10/4/18 Clinical Pearls UNMH Pharmacy Residents Jessica Lewis-Gonzalez, PharmD Valentin Pacuraru, PharmD Amre Elmaoued, PharmD Siena Meador, PharmD Ngoc-Yen Pham, PharmD Management of Adverse Effects of PD1/PDL1 Inhibitors Jessica Lewis-Gonzalez, PharmD PGY-1 Pharmacy Resident University of New Mexico Hospitals 1
10/4/18 Objectives ¡ Pharmacist ¡ Technician § Evaluate and assess the § Identify management of management of adverse adverse effects of the effects of the PD1/PDL1 PD1/PDL1 inhibitors inhibitors Wait…which drugs are those again??? ¡ PD1 Inhibitors ¡ PDL1 Inhibitors § Pembrolizumab § Atezolizumab (Tecentriq) (Keytruda) § Avelumab (Bavencio) § Nivolumab (Opdivo) § Durvalumab (Imfinzi) • These are IV cancer chemotherapy medications that are administered most commonly in the outpatient setting at infusion centers. 2
10/4/18 Why is this important to you? Adverse Events to be Aware of: ¡ Immune related adverse events § Dermatologic § GI § Hepatic § Endocrine § Other less common inflammatory events Postcow. Jour Clin Onc. 2015. 3
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. 4
10/4/18 Treatment of Adverse Events (In General) ¡ Grade 1: Mild, asymptomatic § Management: Observation, intervention not needed ¡ Grade 2: Moderate § Management: Local or noninvasive intervention indicated § Will likely need low-dose oral prednisone /methylprednisolone and may be able to continue treatment ¡ Grade 3: Several or medically significant but not immediately life- threatening § Management: Stop immunotherapy, hospitalization indicated, high dose prednisone /methylprednisolone ¡ Grade 4: Life-threatening consequences § Management: Urgent intervention, will permanently stop immunotherapy ¡ Grade 5: Death related to AE NIH,NCI. Common Terminology Criteria for Adverse Events V. 5.0. 2017. Derm Adverse Event - Maculopapular Rash Grade Hold Steroids Antihistamine Other Immunotherapy 1 Moderate-potency Topical emollient topical 2 Consider holding High-potency topical Topical emollient AND/OR low-dose prednisone /methylprednisolone 3/4 High-potency topical + Urgent Derm low-dose prednisone Consult /methylprednisolone (increase dose if no improvement) NCCN. Management of Immunotherapy-Related Toxicities(Version 1.2018). 5
10/4/18 GI Adverse Event- Diarrhea/Colitis Grade Hold Steroids Permanently DC Other Immunotherapy 1 Consider holding Loperamide, hydration 2 IV methylprednisolone 1mg/kg/day 3 IV Consider Inpatient methylprednisolone Supportive Care (consider resuming 2mg/kg/day after resolution) 4 IV Consider Inpatient methylprednisolone Supportive Care 2 mg/kg/day (NCCN). Management of Immunotherapy-Related Toxicities(Version 1.2018). Hepatic Adverse Event- Acute Pancreatitis Grade Hold Steroids Permanently DC Other Immunotherapy 1 Consider Gastroenterology Referral 2 Low-dose prednisone/ methylprednisolone 3/4 High-dose prednisone/ methylprednisolone (NCCN). Management of Immunotherapy-Related Toxicities(Version 1.2018). 6
10/4/18 Low-dose vs High-dose steroids ¡ Low-dose corticosteroids for grade 2: § prednisone or methylprednisolone 0.5–1 mg/kg/day ¡ High-dose corticosteroids for grade 3 and 4: § prednisone or methylprednisolone 1–2 mg/kg/day ¡ Tapering off systemic corticosteroids over 4–6 weeks after symptoms have resolved to Grade 1 or 2 Rudzki, JD. Memo Springer. 2018. Summary ¡ When it comes to immune-related adverse events with checkpoint inhibitors – Steroids are your friends! § Topical § Low-dose § High-dose ¡ When patients present to the hospital on a PD-1/PDL-1 inhibitor with an acute event: § Consider drug as a potential cause § Grade the reaction (if caused by drug) § Treat based on grading 7
10/4/18 Approach to the Patient with Nausea & Vomiting and QTc Prolongation Valentin Pacuraru, PharmD PGY-1 Pharmacy Resident University of New Mexico Hospitals Learning Objectives Pharmacists Technicians • Define the • Identify the extent of QTc five most prolonging commonly effect of used drugs for several N/V N/V that medications. impact QTc. 8
10/4/18 QTc Prolongation and risk of Torsades de Pointes Torsades https://pedemmorsels.com/prolonged-qtc/ Defining QTc Prolongation QTc Values by Age and Sex (ms) 1 – 15 y/o Adult Males Adult Females Normal <440 ms <430 ms <450 ms Borderline 440 – 460 ms 430 – 450 ms 450 – 470 ms Prolonged >460 ms >450 ms >470 ms Clinically Significant QTc Prolongation • >500 ms 9
10/4/18 Torsades de Pointes Risk Factors ¡ Female Sex ¡ Hypokalemia and/or Hypomagnesemia ¡ Bradycardia ¡ Recent Cardioversion ¡ Structural Heart Disease ¡ Digoxin Therapy ¡ Baseline QT Prolongation ¡ Rapid IV infusion of QT prolonging medications ¡ Pharmacokinetic Interactions Li M. P T. 2017 Lin YL. Pharmacoepidemiol Drug Saf. 2009 Risk Scoring Option Tisdale Risk Score Risk Factor Points QTc Interval Risk Stratification Age >68 1 Risk Category Risk Score Female Gender 1 Low <7 Loop Diuretic 1 Potassium <3.5 mEq 2 QTc >450 on Admit 2 Moderate 7 – 10 Acute MI 2 2+ QTc Prolonging Drugs 3 Sepsis 3 Heart Failure 3 High >11 One QTc Prolonging Med 3 Maximum Risk Score 21 Tisdale JE. Can Pharm J 2016 10
10/4/18 Approaching Nausea and Vomiting Treat the Underlying Etiology First Gastroparesis Infectious Medication Induced Electrolyte or Fluid Abnormality GI Obstruction/Inflammation GERD Diabetes Related Common Inpatient Medications for Nausea and Vomiting Ondansetron Olanzapine Promethazine Trimetho- Prochlorperazine benzamide Haloperidol Metoclopramide 11
10/4/18 Alternate Agents for Nausea & Vomiting Dexamethasone • Best data for PONV and CINV • Side effects limit use in simple N/V Inhaled Isopropyl Alcohol • Promising ED data including superiority to ondansetron Benzodiazepines • Most appropriate for withdrawal, anxiety, and anticipatory related nausea April MD et al. Ann Emerg Med 2018 Beadle KL. Ann Emerg Med. 2016 Haloperidol Published evidence D2 Receptor of QTc prolongation Antagonist ranging from 8 ms – 35 ms Multiple publications of IM, IV, Sol, and Tab torsadogenesis and cardiac dysrhythmia Wenzel-seifert K. Dtsch Arztebl Int. 2011 Van noord C . J Clin Psychopharmacol. 2009 12
10/4/18 Ondansetron Published evidence of Serotonin-3 Receptor QTc prolongation Antagonist ranging from 4 ms – 32 ms Few published cases of torsades or IV, IM, Sol, Tab, ODT, dysrhythmia, but and PO Film associated high IV doses (32 mg) Brygger L. Expert Opin Drug Saf. 2014 Poluzzi E. PLoS ONE 10. 2015 Promethazine H1 and D2 Receptor Published Evidence Antagonist of QTc prolongation Low torsadogenic IM, IV, PR, Sol, and potential Tab available Jo SH. . Pharmacol Res. 2009 Owczuk R. Anaesthesia. 2009 13
10/4/18 Metoclopramide Published D2 Receptor evidence of QTc Antogonist prolongation Few published case reports of IV, IM, Sol, Tab, cardiac and ODT decompensation Smith HS. Ann Palliat Med. 2012 Smith HS. Ann Palliat Med 2012 Chou CC Chang Gung Med J 2001 Ellidokuz E. Aliment Pharmacol Ther. 2003 Prochlorperazine Published evidence D2 Receptor of QTc Antagonist prolongation, particularly in vitro Few case reports of prochlorperazine IM,IV, PR, Sol, and contributing to an Tab arrhythmia Aström-lilja C. Pharmacoepidemiol Drug Saf. 2008 14
10/4/18 Olanzapine D2 Receptor Published evidence Antagonist of QTc prolongation Few case reports of PO, IM, and IV torsades with IV forms available formulation Czekalla J. J Clin Psychiatry. 2001 Suzuki Y. Human Psychopharmacology. 2011 Lam YWF. Brown University Psychopharmacology . 2015 Trimethobenzamide No published D2 Receptor evidence of QTc Antagonist prolongation No published PO and IM forms evidence of available torsadogenesis 15
10/4/18 Ranking Torsadogenic Risk 1) Haloperidol 2) Ondansetron 3) Promethazine 4) Olanzapine 5) Metoclopramide 6) Prochlorperazine 7) Trimethobenzamide Isbister GK. Br J Clin Pharmacol. 2013 Final Thoughts • No one size fits all answer • QTc prolongation ≠ torsadogenic risk • Additional risk factors are important • Risk/Benefit is a patient specific decision • Medication choice should be based on risk/benefit, patient specific characteristics, and route 16
10/4/18 Alternative Uses of Haloperidol Amre Elmaoued, PharmD PGY-1 Pharmacy Resident University of New Mexico Hospitals Objectives ¡ Pharmacists: § Evaluate some alternative uses of haloperidol ¡ Technicians: § Identify some off-label uses of haloperidol 17
10/4/18 Haloperidol - D2 Antagonist Mechanism of Action ¡ 1st generation Antipsychotic (a.k.a. Typical Antipsychotic) ¡ FDA Indication: § Psychosis § Schizophrenia ¡ Typical Dosing: 0.5-2 mg two- three times daily Psychopharmacology Institute. (n.d.) Haloperidol - Characteristics D 2 Activity High 5HT2 Activity Medium Muscarinic Low Activity Alpha-1 Low adrenergic Activity Antihistamine Low Activity Psychopharmacology Institute. (n.d.) 18
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