new drugs of 2016: part 2 pharmedium lunch and learn...

New Drugs of 2016: Part 2PharMEDium Lunch and Learn Series

ProCE, Inc.www.ProCE.com 1

New Drugs of 2016: Part 2

May 12, 2017

Featured Speaker: Mary Lynn Moody, BSPharmDirector, Business DevelopmentDrug Information and Prior Authorization GroupUniversity of Illinois at Chicago

LUNCH AND LEARN

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ProCE, Inc. (Pharmacist and Tech CE)

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Funding: This activity is self‐funded through PharMEDium.

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Mary Lynn Moody BSPharm

Clinical Associate Professor

Department of Pharmacy Practice

University of Illinois at Chicago

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Learning Objectives - Pharmacists

Describe the new drugs approved by the Food and Drug Administration in 2016

Discuss the role of these agents in therapy

Summarize the adverse effects and potential drug interactions of these new agents

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Learning Objectives - Technicians

Describe the new drugs approved by the Food and Drug Administration in 2016

Discuss any unique preparation and/or dispensing requirements for these agents

Summarize the adverse effects and potential drug interactions of these new agents that may require pharmacist intervention

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Brivaracetam (Briviact®)3

Approved February 18, 2016

Indicated as adjunctive therapy in partial-onset seizures

Analog of levetiracetam (Keppra)

New epilepsy drugs are often only approved for this indication

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Brivaracetam 3

Binds selectively to protein 2A (SV2A) in the brain

Modulates neurotransmitter release into the synapse

10- to 30-fold higher affinity for SV2A than levetiracetam

Higher brain permeability, more rapid onset of action than levetiracetam

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Brivaracetam Dosing 3

Starting dosage is 50 mg twice daily (orally)

Can be decreased to 25 mg twice daily or increased to 100 mg twice daily

May be taken with or without food

Liver impairment: Starting dose is 25 mg twice daily and the maximum dose is 75 mg twice daily

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Brivaracetam Pharmacokinetics 3

Tmax- One hour (fasting); delayed 3 hours with high fat meal

Metabolized by hydrolysis

95% excreted in the urine, 10% unchanged

Elimination half-life is 9 hours

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Brivaracetam Efficacy 4

3 randomized, double-blind, placebo-controlled 12-week trials

Primary endpoint of mean reduction in seizure frequency

Study 1 and 2: Brivaracetam was not beneficial for the 20% of patients receiving concomitant levetiracetam

Study 3: Adjunctive brivaracetam significantly reduced seizure frequency among the patients who had previously tried and discontinued levetiracetam.

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Brivaracetam Warnings 3,5

Potential for suicidal behavior

Bronchospasm and angioedema may occur if hypersensitivity-Do not rechallenge

Do not stop brivaracetam abruptly, taper slowly

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Brivaracetam Adverse Effects 3,5

Common adverse effects

Somnolence and sedation (16%)

Dizziness (12%)

Fatigue (9%)

Nausea and vomiting (5%)

Psychiatric adverse reactions (13%), mostly anxiety and depression

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Brivaracetam Drug Interactions 3,5

Rifampin decreases plasma concentrations of brivaracetam by 45%, increase brivaracetam dose by 100%

Brivaracetam increases active metabolite of carbamazepine

Brivaracetam increases levels of phenytoin by 20%, monitor levels

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Brivaracetam Place in Therapy

Modestly effective as add-on treatment in adults with refractory partial-onset seizures

Useful in those who failed to respond to levetiracetam

May also be effective in myoclonic and primarily generalized seizures

Generic levetiracetam costs much less

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Pharmacist Clinical Points

Discuss the risk of suicide ideation

Review the risks associated with abrupt cessation of brivaracetam

Conduct a clinical review of other medications to ensure there are no drug interactions

Warn patient about the risk of CNS side effects

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Technician Points

Establish an alert process for the pharmacist for missed refills to ensure patient compliance

Alert the pharmacist of any new prescription or non-prescription medications to screen for interactions

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Atezolizumab 6,7

Approved May 18, 2016 Indicated for metastatic non-small cell

lung cancer (NSCLC) Accelerated approval In 2017 received approval for use in

metastatic urothelial cancer The mechanism of action is a

Programmed death-ligand (PD-L) blocking antibody

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Atezolizumab MOA 6,7

Binds to Programmed Death-Ligand 1 (PD-L1)

Blocks the interaction with the PD-1 and B7-1 receptors on T-lymphocytes

Blocking these receptors allows for restoration of anti-tumor T-cell activity

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Atezolizumab Dosing 6,7

Give 1200 mg over 60 minutes every 3 weeks

Dilute with 0.9% sodium chloride by withdrawing 20 mL of atezolizumab and placing in 250 mL bag- Do not shake

Withhold dose if Grade 2 or 3 adverse reactions occur. May resume treatment when reduced to Grade 0 or 1

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Atezolizumab Efficacy 8

Two multicenter, international, randomized, open-label trials in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen

Study 2 was a trial in 1225 patients with the primary analysis consisting of the first 850 randomized patients

Study 3 was a trial in 287 patients

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Atezolizumab Efficacy 8

Study 2 Analysis of first 850 patients. 425 patients in atezolizumab arm, 425 patients in

docetaxel arm Lower incidence of death with atezolizumab 271

cases (64%) vs docetaxel with 298 cases (70%) Longer survival time with atezolizumab 13.8 months

vs docetaxel with 9.6 months Study 3

144 pts in atezolizumab arm, 143 in docetaxel arm Lower incidence of death with atezolizumab 90

cases (63%) vs docetaxel 110 cases (77%) Longer survival time with atezolizumab 12.6 months

vs docetaxel 9.7 months

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Atezolizumab Warnings 6,7

Pneumonitis, Hepatitis, Colitis These conditions require use of

corticosteroids; no clear alternate etiology

Administer 1-2 mg/kg/day of prednisone for Grade 2 toxicities, hold atezolizumab dose

Discontinue atezolizumab if Grade 3/4

Endocrine abnormalities

Infection

Infusion-related reaction

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Atezolizumab Adverse Effects 6,7

ADEs reported in 20% of patients Fatigue, decreased appetite, nausea,

pyrexia, UTI and constipation

Serious ADEs Grade 3 or 4 adverse reactions in >2% of

patients○ Intestinal or urinary obstruction, hematuria,

dyspnea, kidney damage, VTE, infection

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Atezolizumab Place in Therapy 7

NSCLC: EGFR or ALK genomic tumor aberrations should have disease progression on FDA approved therapy first

Urothelial Cancer: Not eligible for cisplatin-containing chemotherapy, or have disease progression during/following platinum chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy

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Review potential Grade 3 or 4 toxicities with patient/physician prior to dose

Ensure USP Chapter <800> guidelines are enforced, since the agent is a hazardous drug

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Technician Points

Do not prepare product until patient is in clinic and dose is confirmed

Use immediately following preparation

May store at room temperature for 24 hours

Incorporate USP Chapter <800> guidelines in production

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Reslizumab (Cinqair®) 9

Approved March 23, 2016

2nd Interleukin-5 antagonist approved

Indicated as add-on therapy in severe asthma in adults with eosinophilic phenotype

Reduces the levels of blood eosinophils

Maintenance therapy

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Reslizumab Pharmacokinetics 6,9

Peak serum concentrations reported at the end of the infusion

Vd is 5 L

Metabolism is via enzymatic proteolysis

Half-life -24 days

No studies in hepatic or renal patients

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Reslizumab MOA 9,10

Blocks binding to IL-5 receptors on the surface of eosinophils

Reduces the production and survival of eosinophils and decreases airway inflammation

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Reslizumab Dosing 9

3 mg/kg infused intravenously over 20-50 minutes once every 4 weeks. Do not give IV Push.

Anaphylaxis has occurred as early as 2nd

dose. May occur during or within 20 minutes of completing the infusion.

Withdrawal symptoms could occur if inhaled or systemic corticosteroids are stopped abruptly when reslizumab therapy is started.

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Reslizumab Efficacy 10

4 clinical trials included 981 patients

2 trials were 52 weeks duration

Significant reduction in the rate of asthma exacerbations Less systemic corticosteroid used

Fewer required hospitalization or an ED visit

Significantly improved lung function [increase in forced expiratory volume in 1 second (FEV1) determinations]

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Reslizumab Warnings 9

Black box warning - Anaphylaxis Potentially life-threatening

Reported in 0.3% of patients

Can occur as early as second dose

Monitor patient during and after receiving dose

Discontinue if anaphylaxis occurs

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Reslizumab Adverse Effects 9

Common adverse effects Musculoskeletal adverse reactions on the day of infusion

(2.2% vs 1.5%) Oropharyngeal pain (2.6% vs 2.2%) Creatine phosphokinase (CPK) elevations (14% vs 9%) Myalgia (1.0% vs 0.5%)

Serious adverse events Anaphylaxis (0.3% vs 0%) Malignancy (0.6% vs 0.3%)

Antibodies to reslizumab developed in about 5% of patients treated with the drug in clinical trials; they did not appear to affect the clinical efficacy of the drug.

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Ensure patient is monitored during and after infusion for anaphylaxis

Anaphylaxis can appear as dyspnea, wheezing, decreased oxygen saturation, vomiting, skin and mucosal reactions

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Technician Tips

To minimize foaming, do not shake drug vials

Withdraw dose from vial and slowly add to 50 mL bag of 0.9% sodium chloride

Administer immediately after preparation Do not give as IV push or bolus. Flush line

with 0.9% sodium chloride to ensure complete dose given

Infusion must be complete by 16 hours after compounding

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Ixekizumab 11

Approved March 22, 2016

Moderate to severe plaque psoriasis

Interleukin 17A antagonist

Available as auto-injector and prefilled syringe

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Ixekizumab Pharmacokinetics 11

60-81% absorbed following SQ dose

Higher bioavailability when dosed in thigh

Vd=7.11 L

Metabolism is not characterized

Eliminated via catabolism like IgG

Elimination half-life is 13 days

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Ixekizumab MOA 11,12

IL-17A is a cytokine involved in normal inflammatory and immune responses

Ixekizumab is an IgG4 monoclonal antibody that selectively binds with IL-17A

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Ixekizumab Dosing 6,11

Administered as subcutaneous injection

Give 160 mg (two 80 mg injections) initially and then 80 mg every 2 weeks for a total of 7 doses

Then extend dosing interval to every 4 weeks thereafter

Give into upper arm, thigh or abdomen

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Ixekizumab Efficacy 12

3 clinical trials compare ixekizumab to placebo

PASI 75 and sPGA scores were 12 week endpoints

82% of patients had a positive sPGA score

87-90% had 75% reduction in PASI score

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Ixekizumab Warnings 11

Contraindicated if hypersensitivity to drug or components

Screen patients for tuberculosis

Treat all latent TB before starting ixekizumab. Do not give if active TB.

Increased risk for infection

Avoid live vaccines

Risk for inflammatory bowel disease

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Ixekizumab Adverse Effects 11

Injection site reactions

Upper respiratory tract infections

Nausea

Tinea infection

Oral candidiasis

Conjunctivitis

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Ixekizumab Drug Interactions 11

May normalize CYP450 enzymes

Monitor drugs with narrow therapeutic index Warfarin

Cyclosporine

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Verify patient does not have an infection, including tuberculosis

Reinforce need to avoid live vaccines (e.g. Shingles)

Do not inject into tender or inflamed skin

Discuss what to do if an infection develops

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Technician Tips

Store in the refrigerator, protect from light

Do not shake ixekizumab syringe or auto-injector

Do not substitute the different dosage forms. Patients may not know how to use an auto-injector.

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Glargine/Lixisenatide (Soliqua™) 13

Approved November 21, 2016

Glargine long acting human insulin

Lixisenatide Glucagon-Like Peptide-1 Receptor agonist (GLP-1)

Approved to treat type 2 diabetes mellitus Inadequately controlled on basal insulin or

lixisenatide

Not studied in combination with prandial insulin

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Glargine/Lixisenatide Dosage 6,13

Dosage Form: 3 mL injection pen

Strength: 100 Units glargine per ml and 33 mcg lixisenatide per ml

Administration: Once daily, within 1 hour prior to 1st meal

Administer subcutaneously (SQ) in the

abdomen, arm or thigh Prior Basal Insulin Dose

Initial Soliqua Dose Titration

< 30 Units 15 Units/5 mcg 2-4 Units/week

30-60 Units 30 Units/10 mcg 2-4 Units/week55

Glargine/Lixisenatide Pharmacokinetics 13

Metabolism/elimination:

Glargine 2 active human insulin in SQ

Lixisenatide Renal and proteolytic degradation

Half-life: ~3 hours

Dose adjustments:

eGFR 15-29 ml/min clinical experience is limited

eGFR <15 ml/min do not use

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Glargine/Lixisenatide Efficacy 14

Two phase-3 clinical trials: randomized, active-controlled, and open-label

N = 834 Duration = 30 weeks

Primary endpoint: Change (∆) in HbA1c from baseline to week 30

Results: Mean change in HbA1c from baseline to Week 30.

Study Treatment Arms

BaselineHbA1c(%)

∆ HbA1c (%)

P-value

Study 1 FRC*GlargineLixisenatide

8.088.088.13

-1.63-1.34-0.85

<0.0001<0.0001

Study 2 FRC*Glargine

8.078.08

-1.13-0.62 <0.0001

*FRC = Fixed Ratio Combination 57

Glargine/Lixisenatide Safety 13

Adverse Reactions (≥5%) Nausea 10%

Hypoglycemia 8%

Nasopharyngitis 7%

Diarrhea 7%

URTIs 5.5%

Headache 5.4%

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Glargine/Lixisenatide Warnings 13

Hypoglycemia

Pancreatitis: discontinue if suspected

Acute kidney injury: not recommended in ESKD

Immunogenicity: antibodies may develop to glargine/lixisenatide

Hypokalemia: monitor potassium levels

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Explain importance of adherence to this combination

Review dosing schedule; reinforce dose is within one hour prior to 1st meal

Discuss need to monitor HbA1C

Discuss proper storage and use of product

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Technician Tips

Alert pharmacist if refills are late or missed

Alert pharmacist of any OTC drugs that are being purchased in case of interactions

Ensure patient has necessary supplies

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Conclusions

Much fewer number of drugs approved in 2016

Majority of those approved were orphan, fast track agents

Not much impact on compounding business

Critical to understand these new agents

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References1. United States Food and Drug Administration. Novel Drug Approvals 2016.

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm483775.htm. Accessed January 8, 2017.

2. United States Food and Drug Administration. Novel Drugs Summary 2016. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm534863.htm. Accessed March 3, 2017.

3. Briviact [package insert]. Smyrna GA: UCB Inc. March 2016.4. Mumoli L, Palleria C, Gasparini S et al. Brivaracetam: review of its pharmacology and potential use as

adjunctive therapy in patients with partial onset seizures. Drug Des Devel Ther 2015; 9(10):5719-5725. 5. Brivaracetam (Briviact) for Epilepsy. Med Lett Drugs Ther. 2016;58(1499):95-96.6. Facts and Comparisons. [database online] Indianapolis, IN: Clinical Drug Information. LLC;

http://online.factsandcomparisons.com. Accessed January 15, 2017.7. Tecentriq [package insert]. South San Francisco CA: Genentech Inc. April 2017.8. Atezolizumab (Tecentriq) for Bladder Cancer and NSCLC. Med Lett Drugs Ther. 2017;59(1515):e40-41.9. Cinqair [package insert]. Frazer PA: Teva Respiratory. May 2016.10. Deeks ED, Bruselle G. Reslizumab in eosinophilic asthma: a review. Drugs. 2017;77(7):777-784.11. Taltz [package insert]. Indianapolis IN: Eli Lilly and Company. January 2017.12. Ixekizumab (Taltz) - A Second IL-17A Inhibitor for Psoriasis. Med Lett Drugs Ther. 2016;58(1494):59-60.13. Soliqua [package insert]. Bridgewater NJ: Sanofi-Aventis LLC. May 2016.14. Davies MJ, Leiter LA, Guerci B et al. Impact of baseline HbA1c, diabetes duration and BMI on clinical

outcomes in the LixiLan-O trial testing iGlarLixi (insulin glargine/lixisenatide titratable fixed-ratio combination) versus insulin glargine and lixisenatide monocomponents. Diabetes Obes Metab. 2017 Apr 22. doi: 10.1111/dom.12980. [Epub ahead of print].

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New Drugs of 2016 Table 1- New drugs of 2016, listed in order of approval date1

Generic Name Brand Name Approval Date Indication Elbasvir (ELB as vir) and Grazoprevir (graz OH pre vir)

Zepatier (ZEP-ah-teer)

1-28-2016 Chronic hepatitis C (HCV) genotypes 1 and 4 infection

Brivaracetam (BRIV a RA se tam)

Briviact 2-18-2016 Partial onset seizures

Obiltoxaximab (oh-bil-tox-AX-i-mab)

Anthim 3-18-2016 Inhalational anthrax

Ixekizumab (IX ee KIZ ue mab)

Taltz 3-22-2016 Moderate to severe plaque psoriasis

Reslizumab (res LIZ ue mab)

Cinqair 3-23-2016 Severe asthma

Defibrotide sodium (de FYE broe tide)

Defitelio 3-30-2016 Hepatic veno-occlusive disease following stem cell transplant

Venetoclax (ven ET oh klax)

Venclexta 4-11-2016 Chronic lymphocytic leukemia in patients with a specific chromosomal abnormality

Pimavanserin (PIM a VAN ser in)

Nuplazid 4-29-2016 Treatment of hallucinations and delusions from psychosis in Parkinson’s disease

Atezolizumab (A te zoe LIZ ue mab)

Tecentriq 5-18-2016 Urothelial type bladder cancer

Daclizumab (dah KLIH zyoo mab)

Zinbryta 5-27-2016 Multiple sclerosis

Obeticholic acid (oh BET i KOE lik AS id)

Ocaliva 5-27-2016 Rare chronic liver disease

Fluciclovine F 18 Axumin 5-27-2016 Diagnostic imaging agent for recurrent prostate cancer detection

Gallium Ga 68 dotatate (GAL-ee-um Ga 68 DOE-ta-tate)

NETSPOT 6-1-2016 Diagnostic imaging agent for rare neuroendocrine tumors

Sofosbuvir (soe FOS bue vir) and Velpatasvir (vel PAT as vir)

Epclusa 6-28-2016 Treatment of all 6 major forms of hepatitis C virus

Lifitegrast (LIF e TEG rast)

Xiidra 7-11-2016 Treat signs and symptoms of dry eye

Lixisenatide (LIX i SEN a tide)

Adlyxin 7-27-2016 Diabetes type 2

Eteplirsen (e TEP lir sen)

Exondys 51 9-19-2016 Duchenne muscular dystrophy

Olaratumab (OH lar AT ue mab)

Lartruvo 10-19-2016 Soft tissue sarcoma

Bezlotoxumab (BEZ loe TOX ue mab)

Zinplava 10-21-2016 Reduce the recurrence of Clostridium difficile infection in adults

Crisaborole (KRIS a BOR ole)

Eucrisa 12-14-2016 Atopic dermatitis in patients two years of age or older

Rucaparib (roo KAP a rib)

Rubraca 12-19-2016 Ovarian cancer

Nusinersen (NUE si NER sen)

Spinraza 12-23-2016 Spinal muscular atrophy

References: 1. United States Food and Drug Administration. Novel Drug Approvals 2016.

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm483775.htm. Accessed January 8, 2017.

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