Faculty Disclosure

Pulmonary and Critical Care Medication Update 2020

Mark Malesker, Pharm.D., FCCP, FCCP, FCCM, FASHP, BCPS Professor of Pharmacy Practice and Medicine Creighton University

16th Annual Pulmonary, Critical Care, and Sleep Medicine Conference 2020

Faculty Disclosure

2 Mark A. Malesker, Pharm.D.

Dr. Malesker has listed no financial interest/arrangement that would be considered a conflict of interest

1 Audience Question #1

 How many new novel medications were FDA approved in 2019 ?

 A. 22

 B. 39

 C. 48

 D. 59

Audience Question #2

 What is the dose for budesonide/glycopyrrolate/formoterol (Breztri Aerosphere) ?

 A. One inhalation daily

 B. One inhalation twice daily

 C. Two inhalations daily

 D. Two inhalations twice daily

2 Audience Question #3

 What is the indication for lefamulin (Xenleta) ?

 A. Community acquired pneumonia

 B. IBS with constipation

 C. Partial onset seizures

 D. Sickle cell disease

2019 Drug Approvals

 The FDA approved 48 novel new drugs and biologics  Average of 37 for 2010-2018  First in class (20/48) 42%  Drugs with a new and unique mechanism for treating a medical condition  Orphan drugs (21/48) 44%  Drugs approved for small populations of patients with rare diseases (200,000 or fewer Americans)  6800 rare diseases identified affecting 30 million people  Breakthrough (13/48) 27%  Drugs for serious or life-threatening diseases for which there is unmet need and for which there is preliminary clinical evidence demonstrating that the drug may result in substantial improvement on a clinically significant endpoint

www.fda.gov/drugs 6

3 2019 Drug Approvals

 Fast track (17/48) 35%  Drugs that have potential to address unmet medical needs

 Priority review (28/48) 58%  A drug is given priority review if there is a potential to provide a significant advance in existing medical care, reviewed within eight months (standard 12 months)

 Accelerated approval (9/48) 19%  Early approval based on markers that predict a reasonable benefit, with more testing to confirm clinical benefit after approval

www.fda.gov/drugs 7

2019 Drug Approvals

 First cycle (43/48) 90%  Drugs that were approved without additional information that could delay approval and lead to another cycle of review

 First approved in U.S. (33/48) 69%  Drugs that were approved in the United States before approved in another country

www.fda.gov/drugs 8

4 Novel Drug Approvals 2010-2019

2019 Drug Approvals (1)

10 Brand Generic Description Accrufer Ferric maltol Iron deficiency anemia Adakveo Crizanlizumab- Reduce vaso-occlusive crisis tmca in sickle cell disease Aklief Trifarotene Acne vulgaris Balversa Erdafitinib Metastatic bladder cancer Beovu Brolucizumab- Macular degeneration dbll Brukinsa Zanubrutinib Mantle cell lymphoma Cablivi Caplacizumab- Thrombotic thrombocytopenic yhdp purpura

www.fda.gov 10

5 2019 Drug Approvals (2)

11 Brand Generic Description Caplyta Lumateperone Schizophrenia Dayvigo Lemborexant Insomnia Egaten Triclabendazole Fascioliasis Enhertu Fam-trastuzumab Metastatic breast cancer deruxtec-an-nxki Evenity Romosozumab- Osteoporosis aqqg ExEm Foam Air polymer-type Dx agent for fallopian tube A assessment Fetroja Cefiderocol Complicated UTI

www.fda.gov 11

2019 Drug Approvals (3)

12 Brand Generic Description Fluorodopa F18 Dx agent Parkinsonian syndrome Ga 68 DOTATOC Dx agent neuroendocrine tumors Givlaari Givosiran Acute hepatic porphyria Ibsrela Tenapanor IBS with constipation Inrebic Fedratinib Myelofibrosis Jeuveau Prabotulinumtoxin Lines between eye-brows A-xvfs Mayzent Siponimod Multiple sclerosis Nourianz Istradefylline Parkinson’s “off” episodes www.fda.gov 12

6 2019 Drug Approvals (4)

13 Brand Generic Description Nubeqa Darolutamide Prostate cancer Oxbryta Voxelotor Sickle cell disease Padcev Enfortumab- Refractory bladder cancer vedotin-ejfv Piqray Alpelisib Metastatic breast cancer Polivy Polatuzumab- Large B-cell lymphoma vedotin-piiq Pretomanid Resistant tuberculosis Reblozyl Luspatercept- Anemia associated with beta aamt thalessemia

www.fda.gov 13

2019 Drug Approvals (5)

14 Brand Generic Description Recarbrio Imipenem, Complicated UTIs and cilastatin complicated intra-abdominal relebactam infections Reyvow Lasmiditan Migraine w/out aura Rinvoq Upadacitinib Rheumatoid arthritis Rozlytrek Entrectinib Non-small cell lung cancer Scenesse Afamelanotide Erythropoietic protoporphyria Skyrizi Risankizumab- Plaque psoriasis rzaa Spravato Esketamine Nasal spray for depression Sunosi Solriamfetol Narcolepsy or OSA www.fda.gov 14

7 2019 Drug Approvals (6)

15 Brand Generic Description TissueBlue Brilliant blue G Dye used in eye surgery Trikafta Elexacaftor, Cystic fibrosis tezacaftor, ivacaftor Turalio Pexidartinib Giant cell tumor Ubrelvy Ubrogepant Migraine Vumerity Diroximel Multiplesclerosis Vyleesi Bremelanotide Hypoactive sexual desire in premenopausal women Vyndaqel Tafamidis Amyloidosis meglumine

www.fda.gov 15

2019 Drug Approvals (7)

16 Brand Generic Description Vyondys 53 Golodirsen Duchenne muscular dystrophy Wakix Pitolisant Narcolepsy Xcopri Cenobamate Partial-onset seizures Xenlata Lefamulin CABP Xpovio Selinexor Multiple myeloma Zulresso Brexanolone Postpartum depression

www.fda.gov 16

8 2019 New Indications

17 Brand Generic Description Dupixent Dupilumab Moderate to severe asthma with an eosinophilic phenotype Ofev Nintedanib Interstitial lung disease associated with systemic sclerosis or scleroderma Symdeko Tezacaftor, Age 6 and older with cystic ivacaftor, fibrosis ivacaftor

www.fda.gov 17

2019 New Formulations (1)

18 Brand Generic Description Avaclyr Acyclovir Ophthalmic ointment for acute herpetic keratitis Baqsimi Glucagon Nasal powder for severe hypoglycemia Biorphen Phenylephrine Anesthesia-induced hypotension Conjupri Levamlodipine Isomer of amlodipine Duaklir Aclidinium/ LAMA/LABA inhaler Pressair formoterol Myxredlin Short-acting human 100 units/100 mL insulin in 0.9% sodium chloride www.fda.gov 18

9 2019 New Formulations (2)

19 Brand Generic Description Nayzilam Midazolam Nasal spray Quzyttir Cetirizine Injection for urticaria Secuado Asenapine Transdermal patch Zykadia Ceritinib Tablet formulation

www.fda.gov 19

2020 Drug Approvals (1)

20 Brand Generic Description Anjeso Meloxicam injection Moderate to severe pain Artesunate Artesunate IV formulation for initial treatment of malaria in adults and children Barhemsys Amisulpride Prevention of post-op N/V Breztri Budesonide/ ICS/LAMA/LABA for COPD Aerosphere glycopyrrolate/ Formoterol Brilinta Ticagrelor Risk reduction for CAD patients who have not had MI or stroke Byfavo Reimazolam Procedural sedation Elyxyb Celecoxib Oral solution for migraine Gimoti Metoclopramide Nasal spray for gastroparesis

www.fda.gov 20

10 2020 Drug Approvals (2)

21 Brand Generic Description Ofev Nintedanib Chronic fibrosing ILDs with a progressive phenotype Olinvyk Oliceridine IV opioid for moderate to severe pain Recarbrio Imipenem/ New indication for hospital-acquired cilastatin/ bacterial pneumonia and ventilator- relebactam associated bacterial pneumonia Valtoco Diazepam Nasal spray formulation Xywav Oxybate mixed salts New mixed-salt oxybate for (calcium, magnesium, narcolepsy, 92% lower sodium potassium, sodium) content Trelegy Ellipta Fluticasone/ Label expanded to include asthma umeclidinium/ vilanterol www.fda.gov 21

Midazolam Nasal Spray (Nayzilam)

 Indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy > 12 years  Untreated seizure clusters can increase the risk of physical injury, neurological damage, prolonged seizures, and status epilepticus  Tmax = 17.3 minutes  Schedule IV controlled substance, packaged as single-use treatment that can be carried with a patient  Two doses of 5 mg in clinical studies, 10 minutes apart  Side effects include somnolence, headache, nasal discomfort, throat irritation, rhinorrhea

https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-NAYZILAM-midazolam-nasal-spray 22

11 Diazepam (Valtoco)

 Indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy > 6 years

 Tmax = 1.5 hours

 Nasal spray dose is 0.2 mg/kg or 0.3 mg/kg depending upon patient’s age and weight

https://www.valtoco.com/ 23

Diazepam (Valtoco)

 Second Dose (if needed)  A second dose, when required, may be administered after at least 4 hours after the initial dose.  If the second dose is to be administered, use a new blister pack  Maximum Dosage and Treatment Frequency  Do not use more than 2 doses to treat a single episode  It is recommended that VALTOCO be used to treat no more than one episode every five days and no more than five episodes per month  Available in 5 mg, 7.5 mg, and 10 mg strengths, each nasal spray device contains 0.1 mL solution  Most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort

https://www.valtoco.com/ 24

12 Lemborexant (Dayvigo)

 Orexin receptor antagonist indicated for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance  Inhibits neuropeptides orexin A and B, which promote wakefulness  Dose is 5 mg immediately before going to bed, with at least 7 hours before the planned time of awakening  In safety studies, 5 mg was not significantly different from placebo in next-day postural stability, memory, attention, and driving ability  Dosage may be increased to 10 mg based on clinical response and tolerability  Schedule IV controlled substance

https://www.dayvigohcp.com/-/media/Files/DAYVIGOHCP/PDF/prescribing-information.pdf 25

Cefiderocol (Fetroja)

 Cephalosporin antibacterial indicated in patients >18 years who have limited or no alternative treatment options, for complicated urinary tract infections (cUTI), including pyelonephritis caused by susceptible Gram-negative microorganisms  Binds to extracellular iron and uses the bacterial transport system to penetrate the outer membrane of gram- negative bacteria  Active against drug-resistant Enterobacterales and some nonfermenting gram-negative bacilli, including those producing extended-spectrum beta-lactamases (ESBLs) and carbapenemases  Dose is 2 g every 8 hours by IV infusion over 3 hours  Adjust dose with renal dysfunction

https://www.shionogi.com/content/dam/shionogi/si/products/pdf/fetroja.pdf 26

13 Pretomanid

 Antimycobacterial indicated, as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug- resistant (MDR) tuberculosis (TB).  Limitations of Use - Pretomanid Tablets are not indicated for patients with:  Drug-sensitive (DS) tuberculosis  Latent infection due to Mycobacterium tuberculosis  Extra-pulmonary infection due to Mycobacterium tuberculosis  MDR-TB that is not treatment-intolerant or nonresponsive to standard therapy

https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf 27

Imipenem/Cilastatin/Relebactam (Recarbrio) 28

 Combination antibiotic, renal dehydropeptidase inhibitor, and beta-lactamase inhibitor indicated in patients > 18 years  Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)  Complicated urinary tract infections, including pyelonephritis(cUTI)in patients who have limited or no alternative treatment options  Complicated intra-abdominal infections (cIAI) in patients who have limited or no alternative treatment options

https://www.merck.com/product/usa/pi_circulars/r/recarbrio/recarbrio_pi.pdf 28

14 Imipenem/Cilastatin/Relebactam (Recarbrio) 29

 Adverse reactions  HABP/VABP: > 5% (increased alanine aminotransferase, increased aspartate aminotransferase, anemia, diarrhea, hypokalemia, and hyponatremia)  cUTI and clAl: >2 % (diarrhea, nausea, headache, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, phlebitis/infusion site reactions, pyrexia, and hypertension)

https://www.merck.com/product/usa/pi_circulars/r/recarbrio/recarbrio_pi.pdf 29

Solriamfetol (Sunosi)

 Dopamine and norepinephrine reuptake inhibitor (DNRI) for excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea  Administer once daily upon awakening  Avoid within 9 hours of planned bedtime  Starting dose for narcolepsy: 75 mg once daily  Starting dose for OSA: 37.5 mg once daily  Adjust dose with renal impairment  Can cause blood pressure and heart rate elevations, headache, nausea, decreased appetite, insomnia  No direct trial comparisons with other medications  Schedule IV controlled substance

https://www.sunosi.com 30

15 Elexacaftor/tezacaftor/ivacaftor (Trikafta) 31

 Transmembrane conductance regulator (CFTR) modulator therapy for cystic fibrosis patients > 12 years with at least one F508del mutation in the CFTR gene – estimated 90% of patients with CF  Dose: adults and pediatrics > 12 years:  Morning dose: two elexacaftor 100 mg, tezacaftor 50 mg and ivacaftor 75 mg tablet  Evening dose: one ivacaftor 150mg tablet  Morning and evening dose should be taken approximately 12 hours apart with fat-containing food  Cost is approximately $311,000 per year, taken indefinitely

https://pi.vrtx.com/files/uspi_elexacaftor_tezacaftor_ivacaftor.pdf 31

Lefamulin (Xenleta)

 Semisynthetic pleuromutilin antibiotic, approved for IV and oral treatment of community-acquired bacterial pneumonia (CABP) in adults  Approved as specialty medication (limited availability)  Caused by susceptible organisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates), Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae  Not approved for treatment of CABP caused by MRSA because data establishing clinical efficacy are limited  Not active against Enterobacteriaceae or Pseudomonas aeruginosa  Binds to the peptidyl transferase center of the 50S subunit of the bacterial ribosome, inhibiting bacterial protein synthesis  Low probability of cross-resistance to beta-lactams, macrolides, fluoroquinolones, tetracyclines, or glycopeptides  Warning and precautions  QT Prolongation: Avoid in patients with known QT prolongation  Embryo-Fetal Toxicity: May cause fetal harm  Clostridium difficile-associated diarrhea

https://www.xenleta.com/pdf/xenleta-prescribing-information.pdf 32

16 Lefamulin (Xenleta)

 Dose:  150 mg Q 12° IV for 5-7 days or 600 mg PO q 12° for 5 days  IV: Infused over 60 minutes  PO: Do not crush, take 1°AC or 2°PC with 6-8 oz water  Hepatic impairment: Reduce dose to 150 mg IV q 24°, PO not recommended  Renal impairment: No dose adjustment including dialysis  Side effects (>2%)  Injection: administration site reactions, hepatic enzyme elevation, nausea, hypokalemia, insomnia, headache  Tablets: diarrhea, nausea, vomiting, hepatic enzyme elevation  Metabolized primarily by CYP3A4 and may interact with drugs that are substrates or strong or moderate inhibitors or inducers of CYP3A4

https://www.xenleta.com/pdf/xenleta-prescribing-information.pdf 33

Lefamulin Drug Interactions

IV Formulation Strong or moderate CYP3A inducers or ● Can decrease lefamulin serum concentrations P-gp inducers (phenytoin, rifampin) and possibly its efficacy ● Avoid concurrent use Drugs that prolong the QT interval ● Avoid concurrent use PO Formulation Strong or moderate CYP3A inducers or ● Can decrease lefamulin serum concentrations P-gp inducers (phenytoin, rifampin) and possibly its efficacy ● Avoid concurrent use Strong CYP3A inhibitors or P-gp inhibitors ● Can increase lefamulin serum concentration (itraconazole, ketoconazole, voriconazole) ● Avoid concurrent use Moderate CYP3A inhibitors or P-gp inhibitors ● Can increase lefamulin serum concentration (diltiazem) ● Monitor for adverse reaction

CYP3A substrates that prolong the QT interval ● Concurrent use is contraindicated (amiodarone) Midazolam and other sensitive CYP3A substrates ● Monitor for adverse reactions that do not prolong QT interval Drugs that prolong the QT interval ● Avoid concurrent use

17 Budesonide/Glycopyrrolate/Formoterol (Breztri Aerosphere) 35

 Pressurized metered dose inhaler containing a combination of budesonide (160 mcg), glycopyrrolate (9 mcg), and formoterol fumarate (4.8 mcg) per inhalation  Indicated for the maintenance treatment of patients with COPD  Dose is 2 inhalations twice daily  Most common adverse reactions (incidence ≥ 2%) are upper respiratory tract infection, pneumonia, back pain, oral candidiasis, influenza, muscle spasm, urinary tract infection, cough, sinusitis and diarrhea  Drug interactions: Use with caution with strong CYP P450 3A4 inhibitors (ritonavir)

https://www.azpicentral.com/breztri/breztri.pdf#page=1 35

https://www.fda.gov/media/135840/download 36

18 Audience Question #4

 What is the recent approved dosage form for meloxicam ?

 A. Injection

 B. Oral disintegrating tablet

 C. Oral solution

 D. Topical patch

Audience Question #5

 What is the mechanism of action for lemborexant (Dayvigo) ?

 A. Antihistamine

 B. GABA agonist

 C. Melatonin receptor agonist

 D. Orexin receptor antagonist

19 Audience Question #6

 Pretomanid is used as monotherapy for the treatment of adults with pulmonary extensively drug resistant tuberculosis ?

 A. True

 B. False

The End Outstanding Presentation

Mark Malesker, PharmD [email protected] 40