#fshp2018 disclosure cannabinoid hyperemesis · cannabinoid hyperemesis syndrome kellie wang,...

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Treating Smoke with Fire: Cannabinoid Hyperemesis

Syndrome


SyndromeKellie Wang, PharmD, BCPS

Emergency Medicine Clinical Pharmacist Sarasota Memorial Health Care System

August 4th, 2018

#FSHP2018DisclosureDisclosure

I have no financial interests or relationships to disclose.

#FSHP2018

ObjectivesObjectives1. Describe the diagnostic criteria and clinical presentation

of Cannabinoid Hyperemesis Syndrome (CHS)2. Identify potential treatment options for CHS3. Discuss the role of topical capsaicin in the management

of CHS

#FSHP2018

CannabisCannabisMost commonly used drug in the US and worldwide

• 8.3% of Americans occasional users in 2015

• Past-year cannabis use doubled over last decade

• 456,000 cannabis-related ED visits in 2011

#FSHP2018http://www.governing.com

Richards JR. J Emerg Med. 2018 Mar;54(3):354-363.

Cannabinoid Hyperemesis SyndromeCannabinoid Hyperemesis Syndrome

Diagnosis

Long-term cannabis use

Severe cyclic nausea and vomiting

Abdominal discomfort

Relieved by hot bathing or showering

#FSHP2018Allen J. Gut. 2004;53(11):1566-1570.Simonetto DA. Mayo Clin Proc. 2012 Feb; 87(2): 114–119.

Prodrome

HyperemesisRecovery

Treatment optionsTreatment options

#FSHP2018

https://www.curejoy.com/

Cessation of cannabis use

Dopamine antagonists

Serotonin antagonists

Antihistamines &

AnticholinergicsBenzodiazepines Opioids

Corticosteroids Capsaicin Hot showers

Richards JR. J Emerg Med. 2018 Mar;54(3):354-363.

Capsaicin

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Mechanism of CapsaicinMechanism of Capsaicin

#FSHP2018Moon AM et al. ACG Case Rep J. 2018 Jan 3;5:e3.

Capsaicin in CHSCapsaicin in CHS

#FSHP2018

Study Design Patients Intervention

Lapoint. (2014) Case series n=5 Topical capsaicin (0.075%)

Biary et al. (2014) Case report n=1 Topical capsaicin (0.025%)

Roman et al. (2016) Case report n=1 Topical capsaicin (0.075%)

Graham et al. (2017) Case series n=2 Topical capsaicin (0.025%)

Dezieck et al. (2017) Retrospective n=13 Topical capsaicin (0.025%, 0.075%, 1.5%)

Moon et al. (2018) Case report n=1 Topical capsaicin (0.075%)

Miller. (in progress) RCT n=20 Topical capsaicin (0.075%) vs. placebo

1. Lapoint J. Clin Toxicol. 2014; 52:707.2. Biary R. Clin Toxicol. 2014;52:787. 3. Roman F. Med Clin (Barc). 2016;147:517–518.4. Graham J. Pediatrics. 2017;140(6):e201637955. Dezieck L. Clin Toxicol (Phila). 2017;55(8):908-913.6. Moon AM. ACG Case Rep J 2018;5:e3.7. ClinicalTrials.gov [Internet]. NCT03223350. 2017 July 21.

Using Capsaicin for CHSUsing Capsaicin for CHS

#FSHP2018

• 0.025%, 0.075% or 1.5%

Formulation

• Apply topically to abdomen, arms or back

Administration

• Burning, itching• May rinse area with milk to alleviate irritation

Adverse effects

Rohrig B. Chem Matters. 2014.

https://www.mskcc.org

Take-home pointsTake-home points

#FSHP2018

Cannabinoid hyperemesis syndrome presents in chronic marijuana users as severe cyclic vomiting relieved with hot showers

Antiemetics are often ineffective

Topical capsaicin appears to be a safe and effective treatment option


Syndrome


SyndromeKellie Wang, PharmD, BCPS

Emergency Medicine Clinical Pharmacist Sarasota Memorial Health Care System

August 4th, 2018

#FSHP2018

Common Med Errors Among Hospitalized HIV PatientsCommon Med Errors Among Hospitalized HIV PatientsCarolina Gutierrez, Pharm.D.

Memorial Hospital Pembroke

Pembroke Pines, FL

#FSHP2018

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DisclosureDisclosure• Nothing to disclose

#FSHP2018

ObjectivesObjectives• Identify common medication errors among hospitalized HIV patients

• Discuss clinical scenarios of medication errors in hospitalized HIV patients

• Identify strategies to overcome med errors in hospitalized HIV patients

#FSHP2018

Medication ErrorMedication ErrorPreventable event that may cause or lead to inappropriate

medication use or patient harm

#FSHP2018http://www.nccmerp.org/about-medication-errors

Medication use process Medication use process

#FSHP2018

MonitoringAdministrationDispensingCompoundingTranscribingPrescribing

At what point during the medication use process, a medication error can occur?At what point during the medication use process, a medication error can occur?

#FSHP2018

Prescribing

Transcribing

Compounding

Monitoring

Dispensing

Administration

All of the above

The ReasonsThe Reasons

#FSHP2018

Complex Therapies

Comorbidities

Polypharmacy

Drug Interactions

Lack of Knowledge and Expertise

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Literature ReviewLiterature Review

#FSHP2018 #FSHP2018

Prospective study in a 750-bed tertiary-care teaching hospital in Barcelona, Spain

247 admissions (189 HIV patients on ART)

60 ART related errors were identified in 41 patients (21.7%)

HIV Medicine (2011), 12, 494–499. DOI: 10.1111/j.1468-1293.2011.00915.x

#FSHP2018

Incorrect dose17%Dose omission

15%

Dose adjustment12%

ART omission10%

ART addition8%

Incorrect schedule5%

Types of highly active antiretroviral therapy (HAART)-related error n=60

HIV Medicine (2011), 12, 494–499. DOI: 10.1111/j.1468-1293.2011.00915.x

Contraindication33 %

#FSHP2018

One year retrospective study at University of Nebraska Medical Center

177 HIV patients on ART (416 hospital admissions)

289 medication errors were identified in a total of 146/416 hospital admissions

The most common error was drug omission (69%)

J Antimicrob Chemother. 2014 Jan;69(1):262-7. doi: 10.1093/jac/dkt323. Epub 2013 Aug 16

#FSHP2018

69%

13%8% 7%

2% 1%0

10

20

30

40

50

60

70

80

90

100

Omission Incorrect scheduling Overdose Underdose Incorrect therapy Duplicate therapy

ART Errors by categoryn= 289

J Antimicrob Chemother. 2014 Jan;69(1):262-7. doi: 10.1093/jac/dkt323. Epub 2013 Aug 16

#FSHP2018

Retrospective, comparative cohort study, academic medical center in Texas

To assess the impact of an Antimicrobial Stewardship strategyPharmacist-led ARV checklist at order verification

234 admissions included in the study126 Before intervention108 Post-intervention

Am J Health Syst Pharm. 2018 May 2. pii: ajhp170420. doi: 10.2146/ajhp170420

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#FSHP2018Am J Health Syst Pharm. 2018 May 2. pii: ajhp170420. doi: 10.2146/ajhp170420

Common ART Med ErrorsCommon ART Med Errors• Omission or incomplete regimens

• Drug interactions

• Incorrect dosing

• Incorrect scheduling

#FSHP2018

ART medication errors are common and can lead to drug resistance and treatment failureART medication errors are common and can lead to drug resistance and treatment failure

#FSHP2018

True

False

#FSHP2018

Antiretroviral Therapy

https://aidsinfo.nih.gov/guidelines on 5/24/2018

Protease Inhibitors INSTI’s NNRTI’s NRTI’s CCR5 Antagonist

Atazanavir (ATV) Raltegravir (RAL) Efavirenz (EFV) Emtricitabine (FTC) Maraviroc (MVC)

Darunavir (DRV) Elvitegravir (EVG) Rilpivirine (RPV) Lamivudine (3TC)

Ritonavir (RTV) Dolutegravir (DTG) Nevirapine (NVP) Abacavir (ABC)

Fosamprenavir (FPV) Etravirine (ETR) Tenofovir Fumarate (TDF)

Tipranavir (TPV) Tenofovir Alafenamide(TAF)

Lopinavir (LPV) Zidovudine (ZDV)

Nelfinavir (NFV)

#FSHP2018

ART Common Drug InteractionsARV Antacids Statins Anticoagulants

ProteaseInhibitors

↓ ATV↓ TPV

2 hr before or 1hr after↑ Lovastatin↑ Simvastatin

↑ DOAC’sNot recommended*

Use warfarin

INSTI’s↓ DTG↓ EVG

2 hr before or 6 hr after↓ RAL

Do not coadminister

↑ Lovastatin↑ Simvastatin

DOAC’s not recommended with EVG/c*DOAC’s ok with DTG or RAL

Use Warfarin

NNRTI’s↓ RPV

2 hr before or 4 hr after

Adjust statin dose according to lipid responses

Pitavastatin and Rosuvastatinno adjustment needed

↓ Apixaban and Rivaroxaban*Consider alternative

Dabigatran no adjustment needed(unless given with ETR)*

Use Warfarin

https://aidsinfo.nih.gov/guidelines on 5/24/2018

*PI: Apixaban can be given at 50% of the dose if warfarin cannot be used, and dabigatran may be considered if on ritonavir-boosted PI*INSTI: Apixaban can be given at 50% of the dose*NNRTI: RPV does not affect rivaroxaban neither apixaban. ETR increases Dabigatran concentration

Clinical ScenariosClinical Scenarios

#FSHP2018

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Strategies for ImprovementStrategies for Improvement

#FSHP2018

Role of the PharmacistRole of the Pharmacist• Educate staff• Educate patients (counseling)• Medication Reconciliation• Attempts should be made to confirm regimen with

provider and outpatient pharmacy• Formulary interventions (periodic evaluations)• Use the resources

#FSHP2018

Resources AvailableResources Available

• HIV Guidelines http://www.aidsinfo.nih.gov

• American Academy of HIV Medicine (AAHIVM)Credential http://www.aahivm.org

• University of Liverpool http://www.hiv-druginteractions.org

• AIDS Education and Training Centers www.aids-ed.org

#FSHP2018

Thank youThank you

#FSHP2018

Implementation of the Kaiser Sepsis Calculator to Decrease Use of Antibiotics in Newborns


Sindhuri Avula, PharmD

Arnold Palmer Medical Center

#FSHP2018ObjectivesObjectives

• Identify risk factors for development of early onset sepsis (EOS) in the neonate

• Review current CDC and AAP guidelines for the prevention and treatment of neonatal EOS

• Evaluate literature for use of the Kaiser Sepsis Calculator in the management of neonatal EOS

#FSHP2018

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Neonatal Early Onset Sepsis

• Onset of sepsis ≤ 72 hours of life (premature infants) or < 7 days in term infants

• Estimated incidence of 0.5 per 1,000 live births• Incidence and mortality increases with decreasing gestational age and birth

weight

• Most commonly caused by Group B Streptococcus (GBS) or Escherichia coli

#FSHP2018Simonsen et at. Clin Microbiol Rec. Jan 2014

Risk Factors

#FSHP2018

• Chorioamnionitis • Prolonged rupture of membranes

• ≥ 18 hours• Elevated intrapartum temperature

• ≥38ºC (100.4ºF)• Intrapartum antibiotics• Maternal GBS status• Gestational age

• <37 weeks • Birthweight

Polin et al. Pediatrics. 2012Puopolo et al. Pediatrics. 2011;128:e1155

CDC Guidelines, 2010

• Empiric treatment• All infants with signs and

symptoms of sepsis• All infants born to a mother

with chorioamnionitis

#FSHP2018Verani et al. MMWR 59. 2010.

AAP Guidelines, 2012

#FSHP2018

Signs of sepsisChorioamnionitis

Blood culture at birthWBC/Diff ±CRP at age

6-12 hours

Empiric broad spectrum antibiotics

Polin et al. MMWR 59. 2010.

Challenges

• Nonspecific signs and symptoms

• Low specificity of diagnostics

• Clinical diagnosis of chorioamnionitis

• Infant’s individual risk of sepsis

• Who receives antibiotics

#FSHP2018

Kaiser Sepsis Calculator

#FSHP2018https://neonatalsepsiscalculator.kaiserpermanente.org/InfectionProbabilityCalculator.aspx

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#FSHP2018

Incidence of Early-Onset Sepsis Options:• 0.3/1000 live births (KPNC incidence)• 0.4/1000 live births• 0.5/1000 live births (CDC national incidence)• 0.6/1000 live births

#FSHP2018

Kaiser Sepsis Calculator Utilization

Kerste et al

Kuzniewicz et al

Warren et al

Beavers et al

#FSHP2018

2016

2017

2017

2018


#FSHP2018

Study Objective Patient Population Results

Kerste et al., 2015

Application of sepsis calculator in newborns with suspected infection

Compare current management of antibiotic use with use after implementation of the Kaiser Sepsis Calculator in newborns ≥ 34 weeks gestation with suspected EOS

108 newborns ≥ 34 weeks treated with antibiotics within 72 hours of life

57 newborns (53%) – calculator advised to not start antibiotics

2 positive blood culture- GBS and Enterococcus faecilis

Kuzniewicz et al., 2017

A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis

Examine the effects of neonatal EOS risk prediction model on sepsis evaluations and antibiotic use and assess their safety in a large integrated health care system

204,485 infants born at ≥ 35 weeks gestation

95,343 baseline group56,261 EOS calculator group

Blood culture use decrease from 14.5% to 4.9%

Empiric antibiotic use in the first 24 hours decreased from 5.0% to 2.6%

Incidence of culture confirmed EOS and readmission rates were similar


#FSHP2018

Study Objective Patient Population Results

Warren et al., 2017

Impact of neonatal early-onset sepsis calculator on antibiotic use within two tertiary healthcare centers

Impact of applying the calculator to infants treated with EOS

205 infants ≥ 34 weeks gestation

Empiric antibiotics -CDC: 188 (92%)- Calculator: 47 (23%)

No cases of culture proven sepsis

Beavers et al., 2018

Implementation and Evaluation of the Early-Onset Sepsis Risk Calculator in a High-Risk University Nursery

Compare before and after outcomes of EOS implementation in level III NICU

Before implementation: 180 neonates

After implementation: 76 neonates

Following implementation- NICU admission rates: ↓54%- # of blood cultures: ↓42%- Antibiotic use: ↓59%

No positive blood cultures

Clinical ApplicationClinical Application

Bboy Smith born at 37 weeks gestation apneic with poor perfusion

• Mother diagnosed with chorioamnionitis

• Started on empiric antibiotics for 48 hours

• Maternal temperature 101.2oF

• ROM x 12 hours

• Maternal GBS status: unknown

• Intrapartum antibiotics: Ampicillin + Gentamicin >4 hours

• Clinical Exam: Well appearing

#FSHP2018ROM: Rupture of membranes

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#FSHP2018

AdvantagesAdvantages

• Evaluates objective data

• Decrease practice variability

• Promote antimicrobial stewardship

• Improve maternal-infant bonding

• Decrease distress from procedures

• Decrease cost of hospital stay

#FSHP2018

DisadvantagesDisadvantages

• Limited prospective studies

• Elevated local sepsis incidence rate

• Infants with low risk for sepsis developing EOS

• Delayed antibiotic therapy

• Not applicable to infants <34 weeks gestation

#FSHP2018

Implementation at APMCImplementation at APMC

• Infants ≥ 34 weeks gestation

• Mothers with chorioamnionitis

• Incidence of sepsis• 0.5/1000 live births (CDC national incidence)

• Nursery or Neonatal ICU

#FSHP2018



Sindhuri Avula, PharmD

Arnold Palmer Medical Center

#FSHP2018

Therapeutic Drug Monitoring for Biologics in Inflammatory Bowel Disease

Therapeutic Drug Monitoring for Biologics in Inflammatory Bowel Disease Lanh Dang, PharmDClinical Ambulatory Pharmacist - UF Health Jacksonville August 4, [email protected]

#FSHP2018

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DisclosuresDisclosuresI have no actual or potential conflict of interest in relation to

this presentation

#FSHP2018

ObjectivesObjectives• Describe the role of biologic therapy with inflammatory

bowel disease (IBD) • Demonstrate understanding of suggested trough

concentrations for patients on maintenance therapy with tumor necrosis factor (TNF) inhibitors

#FSHP2018

Inflammatory Bowel Disease Inflammatory Bowel Disease

#FSHP2018

Definition•Chronic, uncontrolled inflammation of

intestinal mucosa, that can affect any part of GI tract

Epidemiology•~1.4 million Americans suffer from

Crohn’s Disease (CD) or Ulcerative Colitis (UC) •CD occurs in 201 per 100,000 adults•UC occurs in 238 per 100,000 adults

(from 2007)

GeneticsEnvironmental• Occupation• Hygiene

hypothesis

Ethnicity/Age Diet

SmokingMedication•Antibiotics •NSAIDs

Risk Factors

Inflamm Bowel Dis. 2006;12 Suppl 1:S3-9., “About the Epidemiology of IBD.” Crohn's & Colitis Foundation, “Epidemiology of the IBD.” Centers for Disease Control and Prevention, Clin Epidemiol. 2013;5:237-47

Crohn’s Disease Crohn’s Disease

#FSHP2018

•Distal ileum and colonLocation

•Discontinuous, patchy inflammation with skip lesions

Pathology

•Transmural Histology

Neurath MF. Nat Rev Immunol. 2014;14(5):329-42., Terdiman JP et al. Gastroenterology. 2013;145(6):1459-63.

Ulcerative Colitis Ulcerative Colitis

#FSHP2018Neurath MF. Nat Rev Immunol. 2014;14(5):329-42., Dassopoulos T et al. Gastroenterology. 2015;149(1):238-45.

•Colon only Location

•Continuous inflammation from rectum to proximal parts of colon

Pathology

•Superficial (mucosa and submucosa) Histology

TNF-alpha Inhibitors TNF-alpha Inhibitors

#FSHP2018

Produce TNF

Activation, pro-inflammatory

cytokine production

Cell death and impaired barrier

function

Tissue destruction

TNF-alpha inhibitor

CD FDA Approval

UC FDA Approval

Adalimumab ✓ ✓

Infliximab ✓ ✓

Certolizumab ✓

Golimumab ✓Neurath MF. Nat Rev Immunol. 2014;14(5):329-42.

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AGA Recommendations on Therapeutic Monitoring in IBD AGA Recommendations on Therapeutic Monitoring in IBD

#FSHP2018

Reactive therapeutic monitoring in patients with active IBD on maintenance therapy with TNF inhibitors

Thiopurine methyltransferase (TPMT) testing to guide thiopurine dosing

• Dosing dependent on enzymatic/genotype activity

Reactive thiopurine metabolite monitoring for effectiveness and toxicity

• Measuring 6-thioguanine metabolites Feuerstein JD et al. Gastroenterology. 2017;153(3):827-834

Therapeutic Monitoring of TNF inhibitors Therapeutic Monitoring of TNF inhibitors

#FSHP2018

In adults with active IBD treated with anti-TNF agents, the AGA suggests reactive therapeutic drug monitoring to guide treatment changes

(conditional recommendation, very low quality of evidence)

Drug

Suggested trough concentration Comments

Infliximab ≥ 5 µg/mL Six studies - Proportion of patients not in remission:

Adalimumab ≥ 7.5 µg/mL Four studies - Proportion of patients not in remission:

Studies didn’t differentiate adalimumab dosing (q2w vs. q1w)

Certolizumab pegol ≥ 20 µg/mL Pooled analysis of 9 studies - Proportion of patients not in remission:

Golimumab Unknown Insufficient data

≥ 1 µg/mL = 25% ≥ 3 µg/mL = 15% ≥ 7 µg/mL = 4%

≥ 5 ± 1 µg/mL = 17% ≥ 7.5 ± 1 µg/mL = 10%

≥ 10 µg/mL = 42% ≥ 20 µg/mL = 26%

Feuerstein JD et al. Gastroenterology. 2017;153(3):827-834

Optimizing Anti-TNF-α Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases

Optimizing Anti-TNF-α Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases

#FSHP2018

Design Results

• Retrospective cohort study (n=135)

• Infliximab (n = 78) or adalimumab (n = 67)

• Inclusion: colonoscopy while treated with infliximab or adalimumab and had available serum levels

• Study goal: correlation between anti-TNF drug levels and mucosal healing (MH)

Baseline characteristics: majority CD, median disease duration: 10 yrs• Higher infliximab drug levels correlated with MH (4.3 vs 1.7, p=0.0002)• Higher adalimumab drug levels correlated with MH (6.2 vs 3.1, p=0.01)

Ungar B et al. Clin Gastroenterol Hepatol. 2016;14(4):550-557.e2.

Limitations of AGA RecommendationsLimitations of AGA Recommendations

#FSHP2018

CD versus UC trough levels

Did not address vedolizumab or ustekinumab

Reactive instead of proactive approach

Optimal timing for measuring trough concentrations and how often to repeat testing

Trough levels for MH may not equal levels required for clinical response


Clinical Application Clinical Application

• Reactive testing in patients with active disease• Assess symptoms and

endoscopic results

• Use the same assay for testing

#FSHP2018

Low trough level, low antibody

shortening dosing interval and/or increasing drug

dose and/or adding immunomodulator

High trough level, low antibody

switch within drug class or switch to another drug

class

Low trough level, high antibody

switch within drug class or switch to another drug

class


Summary Summary

#FSHP2018

TNF inhibitors used in moderate-severe CD and UC

Recommended trough levels to maintain remission with infliximab ≥ 5 µg/mL, adalimumab ≥ 7.5 µg/mL, and certolizumab ≥ 20 µg/mL

Treat the patient, not the numbers

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#FSHP2018

Lanh Dang, PharmDClinical Ambulatory Pharmacist - UF Health Jacksonville August 4, [email protected]

References

• “About the Epidemiology of IBD.” Crohn's & Colitis Foundation, 1 June 2012, www.crohnscolitisfoundation.org/resources/epidemiology.html.

• Dassopoulos T, Cohen RD, Scherl EJ, Schwartz RM, Kosinski L, Regueiro MD. Ulcerative Colitis Care Pathway. Gastroenterology. 2015;149(1):238-45.

• “Epidemiology of the IBD.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 31 Mar. 2015, www.cdc.gov/ibd/ibd-epidemiology.htm.

• Feuerstein JD, Nguyen GC, Kupfer SS, Falck-ytter Y, Singh S. American Gastroenterological Association Institute Guideline on Therapeutic Drug Monitoring in Inflammatory Bowel Disease. Gastroenterology. 2017;153(3):827-834.

• Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis. 2006;12Suppl 1:S3-9.

• Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329-42.• Ponder A, Long MD. A clinical review of recent findings in the epidemiology of inflammatory bowel disease. Clin Epidemiol.

2013;5:237-47.• Terdiman JP, Gruss CB, Heidelbaugh JJ, Sultan S, Falck-ytter YT. American Gastroenterological Association Institute guideline on the

use of thiopurines, methotrexate, and anti-TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology. 2013;145(6):1459-63.

• Ungar B, Levy I, Yavne Y, et al. Optimizing Anti-TNF-α Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2016;14(4):550-557.e2.

ACEI-Induced AngioedemaACEI-Induced Angioedema

#FSHP2018

Gabriella Sarver, PharmD

DisclosuresDisclosures

I do not have (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation.

#FSHP2018

ObjectivesObjectives

1. Discuss the pathophysiology of angiotensin converting enzyme inhibitor (ACEI)‐induced angioedema

2. Develop a pharmacologic plan for the management of ACEI‐induced angioedema

3. Evaluate the literature supporting the use of icatibant for ACEI‐induced angioedema

#FSHP2018

Angioedema• Characterized by local deep dermal, subcutaneous, and/or mucosal edema

resulting from:• Increased vasodilation• Increased vascular permeability

• Can be hereditary or drug-induced

• Drug induced can be further classified as either allergic or nonallergic• Allergic = IgE mediated• Nonallergic = consequence of underlying drug mechanism

#FSHP2018

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ACEI-Induced Angioedema

• Typically involves the lips, tongue, or face• May also involve the pharynx, larynx, and subglottic area• Rarely may involve the bowel

• May remit spontaneously, however may reoccur with repeated exposure

• Potential risk for intubation

• Risk is greatest during the first month of exposure to ACEIs

#FSHP2018

Pathophysiology

#FSHP2018

Diagnosis

• Diagnosis of ACEI-induced angioedema is made clinically• Presence of angioedema• Without itching or urticaria• Affecting characteristic anatomic site• Patient is on ACEI

• There are no definitive lab tests to diagnosis ACEI-induced angioedema• Serum complement protein 4 (C4)

• Diagnosis is generally confirmed when discontinuation of ACEI leads to resolution of symptoms

#FSHP2018

Initial Management

• Primary treatment of ACEI-induced angioedema includes:• Acute airway management

• Assessment of airway, manage as appropriate• May require intubation and ventilation

• Discontinuation of ACEI• Angioedema caused by ACEI generally resolves in 24 – 72 hours• If ACEI are continued, patients would be at an increased risk of recurrence

that may become more severe• Patients should not receive another agent in this class

#FSHP2018

Traditional Therapies

• May be given in the acute setting for isolated angioedema that appears to be allergic but not part of a larger anaphylactic reaction

• H1 Receptor antagonists (1st or 2nd gen)• Standard doses

• H2 Receptor antagonists• Standard doses

• Corticosteroids• Prednisone 20 – 40 mg PO• Methylprednisolone 60 – 80 mg IV

#FSHP2018

Firazyr (icatibant)

• FDA approved indication: hereditary angioedema (HAE)

• ACEI-induced angioedema is considered an off-label use

• Dose: 30 mg subcutaneously• May be repeated in 6 hours if angioedema continues or worsens

• Most benefit seen if given within a few hours of symptom onset

• ADRs: injection site reaction (97%), increased serum transaminases (4%), fever (4%), dizziness (3%)

#FSHP2018

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What does the data say?

#FSHP2018

Trial Design Study Population Intervention Endpoints Results/Conclusion

Baş,et al

Multicenter, double-blind,

double-dummy, randomized Phase

2 trial

n = 30Average pt:

male in 60s on enalapril or

ramipril

Icatibant or standard

therapy (IV prednisone + clemastine)

1˚: complete resolution of edema2˚: use of rescue therapy; complete

resolution @ 4hr; time of onset of symptom relief; Δ in composite scores

pre/post tx

Complete resolution of edema achieved sig. more quickly in the icatibant group

Sinert, et al

Multicenter, international, randomized, double-blind, Phase III trial

n = 118Average pt: AA male <65 y/o on lisinopril >90 days

w/ moderate angioedema

Icatibant or placebo

1˚: time to meeting discharge criteria2˚: time to onset of symptom relief,

occurrence of airway intervention, hospital admission, use of alternative therapies;

achievement of 1˚ outcome at 4, 6, and 8 hr after tx

Icatibant was no more effective than placebo in treating a least moderately severe ACI-induced

angioedema

Straka, et al

Multicenter, double-blind, randomized,

placebo-controlled trial

n = 31;Average pt: AA female <65 y/o w/ ACEI use >1

year

Icatibant or placebo

PLUS standard of

care

1˚: time of symptom resolution2˚: frequency of concomitant medications, incidence of ICU admission, ADRs, effect of

tx on BP

Icatibant was no more effective than placebo in treated

ACEI-induced angioedema

Other therapies

• Ecallentide – inhibits the conversion of high molecular weight kininogen to bradykinin by inhibiting plasma kallikrein

• Evidence for use is mixed; ACEI-induced angioedema is due to lack of metabolism vs overproduction

• C1 inhibitor concentrate – inhibits kallikrein; shown some benefit in case reports

• Fresh frozen plasma – contains the enzyme ACE, thought to degrade high levels of bradykinin

#FSHP2018

Key Points

#1: Remember to discontinue ACEI and add to patient allergies

#2: Icatibant can be considered for patients with ACEI-induced angioedema who do not respond to traditional therapy

#3: Icatibant dosing may be repeated in 6 hours if no response to initial dose

#FSHP2018

References

1. Stone C, Brown NJ. Angiotensin-converting enzyme inhibitor and other drug-associated angioedema. Immunology and Allergy Clinics of North America. 2017;37(3):483-495

2. Baş M, Greve J, Stelter K, et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015;372(5):418-425.[PubMed 25629740]

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ACEI-Induced AngioedemaACEI-Induced Angioedema

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