Know the New: 2018 Novel Drug Approvals

Kimmy Nguyen, PharmD, BCACP Assistant Professor Wilkes University, Nesbitt School of Pharmacy January 26, 2018 avatrombopagrifamycin pegvaliaseemapalumab-pqpz-lzsg cenegermin-bkbj baricitinibglasdegib lanadelumab moxidectinlarotrectinib lutetiumeravacycline Lu 177 dotatate stiripentolamifampridine bictegravirdoravirine , embitcitabine, Fill in the Blank plazomicingilteritinib tenofovirmoxetumomab alafenamide pasudotox -tdfk binimetinibprucalopride tezacaftorfremanezumab; ivacaftor-vfrm encorafenibcalaspargase pegol-mknl 59 apalutamideduvelisib tecovirimattagraxofusp -erzs ibalizumabgalcanezumab-uiyk-gnlm ivosidenibravulizumab tildrakizumabdacomitinib novel drug tafenoquineandexanet alfa fostamatinibcemiplimab-rwlc elagolixlofexidine sodium approvals in burosumabsarecycline -twza fishcannabidiol oil triglycerides fosnetupitantomadacycline and 2018 lusutrombopag migalastatelapegademase -lvlr mogamulizumab-kpkc erenumabinotersen -aooe patisiran sodiumtalazoparib zirconium cyclosilicate Novel Drug Approvals. FDA. 2018 segesterone acetate and ethinyl estradiolbaloxavir vaginalmarboxil system lorlatinib revefenacin

Objectives

1. List the FDA approved indications and recommended dosing for , lofexidine, and .

2. Describe the mechanisms of action and common adverse effects for each of the three newly approved drugs.

3. Discuss the evidence supporting each drug’s approval and its potential role in therapy. Pre-Test Andexanet alfa is indicated for the reversal of anticoagulation due to life-threatening or uncontrolled bleeding for patients treated with which of the following ?

A. B. C. D. A and B E. All of the above Pre-Test Lofexidine is approved for which of the following indications?

A. Opioid use disorder B. Mitigation of opioid withdrawal symptoms C. Insomnia D. Seizure Pre-Test Cannabidiol has been approved for both the treatment of rare, severe forms of seizures and post-traumatic stress disorder.

A. True B. False Pre-Test Lofexidine is associated with which of the following side effects?

A. Infusion-related reactions B. Blurry vision, tachycardia, hypertension C. Dizziness, bradycardia, hypotension D. Decreased appetite, elevated transaminases Pre-Test Which of the following agents require gradual dose reduction upon discontinuation?

A. Andexanet alfa B. Lofexidine C. Cannabidiol D. B and C E. All of the above Pre-Test Which of the following agents require both renal and hepatic dose adjustment?

A. Andexanet alfa B. Lofexidine C. Cannabidiol D. All of the above Andexanet alfa (Andexxa®) Background

Direct Oral Anticoagulants (DOACs) Advantage Clinical Relevance Rapid onset of action No bridging Predictable effect No routine monitoring Specific coagulation enzyme target Low risk for off-target adverse effects Low risk for food-drug interactions No dietary precautions; few interactions

Eikelbloom JW, Weitz JI. Circulation. 2010. Edoxaban

Dabigatran Rivaroxaban Apixaban Andexanet alfa

2010 2011 2012 2015 2017 2018

Rivaroxaban Apixaban Edoxaban Betrixaban

Warfarin

(approved in 1954) Idarucizumab Unger EF. FDA. 2015. Drug Approval Packages. FDA. 2018. Katzung BG, Kruidering-Hall M, Trevor AJ. Chapter 34: Drugs used in coagulation disorders. Katzung & Trevor's Pharmacology: Examination & Board Review, 12e. 1998.

Indication

● Reversal of anticoagulation due to life-threatening or uncontrolled bleeding in patients treated with rivaroxaban or apixaban

● Approved via the FDA Accelerated Approval pathway ○ U.S. Orphan Drug ○ FDA Breakthrough Therapy

Andexxa. , Inc. 2018. FDA Food and Drug Administration Normal Physiology

Prothrombin

Thrombin

Prothrombinase Factor Factor Complex Va Xa

Platelet Surface

Andexxa. Portola Pharmaceuticals, Inc. 2018. Factor Xa Inhibitor apixaban or rivaroxaban

Prothrombin

Prothrombinase Factor Factor Complex Va Xa

Platelet Surface

Andexxa. Portola Pharmaceuticals, Inc. 2018. Andexanet Alfa Mechanism of Action apixaban or rivaroxaban Andexanet

Prothrombin

Thrombin

Prothrombinase Andexanet also inhibits TFPI activity Factor Factor  Increased tissue-factor-initiated thrombin generation Complex Va Xa

Platelet Surface

Andexxa. Portola Pharmaceuticals, Inc. 2018. TFPI Tissue Factor Pathway Inhibitor Return of Anticoagulant Activity Andexanet apixaban or rivaroxaban Andexanet Andexanet

Prothrombin

Half-life: ~1 hour

Anti-FXa activity increases to levels similar to placebo after ~2 hours post-infusion. Prothrombinase Factor Factor Elevated tissue factor-initiated thrombin generation is Complex Va Xa sustained for ~22 hrs.

Platelet Surface Andexxa. Portola Pharmaceuticals, Inc. 2018. Seigel DM, et al. N Engl J Med. 2015 Connolly SJ, et al. N Engl J Med. 2016. Safety and efficacy of >1 dose Dosing has not been evaluated.

STANDARD DOSE Initial IV Bolus Follow-on IV Infusion

4 mg/min for 400 mg at a target rate of up to 120 30 mg/min minutes

HIGH DOSE

Initial IV Bolus Follow-on IV Infusion

800 mg at a 8 mg/min for target rate of up to 120 30 mg/min minutes Standard Dose High Dose

Andexxa. Portola Pharmaceuticals, Inc. 2018. IV Intravenous Dosing Costs

STANDARD DOSE = 880 mg Initial IV Bolus Follow-on IV Infusion AWP $3300 per 100 mg vial 4 mg/min for up

to 120 minutes Low Dose = $29,700 for 9 vials 400 mg = 480 mg High Dose = $59,400 for 18 vials HIGH DOSE = 1760 mg

Initial IV Bolus Follow-on IV Infusion

8 mg/min for up 800 mg to 120 minutes = 960 mg

Andexxa. Portola Pharmaceuticals, Inc. 2018. Andexxa. Red Book. Micromedex. 2018. AWP Average wholesale price Warnings and Precautions

Black Box Warning ● Andexanet alfa has been associated with: ○ Arterial and venous thromboembolic events ○ Ischemic events, including MI and ischemic ○ Cardiac arrests ○ Sudden deaths

● Monitor for thromboembolic events and initiate anticoagulation when medically appropriate

Andexxa. Portola Pharmaceuticals, Inc. 2018. MI Adverse Reactions

● Contraindications: None

● Drug interactions: No known interactions

● Dose adjustments: None

● Adverse Reactions: ○ (≥5%) ○ Urinary tract infections (≥5%) ○ Infusion-related reactions (≥3%)

Andexxa. Portola Pharmaceuticals, Inc. 2018. ANNEXA-4 – Interim Analysis

● Multicenter, prospective, open-label, single-arm trial to evaluate safety and efficacy of andexanet in acute major bleeding

● Population ○ Mean age 77 years, 51% male, 77% Caucasian ○ Site of bleed: GI 49%, Intracerebral 42%, Other 9% ○ Patients on apixaban (20), rivaroxaban (26), enoxaparin (1), or edoxaban

● Primary Outcomes (N=47) ○ Rate of excellent or good hemostasis 12 hrs after andexanet infusion ○ Percent change in anti-FXa activity

Connolly SJ, et al. N Engl J Med. 2016. GI Gastrointestinal ANNEXA-4

● Intervention ○ Apixaban* or rivaroxaban >7 hrs: Standard dose ○ Enoxaparin, edoxaban, or rivaroxaban ≤7 hours or unknown: High dose

● Primary Outcomes (N=47) ○ Rate of excellent or good hemostasis 12 hrs after andexanet infusion • 37/47 patients (79%; 95% CI, 64-89)

Connolly SJ, et al. N Engl J Med. 2016. *All patients receiving apixaban ANNEXA-4

● Primary Outcomes (N=47) ○ Percent change in anti-FXa activity (post-bolus) • Rivaroxaban: 227 ng/mL  16.8 ng/mL = 89% decrease (95% CI, 58-94) • Apixaban: 149.7 ng/mL  10.3 ng/mL = 93% decrease (95% CI, 87-94)

Connolly SJ, et al. N Engl J Med. 2016. Estimated primary completion date: ANNEXA-4 November 2022

● Safety Outcomes (N=67) ○ Thrombotic events in 12 patients during 30-day follow-up (18%) • 1 MI • 5 • 7 DVTs • 1 PE ○ Therapeutic anticoagulation restarted before event in one patient • Anticoagulation resumed in 18 patients within 30 days (27%)

○ 10 deaths (15%) [6 CV-related and 4 non-CV-related]

Connolly SJ, et al. N Engl J Med. 2016. MI Myocardial infarction PE Pulmonary embolism Anexxa-4. U.S. NLM. 2018. DVT Deep vein thrombosis CV Cardiovascular What about PCC?

● A retrospective chart review ● A prospective cohort study ● Population (N=29) ● Population (N=84) ○ Mean age 74 years, 44.8% male, ○ Mean age 75 years, 57.1% male, ○ Site of bleed: GI 13.8%, ICH 72.4%, Other 13.8% ○ Site of bleed: GI 15.5%, ICH 70.2%, Other 14.3% ○ Apixaban (13) and Rivaroxaban (16) ○ Apixaban (39) and rivaroxaban (45) ○ Received single dose of PCC 50 units/kg ○ Median PCC dose of 2000 IU

Primary Outcome Clinical hemostasis was assessed by the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria

Sheikh-Taha M. Intern Emerg Med. 2018. Majeed A, et al. Blood. 2017. PCC Prothrombin complex concentrate What about PCC?

● Primary Outcome ● Primary Outcome ○ Clinical hemostasis in 21 patients (72.4%) ○ Clinical hemostasis in 58 patients (69.1%)

● Safety Outcome ● Safety Outcome ○ One patient (3.4%) had a thromboembolic event ○ Two patients (2.4%) had a thromboembolic event ○ Six deaths (20.7%) within 14 days post-PCC dose ○ 27 deaths (32%) within 30 days of major bleed • 1 case possibly related to PCC administration

● Limitations ● Limitations ○ Did not include 30-day follow-up ○ Observational design ○ Did not measure anti-FXa levels ○ Did not measure anti-Fxa levels

Similar rates of hemostasis, but fewer observed thromboembolic events with PCC

Sheikh-Taha M. Intern Emerg Med. 2018. Majeed A, et al. Blood. 2017. PCC Prothrombin complex concentrate Place in Therapy

● 2018 CHEST guidelines ○ Specific reversal agent preferred (if available) over PCC in serious bleeding

● Non-specific agents ○ Less effective ○ Lack evidence to support improved outcomes ○ Potentially pro-thrombotic

Lip GYH, et al. CHEST guidelines. 2018. PCC Prothrombin complex concentrate Key Points / Counseling

● Andexanet alfa is a factor Xa reversal agent ○ ANNEXA-4 studying effect on edoxaban and enoxaparin

● Risk of thrombotic events requires careful monitoring for safe anticoagulation re-initiation

● Limited availability in June 2018 (Early Supply Program) ○ Approved in January 2019 for Generation 2 manufacturing • Full commercial launch and greater availability

Andexxa. Portola Pharmaceuticals, Inc. 2018. Prior Approval Supplement. News Release. 2019. Lofexidine (Lucemyra®) Background

● 70,237 drug overdose deaths in the U.S. in 2017 ○ 47,600 overdose deaths involved opioids (67.8%) ○ Synthetic opioid-involved overdose death rates increased by 45.2% from 2016-2017

1 WV 17.2 per 100,000 States with the highest prescription 2 MD 11.5 per 100,000 opioid-involved death 3 UT 10.8 per 100,000 rates in 2017

Drug overdose deaths. CDC. 2018. Scholl L, et al. MMWR. 2018 Opioid Withdrawal Symptoms

. Anxiety . Chills . Sweating . Opioid Dependence . Poor sleep . . Runny nose . Sweating . Muscle pain . Cramping Opioid Withdrawal . Watery eyes . Shakiness . Dilated pupils . ↑ HR and BP

Post-withdrawal Treatment

HR Heart rate Opiate and opioid withdrawal. NLM. 2018. BP Blood pressure Opioid Withdrawal Treatments Product Class Indication Special Licensing Limitations Methadone Full opioid Detoxification Yes . BBW addiction and . Diversion/abuse maintenance of opioid addiction Buprenorphine Partial opioid Treatment of Yes . Dependence agonist opioid . Diversion/abuse dependence Clonidine Alpha-2 HTN No . Limited adrenergic ADHD controlled data agonist . Side effects

Methadone. Roxane Laboratories, Inc. 2006. Clonidine. Concordia Pharmaceuticals, Inc. 2015. BBW Black box warning HTN Hypertension Buprenorphine. Roxane Laboratories, Inc. 2015. Clonidine. Boehringer Ingelheim. 2009. ADHD Attention-Deficit/Hyperactivity Disorder Indication

● Mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation ○ Not for treatment of OUD

● First non-opioid drug for managing withdrawal symptoms ○ Already marketed in other countries ○ Initial market introduction in 1992

Lofexidine. US WorldMeds, LLC. 2018. OUD Opioid use disorder Opioid Use Physiology Adrenergic Neuron

Opioid

Analgesia Opioid Receptor Euphoria

Lofexidine. US WorldMeds, LLC. 2018. Norepinephrine Lofexidine Mechanism of Action Adrenergic Neuron L

Opioid

Opioid Receptor Withdrawal L Lofexidine

Lofexidine. US WorldMeds, LLC. 2018. Norepinephrine Dosing

● Starting dose: Three 0.18 mg tablets QID ○ During peak withdrawal symptoms • First 5-7 days following last opioid dose ○ Maintain 5-6 hours between each dose

● Dosing guided by symptoms and side effects ○ Maximum daily dose 2.88 mg (16 tablets) ○ Maximum dose 0.72 mg (4 tablets)

Lofexidine. US WorldMeds, LLC. 2018. Dose Discontinuation

● Treatment up to 14 days

● Discontinue with gradual dose reduction over 2-4 days ○ Reduce by 1 tablet per dose every 1-2 days ○ Avoids lofexidine withdrawal symptoms • Diarrhea, insomnia, anxiety, chills, increased BP

AWP $24.83 per tablet 36 and 96 count bottles

Lofexidine. US WorldMeds, LLC. 2018. Lucemyra. Red Book. IBM Micromedex. 2018. BP Blood pressure AWP Average wholesale price Dose Adjustments

Dosing Adjustment Hepatic Impairment Mild Moderate Severe Child-Pugh Score 5-6 7-9 >9 Recommended 3 tabs QID 2 tabs QID 1 tab QID Dose (2.16 mg/day) (1.44 mg/day) (72 mg/day)

Dosing Adjustments for Renal Impairment Moderate Severe, ESRD, Dialysis eGFR, mL/min/1.732 30-89.9 <30 Recommended Dose 2 tabs QID (1.44 mg/day) 1 tab QID (0.72 mg/day)

Lofexidine. US WorldMeds, LLC. 2018. eGFR Estimated glomerular filtration rate Warnings and Precautions

● Risk of hypotension, bradycardia, and syncope ○ Avoid in patients with severe coronary insufficiency, recent MI, cerebrovascular disease, chronic renal failure, and marked bradycardia

● Risk of QT prolongation ○ Avoid use in patients with congenital long QT syndrome ○ Monitor ECG in patients with CHF, bradyarrhythmias, hepatic impairment, renal impairment, and concomitant use of QT- prolonging agents MI Myocardial infarction ECG Electrocardiogram Lofexidine. US WorldMeds, LLC. 2018. CHF Congestive heart failure Warnings and Precautions

● Increased risk of CNS depression with concomitant use of CNS depressant drugs ○ Benzodiazepines, , barbiturates

● Increased risk of after opioid discontinuation ○ Reduced tolerance to opioids  increased risk of fatal overdose if opioids resumed

Lofexidine. US WorldMeds, LLC. 2018. CNS Central nervous system Adverse Reactions

● Adverse Reactions: (≥10%) ○ Sedation ○ Dry mouth ○ Dizziness ○ Bradycardia ○ Hypotension ○ Somnolence ○ Orthostatic hypotension

Lofexidine. US WorldMeds, LLC. 2018. Drug Interactions

● Contraindications: None

● Drug Interactions: ○ Methadone • QT prolongation; monitor ECG ○ Oral • Decreased naltrexone efficacy if given within 2 hours of lofexidine ○ Paroxetine (CYP2D6 inhibitor) • Increased lofexidine absorption and increased risk of ADRs

ECG Electrocardiogram Lofexidine. US WorldMeds, LLC. 2018. ADR Adverse drug reaction

● Multicenter, double-blind, placebo-controlled study to evaluate efficacy and safety of lofexidine for opioid withdrawal symptoms after abrupt discontinuation

● Population ○ Mean age 35 years, 71% male ○ Met DSM-IV criteria for OUD dependent on short-acting opioids

● Primary Outcome (N=603) ○ SOWS-Gossop total score on days 1-7 of treatment

OUD Opioid use disorder Fishman M, et al. J Addict Med. 2018. SOWS-Gossop Short Opiate Withdrawal Scale of Gossop None (0) Mild (1) Moderate (2) Severe (3) 1. Feeling sick 2. Stomach cramps 3. Muscle spasms 4. Feeling of coldness 5. Heart pounding 6. Muscular tension 7. Aches/pains 8. Yawning 9. Runny eyes 10. Insomnia

Fishman M, et al. J Addict Med. 2018. Clinical Trial

● Intervention 3:3:2 ○ Lofexidine 2.16 mg/day vs lofexidine 2.88 mg/day vs placebo

● Primary Outcome (N=603) ○ SOWS-Gossop score on days 1-7 of treatment • Lofexidine 2.16 mg • -0.21; 95% CI, -0.37 to -0.04; P = 0.02 • Lofexidine 2.88 mg • -0.26; 95% CI, -0.44 to -0.09; P = 0.003

Lofexidine generally safe and effective non-opioid treatment for opioid withdrawal.

Fishman M, et al. J Addict Med. 2018. SOWS-Gossop Short Opiate Withdrawal Scale of Gossop Place in Therapy

● Structural analog of clonidine with comparable efficacy

● Clonidine associated with higher rates of hypotension ○ Difference in alpha-2 receptor selectivity

● UK NICE guidelines lofexidine recommendations ○ In patients who decline methadone or buprenorphine ○ In cases of mild or uncertain dependence ○ Clonidine should not be routinely used for opioid detoxification

NICE Guideline. British Psychological Society. 2008. NICE National Institute for Health & Clinical Excellence Key Points / Counseling

● Lofexidine is the first non-opioid treatment for managing opioid withdrawal symptoms ○ May mitigate, but not completely prevent symptoms

● Patients should self-monitor for symptoms of hypotension and bradycardia

● Avoid abrupt lofexidine discontinuation

● Risk of opioid overdose due to decreased tolerance

Lofexidine. US WorldMeds, LLC. 2018. Cannabidiol (Epidiolex®) Background

● PA’s Medical Marijuana Program signed on April 17, 2016

● Qualifying condition or terminal illness: ○ Amyotrophic lateral sclerosis, autism, cancer, Crohn's disease, damage to the nervous tissue of the central nervous system (brain-spinal cord), dyskinetic and spastic movement disorders, glaucoma, HIV/AIDs, Huntington's disease, inflammatory bowel disease, intractable seizures, multiple sclerosis, neurodegenerative diseases, neuropathies, opioid use disorder for which conventional therapeutic interventions are contraindicated or ineffective, Parkinson's disease, post-traumatic stress disorder, severe chronic or intractable pain, sickle cell anemia

Medical marijuana. PA Department of Health. 2019. Legality

● Medical Marijuana Program does not protect against federal prosecution ○ DOJ may enforce criminal federal laws regarding marijuana possession and use regardless of state law

○ Unlikely to bring enforcement actions against growers/processors, dispensaries, physicians, seriously ill individuals or caregivers as long as they are acting pursuant to the Act

Medical marijuana. PA Department of Health. 2019. DOJ Department of Justice Cannabidiol

● Cannabis sativa plant (marijuana) ○ CBD does not cause intoxication or euphoria ○ THC is the primary psychoactive component

● Controlled substance – Schedule V

CBD Cannabidiol FDA News Release. FDA. 2018. THC Tetrahydrocannabinol Indication

● Treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients ≥2 years of age ○ Rare forms of severe epilepsy that emerge in early childhood

● First approved that contains a purified drug derived from marijuana

● First approved medication for DS

LGS Lennox-Gastaut Syndrome Cannabidiol. Greenwich Biosciences, Inc. 2018. DS Dravet Syndrome

Cannabidiol Mechanism of Action

● Precise mechanism is unknown ○ Does not appear to exert its anticonvulsant effects through interaction with cannabidiol receptors

Cannabidiol. Greenwich Biosciences, Inc. 2018. AWP $1482 per 100 mL Dosing (100 mg/mL)

● Starting dose: 2.5 mg/kg BID

● Maintenance dose: Increase to 5 mg/kg BID after one week ○ Maximum maintenance dose of 10 mg/kg BID ○ Increase by weekly increments of 2.5 mg/kg BID • Do not titrate more frequently than every other day

● Gradual dose decrease needed upon discontinuation to minimize risk of increased seizures

Cannabidiol. Greenwich Biosciences, Inc. 2018. Dosing Adjustments

Hepatic Impairment Starting Dose Maintenance Dose Maximum Dose Mild 2.5 mg/kg BID 5 mg/kg BID 10 mg/kg BID (5 mg/kg/day) (10 mg/kg/day) (20 mg/kg/day) Moderate 1.25 mg/kg BID 2.5 mg/kg BID 5 mg/kg BID (2.5 mg/kg/day) (5 mg/kg/day) (10 mg/kg/day) Severe 0.5 mg/kg BID 1 mg/kg BID 2 mg/kg BID (1 mg/kg/day) (2 mg/kg/day) (4 mg/kg/day)

May need slower dose titration in moderate-to-severe impairment

Cannabidiol. Greenwich Biosciences, Inc. 2018. Warnings and Precautions

● Hepatocellular injury ○ Dose-related elevations in liver transaminases (AST/ALT) • 3x ULN in 13% of patients taking cannabidiol vs 1% with placebo • 17% with 10 mg/kg BID vs 1% in patients taking 5 mg/kg BID ○ Risk increased with concomitant valproate and clobazam

*** Collect baseline ALT, AST, and total bilirubin ***

Cannabidiol. Greenwich Biosciences, Inc. 2018. ULN Upper limit of normal Warnings and Precautions

● Somnolence and Sedation ○ Dose-related; 32% with cannabidiol vs 11% with placebo ○ More common in early treatment and may diminish over time

● Suicidal Behavior and Ideation ○ Monitor for emergence or worsening of depression or unusual changes in mood/behavior

Cannabidiol. Greenwich Biosciences, Inc. 2018. Adverse Reactions

● Adverse Reactions: (≥10%)

○ Rash ○ Diarrhea ○ Fatigue ○ Insomnia ○ Malaise ○ Somnolence ○ Infection ○ Decreased appetite ○ Asthenia ○ Transaminase elevations

Cannabidiol. Greenwich Biosciences, Inc. 2018. Drug Interactions

● Contraindication ○ Hypersensitivity to cannabidiol ○ Allergy to sesame seed oil

● Drug Interactions: ○ Moderate or strong inhibitors of CYP3A4 or CYP2C19 ■ Increases cannabidiol concentrations  increased side effects

○ Strong CYP3A4 or CYP2C19 Inducers ■ Decreases cannabidiol concentrations  decreased efficacy

○ Clobazam  3-fold increase in clobazam active metabolite

Cannabidiol. Greenwich Biosciences, Inc. 2018. Drug Abuse/Dependence

● No cannabinoid-like behavioral responses in animal studies ○ No animal self-administration  No rewarding effects

● Human abuse potential study measuring Drug Liking and Take Drug Again ○ Cannabidiol – Similar to placebo ○ Dronabinol (schedule III) and alprazolam (schedule IV) • Large increases in subjective measures

● Cannabidiol did not produce signs or symptoms of withdrawal after treating for 28 days ○ Suggests that cannabidiol does not produce physical dependence Cannabidiol. Greenwich Biosciences, Inc. 2018. Clinical Trials

● Lennox-Gastaut ○ Two randomized, double-blind, placebo-controlled trials in patients aged 2 to 55 years • Trial #1: Add-on cannabidiol (20 mg/kg/day) vs placebo • Trial #2: Add-on cannabidiol (10 and 20 mg/kg/day) vs placebo

● Primary outcome: Percent change from baseline in frequency of drop seizures over a 14-week period

Thiele EA, et al. Lancet. 2018. Devinsky O, et al. N Eng J Med. 2018. Lennox-Gastaut Trial #1

Thiele EA, et al. Lancet. 2018. Lennox-Gastaut Trial #2

Devinsky O, et al. N Eng J Med. 2018. Clinical Trials

● Dravet Syndrome ○ Randomized, double-blind, placebo-controlled trial • Add-on cannabidiol (20 mg/kg/day) vs placebo

● Primary outcome: Percent change from baseline in frequency of seizures over a 14-week period

Devinsky O, et al. N Eng J Med. 2017. Dravet Syndrome

Devinsky O, et al. N Eng J Med. 2018. Place in Therapy

● Lennox-Gastaut Syndrome treatment ○ First-line……..Valproate ○ Adjunctive…..Lamotrigine ○ Other………….Rufinamide or topiramate; felbamate (last-line)

● Current evidence suggests benefit in treatment-resistant, pediatric-onset, intractable epilepsy

NICE Guideline. Epilepsies. 2012. NICE National Institute for Health & Clinical Excellence Place in Therapy

● Dravet Syndrome treatment ○ First-line……..Valproate or topiramate ○ Adjunctive…..Clobazam or stiripentol ○ Other………….Clonazepam, levetiracetam, zonisamide, ethosuximide

● The American Epilepsy Society (AES) urges weighing risks vs benefits of available treatment options

NICE Guideline. Epilepsies. 2012. What is Dravet Syndrome. Dravet Syndrome Foundation. 2019 Treatment for epileptic seizures. AES. 2018. Key Points / Counseling

● Cannabidiol comes with a calibrated measuring device ○ 1 mL or 5 mL oral syringe ○ Do not use household teaspoon or tablespoon

● Discard unused cannabidiol 12 weeks after opening

● Food may affect cannabidiol levels

● Self-monitor for signs of hepatic dysfunction ○ Unexplained , vomiting, fatigue, anorexia, jaundice/dark urine

Cannabidiol. Greenwich Biosciences, Inc. 2018. Post-Test Andexanet alfa is indicated for the reversal of anticoagulation due to life-threatening or uncontrolled bleeding for patients treated with which of the following anticoagulants?

A. Apixaban B. Rivaroxaban C. Edoxaban D. A and B E. All of the above Post-Test Lofexidine is approved for which of the following indications?

A. Opioid use disorder B. Mitigation of opioid withdrawal symptoms C. Insomnia D. Seizure Post-Test Cannabidiol has been approved for both the treatment of rare, severe forms of seizures and post-traumatic stress disorder.

A. True B. False Post-Test Lofexidine is associated with which of the following side effects?

A. Infusion-related reactions B. Blurry vision, tachycardia, hypertension C. Dizziness, bradycardia, hypotension D. Decreased appetite, elevated transaminases Post-Test Which of the following agents require gradual dose reduction upon discontinuation?

A. Andexanet alfa B. Lofexidine C. Cannabidiol D. B and C E. All of the above Post-Test Which of the following agents require both renal and hepatic dose adjustment?

A. Andexanet alfa B. Lofexidine C. Cannabidiol D. All of the above Know the New: 2018 Novel Drug Approvals

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