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Know the New: 2018 Novel Drug Approvals

Kimmy Nguyen, PharmD, BCACP Assistant Professor Wilkes University, Nesbitt School of Pharmacy January 26, 2018

novel drug

approvals in

2018

Fill in the Blank

59

lutetium Lu 177 dotatate

bictegravir, embitcitabine,

tenofovir alafenamide

tezacaftor; ivacaftor

apalutamide

ibalizumab-uiyk

tildrakizumab

fostamatinib

burosumab-twza

fosnetupitant and palonosetron

migalastat

erenumab-aooe

sodium zirconium cyclosilicate

avatrombopag

pegvaliase-pqpz

baricitinib

moxidectin

stiripentol

plazomicin

binimetinib

encorafenib

tecovirimat

ivosidenib

tafenoquine

elagolix sodium

fish oil triglycerides

lusutrombopag

mogamulizumab-kpkc

patisiran

segesterone acetate and ethinyl

estradiol vaginal system

cenegermin-bkbj

lanadelumab

eravacycline

doravirine

moxetumomab pasudotox-tdfk

fremanezumab-vfrm

duvelisib

galcanezumab-gnlm

dacomitinib

cemiplimab-rwlc

sarecycline

omadacycline

elapegademase-lvlr

inotersen

talazoparib

baloxavir marboxil

lorlatinib

revefenacin

rifamycin

emapalumab-lzsg

glasdegib

larotrectinib

amifampridine

gilteritinib

prucalopride

calaspargase pegol-mknl

tagraxofusp-erzs

ravulizumab

andexanet alfa

lofexidine

cannabidiol

Novel Drug Approvals. FDA. 2018

Objectives 1. List the FDA approved indications and recommended dosing for

andexanet alfa, lofexidine, and cannabidiol.

2. Describe the mechanisms of action and common adverse effects

for each of the three newly approved drugs.

3. Discuss the evidence supporting each drug’s approval and its

potential role in therapy.

Pre-Test Andexanet alfa is indicated for the reversal of anticoagulation

due to life-threatening or uncontrolled bleeding for patients

treated with which of the following anticoagulants?

A. Apixaban

B. Rivaroxaban

C. Edoxaban

D. A and B

E. All of the above

Pre-Test Lofexidine is approved for which of the following indications?

A. Opioid use disorder

B. Mitigation of opioid withdrawal symptoms

C. Insomnia

D. Seizure

Pre-Test Cannabidiol has been approved for both the treatment of rare,

severe forms of seizures and post-traumatic stress disorder.

A. True

B. False

Pre-Test Lofexidine is associated with which of the following

side effects?

A. Infusion-related reactions

B. Blurry vision, tachycardia, hypertension

C. Dizziness, bradycardia, hypotension

D. Decreased appetite, elevated transaminases

Pre-Test Which of the following agents require gradual dose reduction

upon discontinuation?

A. Andexanet alfa

B. Lofexidine

C. Cannabidiol

D. B and C

E. All of the above

Pre-Test Which of the following agents require both renal and hepatic

dose adjustment?

A. Andexanet alfa

B. Lofexidine

C. Cannabidiol

D. All of the above

Andexanet alfa (Andexxa®)

Background

Direct Oral Anticoagulants (DOACs)

Advantage Clinical Relevance

Rapid onset of action No bridging

Predictable anticoagulant effect No routine monitoring

Specific coagulation enzyme target Low risk for off-target adverse effects

Low risk for food-drug interactions No dietary precautions; few interactions

Antidote

Eikelbloom JW, Weitz JI. Circulation. 2010.

Dabigatran

2010

Rivaroxaban

2011

Apixaban

2012

Edoxaban

Idarucizumab

2015

Betrixaban

2017

Andexanet alfa

2018

Warfarin

Rivaroxaban

Apixaban

Edoxaban

Betrixaban

Dabigatran

Unger EF. FDA. 2015.

Drug Approval Packages. FDA. 2018.

Katzung BG, Kruidering-Hall M, Trevor AJ. Chapter 34: Drugs used in coagulation disorders. Katzung & Trevor's Pharmacology: Examination & Board Review, 12e. 1998.

(approved in 1954)

Idarucizumab

Indication ● Reversal of anticoagulation due to life-threatening or

uncontrolled bleeding in patients treated with rivaroxaban or

apixaban

● Approved via the FDA Accelerated Approval pathway

○ U.S. Orphan Drug

○ FDA Breakthrough Therapy

Andexxa. Portola Pharmaceuticals, Inc. 2018. FDA Food and Drug Administration

Platelet Surface

Factor

Va

Factor

Xa

Prothrombinase

Complex

Prothrombin

Thrombin

Normal Physiology

Andexxa. Portola Pharmaceuticals, Inc. 2018.

Platelet Surface

Factor

Va

Factor

Xa

Prothrombinase

Complex

Prothrombin

Factor Xa Inhibitor


apixaban or rivaroxaban

Andexanet Alfa Mechanism of Action

Platelet Surface

Factor

Va

Factor

Xa

Prothrombinase

Complex

Prothrombin

Thrombin

Andexanet


apixaban or rivaroxaban

Andexanet also inhibits TFPI activity Increased tissue-factor-initiated thrombin generation

TFPI Tissue Factor Pathway Inhibitor

Platelet Surface

Factor

Va

Factor

Xa

Prothrombinase

Complex

Prothrombin

Return of Anticoagulant Activity apixaban or rivaroxaban


Connolly SJ, et al. N Engl J Med. 2016.

Andexanet

Andexanet

Andexanet

Half-life: ~1 hour

Anti-FXa activity increases to levels similar to placebo after ~2

hours post-infusion.

Elevated tissue factor-initiated thrombin generation is

sustained for ~22 hrs.

Seigel DM, et al. N Engl J Med. 2015

Dosing

Initial IV Bolus Follow-on IV Infusion


400 mg at a

target rate of

30 mg/min

800 mg at a

target rate of

30 mg/min

4 mg/min for

up to 120

minutes

8 mg/min for

up to 120

minutes


Standard Dose High Dose

STANDARD DOSE

HIGH DOSE

Safety and efficacy of >1 dose

has not been evaluated.

IV Intravenous

Dosing Costs



400 mg

800 mg

4 mg/min for up

to 120 minutes

= 480 mg

8 mg/min for up

to 120 minutes

= 960 mg

STANDARD DOSE

HIGH DOSE

= 880 mg

= 1760 mg

AWP $3300 per 100 mg vial

Low Dose = $29,700 for 9 vials

High Dose = $59,400 for 18 vials

AWP Average wholesale price


Andexxa. Red Book. Micromedex. 2018.

Warnings and Precautions

● Andexanet alfa has been associated with:

○ Arterial and venous thromboembolic events

○ Ischemic events, including MI and ischemic stroke

○ Cardiac arrests

○ Sudden deaths

● Monitor for thromboembolic events and initiate

anticoagulation when medically appropriate

MI Myocardial infarction Andexxa. Portola Pharmaceuticals, Inc. 2018.

Black Box Warning

● Contraindications: None

● Drug interactions: No known interactions

● Dose adjustments: None

● Adverse Reactions:

○ Pneumonia (≥5%)

○ Urinary tract infections (≥5%)

○ Infusion-related reactions (≥3%)


Adverse Reactions

● Multicenter, prospective, open-label, single-arm trial to evaluate

safety and efficacy of andexanet in acute major bleeding

● Population ○ Mean age 77 years, 51% male, 77% Caucasian

○ Site of bleed: GI 49%, Intracerebral 42%, Other 9%

○ Patients on apixaban (20), rivaroxaban (26), enoxaparin (1), or edoxaban

● Primary Outcomes (N=47) ○ Rate of excellent or good hemostasis 12 hrs after andexanet infusion

○ Percent change in anti-FXa activity

ANNEXA-4 – Interim Analysis

Connolly SJ, et al. N Engl J Med. 2016. GI Gastrointestinal

● Intervention ○ Apixaban* or rivaroxaban >7 hrs: Standard dose

○ Enoxaparin, edoxaban, or rivaroxaban ≤7 hours or unknown: High dose

● Primary Outcomes (N=47) ○ Rate of excellent or good hemostasis 12 hrs after andexanet infusion

• 37/47 patients (79%; 95% CI, 64-89)

ANNEXA-4

Connolly SJ, et al. N Engl J Med. 2016. *All patients receiving apixaban

● Primary Outcomes (N=47) ○ Percent change in anti-FXa activity (post-bolus)

• Rivaroxaban: 227 ng/mL 16.8 ng/mL = 89% decrease (95% CI, 58-94)

• Apixaban: 149.7 ng/mL 10.3 ng/mL = 93% decrease (95% CI, 87-94)

ANNEXA-4


● Safety Outcomes (N=67) ○ Thrombotic events in 12 patients during 30-day follow-up (18%)

• 1 MI

• 5 Strokes

• 7 DVTs

• 1 PE

○ Therapeutic anticoagulation restarted before event in one patient • Anticoagulation resumed in 18 patients within 30 days (27%)

○ 10 deaths (15%) [6 CV-related and 4 non-CV-related]

ANNEXA-4


Anexxa-4. U.S. NLM. 2018.

Estimated primary completion date:

November 2022

PE Pulmonary embolism

CV Cardiovascular

MI Myocardial infarction

DVT Deep vein thrombosis

Primary Outcome Clinical hemostasis was assessed by the International Society of Thrombosis and

Hemostasis Scientific and Standardization Subcommittee criteria

What about PCC?

Sheikh-Taha M. Intern Emerg Med. 2018.

Majeed A, et al. Blood. 2017.

● A prospective cohort study

● Population (N=84) ○ Mean age 75 years, 57.1% male,

○ Site of bleed: GI 15.5%, ICH 70.2%, Other 14.3%

○ Apixaban (39) and rivaroxaban (45)

○ Median PCC dose of 2000 IU

● A retrospective chart review

● Population (N=29) ○ Mean age 74 years, 44.8% male,

○ Site of bleed: GI 13.8%, ICH 72.4%, Other 13.8%

○ Apixaban (13) and Rivaroxaban (16)

○ Received single dose of PCC 50 units/kg

PCC Prothrombin complex concentrate

● Primary Outcome ○ Clinical hemostasis in 21 patients (72.4%)

● Safety Outcome ○ One patient (3.4%) had a thromboembolic event

○ Six deaths (20.7%) within 14 days post-PCC dose

● Limitations ○ Did not include 30-day follow-up

○ Did not measure anti-FXa levels

What about PCC? ● Primary Outcome

○ Clinical hemostasis in 58 patients (69.1%)

● Safety Outcome ○ Two patients (2.4%) had a thromboembolic event

○ 27 deaths (32%) within 30 days of major bleed • 1 case possibly related to PCC administration

● Limitations ○ Observational design

○ Did not measure anti-Fxa levels

Sheikh-Taha M. Intern Emerg Med. 2018.

Majeed A, et al. Blood. 2017.

Similar rates of hemostasis, but fewer

observed thromboembolic events with PCC

PCC Prothrombin complex concentrate

● 2018 CHEST guidelines

○ Specific reversal agent preferred (if available) over PCC in

serious bleeding

● Non-specific agents

○ Less effective

○ Lack evidence to support improved outcomes

○ Potentially pro-thrombotic

Lip GYH, et al. CHEST guidelines. 2018. PCC Prothrombin complex concentrate

Place in Therapy

Key Points / Counseling ● Andexanet alfa is a factor Xa reversal agent

○ ANNEXA-4 studying effect on edoxaban and enoxaparin

● Risk of thrombotic events requires careful monitoring for safe

anticoagulation re-initiation

● Limited availability in June 2018 (Early Supply Program) ○ Approved in January 2019 for Generation 2 manufacturing

• Full commercial launch and greater availability


Prior Approval Supplement. News Release. 2019.

Lofexidine (Lucemyra®)

Background ● 70,237 drug overdose deaths in the U.S. in 2017

○ 47,600 overdose deaths involved opioids (67.8%)

○ Synthetic opioid-involved overdose death rates increased by

45.2% from 2016-2017

Drug overdose deaths. CDC. 2018.

Scholl L, et al. MMWR. 2018

1 WV 17.2 per 100,000

2 MD 11.5 per 100,000

3 UT 10.8 per 100,000

States with the

highest prescription

opioid-involved death

rates in 2017

Opioid Withdrawal Symptoms

Anxiety

Sweating

Poor sleep

Runny nose

Muscle pain

Watery eyes

Dilated pupils

Chills

Diarrhea

Vomiting

Sweating

Cramping

Shakiness

↑ HR and BP

Opioid Dependence

Post-withdrawal Treatment

Opioid Withdrawal

Opiate and opioid withdrawal. NLM. 2018.

HR Heart rate

BP Blood pressure

Opioid Withdrawal Treatments Product Class Indication Special Licensing Limitations

Methadone Full opioid

agonist

Detoxification

and

maintenance

of opioid

addiction

Yes BBW addiction

Diversion/abuse

Buprenorphine Partial opioid

agonist

Treatment of

opioid

dependence

Yes Dependence

Diversion/abuse

Clonidine Alpha-2

adrenergic

agonist

HTN

ADHD

No Limited

controlled data

Side effects

Methadone. Roxane Laboratories, Inc. 2006.

Buprenorphine. Roxane Laboratories, Inc. 2015.

Clonidine. Concordia Pharmaceuticals, Inc. 2015.

Clonidine. Boehringer Ingelheim. 2009.

BBW Black box warning

ADHD Attention-Deficit/Hyperactivity Disorder

HTN Hypertension

● Mitigation of opioid withdrawal symptoms to facilitate abrupt

opioid discontinuation

○ Not for treatment of OUD

● First non-opioid drug for managing withdrawal symptoms

○ Already marketed in other countries

○ Initial market introduction in 1992

Indication

Lofexidine. US WorldMeds, LLC. 2018. OUD Opioid use disorder

Opioid Use Physiology

Opioid

Opioid

Receptor Euphoria

Analgesia

Adrenergic

Neuron

Norepinephrine Lofexidine. US WorldMeds, LLC. 2018.

Lofexidine Mechanism of Action

Opioid

Receptor

Norepinephrine

Opioid

Withdrawal

Adrenergic

Neuron

L Lofexidine

L

Lofexidine. US WorldMeds, LLC. 2018.

Dosing ● Starting dose: Three 0.18 mg tablets QID

○ During peak withdrawal symptoms • First 5-7 days following last opioid dose

○ Maintain 5-6 hours between each dose

● Dosing guided by symptoms and side effects

○ Maximum daily dose 2.88 mg (16 tablets)

○ Maximum dose 0.72 mg (4 tablets)


Dose Discontinuation ● Treatment up to 14 days

● Discontinue with gradual dose reduction over 2-4 days

○ Reduce by 1 tablet per dose every 1-2 days

○ Avoids lofexidine withdrawal symptoms • Diarrhea, insomnia, anxiety, chills, increased BP

AWP $24.83 per tablet

36 and 96 count bottles


Lucemyra. Red Book. IBM Micromedex. 2018. AWP Average wholesale price BP Blood pressure

Dose Adjustments Dosing Adjustment Hepatic Impairment

Mild Moderate Severe

Child-Pugh Score 5-6 7-9 >9

Recommended

Dose

3 tabs QID

(2.16 mg/day)

2 tabs QID

(1.44 mg/day)

1 tab QID

(72 mg/day)

Dosing Adjustments for Renal Impairment

Moderate Severe, ESRD, Dialysis

eGFR, mL/min/1.732 30-89.9 <30

Recommended Dose 2 tabs QID (1.44 mg/day) 1 tab QID (0.72 mg/day)

Lofexidine. US WorldMeds, LLC. 2018. eGFR Estimated glomerular filtration rate

Warnings and Precautions ● Risk of hypotension, bradycardia, and syncope

○ Avoid in patients with severe coronary insufficiency, recent MI,

cerebrovascular disease, chronic renal failure, and marked

bradycardia

● Risk of QT prolongation

○ Avoid use in patients with congenital long QT syndrome

○ Monitor ECG in patients with CHF, bradyarrhythmias, hepatic

impairment, renal impairment, and concomitant use of QT-

prolonging agents


MI Myocardial infarction

ECG Electrocardiogram

CHF Congestive heart failure

Warnings and Precautions ● Increased risk of CNS depression with concomitant use of

CNS depressant drugs

○ Benzodiazepines, alcohol, barbiturates

● Increased risk of opioid overdose after opioid discontinuation

○ Reduced tolerance to opioids increased risk of fatal

overdose if opioids resumed

Lofexidine. US WorldMeds, LLC. 2018. CNS Central nervous system

● Adverse Reactions: (≥10%)

○ Sedation

○ Dry mouth

○ Dizziness

○ Bradycardia

○ Hypotension

○ Somnolence

○ Orthostatic hypotension

Adverse Reactions


● Drug Interactions:

○ Methadone • QT prolongation; monitor ECG

○ Oral naltrexone • Decreased naltrexone efficacy if given within 2 hours of lofexidine

○ Paroxetine (CYP2D6 inhibitor) • Increased lofexidine absorption and increased risk of ADRs

Drug Interactions


● Contraindications: None

ECG Electrocardiogram

ADR Adverse drug reaction

● Multicenter, double-blind, placebo-controlled study to evaluate

efficacy and safety of lofexidine for opioid withdrawal symptoms

after abrupt discontinuation

● Population ○ Mean age 35 years, 71% male

○ Met DSM-IV criteria for OUD dependent on short-acting opioids

● Primary Outcome (N=603) ○ SOWS-Gossop total score on days 1-7 of treatment

Clinical Trial

OUD Opioid use disorder

SOWS-Gossop Short Opiate Withdrawal Scale of Gossop Fishman M, et al. J Addict Med. 2018.

Fishman M, et al. J Addict Med. 2018.

None (0) Mild (1) Moderate (2) Severe (3)

1. Feeling sick

2. Stomach cramps

3. Muscle spasms

4. Feeling of coldness

5. Heart pounding

6. Muscular tension

7. Aches/pains

8. Yawning

9. Runny eyes

10. Insomnia

● Intervention 3:3:2 ○ Lofexidine 2.16 mg/day vs lofexidine 2.88 mg/day vs placebo

Clinical Trial

SOWS-Gossop Short Opiate Withdrawal Scale of Gossop

Lofexidine generally safe and effective non-opioid

treatment for opioid withdrawal.

Fishman M, et al. J Addict Med. 2018.

● Primary Outcome (N=603) ○ SOWS-Gossop score on days 1-7 of treatment

• Lofexidine 2.16 mg • -0.21; 95% CI, -0.37 to -0.04; P = 0.02

• Lofexidine 2.88 mg • -0.26; 95% CI, -0.44 to -0.09; P = 0.003

● Structural analog of clonidine with comparable efficacy

● Clonidine associated with higher rates of hypotension

○ Difference in alpha-2 receptor selectivity

● UK NICE guidelines lofexidine recommendations

○ In patients who decline methadone or buprenorphine

○ In cases of mild or uncertain dependence

○ Clonidine should not be routinely used for opioid detoxification

NICE Guideline. British Psychological Society. 2008. NICE National Institute for Health & Clinical Excellence

Place in Therapy

● Lofexidine is the first non-opioid treatment for managing opioid

withdrawal symptoms ○ May mitigate, but not completely prevent symptoms

● Patients should self-monitor for symptoms of hypotension and

bradycardia

● Avoid abrupt lofexidine discontinuation

● Risk of opioid overdose due to decreased tolerance

Key Points / Counseling


Cannabidiol (Epidiolex®)

Background ● PA’s Medical Marijuana Program signed on April 17, 2016

● Qualifying condition or terminal illness: ○ Amyotrophic lateral sclerosis, autism, cancer, Crohn's disease, damage to

the nervous tissue of the central nervous system (brain-spinal cord),

dyskinetic and spastic movement disorders, glaucoma, HIV/AIDs,

Huntington's disease, inflammatory bowel disease, intractable seizures,

multiple sclerosis, neurodegenerative diseases, neuropathies, opioid use

disorder for which conventional therapeutic interventions are

contraindicated or ineffective, Parkinson's disease, post-traumatic stress

disorder, severe chronic or intractable pain, sickle cell anemia

Medical marijuana. PA Department of Health. 2019.

Legality ● Medical Marijuana Program does not protect against

federal prosecution

○ DOJ may enforce criminal federal laws regarding marijuana

possession and use regardless of state law

○ Unlikely to bring enforcement actions against

growers/processors, dispensaries, physicians, seriously ill

individuals or caregivers as long as they are acting pursuant

to the Act

Medical marijuana. PA Department of Health. 2019. DOJ Department of Justice

Cannabidiol ● Cannabis sativa plant (marijuana)

○ CBD does not cause intoxication or euphoria

○ THC is the primary psychoactive component

● Controlled substance – Schedule V

FDA News Release. FDA. 2018.

CBD Cannabidiol

THC Tetrahydrocannabinol

● Treatment of seizures associated with Lennox-Gastaut

syndrome (LGS) or Dravet syndrome (DS) in patients ≥2

years of age

○ Rare forms of severe epilepsy that emerge in early childhood

● First approved medication that contains a purified drug

derived from marijuana

● First approved medication for DS

Indication

Cannabidiol. Greenwich Biosciences, Inc. 2018.

LGS Lennox-Gastaut Syndrome

DS Dravet Syndrome

Cannabidiol Mechanism of Action

● Precise mechanism is unknown

○ Does not appear to exert its

anticonvulsant effects through interaction

with cannabidiol receptors


Dosing ● Starting dose: 2.5 mg/kg BID

● Maintenance dose: Increase to 5 mg/kg BID after one week

○ Maximum maintenance dose of 10 mg/kg BID

○ Increase by weekly increments of 2.5 mg/kg BID • Do not titrate more frequently than every other day

● Gradual dose decrease needed upon discontinuation to

minimize risk of increased seizures

AWP $1482 per 100 mL

(100 mg/mL)


Dosing Adjustments Hepatic Impairment Starting Dose Maintenance Dose Maximum Dose

Mild 2.5 mg/kg BID

(5 mg/kg/day)

5 mg/kg BID

(10 mg/kg/day)

10 mg/kg BID

(20 mg/kg/day)

Moderate 1.25 mg/kg BID

(2.5 mg/kg/day)

2.5 mg/kg BID

(5 mg/kg/day)

5 mg/kg BID

(10 mg/kg/day)

Severe 0.5 mg/kg BID

(1 mg/kg/day)

1 mg/kg BID

(2 mg/kg/day)

2 mg/kg BID

(4 mg/kg/day)

May need slower dose titration in

moderate-to-severe impairment


Warnings and Precautions ● Hepatocellular injury

○ Dose-related elevations in liver transaminases (AST/ALT) • 3x ULN in 13% of patients taking cannabidiol vs 1% with placebo

• 17% with 10 mg/kg BID vs 1% in patients taking 5 mg/kg BID

○ Risk increased with concomitant valproate and clobazam

Cannabidiol. Greenwich Biosciences, Inc. 2018. ULN Upper limit of normal

*** Collect baseline ALT, AST, and total bilirubin ***

Warnings and Precautions ● Somnolence and Sedation

○ Dose-related; 32% with cannabidiol vs 11% with placebo

○ More common in early treatment and may diminish over time

● Suicidal Behavior and Ideation

○ Monitor for emergence or worsening of depression or unusual

changes in mood/behavior


● Adverse Reactions: (≥10%)

○ Rash

○ Fatigue

○ Malaise

○ Infection

○ Asthenia

Adverse Reactions


○ Diarrhea

○ Insomnia

○ Somnolence

○ Decreased appetite

○ Transaminase elevations

● Contraindication ○ Hypersensitivity to cannabidiol

○ Allergy to sesame seed oil

● Drug Interactions: ○ Moderate or strong inhibitors of CYP3A4 or CYP2C19

■ Increases cannabidiol concentrations increased side effects

○ Strong CYP3A4 or CYP2C19 Inducers

■ Decreases cannabidiol concentrations decreased efficacy

○ Clobazam 3-fold increase in clobazam active metabolite

Drug Interactions


● No cannabinoid-like behavioral responses in animal studies ○ No animal self-administration No rewarding effects

● Human abuse potential study measuring Drug Liking and Take

Drug Again ○ Cannabidiol – Similar to placebo

○ Dronabinol (schedule III) and alprazolam (schedule IV)

• Large increases in subjective measures

● Cannabidiol did not produce signs or symptoms of withdrawal

after treating for 28 days ○ Suggests that cannabidiol does not produce physical dependence

Drug Abuse/Dependence


● Lennox-Gastaut

○ Two randomized, double-blind, placebo-controlled trials in

patients aged 2 to 55 years • Trial #1: Add-on cannabidiol (20 mg/kg/day) vs placebo

• Trial #2: Add-on cannabidiol (10 and 20 mg/kg/day) vs placebo

● Primary outcome: Percent change from baseline in frequency of

drop seizures over a 14-week period

Clinical Trials

Thiele EA, et al. Lancet. 2018.

Devinsky O, et al. N Eng J Med. 2018.

Lennox-Gastaut Trial #1

Thiele EA, et al. Lancet. 2018.

Lennox-Gastaut Trial #2


● Dravet Syndrome

○ Randomized, double-blind, placebo-controlled trial • Add-on cannabidiol (20 mg/kg/day) vs placebo

● Primary outcome: Percent change from baseline in frequency of

seizures over a 14-week period

Clinical Trials


Dravet Syndrome


● Lennox-Gastaut Syndrome treatment

○ First-line……..Valproate

○ Adjunctive…..Lamotrigine

○ Other………….Rufinamide or topiramate; felbamate (last-line)

● Current evidence suggests benefit in treatment-resistant,

pediatric-onset, intractable epilepsy

NICE National Institute for Health & Clinical Excellence

Place in Therapy

NICE Guideline. Epilepsies. 2012.

● Dravet Syndrome treatment

○ First-line……..Valproate or topiramate

○ Adjunctive…..Clobazam or stiripentol

○ Other………….Clonazepam, levetiracetam, zonisamide, ethosuximide

● The American Epilepsy Society (AES) urges weighing risks vs

benefits of available treatment options

Place in Therapy

NICE Guideline. Epilepsies. 2012.

What is Dravet Syndrome. Dravet Syndrome Foundation. 2019

Treatment for epileptic seizures. AES. 2018.

● Cannabidiol comes with a calibrated measuring device ○ 1 mL or 5 mL oral syringe

○ Do not use household teaspoon or tablespoon

● Discard unused cannabidiol 12 weeks after opening

● Food may affect cannabidiol levels

● Self-monitor for signs of hepatic dysfunction ○ Unexplained nausea, vomiting, fatigue, anorexia, jaundice/dark urine

Key Points / Counseling


Post-Test Andexanet alfa is indicated for the reversal of anticoagulation

due to life-threatening or uncontrolled bleeding for patients

treated with which of the following anticoagulants?

A. Apixaban

B. Rivaroxaban

C. Edoxaban

D. A and B

E. All of the above

Post-Test Lofexidine is approved for which of the following indications?

A. Opioid use disorder

B. Mitigation of opioid withdrawal symptoms

C. Insomnia

D. Seizure

Post-Test Cannabidiol has been approved for both the treatment of rare,

severe forms of seizures and post-traumatic stress disorder.

A. True

B. False

Post-Test Lofexidine is associated with which of the following

side effects?

A. Infusion-related reactions

B. Blurry vision, tachycardia, hypertension

C. Dizziness, bradycardia, hypotension

D. Decreased appetite, elevated transaminases

Post-Test Which of the following agents require gradual dose reduction

upon discontinuation?

A. Andexanet alfa

B. Lofexidine

C. Cannabidiol

D. B and C

E. All of the above

Post-Test Which of the following agents require both renal and hepatic

dose adjustment?

A. Andexanet alfa

B. Lofexidine

C. Cannabidiol

D. All of the above

Know the New: 2018 Novel Drug Approvals

Questions?

References 1. Novel Drug Approvals for 2018. U.S. Food and Drug Administration. Available from

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm592464.htm.

2. Eikelbloom JW, Weitz JI. New anticoagulants: Update on antithrombotic therapy. Circulation. 2010 Apr 6;121(13):1523-32. Available from

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