LUNCH AND LEARN. May 12, CE Activity Information & Accreditation

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1 LUNCH AND LEARN New Drugs of 2016: Part 2 May 12, 2017 Featured Speaker: Mary Lynn Moody, BSPharm Director, Business Development Drug Information and Prior Authorization Group University of Illinois at Chicago CE Activity Information & Accreditation (Pharmacist and Tech CE) 1.0 contact hour Funding: This activity is self funded through PharMEDium. It is the policy of to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Ms. Moody has served as a speaker for Baxter Healthcare and Salveo Health Communications

2 Online Evaluation, Self-Assessment and CE Credit Submission of an online self assessment and evaluation is the only way to obtain CE credit for this webinar Go to Print your CE Statement online Live CE Deadline: June 9, 2017 CPE Monitor CE information automatically uploaded to NABP/CPE Monitor upon completion of the self assessment and evaluation (user must complete the claim credit step) Attendance Code Code will be provided at the end of today s activity Attendance Code not needed for On Demand 3 Ask a Question Submit your questions to your site manager. Questions will be answered at the end of the presentation. Your question...? 4 2

3 Resources Visit to access: Handouts Activity information Upcoming live webinar dates Links to receive CE credit 5 Mary Lynn Moody BSPharm Clinical Associate Professor Department of Pharmacy Practice University of Illinois at Chicago 6 3

4 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 7 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 8 4

5 9 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

6 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 11 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

7 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 13 Brivaracetam Efficacy 4 3 randomized, double-blind, placebocontrolled 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

8 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 15 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

9 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 17 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

10 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 19 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

11 21 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

12 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 23 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

13 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 25 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 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

14 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 27 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

15 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 29 Pharmacist Clinical Points 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

16 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

17 Reslizumab (Cinqair ) 9 Approved March 23, nd 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 33 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

18 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 35 Reslizumab Dosing 9 3 mg/kg infused intravenously over minutes once every 4 weeks. Do not give IV Push. Anaphylaxis has occurred as early as 2 nd 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

19 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 (FEV 1 ) determinations] 37 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

20 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. 39 Pharmacist Clinical Points Ensure patient is monitored during and after infusion for anaphylaxis Anaphylaxis can appear as dyspnea, wheezing, decreased oxygen saturation, vomiting, skin and mucosal reactions

21 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

22 Ixekizumab 11 Approved March 22, 2016 Moderate to severe plaque psoriasis Interleukin 17A antagonist Available as auto-injector and prefilled syringe 43 Ixekizumab Pharmacokinetics % 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

23 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 45 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

24 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 47 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

25 Ixekizumab Adverse Effects 11 Injection site reactions Upper respiratory tract infections Nausea Tinea infection Oral candidiasis Conjunctivitis 49 Ixekizumab Drug Interactions 11 May normalize CYP450 enzymes Monitor drugs with narrow therapeutic index Warfarin Cyclosporine

26 Pharmacist Clinical Points 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 51 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

27 53 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

28 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 1 st 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 Units 30 Units/10 mcg 2-4 Units/week 55 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 ml/min clinical experience is limited egfr <15 ml/min do not use

29 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 Baseline HbA1c(%) HbA1c (%) P-value Study 1 FRC* Glargine Lixisenatide < < Study 2 FRC* Glargine < *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%

30 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 59 Pharmacist Clinical Points Explain importance of adherence to this combination Review dosing schedule; reinforce dose is within one hour prior to 1 st meal Discuss need to monitor HbA1C Discuss proper storage and use of product

31 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 61 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

32 References 1. United States Food and Drug Administration. Novel Drug Approvals Accessed January 8, United States Food and Drug Administration. Novel Drugs Summary Accessed March 3, Briviact [package insert]. Smyrna GA: UCB Inc. March 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): Brivaracetam (Briviact) for Epilepsy. Med Lett Drugs Ther. 2016;58(1499): Facts and Comparisons. [database online] Indianapolis, IN: Clinical Drug Information. LLC; Accessed January 15, Tecentriq [package insert]. South San Francisco CA: Genentech Inc. April Atezolizumab (Tecentriq) for Bladder Cancer and NSCLC. Med Lett Drugs Ther. 2017;59(1515):e Cinqair [package insert]. Frazer PA: Teva Respiratory. May Deeks ED, Bruselle G. Reslizumab in eosinophilic asthma: a review. Drugs. 2017;77(7): Taltz [package insert]. Indianapolis IN: Eli Lilly and Company. January Ixekizumab (Taltz) - A Second IL-17A Inhibitor for Psoriasis. Med Lett Drugs Ther. 2016;58(1494): Soliqua [package insert]. Bridgewater NJ: Sanofi-Aventis LLC. May 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 Apr 22. doi: /dom [Epub ahead of print]

33 New Drugs of 2016 Table 1- New drugs of 2016, listed in order of approval date 1 Generic Name Brand Name Approval Date Indication Elbasvir (ELB as vir) and Zepatier (ZEP-ah-teer) Chronic hepatitis C (HCV) genotypes 1 and 4 infection Grazoprevir (graz OH pre vir) Brivaracetam Briviact Partial onset seizures (BRIV a RA se tam) Obiltoxaximab Anthim Inhalational anthrax (oh-bil-tox-ax-i-mab) Ixekizumab Taltz Moderate to severe plaque psoriasis (IX ee KIZ ue mab) Reslizumab Cinqair Severe asthma (res LIZ ue mab) Defibrotide sodium (de FYE broe tide) Defitelio Hepatic veno-occlusive disease following stem cell transplant Venetoclax (ven ET oh klax) Venclexta Chronic lymphocytic leukemia in patients with a specific chromosomal abnormality Pimavanserin (PIM a VAN ser in) Nuplazid Treatment of hallucinations and delusions from psychosis in Parkinson s disease Tecentriq Urothelial type bladder cancer Atezolizumab (A te zoe LIZ ue mab) Daclizumab Zinbryta Multiple sclerosis (dah KLIH zyoo mab) Obeticholic acid Ocaliva Rare chronic liver disease (oh BET i KOE lik AS id) Fluciclovine F 18 Axumin Diagnostic imaging agent for recurrent prostate cancer detection Gallium Ga 68 dotatate NETSPOT Diagnostic imaging agent for rare (GAL-ee-um Ga 68 DOE-ta-tate) neuroendocrine tumors Sofosbuvir (soe FOS bue vir) Epclusa Treatment of all 6 major forms of and hepatitis C virus Velpatasvir (vel PAT as vir) Lifitegrast (LIF e TEG rast) Lixisenatide (LIX i SEN a tide) Eteplirsen (e TEP lir sen) Olaratumab (OH lar AT ue mab) Bezlotoxumab (BEZ loe TOX ue mab) Crisaborole (KRIS a BOR ole) Rucaparib (roo KAP a rib) Nusinersen (NUE si NER sen) Xiidra Treat signs and symptoms of dry eye Adlyxin Diabetes type 2 Exondys Duchenne muscular dystrophy Lartruvo Soft tissue sarcoma Zinplava Reduce the recurrence of Clostridium difficile infection in adults Eucrisa Atopic dermatitis in patients two years of age or older Rubraca Ovarian cancer Spinraza Spinal muscular atrophy References: 1. United States Food and Drug Administration. Novel Drug Approvals Accessed January 8, 2017.