Clinical Pearls UNMH Pharmacy Residents Jessica Lewis-Gonzalez, - - PDF document
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
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UNMH Pharmacy Residents Jessica Lewis-Gonzalez, PharmD Valentin Pacuraru, PharmD Amre Elmaoued, PharmD Siena Meador, PharmD Ngoc-Yen Pham, PharmD
Jessica Lewis-Gonzalez, PharmD PGY-1 Pharmacy Resident University of New Mexico Hospitals
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¡ Pharmacist § Evaluate and assess the
management of adverse effects of the PD1/PDL1 inhibitors
¡ Technician § Identify management of
adverse effects of the PD1/PDL1 inhibitors
¡ PD1 Inhibitors § Pembrolizumab
(Keytruda)
§ Nivolumab (Opdivo) ¡ PDL1 Inhibitors § Atezolizumab (Tecentriq) § Avelumab (Bavencio) § Durvalumab (Imfinzi)
administered most commonly in the outpatient setting at infusion centers.
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¡ Immune related adverse events § Dermatologic § GI § Hepatic § Endocrine § Other less common inflammatory events
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¡ Per Common Terminology Criteria for Adverse Events (CTCAE):
NIH,NCI. Common Terminology Criteria for Adverse Events V. 5.0. 2017.
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¡ 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.
Grade Hold Immunotherapy Steroids Antihistamine Other 1 Moderate-potency topical Topical emollient 2 Consider holding High-potency topical AND/OR low-dose prednisone /methylprednisolone Topical emollient 3/4 High-potency topical + low-dose prednisone /methylprednisolone (increase dose if no improvement) Urgent Derm Consult
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Grade Hold Immunotherapy Steroids Permanently DC Other
1
Consider holding Loperamide, hydration
2
IV methylprednisolone 1mg/kg/day
3
(consider resuming after resolution) IV methylprednisolone 2mg/kg/day Consider Inpatient Supportive Care
4
IV methylprednisolone 2 mg/kg/day Consider Inpatient Supportive Care
(NCCN). Management of Immunotherapy-Related Toxicities(Version 1.2018).
Grade Hold Immunotherapy Steroids Permanently DC Other
1
Consider Gastroenterology Referral
2
Low-dose prednisone/ methylprednisolone
3/4
High-dose prednisone/ methylprednisolone
(NCCN). Management of Immunotherapy-Related Toxicities(Version 1.2018).
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¡ 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.
¡ 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
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Valentin Pacuraru, PharmD PGY-1 Pharmacy Resident University of New Mexico Hospitals
extent of QTc prolonging effect of several N/V medications.
five most commonly used drugs for N/V that impact QTc.
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https://pedemmorsels.com/prolonged-qtc/
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
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¡ 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
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
High >11
Heart Failure 3 One QTc Prolonging Med 3 Maximum Risk Score 21
Tisdale JE. Can Pharm J 2016
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Gastroparesis Infectious Medication Induced Electrolyte or Fluid Abnormality GI Obstruction/Inflammation GERD Diabetes Related
Treat the Underlying Etiology First
Ondansetron Promethazine Prochlorperazine Metoclopramide Haloperidol Trimetho- benzamide Olanzapine
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Dexamethasone
Inhaled Isopropyl Alcohol
Benzodiazepines
April MD et al. Ann Emerg Med 2018 Beadle KL. Ann Emerg Med. 2016
D2 Receptor Antagonist Published evidence
ranging from 8 ms – 35 ms Multiple publications of torsadogenesis and cardiac dysrhythmia IM, IV, Sol, and Tab
Wenzel-seifert K. Dtsch Arztebl Int. 2011 Van noord C . J Clin Psychopharmacol. 2009
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Serotonin-3 Receptor Antagonist Published evidence of QTc prolongation ranging from 4 ms – 32 ms Few published cases
dysrhythmia, but associated high IV doses (32 mg) IV, IM, Sol, Tab, ODT, and PO Film
Brygger L. Expert Opin Drug Saf. 2014 Poluzzi E. PLoS ONE 10. 2015
H1 and D2 Receptor Antagonist Published Evidence
Low torsadogenic potential IM, IV, PR, Sol, and Tab available
Jo SH. . Pharmacol Res. 2009 Owczuk R. Anaesthesia. 2009
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D2 Receptor Antogonist Published evidence of QTc prolongation Few published case reports of cardiac decompensation IV, IM, Sol, Tab, and ODT
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
D2 Receptor Antagonist Published evidence
prolongation, particularly in vitro Few case reports of prochlorperazine contributing to an arrhythmia IM,IV, PR, Sol, and Tab
Aström-lilja C. Pharmacoepidemiol Drug Saf. 2008
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D2 Receptor Antagonist Published evidence
Few case reports of torsades with IV formulation PO, IM, and IV forms available
Czekalla J. J Clin Psychiatry. 2001 Suzuki Y. Human Psychopharmacology. 2011 Lam YWF. Brown University Psychopharmacology . 2015
D2 Receptor Antagonist No published evidence of QTc prolongation No published evidence of torsadogenesis PO and IM forms available
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7) Trimethobenzamide 6) Prochlorperazine 5) Metoclopramide 4) Olanzapine 3) Promethazine 2) Ondansetron 1) Haloperidol
Isbister GK. Br J Clin Pharmacol. 2013
patient specific characteristics, and route
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Amre Elmaoued, PharmD PGY-1 Pharmacy Resident University of New Mexico Hospitals
¡ Pharmacists: § Evaluate some alternative uses of haloperidol ¡ Technicians: § Identify some off-label uses of haloperidol
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¡ 1st generation
Antipsychotic (a.k.a. Typical Antipsychotic)
¡ FDA Indication:
§ Psychosis § Schizophrenia
¡ Typical Dosing: 0.5-2 mg
two- three times daily
Mechanism of Action
Psychopharmacology Institute. (n.d.)
Psychopharmacology Institute. (n.d.)
D2 Activity High 5HT2 Activity Medium Muscarinic Activity Low Alpha-1 adrenergic Activity Low Antihistamine Activity Low
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Brief Psych Rating Scale Baseline 4 Hours 24 Hours Diazepam 28.5 11.4 6.3 Haloperidol 30.5 3.8 8
¡
Lerner et. al. (1978):
§
Randomized 40 patients to haloperidol or diazepam
§
Both received via IV route ¡ FDA Warning (2007):
§
Increased risk of QTc prolongation has been seen
§
Studies are showing lower dose, <2mg, no increased QTc
¡
Both equally effective antipsychotics
¡
Doses
§
Haloperidol = 15mg start. 10mg q 1hr. Total average ~ 20-35mg
§
Diazepam = 10-15 mg start. 5-10mg q1hr. Total ~30-40mg ¡
More withdrawal associated with haloperidol
Duprey M. S,Int Car Med. 2016 Lerner, Y. Am of Psy. 1979 Hatta, K. J Clin Psy. 2001
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¡ Compared haloperidol 5mg IV
§
Emergency Department, N= 64
▪ 31 haloperidol ▪ 33 metoclopramide
¡ All patients were pretreated
with diphenhydramine 25mg
¡ VAS measured 0, 20, 40, 60,
80 min
Gaffigan, M. E., J Emerg Med. 2015
¡ Dose: haloperidol lactate 2.5mg-10 mg IM
Ostinelli, E. G. et al. Cochrane Database Syst Rev. 2017
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¡ Usual Dose: 0.5mg - 2.5mg QD or BID ¡ Studied in: § Cancer § Palliative Care § Post-Operative Nausea and Vomiting
Response Complete Response Partial Response No Response Failure Patient-rated Day 2 (n = 33)
8 12 10 3
Patient-rated Day 5 (n = 23)
7 10 2 4
Observer-rated Day 2 (n = 29)
8 15 4 2
Observer-rated Day 5 (n = 19)
6 9 3 1
Adapted from Hardy, J. R., et al. J Pain Symptom Manage. 2010.
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Response Response (CR + PR) n/N(%) Response (All Patients) n/N(%)
Patient-rated Day 2 (n = 33)
20/33 (60) 20/42 (47)
Patient-rated Day 5 (n = 23)
17/23 (74) 17/42 (40)
Observer-rated Day 2 (n = 29)
23/29 (79) 23/42 (54)
Observer-rated Day 5 (n = 19)
15/19 (78) 15/42 (35)
Adapted from Hardy, J. R., et al. J Pain Symptom Manage. 2010.
TRANSLATES TO
Extrapyramidal Side Effects Very High Anticholinergic Effects Very Low Hypotensive Effects Very Low Sedating Effects Very Low D2 Activity High 5HT2 Activity Medium Muscarinic Activity Low Alpha-1 adrenergic Activity Low Antihistamine Activity Low
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RISK FACTORS CONSIDERATIONS
¡ Baseline ECG ¡ If giving IV haloperidol, monitor
ECG closely
¡ Discontinue multiple medications
with QTc prolongation
¡ QTc > 500ms à considered risk
for TdP
§
>450ms for males à considered prolonged
§
>470ms for females
Unmodifiable risk factors Potentially modifiable risk factors Female Gender Hypokalemia or severe hypomagnesaemia Increasing age Bradycardia Genetically long QT syndrome Family history of sudden death History of previous drug- induced QT prolongation > 1 QTc prolonging medication Meds that cause electrolyte abnormalities or may cause renal or hepatic dysfunction Structural heart disease/LV dysfunction Starvation or obesity Impaired elimination due to renal or hepatic disease High drug concentrations due to overdose or rapid IV administration
Siena Meador, PharmD PGY-1 Pharmacy Resident University of New Mexico Hospitals
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¡ Pharmacist: § Discuss the role of recently approved antimicrobial
therapies
¡ Technician: § Identify recently approved antimicrobial therapies
https://jamanetwork.com/journals/jama/article-abstract/2646700
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¡ Fluoroquinolone for
the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults ≥18 years old
Baxdela™ (delafloxacin) [package insert]. 2017.
K. pneumoniae
P.
aeruginosa
E. faecalis
Certain Staphylococcus spp. Certain Streptococcus spp.
¡ By mouth
§ 450 mg tablet every 12 hours § Not renally adjusted § Without regard to food
¡ Intravenous
eGFR Dose Interval ≥30 300 mg 12 hours 15-29 200 mg 12 hours <15 or dialysis Not recommended, consider switching to tablet
Baxdela™ (delafloxacin) [package insert]. 2017.
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¡ Black Box Warnings § Tendinitis/tendon rupture § Peripheral neuropathy § Central nervous system effects § Exacerbation of muscle
weakness in myasthenia gravis
¡ Contraindication § Hypersensitivity ¡ Warnings § C. difficile-associated diarrhea § Drug-resistant bacteria ¡ Adverse Reactions § Nausea (8%) § Diarrhea (8%) § Headache (3%) § Transaminase elevations (3%) § Vomiting (2%) ¡ Requires a medication guide
Baxdela™ (delafloxacin) [package insert]. 2017.
¡ Limited benefit over other fluoroquinolones but more
expensive
¡ Most skin and skin structure infections are caused by Gram
positive bacteria
¡ Gram negative coverage is not usually indicated
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http://www.vabomere.com
¡ Carbapenem + β-
Vabomere™ (meropenem and vaborbactam) [package insert] 2017.
K. pneumoniae Enterobacter cloacae spp
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¡ Intravenous ¡ Only compatible with normal saline ¡ All doses are administered over 3 hours
eGFR Dose Interval Minimum diluent ≥50 4 gm 8 hours 250 mL 30-49 2 gm 8 hours 125 mL 15-29 2 gm 12 hours 125 mL <15 or dialysis 1 gm 12 hours 70 mL
Vabomere™ (meropenem and vaborbactam) [package insert]. 2017.
¡ Contraindication
§ Hypersensitivity (1.8%)
¡ Warnings
§ Seizures § Other CNS experiences § Neuromotor impairment § Reduced valproic acid levels § Thrombocytopenia § C. difficile-associated diarrhea § Drug-resistant bacteria
¡ Adverse effects
§ Headache (8.8%) § Phlebitis/infusion reactions
(4.4%)
§ Diarrhea (3.3%) § Nausea (1.8%) § Transaminase elevations
(1.8%)
§ Pyrexia (1.5%) § Hypokalemia (1.1%)
Vabomere™ (meropenem and vaborbactam) [package insert]. 2017.
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¡ Carbapenem-resistant enterobacteriaceae (CRE) ¡ Does NOT have improved efficacy against multidrug resistant
Pseudomonas spp. or Acinetobacter spp.
¡ Limited by dosing and administration requirements
https://www.solosec.com
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¡ Nitroimidazole for
Solosec™ (secnidazole) [package insert]. 2017.
Bacteriodes spp. Gardnerella vaginalis Prevotella spp. Mobiluncus spp. Megasphaera- like type I/II
¡ Single dose of 2 grams (1 packet) ¡ Sprinkle over applesauce, yogurt, or pudding ¡ Consume within 30 minutes ¡ Do not chew or crunch the granules ¡ May be followed with a glass of water ¡ Do NOT dissolve in any liquid
Solosec™ (secnidazole) [package insert]. 2017.
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¡ Contraindication
§ Hypersensitivity
¡ Warnings
§ Vulvo-vaginal candidiasis
(9.6%)
§ Risk for carcinogenicity § Drug resistance
¡ Adverse effects
§ Headache (3.6%) § Nausea (3.6%) § Dysgeusia (3.4) § Vomiting (2.5%) § Diarrhea (2%) § Abdominal pain (2%) § Vulvovaginal pruritus (2%)
Solosec™ (secnidazole) [package insert]. 2017.
¡ Only single-dose treatment for bacterial vaginosis ¡ Beneficial for patients with adherence concerns ¡ May be useful in hospital-owned outpatient clinics
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https://www.shingrix.com/index.html
¡ For the prevention of herpes zoster in adults ≥50 years old ¡ Two vaccine series, 2 to 6 months apart ¡ 0.5 mL injected intramuscularly ¡ 2 vials per injection ¡ Keep refrigerated, do not freeze
Image from gsksource
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¡ Contraindication
§ Severe allergic reaction to
any component or after a previous dose
¡ Local reactions
§ Pain (78%) § Redness (38.1%) § Swelling (25.9%)
¡ General reactions
§ Myalgia (44.7%) § Fatigue (44.5%) § Headache (37.7%) § Shivering (26.8%) § Fever (20.5%) § GI symptoms (17.3%)
SHINGRIX™ (Zoster Vaccine Recombinant, Adjuvanted) [package insert]. 2017.
¡ Advisory Committee on Immunization Practices (ACIP):
§ Vaccinate all immunocompetent patients ≥50 years old § Recombinant herpes zoster is preferred over the live zoster vaccine § Adults previously vaccinated with the live zoster vaccine should be
revaccinated with Shingrix
Dooling KL, et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines.
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Ngoc-Yen Pham, PharmD. PGY-1 Pharmacy Resident University of New Mexico Hospitals
¡ Pharmacists: § Formulate an appropriate recommendation to manage patients
with Hepatitis B who require immunotherapy management with Rituxan
¡ Technicians: § Identify the therapies used to manage patients with Hepatitis B
who require immunotherapy management with Rituxan
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Non-Hodgkin Lymphoma Chronic Lymphocytic Leukemia ( CLL) Rheumatoid arthritis Vasculitis
Anti-CD20 directed
Infusion reaction Mucocutaneous Reactions Hepatitis B Reactivation Progressive Multifocal leukoencephalopathy
Rituxan (rituximab) [prescribing information].
§ IgM antibody to HBV core antigen § Indicates recent/acute HBV infection in ≤6 months § HBV surface antigen § Indicates a person is infectious
HBsAg
§ Antibody to HBV surface antigen § Indicates immunity
Anti-HBs
§ IgG antibody to HBV core antigen § Marker of past or current infection with HBV
IgM Anti-HBc
§ Total antibody to HBV core antigen § Indicates exposure to HBV § Correlates with the levels of HBV virus particles § Marker of HBV replication and infection § HBV e antigen § Marker of HBV replication and infection
HBeAg Anti-HBc IgG Anti-HBc HBV DNA
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¡ HBV-DNA level ¡ Anthracyclines/steroid use ¡ Transplantation ¡ Presence of lymphoma § Male gender § Lack of HBs antibody § HBsAg positive § Presence of precore mutant
Tsutsumi Y. World J Hepatol. 2013.
Prophylactic antiviral therapy Prophylactic antiviral therapy Or monitoring Monitoring High Moderate Low
Screen patients before immunosuppressive therapy HBsAg+ Anti-HBc + HBsAg- Anti-HBc + HBsAg- Anti-HBc- Check HBV DNA Assess Risk
Hwang J, Nat Rev Gastroenterol Hepatol. 2014. Perrillo R. Gastroenterology. 2015. Pattullo V. Clin Mol Hepatol. 2016.
vaccinations
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Risk Groups HBVr drug estimates
High-risk groups (>10%) B-cell depleting agents
Anthracycline derivatives
Corticosteroids therapy ≥ 4 weeks (prednisone 20mg) Medium risk group (1% - 10%) TNF –α inhibitors Cytokines and integrin inhibitors Tyrosine kinase inhibitors Low-risk groups (<1%) Azathioprine, 6-mercaptopurine Methotrexate Intra-articular corticosteroids
Perrillo R. Gastroenterology. 2015. Hwang J, Nat Rev Gastroenterol Hepatol. 2014. Pattullo V. Clin Mol Hepatol. 2016.
Resistance
Class Boxed warning: lactic acidosis and severe hepatomegaly with steatosis, acute exacerbation of HBV upon discontinuation
Lamivudine
Low barrier to resistance Mutation and resistance
Entecavir
Higher barrier
Renal dose adjustments
Tenofovir
Higher barrier
Renal dose adjustments nephrotoxicity
Han S. J Am Board Fam Med. 2015. Lampertico P. J Hepatol. 2017.
Concerns
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Reference) Antivirals vs controls (n) Antiviral timing Reactivation rates Lau et al.(2003) lamivudine vs pre-emptive treatment 1 week before chemotherapy or deferred until serological evidence
0% verus 53% (P = 0.002) Hsu et al.(2008) lamivudine vs pre-emptive treatment On day 1 of chemotherapy and until 2 months after or started on treatment if ALT levels >1.5xULN 11.5% versus 56% (P = 0.001) Huang et al.(2013) entecavir vs pre- emptive treatment Before chemotherapy to 3 months after or at the time of HBV reactivation At months 6, 12, and 18 0%, 0%, and 4.3% in the ETV prophylactic group versus 8%, 11.2%, and 25.9% (P = .019)
Lau G. Gastroenterology. 2003. Hsu C. Hepatology. 2008. Huang Y. J Clin Oncol. 2013.
Prophylaxis > pre-emptive therapy
Loomba R. Gastroenterology. 2017. Hwang J. J Oncol Pract. 2015. Pattullo V. Clin Mol Hepatol. 2016.
Guideline Duration Monitoring
AGA 2-4 weeks prior to initiation and 6-12 months after last dose LFTs and HBsAg levels: every 3 months until 6 months after last dose EASL Receiving Rituxan: at least 18 months after cessation of therapy Immunosuppressive therapy: at least 12 months During prophylaxis: LFTs and HBV DNA every 3 to 6 months After withdrawal: LFT and HBV DNA at least 12 months after ASCO Up to 12 months after cessation of therapy HBV DNA and ALT levels every 3 months during therapy
AGA: American Gastroenterological Association, EASL: European Association for the Study of the Liver is a European, ASCO: American Society of Clinical Oncology
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¡ Prophylaxis treatment with nucleotide analogs is
recommended in patients with moderate or high risk of HBVr
¡ Institution screening tools should include HBsAg, anti-HBc,
and HBV DNA to assess the risk of reactivation prior to the initiation of Rituxan