Clinical Pearls of PD1/PDL1 Inhibitors UNMH Pharmacy Residents - PDF document

10/4/18 Management of Adverse Effects Clinical Pearls of PD1/PDL1 Inhibitors UNMH Pharmacy Residents Jessica Lewis-Gonzalez, PharmD Valentin Pacuraru, PharmD Amre Elmaoued, PharmD Jessica Lewis-Gonzalez, PharmD Siena Meador, PharmD PGY-1 Pharmacy Resident Ngoc-Yen Pham, PharmD University of New Mexico Hospitals Objectives Wait…which drugs are those again??? ¡ Pharmacist ¡ Technician ¡ PD1 Inhibitors ¡ PDL1 Inhibitors § Evaluate and assess the § Identify management of § Pembrolizumab § Atezolizumab (Tecentriq) management of adverse adverse effects of the (Keytruda) § Avelumab (Bavencio) effects of the PD1/PDL1 PD1/PDL1 inhibitors § Nivolumab (Opdivo) § Durvalumab (Imfinzi) inhibitors • These are IV cancer chemotherapy medications that are administered most commonly in the outpatient setting at infusion centers. Adverse Events to be Aware of: ¡ Immune related adverse events § Dermatologic Why is this important to you? § GI § Hepatic § Endocrine § Other less common inflammatory events Postcow. Jour Clin Onc. 2015. 1

10/4/18 Grading of Adverse Events ¡ Per Common Terminology Criteria for Adverse Events (CTCAE): NIH,NCI. Common Terminology Criteria for Adverse Events V. 5.0. 2017. Treatment of Adverse Events (In General) Derm Adverse Event - Maculopapular Rash Grade Hold Steroids Antihistamine Other Grade 1: Mild, asymptomatic ¡ Immunotherapy § Management: Observation, intervention not needed Grade 2: Moderate ¡ 1 Moderate-potency Topical emollient § Management: Local or noninvasive intervention indicated topical § Will likely need low-dose oral prednisone /methylprednisolone and may be able to continue treatment 2 Consider holding High-potency topical Topical emollient Grade 3: Several or medically significant but not immediately life- AND/OR ¡ threatening low-dose prednisone § Management: Stop immunotherapy, hospitalization indicated, high dose /methylprednisolone prednisone /methylprednisolone 3/4 High-potency topical + Urgent Derm Grade 4: Life-threatening consequences ¡ low-dose prednisone Consult § Management: Urgent intervention, will permanently stop immunotherapy /methylprednisolone Grade 5: Death related to AE ¡ (increase dose if no improvement) NIH,NCI. Common Terminology Criteria for Adverse Events V. 5.0. 2017. NCCN. Management of Immunotherapy-Related Toxicities(Version 1.2018). GI Adverse Event- Diarrhea/Colitis Hepatic Adverse Event- Acute Pancreatitis Grade Hold Steroids Permanently DC Other Grade Hold Steroids Permanently DC Other Immunotherapy Immunotherapy 1 Consider holding Loperamide, 1 Consider hydration Gastroenterology 2 IV Referral methylprednisolone 1mg/kg/day 2 Low-dose 3 IV Consider Inpatient prednisone/ methylprednisolone Supportive Care methylprednisolone (consider resuming 2mg/kg/day 3/4 High-dose after resolution) prednisone/ 4 IV Consider Inpatient methylprednisolone methylprednisolone Supportive Care 2 mg/kg/day (NCCN). Management of Immunotherapy-Related Toxicities(Version 1.2018). (NCCN). Management of Immunotherapy-Related Toxicities(Version 1.2018). 2

10/4/18 Low-dose vs High-dose steroids Summary ¡ When it comes to immune-related adverse events with ¡ Low-dose corticosteroids for grade 2: checkpoint inhibitors – Steroids are your friends! § prednisone or methylprednisolone 0.5–1 mg/kg/day § Topical ¡ High-dose corticosteroids for grade 3 and 4: § Low-dose § prednisone or methylprednisolone 1–2 mg/kg/day § High-dose ¡ Tapering off systemic corticosteroids over 4–6 weeks after ¡ When patients present to the hospital on a PD-1/PDL-1 symptoms have resolved to Grade 1 or 2 inhibitor with an acute event: § Consider drug as a potential cause § Grade the reaction (if caused by drug) § Treat based on grading Rudzki, JD. Memo Springer. 2018. Learning Objectives Approach to the Patient with Nausea & Vomiting and QTc Pharmacists Technicians Prolongation • Define the • Identify the extent of QTc five most Valentin Pacuraru, PharmD prolonging commonly PGY-1 Pharmacy Resident effect of used drugs for University of New Mexico Hospitals several N/V N/V that medications. impact QTc. Defining QTc Prolongation QTc Prolongation and risk of Torsades de Pointes QTc Values by Age and Sex (ms) 1 – 15 y/o Adult Males Adult Females Normal <440 ms <430 ms <450 ms Torsades Borderline 440 – 460 ms 430 – 450 ms 450 – 470 ms Prolonged >460 ms >450 ms >470 ms Clinically Significant QTc Prolongation • >500 ms https://pedemmorsels.com/prolonged-qtc/ 3

10/4/18 Risk Scoring Option Torsades de Pointes Risk Factors Tisdale Risk Score Risk Factor Points QTc Interval Risk Stratification ¡ Female Sex Age >68 1 Risk Category Risk Score ¡ Hypokalemia and/or Hypomagnesemia Female Gender 1 ¡ Bradycardia Loop Diuretic 1 Low <7 ¡ Recent Cardioversion Potassium <3.5 mEq 2 ¡ Structural Heart Disease QTc >450 on Admit 2 ¡ Digoxin Therapy Acute MI 2 Moderate 7 – 10 2+ QTc Prolonging Drugs 3 ¡ Baseline QT Prolongation Sepsis 3 ¡ Rapid IV infusion of QT prolonging medications Heart Failure 3 High >11 ¡ Pharmacokinetic Interactions One QTc Prolonging Med 3 Maximum Risk Score 21 Li M. P T. 2017 Lin YL. Pharmacoepidemiol Drug Saf. 2009 Tisdale JE. Can Pharm J 2016 Common Inpatient Medications for Nausea and Approaching Nausea and Vomiting Vomiting Treat the Underlying Etiology First Ondansetron Gastroparesis Olanzapine Promethazine Infectious Medication Induced Trimetho- Prochlorperazine Electrolyte or Fluid Abnormality benzamide GI Obstruction/Inflammation GERD Haloperidol Metoclopramide Diabetes Related Haloperidol Alternate Agents for Nausea & Vomiting Published evidence Dexamethasone D2 Receptor of QTc prolongation • Best data for PONV and CINV Antagonist ranging from 8 ms – • Side effects limit use in simple N/V 35 ms Inhaled Isopropyl Alcohol • Promising ED data including superiority to ondansetron Multiple Benzodiazepines publications of IM, IV, Sol, and Tab torsadogenesis and • Most appropriate for withdrawal, anxiety, and anticipatory related nausea cardiac dysrhythmia April MD et al. Ann Emerg Med 2018 Wenzel-seifert K. Dtsch Arztebl Int. 2011 Beadle KL. Ann Emerg Med. 2016 Van noord C . J Clin Psychopharmacol. 2009 4

10/4/18 Ondansetron Promethazine Published evidence of Serotonin-3 Receptor QTc prolongation H1 and D2 Receptor Published Evidence Antagonist ranging from 4 ms – Antagonist of QTc prolongation 32 ms Few published cases of torsades or Low torsadogenic IM, IV, PR, Sol, and IV, IM, Sol, Tab, ODT, dysrhythmia, but potential Tab available and PO Film associated high IV doses (32 mg) Brygger L. Expert Opin Drug Saf. 2014 Jo SH. . Pharmacol Res. 2009 Poluzzi E. PLoS ONE 10. 2015 Owczuk R. Anaesthesia. 2009 Metoclopramide Prochlorperazine Published evidence Published D2 Receptor D2 Receptor of QTc evidence of QTc Antogonist Antagonist prolongation, prolongation particularly in vitro Few published Few case reports of case reports of IV, IM, Sol, Tab, prochlorperazine IM,IV, PR, Sol, and cardiac and ODT contributing to an Tab decompensation arrhythmia Smith HS. Ann Palliat Med. 2012 Smith HS. Ann Palliat Med 2012 Chou CC Chang Gung Med J 2001 Aström-lilja C. Pharmacoepidemiol Drug Saf. 2008 Ellidokuz E. Aliment Pharmacol Ther. 2003 Olanzapine Trimethobenzamide No published D2 Receptor Published evidence D2 Receptor evidence of QTc Antagonist of QTc prolongation Antagonist prolongation Few case reports of No published PO, IM, and IV PO and IM forms torsades with IV evidence of forms available available formulation torsadogenesis Czekalla J. J Clin Psychiatry. 2001 Suzuki Y. Human Psychopharmacology. 2011 Lam YWF. Brown University Psychopharmacology . 2015 5

10/4/18 Ranking Torsadogenic Risk Final Thoughts 1) Haloperidol • No one size fits all answer 2) Ondansetron • QTc prolongation ≠ torsadogenic risk 3) Promethazine 4) Olanzapine • Additional risk factors are important 5) Metoclopramide • Risk/Benefit is a patient specific decision 6) Prochlorperazine • Medication choice should be based on risk/benefit, patient specific characteristics, and route 7) Trimethobenzamide Isbister GK. Br J Clin Pharmacol. 2013 Objectives Alternative Uses of Haloperidol ¡ Pharmacists: § Evaluate some alternative uses of haloperidol Amre Elmaoued, PharmD PGY-1 Pharmacy Resident ¡ Technicians: University of New Mexico Hospitals § Identify some off-label uses of haloperidol Haloperidol - D2 Antagonist Haloperidol - Characteristics D 2 Activity High Mechanism of Action ¡ 1st generation 5HT2 Activity Medium Antipsychotic (a.k.a. Typical Antipsychotic) Muscarinic Low ¡ FDA Indication: Activity § Psychosis Alpha-1 Low § Schizophrenia adrenergic ¡ Typical Dosing: 0.5-2 mg Activity two- three times daily Antihistamine Low Activity Psychopharmacology Institute. (n.d.) Psychopharmacology Institute. (n.d.) 6