Know the New: 2018 Novel Drug Approvals

Transcription

1 Know the New: 2018 Novel Drug Approvals Kimmy Nguyen, PharmD, BCACP Assistant Professor Wilkes University, Nesbitt School of Pharmacy January 26, 2018

2 Fill in the Blank 59 novel drug approvals in 2018 Novel Drug Approvals. FDA cenegermin-bkbj baricitinib glasdegib lanadelumab moxidectin larotrectinib lutetium eravacycline Lu 177 dotatate stiripentol amifampridine bictegravir, doravirine embitcitabine, plazomicin tenofovir gilteritinib moxetumomab alafenamide pasudotox-tdfk binimetinib tezacaftor; prucalopride fremanezumab-vfrm ivacaftor encorafenib apalutamide calaspargase pegol-mknl duvelisib tecovirimat ibalizumab-uiyk tagraxofusp-erzs galcanezumab-gnlm ivosidenib tildrakizumab ravulizumab dacomitinib tafenoquine fostamatinib andexanet alfa cemiplimab-rwlc elagolix burosumab-twza lofexidine sodium sarecycline fish fosnetupitant cannabidiol oil triglycerides omadacycline and palonosetron lusutrombopag migalastat elapegademase-lvlr mogamulizumab-kpkc erenumab-aooe inotersen patisiran sodium talazoparib zirconium cyclosilicate segesterone acetate and ethinyl

3 Objectives 1. List the FDA approved indications and recommended dosing for andexanet alfa, lofexidine, and cannabidiol. 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.

4 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 anticoagulants? A. Apixaban B. Rivaroxaban C. Edoxaban D. A and B E. All of the above

5 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

6 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

7 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

8 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

9 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

10 Andexanet alfa (Andexxa )

11 Background Direct Oral Anticoagulants (DOACs) Advantage Clinical Relevance Rapid onset of action No bridging Predictable anticoagulant 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 Antidote Eikelbloom JW, Weitz JI. Circulation

12 Dabigatran Rivaroxaban Apixaban Edoxaban Idarucizumab Betrixaban Andexanet alfa Rivaroxaban Apixaban Edoxaban Betrixaban Warfarin (approved in 1954) Dabigatran Idarucizumab Unger EF. FDA Drug Approval Packages. FDA Katzung BG, Kruidering-Hall M, Trevor AJ. Chapter 34: Drugs used in coagulation disorders. Katzung & Trevor's Pharmacology: Examination & Board Review, 12e

13 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. Portola Pharmaceuticals, Inc FDA Food and Drug Administration

14 Normal Physiology Prothrombin Thrombin Prothrombinase Complex Factor Va Factor Xa Platelet Surface Andexxa. Portola Pharmaceuticals, Inc

15 Factor Xa Inhibitor apixaban or rivaroxaban Prothrombin Prothrombinase Complex Factor Va Factor Xa Platelet Surface Andexxa. Portola Pharmaceuticals, Inc

16 Andexanet Alfa Mechanism of Action apixaban or rivaroxaban Andexanet Prothrombin Thrombin Prothrombinase Complex Factor Va Factor Xa Andexanet also inhibits TFPI activity Increased tissue-factor-initiated thrombin generation Platelet Surface Andexxa. Portola Pharmaceuticals, Inc TFPI Tissue Factor Pathway Inhibitor

17 Return of Anticoagulant Activity apixaban or rivaroxaban Andexanet Andexanet Andexanet Prothrombin Half-life: ~1 hour Prothrombinase Complex Factor Va Factor Xa Anti-FXa activity increases to levels similar to placebo after ~2 hours post-infusion. Elevated tissue factor-initiated thrombin generation is sustained for ~22 hrs. Andexxa. Portola Pharmaceuticals, Inc Connolly SJ, et al. N Engl J Med Platelet Surface Seigel DM, et al. N Engl J Med. 2015

18 Dosing Safety and efficacy of >1 dose has not been evaluated. Initial IV Bolus STANDARD DOSE Follow-on IV Infusion 400 mg at a target rate of 30 mg/min 4 mg/min for up to 120 minutes HIGH DOSE Initial IV Bolus Follow-on IV Infusion 800 mg at a target rate of 30 mg/min 8 mg/min for up to 120 minutes Standard Dose High Dose Andexxa. Portola Pharmaceuticals, Inc IV Intravenous

19 Dosing Costs Initial IV Bolus 400 mg STANDARD DOSE = 880 mg Follow-on IV Infusion 4 mg/min for up to 120 minutes = 480 mg AWP $3300 per 100 mg vial Low Dose = $29,700 for 9 vials High Dose = $59,400 for 18 vials HIGH DOSE = 1760 mg Initial IV Bolus 800 mg Follow-on IV Infusion 8 mg/min for up to 120 minutes = 960 mg Andexxa. Portola Pharmaceuticals, Inc Andexxa. Red Book. Micromedex AWP Average wholesale price

20 Warnings and Precautions Black Box Warning Andexanet alfa has been associated with: Arterial and venous thromboembolic events Ischemic events, including MI and ischemic stroke Cardiac arrests Sudden deaths Monitor for thromboembolic events and initiate anticoagulation when medically appropriate Andexxa. Portola Pharmaceuticals, Inc MI Myocardial infarction

21 Adverse Reactions Contraindications: None Drug interactions: No known interactions Dose adjustments: None Adverse Reactions: Pneumonia ( 5%) Urinary tract infections ( 5%) Infusion-related reactions ( 3%) Andexxa. Portola Pharmaceuticals, Inc

22 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 GI Gastrointestinal

23 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 *All patients receiving apixaban

24 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: ng/ml 10.3 ng/ml = 93% decrease (95% CI, 87-94) Connolly SJ, et al. N Engl J Med

25 ANNEXA-4 Estimated primary completion date: November 2022 Safety Outcomes (N=67) Thrombotic events in 12 patients during 30-day follow-up (18%) 1 MI 5 Strokes 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 Anexxa-4. U.S. NLM MI Myocardial infarction DVT Deep vein thrombosis PE CV Pulmonary embolism Cardiovascular

26 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) Received single dose of PCC 50 units/kg Apixaban (39) and rivaroxaban (45) 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 Majeed A, et al. Blood PCC Prothrombin complex concentrate

27 What about PCC? Primary Outcome Clinical hemostasis in 21 patients (72.4%) Primary Outcome 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 Did not include 30-day follow-up Did not measure anti-fxa levels Limitations Observational design Did not measure anti-fxa levels Similar rates of hemostasis, but fewer observed thromboembolic events with PCC Sheikh-Taha M. Intern Emerg Med Majeed A, et al. Blood PCC Prothrombin complex concentrate

28 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 PCC Prothrombin complex concentrate

29 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 Prior Approval Supplement. News Release

30 Lofexidine (Lucemyra )

31 Background 70,237 drug overdose deaths in the U.S. in ,600 overdose deaths involved opioids (67.8%) Synthetic opioid-involved overdose death rates increased by 45.2% from WV 17.2 per 100,000 2 MD 11.5 per 100,000 3 UT 10.8 per 100,000 States with the highest prescription opioid-involved death rates in 2017 Drug overdose deaths. CDC Scholl L, et al. MMWR. 2018

32 Opioid Withdrawal Symptoms Anxiety Sweating Poor sleep Runny nose Muscle pain Watery eyes Dilated pupils Chills Diarrhea Vomiting Sweating Cramping Shakiness HR and BP Opioid Dependence Opioid Withdrawal Post-withdrawal Treatment Opiate and opioid withdrawal. NLM HR Heart rate BP Blood pressure

33 Opioid Withdrawal Treatments Product Class Indication Special Licensing Limitations Methadone Full opioid agonist Buprenorphine Partial opioid agonist Clonidine Alpha-2 adrenergic agonist Detoxification and maintenance of opioid addiction Treatment of opioid dependence HTN ADHD Yes BBW addiction Diversion/abuse Yes Dependence Diversion/abuse No Limited controlled data Side effects Methadone. Roxane Laboratories, Inc Buprenorphine. Roxane Laboratories, Inc Clonidine. Concordia Pharmaceuticals, Inc Clonidine. Boehringer Ingelheim BBW Black box warning HTN Hypertension ADHD Attention-Deficit/Hyperactivity Disorder

34 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 OUD Opioid use disorder

35 Opioid Use Physiology Adrenergic Neuron Opioid Opioid Receptor Euphoria Analgesia Lofexidine. US WorldMeds, LLC Norepinephrine

36 Lofexidine Mechanism of Action Adrenergic Neuron L Opioid Opioid Receptor Lofexidine. US WorldMeds, LLC Withdrawal L Lofexidine Norepinephrine

37 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

38 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 Lucemyra. Red Book. IBM Micromedex BP Blood pressure AWP Average wholesale price

39 Dose Adjustments Dosing Adjustment Hepatic Impairment Mild Moderate Severe Child-Pugh Score >9 Recommended Dose 3 tabs QID (2.16 mg/day) 2 tabs QID (1.44 mg/day) Dosing Adjustments for Renal Impairment Moderate 1 tab QID (72 mg/day) Severe, ESRD, Dialysis egfr, ml/min/ <30 Recommended Dose 2 tabs QID (1.44 mg/day) 1 tab QID (0.72 mg/day) Lofexidine. US WorldMeds, LLC egfr Estimated glomerular filtration rate

40 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 QTprolonging agents Lofexidine. US WorldMeds, LLC MI Myocardial infarction ECG Electrocardiogram CHF Congestive heart failure

41 Warnings and Precautions Increased risk of CNS depression with concomitant use of CNS depressant drugs Benzodiazepines, alcohol, barbiturates Increased risk of opioid overdose after opioid discontinuation Reduced tolerance to opioids increased risk of fatal overdose if opioids resumed Lofexidine. US WorldMeds, LLC CNS Central nervous system

42 Adverse Reactions Adverse Reactions: ( 10%) Sedation Dry mouth Dizziness Bradycardia Hypotension Somnolence Orthostatic hypotension Lofexidine. US WorldMeds, LLC

43 Drug Interactions Contraindications: None Drug Interactions: Methadone QT prolongation; monitor ECG Oral naltrexone Decreased naltrexone efficacy if given within 2 hours of lofexidine Paroxetine (CYP2D6 inhibitor) Increased lofexidine absorption and increased risk of ADRs Lofexidine. US WorldMeds, LLC ECG Electrocardiogram ADR Adverse drug reaction

44 Clinical Trial 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 Fishman M, et al. J Addict Med OUD Opioid use disorder SOWS-Gossop Short Opiate Withdrawal Scale of Gossop

45 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 None (0) Mild (1) Moderate (2) Severe (3) Fishman M, et al. J Addict Med

46 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, to -0.04; P = 0.02 Lofexidine 2.88 mg -0.26; 95% CI, to -0.09; P = Lofexidine generally safe and effective non-opioid treatment for opioid withdrawal. Fishman M, et al. J Addict Med SOWS-Gossop Short Opiate Withdrawal Scale of Gossop

47 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 NICE National Institute for Health & Clinical Excellence

48 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

49 Cannabidiol (Epidiolex )

50 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

51 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 DOJ Department of Justice

52 Cannabidiol Cannabis sativa plant (marijuana) CBD does not cause intoxication or euphoria THC is the primary psychoactive component Controlled substance Schedule V FDA News Release. FDA CBD Cannabidiol THC Tetrahydrocannabinol

53 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 medication that contains a purified drug derived from marijuana First approved medication for DS Cannabidiol. Greenwich Biosciences, Inc LGS Lennox-Gastaut Syndrome DS Dravet Syndrome

54 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

55 Dosing AWP $1482 per 100 ml (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

56 Dosing Adjustments Hepatic Impairment Starting Dose Maintenance Dose Maximum Dose Mild Moderate Severe 2.5 mg/kg BID (5 mg/kg/day) 1.25 mg/kg BID (2.5 mg/kg/day) 0.5 mg/kg BID (1 mg/kg/day) 5 mg/kg BID (10 mg/kg/day) 2.5 mg/kg BID (5 mg/kg/day) 1 mg/kg BID (2 mg/kg/day) 10 mg/kg BID (20 mg/kg/day) 5 mg/kg BID (10 mg/kg/day) 2 mg/kg BID (4 mg/kg/day) May need slower dose titration in moderate-to-severe impairment Cannabidiol. Greenwich Biosciences, Inc

57 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 ULN Upper limit of normal

58 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

59 Adverse Reactions Adverse Reactions: ( 10%) Rash Fatigue Malaise Infection Asthenia Diarrhea Insomnia Somnolence Decreased appetite Transaminase elevations Cannabidiol. Greenwich Biosciences, Inc

60 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

61 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

62 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 Devinsky O, et al. N Eng J Med

63 Lennox-Gastaut Trial #1 Thiele EA, et al. Lancet

64 Lennox-Gastaut Trial #2 Devinsky O, et al. N Eng J Med

65 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

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

67 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 NICE National Institute for Health & Clinical Excellence

68 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 What is Dravet Syndrome. Dravet Syndrome Foundation Treatment for epileptic seizures. AES

69 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 nausea, vomiting, fatigue, anorexia, jaundice/dark urine Cannabidiol. Greenwich Biosciences, Inc

70 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

71 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

72 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

73 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

74 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

75 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

76 Know the New: 2018 Novel Drug Approvals Questions?

77 References 1. Novel Drug Approvals for U.S. Food and Drug Administration. Available from 2. Eikelbloom JW, Weitz JI. New anticoagulants: Update on antithrombotic therapy. Circulation Apr 6;121(13): Available from 3. Unger EF. Atrial fibrillation and new oral anticoagulant drugs. U.S. Food and Drug Administration Oct 16. Available from 4. Dabigatran Drug Approval Package. U.S. Food and Drug Administration. Available from 5. Rivaroxaban Drug Approval Package. U.S. Food and Drug Administration. Available from 6. Apixaban Drug Approval Package. U.S. Food and Drug Administration. Available from 7. Idarucizumab Drug Approval Package. U.S. Food and Drug Administration. Available from 8. Edoxaban Drug Approval Package. U.S. Food and Drug Administration. Available from 9. Betrixaban Drug Approval Package. U.S. Food and Drug Administration. Available from 10.Andexxa. [prescribing information]. South San Francisco, CA. Portola Pharmaceuticals, Inc Available from

78 References 11.Siegal DM, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med Dec;373(25): Available from 12.Connolly SJ, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med (12): Available from 13.Andexxa. Red Book. IBM Micromedex Andexxa-4. U.S. National Library of Medicine. Available from 15.Sheikh-Taha M. Treatment of apixaban- and rivaroxaban-associated major bleeding using 4-factor prothrombin complex concentrate. Intern Emerg Med Nov 9. [Epub ahead of print]. Available from 16.Majeed A, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood Oct 12;130(15): Available from 17.Lip GYH, et al. Antithrombotic therapy for atrial fibrillation. CHEST guideline and expert panel report Nov;154(5): Available from US FDA approves Portola Pharmaceuticals Prior Approval Supplement for Andexxa generation 2 manufacturing process. [news release]. Portola Pharmaceuticals Jan 2. Available from 19.Opioid overdose: Drug overdose deaths. Centers for Disease Control and Prevention Dec 18. Available from 20.Scholl L, et al. Drug and Opioid-Involved Overdose Deaths United States, Morb Mortal Wkly Rep. epub: 21 December Available from

79 References 21.Opiate and opioid withdrawal. Medline Plus. U.S. NLM May 05. Available from 22.Methadone. [prescribing information]. Columbus, OH. Roxane Laboratories, Inc Available from 23.Buprenorphine. [prescribing information]. Columbus, OH. Roxane Laboratories, Inc Available from HCl%20Sublingual%20Tabs.pdf. 24.Clonidine (Kapvay). [prescribing information]. St. Michael, Barbados. Concordia Pharmaceuticals, Inc Available from 25.Clonidine (Catapres). [prescribing information]. Mexico City, Mexico. Boehringer Ingelheim Available from 26.Lofexidine (Lucemyra). [prescribing information]. Louisville, KY. US WorldMeds, LLC Available from 27.Lucemyra. Red Book. IBM Micromedex Fishman M, et al. Safety and efficacy of lofexidine for medically managed opioid withdrawal: A randomized controlled clinical trial. J Addict Med Nov 29. [Epub ahead of print]. Available from 29.Drug misuse: opioid detoxification. NICE Available from nice.org.uk/guidance/cg52/evidence/drug-misuse-opioid-detoxification-fullguideline FDA approves first drug comprised of an active ingredient deried from marijuana to treat rare, severe forms of epilepsy. U.S. FDA Jun Available from

80 References 31.Medical marijuana. PA Department of Health Available from 32.Cannabidiol (Epidiolex). [prescribing information]. Carlsbad, CA. Greenwich Biosciences, Inc Available from 33.Epilepsies: diagnosis and management. NICE Jan 11. Available from 34.Thiele EA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Mar 17;391(10125): Available from 6B1F442C9A35459C098D9502A678761BFDDB8F64E7CAFF. 35.Devinsky O, et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med May 17;378(20): Available from 36.Devinsky O, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Eng J Med May 25;376(21): Available from 37.What is Dravet Syndrome. Dravet Syndrome Foundation Available from 38.Treatment for epileptic seizures. AES Dec 18. Available from