Review product-specific labeling. Consider risks/benefits in reviewing medication-specific labeling. Drug Interactions of Major Significance 1) Concomitant use of CNS depressants 2) Concomitant use of agents that cause EPS (including droperidol, metoclopramide, amoxapine, metyrosine, pimozide, reserpine) 3) Concomitant use of hypotension producing agents 4) Levodopa 5) Antithyroid agents 6) Drugs that prolong the QT interval 7) Strong inhibitors or inducers of Cytochrome 450 8) The following are the major metabolic pathways for the atypical antipsychotics: Risperidone: CYP 2D6 Olanzapine: CYP 1A2 Quetiapine: CYP 3A4 Aripiprazole: CYP 2D6 and 3A4 Ziprasidone: aldehyde oxidase Paliperidone: (non-hepatic, primarily renal elimination) Asenapine: CYP 1A2 and UGT1A4 (direct glucuronidation) Iloperidone: CYP 3A4 and 2D6 Lurasidone: CYP 3A4 Brexpiprazole: CYP3A4 and 2D6 Cariprazine: CYP3A4 and lesser extent 2D6 SEE TABLE A: Cytochrome P450 Drug Metabolism/Inhibition Age-Specific Considerations Aripiprazole, asenapine, lurasidone, olanzapine, paliperidone, quetiapine and risperidone have approved specific indications for designated ages in children and adolescents. The safety and efficacy have not been established in children under the age of 18 for the other medications. Conservative dosing is advised in the elderly. Drug Audit Checklist (Revised ) Page 1

16 ATYPICAL ANTIPSYCHOTICS (continued) risperidone (Risperdal, Risperdal Consta ), olanzapine (Zyprexa, Zyprexa Relprevv ), paliperidone (Invega, Invega Sustenna, Invega Trinza ), quetiapine (Seroquel ), ziprasidone (Geodon ), aripiprazole (Abilify, Abilify Maintena, Aristada ), asenapine (Saphris ), iloperidone (Fanapt ), lurasidone (Latuda ), brexpiprazole (Rexulti ), cariprazine (Vraylar ) PRECAUTIONS TO CONSIDER (continued) Side Effects Which Require Medical Attention 1) Anticholinergic effects 2) Visual changes 3) Extrapyramidal side effects (dystonia, pseudo-parkinsonism) 4) Akathisia 5) Tardive dyskinesia 6) Hypotension 7) Rashes, photosensitivity and altered pigmentation 8) Early symptoms of agranulocytosis (fever, sore throat, weakness) 9) Galactorrhea (risperidone, paliperidone) 10) Amenorrhea (risperidone, paliperidone) 11) Gynecomastia (risperidone, paliperidone) 12) Fluctuating vital signs 13) Altered consciousness 14) Hyperglycemia 15) Clinically significant weight gain 16) Hypercholesterolemia or hyperlipidemia 17) QTc > 500 msec 18) Cataracts (quetiapine) PATIENT MONITORING Patient Monitoring Parameters 1) Pregnancy test as clinically indicated 2) BMI and waist circumference measurements when a new antipsychotic is initiated, at every visit (monthly for inpatients) for 6 months after the new antipsychotic is initiated, and quarterly when the antipsychotic dose is stable. 3) Fasting plasma glucose level or hemoglobin A1c before initiating a new antipsychotic, then every 6 months. 4) Lipid screening [total cholesterol, low- and high-density lipoprotein (LDL and HDL) cholesterol, and triglycerides] Yearly if lipid levels are in the normal range, every 6 months if the LDL level is > 130 mg/dl If no lipid screening has been done within the last year, then a lipid profile should be obtained within 30 days of initiation of the drug. ATYPICAL ANTIPSYCHOTICS (continued) risperidone (Risperdal, Risperdal Consta ), olanzapine (Zyprexa, Zyprexa Relprevv ), paliperidone (Invega, Invega Sustenna, Invega Trinza ), quetiapine (Seroquel ), ziprasidone (Geodon ), aripiprazole (Abilify, Abilify Maintena, Aristada ), asenapine (Saphris ), iloperidone (Fanapt ), lurasidone (Latuda ), brexpiprazole (Rexulti ), cariprazine (Vraylar ) Drug Audit Checklist (Revised ) Page 2

17 PATIENT MONITORING (continued) 5) EKG (for patients on ziprasidone) For patients with known heart disease, a personal history of syncope, a family history of sudden death at an early age (under age 40 years, especially if both parents had sudden death), or congenital long QT syndrome, then a baseline EKG before treatment is initiated. A subsequent EKG is indicated if the patient presents with symptoms associated with a prolonged QT interval (e.g., syncope). 6) EKG (for patients on iloperidone) at baseline 7) Serum potassium and magnesium level baseline and periodic for patients on iloperidone who are at risk for significant electrolyte disturbances 8) Sexual function inquiry inquire for evidence of galactorrhea/gynecomastia, menstrual disturbance, libido disturbance or erectile/ejaculatory disturbance yearly If a patient is receiving an antipsychotic known to be associated with prolactin elevation, then at each visit (quarterly for inpatients) for the first 12 months after starting an antipsychotic or until the medication dose is stable and then yearly. 9) Prolactin level if there is evidence of galactorrhea/gynecomastia, menstrual disturbance, libido disturbance or erectile/ejaculatory yearly. 10) EPS Evaluation (examination for rigidity, tremor, akathisia) before initiation of any antipsychotic medication, then weekly for the first 2 weeks after initiating treatment with a new antipsychotic or until the dose has been stabilized and weekly for 2 weeks after a dose increase. At each visit for outpatients. 11) Tardive dyskinesia evaluation every 3 months and as clinically indicated. 12) Vision questionnaire ask whether the patient has experienced a change in vision and should specifically ask about distance vision and blurry vision yearly 13) Ocular evaluations yearly for patients older than age 40 years; every 2 years for younger patients 14) After each olanzapine pamoate injection continuously observe patient for at least 3 hours for symptoms consistent with olanzapine overdose, including sedation (ranging from mild in severity to coma) and/or delirium (including confusion, disorientation, agitation, anxiety, and other cognitive impairment) (Post-Injection Delirium /Sedation Syndrome) 15) CBC (for patients on cariprazine) baseline and as clinically indicated Dosing See Texas Health and Human Services State Operated Facilities Drug Formulary for dosage guidelines. Exceptions to maximum dosage must be justified as per medication rule. Drug Audit Checklist (Revised ) Page 3

18 INDICATIONS Medication Audit Criteria and Guidelines Drug Audit Checklist 23 Attachment A2 Reviewer: Class: Date: Drug: risperidone (Risperdal, Risperdal Consta ), olanzapine (Zyprexa, Zyprexa Relprevv ), paliperidone (Invega, Invega Sustenna, Invega Trinza ), quetiapine (Seroquel ), ziprasidone (Geodon ), aripiprazole (Abilify, Abilify Maintena, Aristada ), asenapine (Saphris ), iloperidone (Fanapt ), lurasidone (Latuda ), brexpiprazole (Rexulti ), cariprazine (Vraylar ) Audit# Comments Requires Phys. Review Patient# Yes No Ordering Physician 1) Disorders with psychotic symptoms (schizophrenia, schizoaffective disorder, manic disorders, depression with psychotic features, drug-induced psychosis, psychosis 2) Schizophrenia adolescents risperidone (13 to 17 years old), olanzapine (13 to 17 years old), paliperidone (12 to 17 years old), quetiapine (13 to 17 years old), aripiprazole (13 to 17 years old), 3) Severe aggression secondary to a psychiatric disorder. 4) Self Injurious Behavior secondary to a psychiatric disorder 5) Bipolar disorder (not paliperidone, iloperidone, or brexpiprazole). 6) Bipolar disorder, adolescents risperidone (10 to 17 years old, monotherapy), quetiapine (10 to 17 years old, adjunct & monotherapy), olanzapine (13 to 17 years old, acute & maintenance), aripiprazole (10 to 17 years old, adjunct & monotherapy), 7) Irritability associated with autistic disorders in children and adolescent risperidone (5 to 17 years old) and 8) Adjunct for patients on antidepressants for major depressive disorder (aripiprazole, quetiapine, brexpiprazole) Drug Audit Checklist (Revised ) Page 4

19 Relative Contraindications Absolute Drug: risperidone (Risperdal, Risperdal Consta ), olanzapine (Zyprexa, Zyprexa Relprevv ), paliperidone (Invega, Invega Sustenna, Invega Trinza ), quetiapine (Seroquel ), ziprasidone (Geodon ), aripiprazole (Abilify, Abilify Maintena, Aristada ), asenapine (Saphris ), iloperidone (Fanapt ), lurasidone (Latuda ), brexpiprazole (Rexulti ), Audit# Comments Requires Phys. Patient# Yes No Ordering Physician 1) History of anaphylactic reaction and similarly severe significant hypersensitivity to medication prescribed. 2) For ziprasidone - Recent myocardial infarction, uncompensated congestive heart failure or when other drugs are being used that also prolong the QT interval such as (not complete list) quinidine, dofetilide, pimozide, sotalol, 3) For lurasidone use of ketoconazole (3A4 inhibitor) or 1) rifampin Pregnancy/nursing (3A4 inducer). mothers. 2) History of drug induced agranulocytosis or leukopenia. 3) Breast cancer. 4) History of neuroleptic malignant syndrome. 5) Impaired hepatic function. 6) Parkinson s disease. 7) Severe cardiovascular diseases. 8) Known clinically significant QTc prolongation. Drug Audit Checklist (Revised ) Page 5

20 PATIENT MONITORING Patient Monitoring Parameters Drug: risperidone (Risperdal, Risperdal Consta ), olanzapine (Zyprexa, Zyprexa Relprevv ), paliperidone (Invega, Invega Sustenna, Invega Trinza ), quetiapine (Seroquel ), ziprasidone (Geodon ), aripiprazole (Abilify, Abilify Maintena, Aristada ), asenapine (Saphris ), iloperidone (Fanapt ), lurasidone (Latuda ), brexpiprazole (Rexulti ), Audit# Comments Requires Phys. Patient# Yes No Ordering Physician 1) Pregnancy test as clinically indicated. 2) BMI and waist circumference measurements when a new antipsychotic is initiated, at every visit (monthly for inpatients) for 6 months after the new antipsychotic is initiated, and quarterly when the antipsychotic dose is stable. 3) Fasting plasma glucose level or hemoglobin A1c before initiating a new antipsychotic, then yearly. 4) Lipid screening [total cholesterol, low- and high-density lipoprotein (LDL and HDL) cholesterol, and triglycerides] Yearly if lipid levels are in the normal range, every 6 months if the LDL level is > 130 mg/dl If no lipid screening has been done within the last year, then a lipid 5) EKG (for patients on ziprasidone) - For patients with known heart disease, a personal history of syncope, a family history of sudden death at an early age (under age 40 years, especially if both parents had sudden death) or congenital long QT syndrome, then a baseline EKG before treatment is initiated. A subsequent EKG is indicated if the patient presents with symptoms associated with a prolonged QT interval (e.g., syncope) 6) EKG (for patients on iloperidone) at baseline. 7) Serum potassium and magnesium level baseline and periodic for patients on iloperidone who are at risk for significant electrolyte Drug Audit Checklist (Revised ) Page 6

21 Dosing Drug: risperidone (Risperdal, Risperdal Consta ), olanzapine (Zyprexa, Zyprexa Relprevv ), paliperidone (Invega, Invega Sustenna, Invega Trinza ), quetiapine (Seroquel ), ziprasidone (Geodon ), aripiprazole (Abilify, Abilify Maintena, Aristada ), asenapine (Saphris ), iloperidone (Fanapt ), lurasidone (Latuda ), brexpiprazole (Rexulti ), Audit# Comments Requires Phys. Patient# Yes No Ordering Physician 8) Sexual function inquiry inquire for evidence of galactorrhea/gynecomastia, menstrual disturbance, libido disturbance or erectile/ejaculatory disturbance yearly. If a patient is receiving an antipsychotic known to be associated with prolactin elevation, then at each visit (quarterly for inpatients) for the 9) Prolactin level if there is evidence of galactorrhea/gynecomastia, menstrual disturbance, libido 10) EPS Evaluation (examination for rigidity, tremor, akathisia) before initiation of any antipsychotic medication, then weekly for the first 2 weeks after initiating treatment with a new antipsychotic or until the dose has been stabilized and weekly for 2 weeks 11) Tardive dyskinesia evaluation every 3 months and as clinically 12) Vision questionnaire ask whether the patient has experienced a change in vision and should specifically ask about distance vision and blurry 13) Ocular evaluations yearly for patients older than age 40 years; every 2 years for younger patients. 14) After each olanzapine pamoate injection continuously observe patient for at least 3 hours for symptoms consistent with olanzapine overdose, including sedation (ranging from mild in severity to coma) and/or delirium (including confusion, disorientation, agitation, anxiety, and other cognitive 15) CBC (for patients on cariprazine) baseline and as clinically indicated Dosing See Texas Health and Human Services State Operated Facilities Drug Formulary for dosage guidelines. Exceptions to maximum dosage must be Drug Audit Checklist (Revised ) Page 7

22 Drug: risperidone (Risperdal, Risperdal Consta ), olanzapine (Zyprexa, Zyprexa Relprevv ), paliperidone (Invega, Invega Sustenna, Invega Trinza ), quetiapine (Seroquel ), ziprasidone (Geodon ), aripiprazole (Abilify, Abilify Maintena, Aristada ), asenapine (Saphris ), iloperidone (Fanapt ), lurasidone (Latuda ), brexpiprazole (Rexulti ), Audit# Comments Requires Phys. Patient# Yes No Ordering Physician Date Referr Date Review Comments Physician' s Additional Comments: Executive Formulary Committee Minutes 1 February 2, 2018

23 Executive Formulary Committee Minutes 2 February 2, 2018 Attachment B Midazolam use in status epilepticus and acute agitation in those with psychiatric disorders Drug Classification: anticonvulsant, benzodiazepine Controlled Substance: Classified as a C-IV FDA Approved Indications: 1 (Labeled) Anesthesia Sedation/anxiolysis/amnesia (preoperative/procedural) Sedation for mechanically-ventilated patients Non-FDA Approved Indications (off-label use): Seizures in both children and adolescents Status epilepticus in children, adolescents, and adults Refractory status epilepticus in children, adolescents, and adults Palliative sedation Acute agitation Dosage: NOTE: Midazolam dosing is tailored to each patient, depending on different factors: underlying disease state, the patient s age, and current medications being taken with midazolam. Dose reduction of 20% to 50% should be considered for patients that are debilitated, chronically ill, or elderly, as well as patients concurrently taking opioids or other CNS depressants. Status epilepticus (off-label use): 1 Children and adolescents IM is the preferred route in patients without IV access. For pediatric patients weighing <13 kg, not established. For pediatric patients weighing 13 to 40 kg, give 5 mg IM once. For pediatric patients weighing >40 kg, give 10 mg IM once. o Intranasal and buccal midazolam use in pediatric patients has limited data. Intranasal dose 0.2 mg/kg To deliver dose, use a 5 mg/ml injectable concentrated solution via atomizer. Burning upon administration is likely to occur due to low ph. Buccal dose 0.5 mg/kg Injectable solution is generally used Adults IM is the preferred route in patients without IV access. Dose 10 mg IM once or 0.2 mg/kg once with a maximum dose of 10 mg. o Intranasal and buccal midazolam use in adult patients has limited data. Intranasal dose 0.2 mg/kg To deliver dose, use a 5 mg/ml injectable concentrated solution via atomizer. Burning upon administration is likely to occur due to low ph. Buccal dose 0.5 mg/kg Injectable solution is generally used Acute Agitation (off-label use): 2-3 Children and adolescents

24 For pediatric patients aged 6-12 years: Intramuscular dose mg/kg/dose 2 Adults Dose 2.5 mg to 5 mg IM o In severely agitated patients, dose may be repeated every three to five minutes 3 o Higher doses have been studied although they may result in increased risk for respiratory depression/oxygen desaturation and CNS depression Dosing in Special Populations: 1 Renal Impairment: For patients with renal impairment using midazolam, there are no dosage adjustments necessary, but midazolam should be used with caution. Hepatic Impairment: For patients with hepatic impairment using midazolam, there are no dosage adjustments necessary, but midazolam should be used with caution. Administration: 1 For IM administration, administer midazolam undiluted deep into the large muscle. For intranasal administration, since the low ph of midazolam causes burning when administered, using an atomizer is recommended to aid in reducing burning sensation (e.g. MAD 300 Mucosal Atomizer which attaches to a tuberculin syringe). The use of a higher concentration injectable solution is recommended to minimize volume administered intranasal. A smaller volume will reduce irritation and swallowing of administered dose. The maximum recommended dose volume per nare is generally 1 ml. For buccal dosing for prolonged seizures the injectable solution rather than the syrup is generally used. 4 Mechanism of Action: Midazolam works in the central nervous system by binding to benzodiazepine receptors on the postsynaptic GABA neurons and acting as a short-acting CNS depressant. Pharmacodynamics/Pharmacokinetics: 1 Onset of action: o Via IM route, children become sedated within 5 minutes, and adults become sedated within 15 minutes. o Via intranasal route, children become sedated between 3-7 minutes, and adults become sedated within 5 minutes. Peak effect: o Via IM route, children minutes and adults minutes. Time to peak serum level 30 min to 1 hour. o Via intranasal route, children 10 minutes o Via oral route time to peak serum level 0.17 to 2.65 hours. Duration: o Via IM route, midazolam is effective for up to 6 hours, on average 2 hours. o Via intranasal route, midazolam is effective in children for about 23 minutes. Absorption: o Via IM route, midazolam is absorbed rapidly and completely. IM bioavailability > 90%. o Via intranasal and oral route, midazolam is absorbed rapidly. Oral bioavailability 40-50% (36% in children) and intranasal bioavailability approximately 60%. Distribution: Midazolam is widely distributed in the body, including in the cerebrospinal fluid. Protein binding: 97%, primarily to albumin, protein binding is reduced in those with cirrhosis with a free fraction of around 5%. Metabolism: Midazolam is metabolized extensively through hepatic CYP3A4, and is mostly (60% to 70%) metabolized to an active metabolite (1-hydroxy-midazolam) Half-life elimination: o In children, the half-life elimination time for midazolam syrup is 2.2 to 6.8 hours. Executive Formulary Committee Minutes 3 February 2, 2018

25 o In adults, the half-life elimination time is about 3 hours. o In special populations, such as patients with cirrhosis, obesity, renal failure, heart failure, and the elderly, the half-life elimination time is prolonged and may lead to drug accumulation and exaggerated effects. Therefore, closer monitoring and greater caution needs to be taken in these patients. Excretion: Midazolam is primarily excreted in the urine as glucuronide conjugates of the hydroxylated metabolites. Storage: Injectable solution should be stored at 20 o C to 25 o C or 68 o F or 77 o F. Contraindications: 1,5 Hypersensitivity to midazolam Use of oral midazolam while concurrently taking a protease inhibitor (i.e. darunavir, ritonavir, atazanavir) Possible cross-sensitivity and cross-reactivity to midazolam if a prior allergic reaction to a benzodiazepine has occurred Patients with acute narrow angle glaucoma Precautions/Warnings: 1,5 Cardiorespiratory effects: [US Boxed Warning]: Midazolam has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings; airway obstruction, desaturation, hypoxia, and apnea have also been reported, most often when used concomitantly with other CNS depressants (eg, opioids). In some cases, death or hypoxic encephalopathy resulted. Use only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory and cardiac function (ie, pulse oximetry). Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Injection: [US Boxed Warning]: Midazolam must never be used without individualization of dosage. The initial IV dose for sedation in adults may be as little as 1 mg, but should not exceed 2.5 mg in a healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant opioids or other CNS depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/ml formulation or dilution of the 1 mg/ml or 5 mg/ml formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure, and route dependent. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation Tolerance: Although midazolam has a short half-life, tolerance does develop in patients using midazolam for the sedative and/or anticonvulsant effects. Executive Formulary Committee Minutes 4 February 2, 2018

26 Anterograde amnesia: Anterograde amnesia has occurred in patients using benzodiazepines. CNS depression: If CNS depression occurs in patients using midazolam, patients must be cautioned to wait at least one day after the last midazolam dose to attempt performing any task(s) that requires mental alertness, such as operating machinery or driving a vehicle, since physical and mental abilities may be impaired. Hypotension: May be more likely to occur in patients having taken opioid analgesics, pediatric patients, or patients that are hemodynamically unstable. Paradoxical reactions: Patients taking benzodiazepines have reported paradoxical reactions manifesting as agitation, hyperactivity, aggression, involuntary movements (including tonic/clonic movements and muscle tremor), and combativeness. Patients should be made aware that true paradoxical reactions or hypoxia may occur. If paradoxical reactions do occur, do not proceed with midazolam until response has been evaluated. Heart failure: Caution when using midazolam in patients with heart failure. Glaucoma: Caution when using midazolam in patients with glaucoma. Impaired gag reflex: Caution when using midazolam in patients with impaired gag reflex. Respiratory disease: Caution when using midazolam in patients with respiratory disease as these patients may be more sensitive to respiratory depressant effects of midazolam. Debilitated patients: Caution when using midazolam in debilitated patients. A lower dose is recommended. Elderly: Caution when using midazolam in elderly patients. A lower dose is recommended. Oral midazolam use is not recommended. Fall risk: Extreme caution in patients who have risk of falling. Obese patients: Caution when using midazolam in obese patients. Midazolam may have extended action when discontinued in these patients. Withdrawal: If midazolam is abruptly discontinued or there are large decreases in dose, withdrawal symptoms may present. These symptoms include convulsions, hallucinations, tremor, vomiting and sweating, or muscle and abdominal cramps. Decrease midazolam slowly and monitor for withdrawal symptoms if withdrawing or reducing treatment. Pregnancy: Midazolam is a pregnancy risk factor D medication and crosses the human placenta. Teratogenic effects have occurred in pregnant patients using benzodiazepines. Not enough studies and data are available at this time. Drug Interactions: 1,5 There are several drug interactions associated with midazolam. The risk of drug interactions with midazolam include amodiaquine, antihepaciviral combination products, azelastine (nasal), boceprevir, cobicistat, conivaptan, fusidic acid (systemic), idelalisib, itraconazole, ketoconazole, olanzapine, orphenadrine, oxomemazine, paraldehyde, protease inhibitors, sodium oxybate, telaprevir, and thalidomide. Concomitant use of benzodiazepines and opioids may result in profound sedation and respiratory depression. NOTE: Moderate to strong drug interactions with CYP3A4 inducers and CYP3A4 inhibitors. Adverse Effects: 1 The most common side effect of midazolam (greater than 10%) is bradypnea. Other side effects that may occur while taking midazolam include, hypotension, drowsiness, headache, seizure-like activity, drug dependence, severe sedation, hiccups, nystagmus, apnea, and paradoxical reactions such as agitation and involuntary movements. Monitoring: 1 Sedation level Respiratory rate Heart rate Blood pressure Oxygen saturation Executive Formulary Committee Minutes 5 February 2, 2018

27 Overdose: 1,5 The manifestations of midazolam overdose appear similar to other benzodiazepines, including somnolence, sedation, confusion, diminished reflexes, impaired coordination, coma, and deleterious effects on vital signs. Treatment of Overdose: General supportive measures should be taken to control and continuously monitor respiration, pulse rate, and blood pressure. Oxygen may need to be administered to support ventilation. IV fluid therapy, repositioning, vasopressors, and other measures may need to be employed should hypotension develop. For oral ingestion, lavage and/or activated charcoal are recommended after the patient s airway is secure. If overdose is known or suspected, flumazenil is indicated for the partial or complete reversal of midazolam s sedative effects. Flumazenil is a specific benzodiazepine-receptor antagonist. Flumazenil is not a substitute for proper management of benzodiazepine overdose, but intended to be used in addition. Midazolam use in the treatment of status epilepticus: The current formulary agent that is FDA approved for the treatment of prolonged seizures/status epilepticus is rectal diazepam gel. Therefore, studies comparing efficacy and safety of midazolam (via various routes of administration, i.e. IM, buccal and intranasal) to rectal diazepam gel were included. A large study by Mpimbasa et al. comparing buccal midazolam to rectal diazepam for treatment of seizures took place in Uganda and involved 330 children. 6 A higher rate of treatment failure was found in the rectal diazepam group compared to the buccal midazolam group (p = 0.016). Treatment failure was defined as seizures lasting more than 10 minutes after medication or if another occurred within an hour. Another study by Holsti M et al. compared intranasal midazolam to rectal diazepam for treatment of seizures. 7 In this study, 92 children experiencing pre-hospital seizures lasting longer than 5 minutes received either intranasal midazolam (0.2 mg/kg, maximum dose 10 mg) or rectal diazepam (0.3 to 0.5 mg/kg, maximum dose 20 mg). No difference was identified when comparing the total seizure time after medication administration. In another study by McIntyre J et al., a multicenter, randomized controlled trial included 177 children, aged 6 months and older, experiencing 219 separate seizures and without IV access. 8 Patients were given either buccal midazolam or rectal diazepam for treatment of seizures in doses varying between 2.5 mg and 10 mg depending on age. The primary outcome was seizures ceasing within 10 minutes and for at least an hour, without requiring intervention due to respiratory depression. Buccal midazolam had a 56% therapeutic success rate (61 of 109), while rectal diazepam had a 27% therapeutic success rate (30 of 110). The rate of respiratory depression between the two groups did not differ. In a systematic review with meta-analysis, including randomized controlled trials comparing nonintravenous midazolam to intravenous or rectal diazepam for treatment of early status epilepticus in patients of all ages, no difference in serious adverse effects was found (1933 seizures in 1602 patients). 9 The review concluded that nonintravenous midazolam is as safe as intravenous or rectal diazepam in terminating early status epilepticus in children and likely in adults as well. Guideline for Seizures/Status Epilepticus 10 According to the American Epilepsy Society Convulsive Status Epilepticus Guideline in children and adults, if a seizure lasts between 5 and 20 minutes, patients are to be treated with a benzodiazepine as the initial therapy of choice using one of the following first line options: intramuscular midazolam, intravenous lorazepam, or intravenous diazepam. If the first line Executive Formulary Committee Minutes 6 February 2, 2018

28 options are unavailable, one of the following options is recommended: intravenous phenobarbital, rectal diazepam, or intranasal/buccal midazolam. The guideline recommendations are based on conclusions drawn from studies that found IM midazolam to be more efficacious than IV lorazepam for treating status epilepticus in adults lacking IV access, found intranasal midazolam to have greater efficacy than rectal diazepam terminating seizures, and found non-iv midazolam (intranasal/im/buccal) to likely be more efficacious than (IV/rectal) diazepam in treating children with status epilepticus. For prehospital settings or where the three first-line benzodiazepine options are not available, rectal diazepam, intranasal midazolam and buccal midazolam are reasonable initial therapy alternatives. NOTE: Midazolam requires monitoring of respiration, oxygenation, and vital signs. 4 Both the injectable and oral syrup formulations current FDA approved labeling for midazolam have a boxed warning stating midazolam should only be used in settings that can provide for continuous monitoring or respiratory and cardiac function and immediate availability of resuscitative drugs for ventilation and intubation and personnel trained in their use and skilled in airway management. 1,5 Currently the US does not have an FDA approved commercially available intranasal or buccal product as some other countries (i.e. Buccolam, Epistatus available in the UK). Midazolam for acute agitation in those with psychiatric disorders: Several intramuscular formulary agents are currently available for use in acute agitation and aggression including antipsychotics such as haloperidol, olanzapine and ziprasidone as well as the benzodiazepine lorazepam. Therefore, studies comparing efficacy and safety of midazolam to antipsychotics and lorazepam were included in the review. A review of studies assessing the management of pediatric aggression on inpatient units found treating agitation with benzodiazepines to be associated with paradoxical reactions (side effects) including restlessness, agitation, involuntary movement, and aggressive or violent behavior Further, a case report suggested that physically abused children may experience medicationinduced psychotic symptoms with benzodiazepine use. Studies on treating acute agitation with benzodiazepines in the children and adolescent population are limited. 11 A review of sixteen randomized trials published between 1980 and 2016 conducted in psychiatric settings comparing midazolam or lorazepam given intramuscularly as either monotherapy or addon therapy were evaluated. 13 Studies included had more than 10 patients with ages ranging from 18 to 65 years old. In five of the studies, subjects were severely ill patients with disruptive behavior and psychosis, while the subjects in the other nine studies had mania, schizophrenia, or mixture of psychiatric disorders. No studies included in the review were found comparing midazolam IM to a placebo. The outcome measures were identified as statistical superiority and statistical inferiority, using a significance threshold of P < In instances where no statistical significance was reached, there was no difference identified between the two interventions. Results were as follows: 275 patients out of 329 total patients in the midazolam group were given midazolam IM 5-15 mg as monotherapy. 13 Four comparisons were made between midazolam IM monotherapy and other antipsychotic IM monotherapies. Three of the studies found midazolam to be superior (midazolam IM 5mg > haloperidol IM 5 mg [Wyant et al ]; midazolam IM 5 mg > droperidol IM 5 mg > ziprasidone IM 20 mg [Martel et al ]; midazolam IM 5 mg = lorazepam IM 2mg > haloperidol IM 5 mg [Nobay et al ]) and one study found comparable efficacy (midazolam IM 10 mg = droperidol IM 10 mg [Ibster et al ]). Further, midazolam IM mg was superior to a combination of haloperidol IM 5-10 mg plus promethazine mg IM [Huf et al ]. In the Nobay et al. study comparing efficacy of IM midazolam 5 mg to IM lorazepam 2 mg monotherapy, no difference was found in time to sedation. 16 Only five of the sixteen midazolam studies included information on adverse effects. 13 Adverse effects with midazolam included a drop in oxygen saturation, sedation, and respiratory failure. Despite the potential safety concerns noted in the Ibster study, 17 particularly with the higher doses of midazolam IM, the review concluded that both midazolam IM (5-15 mg) and lorazepam IM (2-4 mg) were acceptable psychopharmacological therapies to use in acutely agitated, non-elderly Executive Formulary Committee Minutes 7 February 2, 2018

29 patients. 13 However, in the Huf et al. study most of the participants were given the higher dose of midazolam 15 mg vs. the lower dose of 7.5 mg and although there was benefit noted at 20 and 40 minutes after the injection there was no difference 1 hour after the injection. 18 In addition, 6% more patients in the midazolam group had another episode of aggression within 24 hours. In this study there was an episode of respiratory depression/cyanosis with midazolam 15 mg after 15 minutes and the patient had to be administered flumazenil 0.25 mg IV for reversal. The Martel et al study was a double-blind, randomized, controlled trial comparing the efficacy and safety of IM midazolam, droperidol, and ziprasidone in managing acute undifferentiated agitation in the emergency room, 5 mg of IM midazolam was found to be as efficacious as 5 mg of IM droperidol and 20mg of IM ziprasidone. 15 Considering safety of the treatment, there were no differences found when comparing major side effects (cardiac dysrhythmias, respiratory depression, endotracheal intubation) between the groups. In the Isbister study a blinded, randomized controlled trial of IM droperidol versus IM midazolam versus a combination of both for the sedation of acute agitation and violence, the primary outcome was the duration of the behavior. 17 The study took place between August 2008 and July Patients were 18 years or older and inclusion criteria were presentation to the ED with violent and acute behavioral disturbance, and requiring both parenteral sedation and physical restraint. The exclusion criteria were de-escalation when confronted by show of force or verbal deescalation, other sedative medication already administered, patient agreement to IV or oral sedation, or if patient did not stay in the ED. All patients had equipment necessary for resuscitation at bedside, continuous cardiac monitoring, pulse oximetry, and blood pressure monitoring. Any major adverse effects were to be reviewed and reported. Major side effects included: respiratory depression requiring intubation, extrapyramidal side effects requiring benztropine administration, arrhythmias including torsade des pointes, anaphylaxis, or any other serious unexpected effect. Data collection required observations of pulse rate, oxygen saturations, respiratory rate, blood pressure, and the Altered Mental Status Scale taken every 5 minutes for the first 30 minutes, every 15 minutes for the next 90 minutes, and then every hour until the completion of 6 hours after drug administration. Physicians were encouraged to wait at least 10 minutes after administering the drug before making the decision of whether or not to give additional sedation to the patient. The primary outcome was the duration of violent and acute behavioral disturbance episode, from the time the initial call was made to security until the time patient was safely restrained, sedated or settling, and any verbal abuse was minimizing or absent, in which case security was released. The secondary outcomes included the time until additional sedative medication had to be administered and any drug-related adverse effect (airway obstruction requiring intervention, tracheal intubation, oxygen desaturation, cardiac arrhythmias, hypotension, prolonged QT interval, akathisia, anaphylaxis, and extrapyramidal side effects). During the one-year period, 91 patients were included in the trial, received one of the study medications, and had their data collected. Of those, 29 patients received 10 mg intramuscular midazolam monotherapy, 33 received 10 mg intramuscular droperidol monotherapy, and 29 received a dose containing 5 mg midazolam and 5 mg droperidol. The median time of violent and acute behavioral disturbance for the combination group was 25 minutes, for the midazolam group 24 minutes, and for the droperidol group it was 20 minutes (p = 0.66; not significant). Comparing the secondary outcomes between the 3 groups, additional sedation was required for 18 patients (62%) in the midazolam group, 12 patients (41%) in the combination group, and 11 patients (33%) in the droperidol group. There were also more drug-related adverse effects seen with midazolam than with the other two groups: 8 drug-related adverse effects in the midazolam group (28%), 2 drug-related adverse effects in the combination group (7%), and 2 drug-related adverse effects in the droperidol group (6%). Of those receiving midazolam monotherapy, 24% experienced a drop in oxygen saturation (desaturation noted to be < 90%). Only 2 cases of desaturation were reported in the droperidol monotherapy group and only 1 case in the combination group with the lower dose of midazolam IM and droperidol IM. Investigators reported an unpredictable effect of intramuscular midazolam, which caused oversedation, with more Executive Formulary Committee Minutes 8 February 2, 2018

30 sedative-related adverse effects. They also expressed concern regarding use of midazolam in environments without adequate staffing to address airway adverse events promptly as they had a dedicated researcher available at all times in this study. Ultimately, no difference was found when comparing the effectiveness of 10 mg of IM midazolam to 10 mg of IM droperidol, but more side effects did present in the midazolam group and additional sedation was required more frequently in patients being treated with midazolam. Guidelines on Midazolam for Acute Agitation According to, Issues in the Management of Acute Agitation: How Much Current Guidelines Consider Safety?, Diazepam and midazolam administration bear a strong respiratory function depression risk, especially in patients with conditions limiting respiratory functions or benzodiazepine metabolism (hepatic impairment or alcohol abuse). 19 Interestingly, in the Rationale and Guidelines for Inpatient Treatment of Acute Psychosis, respiratory depression associated with benzodiazepine use is not mentioned and neither is the preventative requirement of having flumazenil on hand, but benzodiazepine s are recommended within the guideline to control breakthrough agitation. The Expert Consensus Guideline on Assessment and Management of Agitation in Psychiatry bases recommendations on effectiveness; however, they fail to adequately address safety concerns. 20 According to, Protocol for the Management of Psychiatric Patients with Psychomotor Agitation, benzodiazepines are a considerable treatment option in non-psychotic agitation, but are not considered if the agitation is due to psychotic symptoms. Patients presenting with psychomotor agitation stemming from alcohol abstinence, anxiety disorder, affective disorder, or personality and adjustment disorder would be considered for pharmacological treatment with 5 mg of midazolam IM, among other benzodiazepines. 21 In situations where the patient presents with undifferentiated agitation, caution must be exercised. Availability and Cost: Buccal midazolam in its liquid form preparation, Buccolam or Epistatus, is made available in the U.K., but not in the U.S. For buccal or intranasal midazolam use in the U.S., the parenteral injection formulation is typically used. 1,4 The atomizer for intranasal use as well as syringes for intramuscular, buccal or intranasal use would carry additional cost outside of medication acquisition costs. The midazolam injectable product is currently in short supply, but the costs below are the most recent estimated acquisition prices: 1 mg/ml for 2 ml vial ranged from $6.77 for 25 to $10.90 for 25 5 mg/ml 1 ml vial ranged from $18.21 for 25 to $9.52 for 10 5 mg/ml 2 ml vial ranged from $27.08 for 25 to $12.50 for 10 Executive Formulary Committee Minutes 9 February 2, 2018

31 References 1. Midazolam. In: Lexi-drugs online [Database on the Internet]. [cited 11 January 2018]. 2. Newberry JA, Wang NE. Emergency Department Management of the Agitated Pediatric Patient. AHC Media: Continuing Medical Education. September 1, Moore, Gregory et al. Assessment and Management of the Acutely Agitated or Violent Adult. UpToDate. Accessed January 31, Satinder A, Sharma S. Application for Inclusion of Buccal Midazolam in the WHO List of Essential Medicines Precision Dose Inc. Midazolam Hydrochloride. Updated 4 June Mpimbaza A, Ndeezi G, Staedke S, et al. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: A randomized clinical trial. Pediatrics 2008;121:e Holsti M, Dudley N, Schunk J, et al. Intranasal midazolam vs. rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med 1020;164: McIntyre J, Robertson S, Norris E et al. Safety and Efficacy of Buccal Midazolam versus Rectal Diazepam for Emergency Treatment of Seizures in Children: A Randomised Controlled Trial. Lancet 2005; 366(9481): Brigo F, Nardone R, Tezzon F, et al. Nonintravenous Midazolam Versus Intravenous or Rectal Diazepam for the Treatment of Early Status Epilepticus: A Systematic Review with Meta-Analysis. Epilepsy Behav 2015;49: Glauser MD, Tracy et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Reports of the Guideline Committee of the American Epilepsy Society. Epilepsy Currents 2016;16(1): Deshmukh P, Kulkarni G, Barzman D. Recommendations for Pharmacological Management of Inpatient Aggression in Children and Adolescents. Psychiatry (Edgmont) 2010;7(2): Moon YE. Paradoxical Reaction to Midazolam in Children. Korean J Anesthesiol 2013;65(1): Kousgaard SJ, Licht RW, Nielsen RE. Effects of Intramuscular Midazolam and Lorazepam on Acute Agitation in Non-Elderly Subjects- A Systematic Review. Benzodiazepines for Acute Agitation. Pharmacopsychiatry 2017;50: Wyant M. Diamond BI, O Neal E etl al. The use of midazolam in acutely agitation psychiatric patients. Psychopharmacology Bull 1990; 26: Martel M, Sterzinger A, Minder J et al. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone and midazolam. Acad Emerg Med 2005;12: Nobay F, Simon BC, Levitt MA et al. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in chemical restraint of violent and severely agitated patients. Acad Emerg Med 2004;11: Executive Formulary Committee Minutes 10 February 2, 2018

32 17. Isbister GK, Calver LA, Page CB, et al. Randomized Controlled Trial of Intramuscular Droperidol Versus Midazolam for Violence and Acute Behavioral Disturbance: The DORM Study. Annals of Emergency Medicine 2010;56(4): Huf G, Evandro SF, Coutinho CEA. Rapid tranquillisation for agitated patient sin emergency psychiatric rooms: a randomized trial of midazolam versus haloperidol plus promethazine. BMJ 2003;327: Pacciardi B, Mauri M, Cargioli C, et al. Issues in the Management of Acute Agitation: How Much Current Guidelines Consider Safety? Frontiers in Psychiatry 2013;4: Garriga, M, Pacchiarotti I, Kasper S, et al. Assessment and Management of Agitation in Psychiatry: Expert Consensus. The World Journal of Biological Psychiatry 2016;16(2): Vieta E, Garriga M, Cardete L, et al. Protocol for the Management of Psychiatric Patients with Psychomotor Agitation. BMC Psychiatry 2017;17(1):328. Clinical Review Prepared by: Evita Lopez 2018 Pharm.D. Candidate A&M College of Pharmacy February 2018 Reviewed by: Lisa M. Mican, Pharm.D., BCPP Assistant Director of Pharmacy Austin State Hospital Executive Formulary Committee Minutes 11 February 2, 2018

33 Vraylar (cariprazine) Classification Second generation (atypical) antipsychotic Indications Treatment of schizophrenia Acute treatment of manic or mixed episodes associated with bipolar I disorder Attachment C-1 Pharmacology Cariprazine is a dopamine D3 and D2 receptor partial agonist. It differs from other antipsychotics in that it has almost 10-fold greater affinity for D3 than D2 receptors in vitro and high and balanced in vivo occupancy of both D2 and D3 in rats and humans. The D3 receptor is thought to modulate mood and cognition and may play a role in the treatment of the negative symptoms of schizophrenia. Cariprazine is also a serotonin 5-HT1A receptor partial agonist and a serotonin 5- HT2A receptor antagonist. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR) that have in vitro receptor binding profiles similar to the parent drug. Dosage and Administration Administer Vraylar once daily with or without food. Because of the long half-life of cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Prescribers should monitor patients for adverse reactions and treatment response for several weeks after starting Vraylar and after each dosage change. Starting dose Recommended dose Schizophrenia 1.5 mg/day 1.5 mg to 6 mg/day Bipolar Mania 1.5 mg/day 3 mg to 6 mg/day Schizophrenia: The dosage can be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. Manic or mixed episodes associated with bipolar I disorder: The dose should be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. Hepatic impairment No dosage adjustment for VRAYLAR is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9). Usage of VRAYLAR is not recommended in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). VRAYLAR has not been evaluated in this patient population. Renal impairment No dosage adjustment for VRAYLAR is required in patients with mild to moderate (CrCL > 30 ml/minute) renal impairment. Usage of VRAYLAR is not recommended in patients with severe renal impairment (CrCL < 30 ml/minute). VRAYLAR has not been evaluated in this patient population. Dosage Adjustments for CYP3A4 Inhibitors and Inducers CYP3A4 is responsible for the formation and elimination of the major active metabolites of cariprazine. Dosage recommendation for patients initiating a strong CYP3A4 inhibitor while on a stable dose of VRAYLAR: If a strong CYP3A4 inhibitor is initiated, reduce the current dosage of VRAYLAR by half. For patients taking 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking 1.5 mg daily, the dosing regimen should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, VRAYLAR dosage may need to be increased. Dosage recommendation for patients initiating VRAYLAR therapy while already on a strong CYP3A4 Executive Formulary Committee Minutes 12 February 2, 2018

34 inhibitor: Patients should be administered 1.5 mg of VRAYLAR on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, VRAYLAR dosage may need to be increased. Dosage recommendation for patients concomitantly taking VRAYLAR with CYP3A4 inducers: Concomitant use of VRAYLAR and a CYP3A4 inducer has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear. Dosage Forms and Strengths Capsules: 1.5 mg, 3 mg, 4.5 mg, and 6 mg Pharmacokinetics Absorption After single dose administration, the peak plasma cariprazine concentration occurred in approximately 3-6 hours. Administration of a single dose of 1.5 mg with a high-fat meal did not significantly affect the Cmax and AUC of cariprazine or DCAR. Distribution Cariprazine and its major active metabolites are highly bound (91 to 97%) to plasma proteins. Metabolism Cariprazine s pharmacologic activity is thought to be the result of the parent drug (cariprazine) and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), which are pharmacologically equipotent to cariprazine. Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to DCAR and DDCAR. DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite. In a 12-week study of daily cariprazine administration, mean cariprazine and DCAR concentrations reached steady state at around week 1 to week 2 and mean DDCAR concentrations approached steady state around week 4 to week 8. DDCAR s time to reach steady state was variable across patients with some patients not achieving steady state at the end of 12 weeks. The estimated half-lives are 2-4 days for cariprazine, and approximately 1 to 3 weeks for DDCAR. By the end of 12-weeks, average concentrations of DCAR and DDCAR are approximately 30% and 400%, respectively, of cariprazine. Excretion Cariprazine and its major active metabolites are minimally excreted in the urine. Following Executive Formulary Committee Minutes 13 February 2, 2018

35 administration of 12.5 mg/d cariprazine to patients with schizophrenia for 27 days, about 21% of the daily dose was found in urine, with approximately 1.2% of the daily dose excreted in the urine as unchanged cariprazine. Contraindications Known hypersensitivity to VRAYLAR. Reactions have ranged from rash, pruritus, urticarial, and events suggestive of angioedema (e.g., swollen tongue, lip swelling, face edema, pharyngeal edema, and swelling face). Warnings and Precautions Increased mortality in elderly patients with dementia-related psychosis Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis Neuroleptic malignant syndrome Tardive dyskinesia Late-occurring adverse reactions Adverse events may first appear several weeks after the initiation of VRAYLAR treatment, probably because plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures. Monitor for adverse reactions, including EPS or akathisia, and patient response for several weeks after a patient has begun VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug. Metabolic changes Atypical antipsychotic drugs, including VRAYLAR, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and diabetes mellitus Schizophrenia In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dl) to high (> 126 mg/dl) and borderline (> 100 and <126 mg/dl) to high were similar in patients treated with VRAYLAR and placebo. In the long-term, open-label schizophrenia studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (> 6.5%). Bipolar mania In the 3-week, placebo-controlled trials of adult patients with bipolar disorder, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dl) to high (> 126) and borderline (> 100 and <126 mg/dl) to high were similar in patients treated with VRAYLAR and placebo. In the long-term, open-label bipolar disorder studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (> 6.5%). Weight gain Table 1. Change in body weight (kg) in 6-week schizophrenia trials VRAYLAR Placebo (n = 573) mg/d (n = 512) mg/d (n = 570) 9-12 mg/d (n = 203) Mean change at endpoint Proportion of patients with weight increase (>7%) 5% 8% 8% 17% Data shown by modal daily dose, defined as most frequently administered dose per patient Executive Formulary Committee Minutes 14 February 2, 2018

36 Table 2. Change in body weight (kg) in 3-week bipolar mania trials VRAYLAR Placebo 3-6 mg/d (n = 439) (n = 259) 9-12 mg/d (n = 360) Mean change at endpoint Proportion of patients with weight increase (>7%) 2% 1% 3% Data shown by modal daily dose, defined as most frequently administered dose per patient In long-term, uncontrolled trials with VRAYLAR in schizophrenia, the mean changes in baseline in weight at 12, 24, and 48 weeks were 1.2 kg, 1.7 kg, and 2.5 kg, respectively. Leukopenia, neutropenia, and agranulocytosis Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including VRAYLAR. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue VRAYLAR in patients with absolute neutrophil count <1000/mm 3 and follow their WBC until recovery. Orthostatic hypotension and syncope Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Symptomatic orthostatic hypotension was infrequent in trials of VRAYLAR and was not more frequent on VRAYLAR than placebo. Syncope was not observed. VRAYLAR has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from premarketing trials. Falls VRAYLAR may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls, and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. Seizures Potential for cognitive and motor impairment VRAYLAR, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In 6-week schizophrenia trials, somnolence (hypersomnia, sedation, and somnolence) was reported in 7% of VRAYLAR-treated patients compared to 6% of placebo-treated patients. In 3- week bipolar mania trials, somnolence was reported in 8% of VRAYLAR-treated patients compared to 4% of placebo-treated patients. Body temperature dysregulation Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with VRAYLAR. VRAYLAR and other antipsychotic drugs should be used cautiously in patients at risk for aspiration. Executive Formulary Committee Minutes 15 February 2, 2018

37 Drug Interactions Drugs Having Clinically Important Interactions with VRAYLAR Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of VRAYLAR with a strong CYP3A4 inhibitor increases the exposures of cariprazine and its major active metabolite, didesmethylcariprazine (DDCAR), compared to use of VRAYLAR alone. Intervention: If VRAYLAR is used with a strong CYP3A4 inhibitor, reduce VRAYLAR dosage. Examples: itraconazole, ketoconazole CYP3A4 Inducers Clinical Impact: CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the exposure of VRAYLAR has not been evaluated, and the net effect is unclear. Intervention: Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended. Examples: rifampin, carbamazepine Drugs Having No Clinically Important Interactions with VRAYLAR Based on in vitro studies, VRAYLAR is unlikely to cause clinically significant pharmacokinetic drug interactions with substrates of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E, and CYP3A4, or OATP1B1, OATP1B3, BCRP, OCT2, OAT1 and OAT3. Cost Per GoodRx, month s supply = $1, Clinical Trials Durgam S, Cutler AJ, Lu K, et al In a phase 3, multinational, randomized, double-blind, placebo- and active-controlled study, Durgam and colleagues evaluated the efficacy, safety, and tolerability of cariprazine in patients with acute exacerbation of schizophrenia. Inclusion criteria included current psychotic episode of < 2 weeks duration, Clinical Global Impressions-Severity of Illness (CGI-S) score > 4, PANSS total score > 80 and < 120, and a score > 4 on at least two of the PANSS positive symptoms of delusions, hallucinatory behavior, conceptual disorganization, or suspiciousness/persecution. Participants were randomized to placebo (n=153), cariprazine 3 mg/d (n=155), cariprazine 6 mg/d (n=157), or aripiprazole 10 mg/d (n=152). Primary and secondary outcomes were mean change from baseline to week 6 in PANSS total score and CGI-S score. The aripiprazole group served as an active control; no statistical comparisons were made between the aripiprazole and cariprazine groups. Patients were hospitalized during washout/screening and at least four weeks of treatment. After day 28, patients who had no significant risk of suicide/violent behavior and whose CGI-S score < 3 qualified for discharge. Compared to patients taking placebo, least squares mean differences (LSMDs) in PANSS total score change favored patients taking cariprazine 3 mg/d (-6.0 [-10.1 to -1.9], adjusted P = ) and 6 mg/d (-8.8 [-12.9 to -4.7], adjusted P < Compared to patients taking placebo, the LSMDs in PANSS total score change for patients taking aripiprazole was -7.0 (-11.0 to -2.9, P< Executive Formulary Committee Minutes 16 February 2, 2018

38 Compared to patients taking placebo, LSMDs in CGI-S score change favored patients taking cariprazine 3 mg/d (-0.4 [-0.6 to -0.2], adjusted P = ) and 6 mg/d (-0.5 [-0.7 to -0.3], adjusted P < ). Compared to patients taking placebo, the LSMDs in CGI-S score change for patients taking aripiprazole was -0.4 [-0.6 to -0.2], P = Executive Formulary Committee Minutes 17 February 2, 2018

39 Executive Formulary Committee Minutes 18 February 2, 2018

40 The table below includes a summary of treatment-emergent adverse events during double-blind treatment period (safety population). Durgam S, Earley W, Li R, et al Durgam and colleagues evaluated the efficacy, safety, and tolerability of cariprazine for relapse prevention in adults with schizophrenia. Total study duration was up to 97 weeks; the trial was randomized, multinational, double-blind, placebo-controlled, and parallel-group. The first 20 weeks of the study consisted of open-label treatment with cariprazine 3-9 mg/d. The first eight weeks were a flexible-dose run-in phase; the remaining 12 weeks were a fixed-dose stabilization phase. Stable patients who completed the open-label portion of the study were eligible for randomization to double-blind treatment with continued cariprazine (3, 6, or 9 mg/d) or placebo. The double-blind phase lasted from 26 to 72 weeks; cariprazine was administered at the same fixed dose as in the stabilization period but dose adjustments were not allowed. Executive Formulary Committee Minutes 19 February 2, 2018

41 The primary outcome measure was time to relapse (worsening of symptom scores, psychiatric hospitalization, aggressive/violent behavior, suicidal risk). Approximately one-third (264/765) of participants completed open-label treatment. Investigators randomized 200 eligible patients to double-blind placebo (n=99) or cariprazine (n = 101). Relapse occurred in 24.8 % of cariprazine- and 47.5% of placebo-treated patients (hazard ratio [95% CI] = 0.45 [0.28,0.73]). Time to relapse was significantly longer in cariprazine- versus placebo-treated patients. In the double-blind phase of the trial, mean (SD) duration of cariprazine and placebo exposure was 257 (184.0) and (176.7) days, respectively. The table below provides an overall summary of adverse events. Executive Formulary Committee Minutes 20 February 2, 2018