Disclosures. Technician Objectives. Pharmacist Objectives. New Drug Stats. New Drug Updates. New Drugs & Disease States 8/31/2016

Transcription

1 Disclosures New Drug Updates Both presenters have nothing to disclose. Lalita Prasad Reddy, PharmD, MS, BCACP, BCPS, CDE Clinical Assistant Professor Chicago State University College of Pharmacy Diana Isaacs, PharmD, BCPS, BC ADM, CDE Clinical Pharmacy Specialist Cleveland Clinic Diabetes Center September 16, 2016 Pharmacist Objectives Describe the place in therapy and mechanisms of action of newly approved drugs in the last 15 months. Compare newly approved agents from current agents utilized in the management of disease. Describe newly approved agents in terms of their place in therapy, effectiveness, safety, and patient administration. Summarize important patient counseling pearls for newly approved agents for the management of disease. Technician Objectives Describe the place in therapy and mechanisms of action of newly approved drugs in the last 15 months. Compare newly approved agents from current agents utilized in the management of disease. Describe newly approved agents in terms of their place in therapy, effectiveness, safety, and patient administration. New Drug Stats From Average 28 novel drugs approved/year New Drugs & Disease States Diabetes Insulin degludec (Tresiba ) Lixisenatide (Adlyxin ) Heart Failure Sacubitril/valsartan (Entresto ) Ivabradine (Corlanor ) In 2015, 45 novel drugs approved 16 (36%) are first in class (ex. Praxbind ) 21 (47%) to treat rare/orphan diseases (ex. Kanuma ) 29 (64%) approved in the US before other countries (ex. Entresto ) In 2016 (as of July) 16 novel drugs approved Gout Lesinurad (Zurampic ) Bleeding reversal Idarucizumab (Praxbind ) Hyperlipidemia Evolocumab (Repatha ) Alirocumab (Praluent ) Asthma Reslizumab (Cinqair ) Mepolizumab (Nucala ) Hepatitis C Sofosbuvir/velpatasvir (Epclusa ) Elbasvir/grazoprevir (Zepatier ) Daclatasvir (Daklinza ) Novel Drugs Summary Available at: Accessed August 8 th,

2 The Ideal Basal Insulin Possess a peakless profile Deliver a consistent and reliable rate of absorption Provide less variability in coverage among all populations Cause no weight gain or hypoglycemia Provide a true 24 hour coverage following a single injection Allow mixing of basal/bolus insulins in same injection syringe Insulin Degludec (Tresiba ) Indications for Insulin Degludec (Ideg) Improve glycemic control in adults with diabetes mellitus FDA approved September, 2015 Specifics After injection, Ideg dihexamers join together creating long, soluble multiheximer chains that prolong duration of action Compared to glargine, exhibits equivalent of even superior glycemic control Available in U 100 and U 200 formulations Tresiba Pacakge Insert, NovoNordisk, 2015 Property Onset (hours) Duration of Action (hours) Half-life (T1/2) Time to Steady State A Comparison of Kinetics Glargine (U-300) Glargine (U-100) Degludec > 42 ~ 19 hours ~ 12 hours 25 hours 5 days 24 hours 3 days Lantus pacakge insert, Sanofi, Diabetes Care 2015 Apr; 38(4): Tresiba Pacakge Insert, NovoNordisk, 2015 Tresiba Clinical Data Study Design Intervention Results: Efficacy Fifty two weeks, randomized, controlled, open label, multinational, parallel design, treat to target, noninferiority trial Fifty two weeks, randomized, controlled, open label, treat totarget, multi national, non inferiority trial Adults with type 2 diabetes inadequately controlled with oral glucose lowering agents were randomized to insulin degludec (n = 773) or insulin glargine (n = 257) once daily, both in combination with metformin. Study B: Adults with type 2 diabetes inadequately controlled with Insulin +/ oral agents were randomized to degludec (n = 755) or insulin glargine (n = 251) in combination with aspart before meals, +/ metformin and/or pioglitazone. Insulin degludec and insulin glargine decreased mean A1C concentrations from baseline by 1.06 and 1.19%, respectively, with an estimated treatment difference of 0.09% (95% CI 0.04 to 0.22%), indicating that degludec was noninferior to insulin glargine. Rates of hypoglycemia were similar, with nocturnal hypoglycemia and severe hypoglycemia occurring less frequently (p < 0.05) with degludec. Insulin degludec and insulin glargine decreased mean A1C concentrations by 1.10 and 1.18%, respectively, with an estimated treatment difference of 0.08% (95% CI 0.05 to 0.21%), meeting criteria for noninferiority for degludec. Rates of overall hypoglycemia and nocturnal hypoglycemia were lower in those treated with insulin Degludec, while rates of severe hypoglycemia were similar between groups. Diabetes Care 35: , Lancet 379: , Degludec vs. Glargine Degludec Can be mixed in one injection syringe with rapid acting insulin Day to day variability of absorption is significantly lower than glargine Flexibility in dosing Glargine Should not be mixed in one injection syringe with rapid acting insulin Day to day variability with glargine seen in multiple patient populations Requires once to twice daily administration Overall, Degludec is associated with improved glycemic control overall with less hypoglycemia Patient Populations who may Benefit from Tresiba Elderly Learning difficulties Dependent on caretakers or healthcare professionals for insulin administration Unable to achieve glycemic control despite optimized glycemic regimens Lantus pacakge insert, Sanofi, Diabetes Care 2015 Apr; 38(4): Tresiba Pacakge Insert, NovoNordisk,

3 Which of the Following is a Difference Between Insulin Degludec and Insulin Glargine? A. Insulin degludec can be mixed with insulin aspart in a syringe B. Insulin degludec can be inhaled C. Insulin glargine causes less hypoglycemia D. Insulin glargine offers more flexibility in dosing Lixisenatide (Adlyxin ) FDA approved: July, 2016 Glucagon like peptide receptor agonist (GLP 1 RA) MOA: improves glycemic control through effects on glucosedependent insulin secretion, glucagon secretion, gastric emptying, and satiety Shorter half life (2 5 hours), more impact on PPG compared with other GLP 1 RAs Lixisenatide. Micromedex 2.0. Available at: Accessed August, 2016 Safety/effectiveness evaluated in 10 clinical trials including 5400 patients with type 2 diabetes Superior to placebo Non inferior to exenatide BID and insulin glulisine Study Study Design Results GetGoal X GetGoal Duo2 Lixisenatide: A Me Too Drug? 634 patients, open label, randomized to lixisenatide 20mcg daily or exenatide 10mcg bid. 896 patients on basal insulin randomized to lixisenatide or insulin glulisine. After 24 weeks, similar reductions in A1C and FBG. More weight loss with exenatide ( 3.98 vs. 2.96kg) and fewer GI events with lixisenatide. After 26 weeks, lixisenatide non inferior to glulisine in A1C reduction ( 0.6% vs. 0.8%) and superior in weight loss (LS mean difference: 1.99kg). Rosenstock et al. Diabetes Care Oct; 36(10): , Anderson et al. Ther Adv Chronic Dis Jan; 7(1): GLP 1 RA Dosing Schedule (SC) CrCL Renal Dose Adjustments Albiglutide (Tanzeum ) 30mg 50mg weekly None ~1% A1c Lowering Dulaglutide (Trulicity ) mg weekly None ~1.5% Exenatide (Byetta ) 5mg 10mg BID 1 60 minutes before meals Exenatide extended 2mg weekly release (Bydureon ) Liraglutide (Victoza ) 0.6mg dailyx1 week, then mg daily Lixisenatide (Aldyxin ) GLP-1 RA Comparison 10mcg daily x 2 weeks, then 20mg daily, 1 hour before breakfast 30 50: use caution <30: not recommended 30 50: use caution <30: not recommended Mild to severe renal impairment: not recommended 30 50: use caution <30: not recommended ~1% ~1.5% ~1.5% ~0.9% PL Detail-Document, Comparison of GLP-1 Agonists. Pharmacist s Letter/Prescriber s Letter. December 2014 Lixisenatide. Micromedex 2.0. Available at: Accessed August, In the Pipeline: iglarlixi Lixisenatide + insulin glargine in a fixed ratio pen Daily dose range: units corresponding to lixisenatide 5 20mcg Which of the Following is an Important Patient Counseling Point for Lixisenatide? A. Take with food to avoid upset stomach B. Do not use if you are already taking insulin C. Common side effects include nausea and diarrhea D. Only needs to be injected once weekly Lixisenatide and Insulin Glargine/Lixisenatide Briefing Document. Available at: Accessed August 11 th,

4 Lesinurad (Zurampic ) Zurampic Clinical Trials FDA approved December, 2015 for hyperuricemia in gout MOA: reduces serum uric acid by inhibiting transporter proteins involved in uric acid reabsportion including uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4) Dose: 200mg QAM with food and in combo with a xanthine oxidase inhibitor Adverse Effects: headache, Scr increase, GERD Place in therapy: add on to allopurinol or febuxostat in patients not at target uric acid levels 3 randomized, placebo controlled studies Drugs Design Results Zurampic + allopurinol vs. allopurinol alone Zurampic + febuxostat vs. febuxostat alone 2 randomized 12 month trials (n=1213) 1 randomized 12 month trial A greater proportion of patients treated with Zurampic combination achieved UA<6mg/dL compared with allopurinol alone (54 vs 28% and 55 vs 23%). No major differences in gout flares from 6 12 months. More uric acid lowering with Zurampic combination. No significant difference in the rate of gout flares. Lesinurad package insert. Available at: Accessed August 12 th, 2016 Lesinurad package insert. Available at: Accessed August 12 th, 2016 Uric Acid Lowering Other Chronic Gout Drugs Drug MOA Usual Dose Place in Therapy Comments Allopurinol Febuxostat Xanthine oxidase inhibitor (XOI) Xanthine oxidase inhibitor (XOI) mg PO daily 40 80mg PO daily Probenecid Uricosuric mg PO BID Colchicine Anti inflammatory 0.6mg PO daily or BID for prophylaxis Pegloticase Catalyzes the oxidation of uric acid to allantoin 8mg IV infusion q 2 weeks 1 st line Generic/cheap 1 st line Brand/expensive Alternative 1 st line if CI or intolerance to XOI 1 st line for acute gout attacks and gout prophylaxis with uric acid lowering therapy Gout refractory to conventional therapy Many drug interactions Many drug interactions/ expensive Many adverse effects/ expensive Lesinurad package insert. Available at: Accessed August 12 th, 2016 Fleischmann et al. Rheumatology (2014) 53 (12): Khanna et al. Arthritis Care & Research Vol. 64, No. 10, October 2012, pp Zurampic Clinical Pearls Avoid if CrCL<45 ml/min Take with food at the same time as xanthine oxidase inhibitor Black box warning: acute renal failure Monitor uric acid, renal function Advise patients to drink 2L of fluid daily Max out allopurinol or febuxostat before adding Lesinurad package insert. Available at: Accessed August 12 th, 2016 Which of the Following Drugs/Doses is Most Appropriate to Combine with Zurampic for Gout Treatment? A. Colchicine 0.6mg PO daily B. Probenecid 500mg PO BID C. Allopurinol 100mg PO daily D. Febuxostat 80mg daily Assume normal renal function 4

5 Idarucizumab (Praxbind ) Praxbind : Important Points Bleeding reversal for dabigatran (Pradaxa ) due to uncontrolled life threatening bleeding or a need to undergo emergency surgery FDA approved October, 2015 First and only DOAC reversal agent MOA: humanized monoclonal antibody fragmentbinds to dabigatran and its metabolites with higher affinity than dabigatran to thrombin, neutralizing its anticoagulant effects Supplied: 2.5 GM/50 ML Dose: 5g (2 vials) IV 1 time dose Keep refrigerated, unopened vials protected from light may be stored at room temp up to 48 hours, 6 hours if in light Use solution within 1 hour of removing from vial Most common adverse effects (>5%): hypokalemia, constipation, fever, delirium Increases thromboembolic risk May restart dabigatran 24 hours later Praxbind package insert. Available at ingelheim.com/prescribing%20information/pis/praxbind/praxbind.pdf. Accessed Aug 11 th, Praxbind package insert. Available at ingelheim.com/prescribing%20information/pis/praxbind/praxbind.pdf. Accessed Aug 11 th, Praxbind : Clinical Trials Approved based on 3 clinical trials in healthy volunteers Patients given dabigatran and then various amounts of Praxbind to establish effective dose and side effects Median age: 36 years Accelerated FDA approval Ongoing trial in patients with life threatening or uncontrolled bleeding or who need emergency surgery/urgent procedures evidence. Accessed August 12 th, 2016 Praxbind : Clinical Trials (Cont) Study Study Design Results RE VERSE AD Goal: Determine safety/efficacy of idarucizumab 2arms of dabigatran: Group A (51 patients): lifethreatening bleeding Group B (39 patients): invasive surgery required that could not be delayed Over 90% received dabigatran for stroke prevention in afib All patients received 5g of IV idarucizumab Median age: 76.5 years Median hospitalization: 8 days Dilute thrombin time was normalized in 98% of patients in group A and 93% of patients in group B Ecarin clotting time normalized in 89% of group A and 88% group B 18 deaths overall (9 in each group) 5 thrombotic events 21 patients with severe adverse events Interim Analysis: plan to enroll ~300 patients Summary: Idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88 to 98% of patients Pollack CV et al. N ENGL J Med; 373;6 Praxbind is Used to Reverse Which Anticoagulant(s)? A. Warfarin only B. Dabigatran only C. Rivaroxaban only D. Any of the DOAC s E. Enoxaparin PCSK9 Inhibitors Indications: Treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease Place in therapy: Those who need additional LDL lowering despite maximally tolerated statin Effects on cardiovascular mortality have NOT been determined! N Engl J Med 2015; 373:

6 PCSK 9 Pharmacology A Comparison of Agents Evolocumab (Repatha ) FDA Approved August, 2015 Reduced LDL ~ 55 75% 140 mg SUB Q every 2 weeks Associated with angioedema Alirocumab (Praluent ) FDA Approved July, 2015 Reduced LDL 46 60% 75 mg SUB Q every 2 weeks Associated with drugneutralizing antibodes N Engl J Med 2015; 373: Which of the Following Statements is True Regarding PCSK 9 Inhibitors? A. They are less effective than statins at LDL lowering B. They are dosed via a weekly IV infusion C. They are associated with angioedema and drug neutralizing antibodies D. They reduce cardiovascular mortality Ivabradine (Corlanor ) FDA Approved April, 2015 Indications To reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure Left ventricular ejection fraction 35% Sinus rhythm with resting heart rate 70 beats per minute Must be on maximally tolerated doses of betablockers or have a contraindication to betablocker use Corlanor pacakge insert, Amgen, 2015 Ivabradine Mechanism of action Selectively and specifically inhibits the cardiac pacemaker current within the SA node that regulates heart rate Administration results in a dose dependent reduction in heart rate Cardiac effects are specific to SA node No effect on blood pressure No effect on myocardial contractility No effect on intra cardiac conduction Does not exhibit negative inotropic effects!!! Corlanor pacakge insert, Amgen, 2015 Ivabradine Dosing and Monitoring Initial Dose Dose Adjustments for Heart Rate Dosage Adjustments 5 mg twice daily with meals If heart rate > 60 bpm: 7.5 mg BID If heart rate < 50 bpm: 2.5 mg BID Efficacy monitoring: Blood pressure, heart rate, heart rhythm Dosage adjustments are required in patients at risk for hemodynamic compromise, heart conduction defects, sinus node dysfunction, and elderly patients Safety monitoring: Heart rate, dizziness, fatigue, syncope If heart rate < 50 bpm on 2.5 mg dose, Corlanor should be discontinued Corlanor pacakge insert, Amgen,

7 Clinical Data: SHIFT Study Primary Composite Endpoint Study Design Intervention Results: Efficacy Results: Safety Randomized, double blind, placebo controlled, parallel group study in patients with systolic HF, NYHA class II, III, IV symptoms, in a stable condition for >4 weeks, on guideline based medical therapy with unchanged HF medications and doses for >4 weeks, and with a documented hospital admission for worsening HF within the previous 12 months Patients were randomized to ivabradine 5mg BID (titrated to max 7.5mg BID) or matching placebo Background medications were continued which included betablockers, ACEinhibitors, diuretics, and aldosterone antagonists Ivabradine was associated with a significant reduction in the primary outcome (24% in the ivabradine group vs. 29% in the placebo group) (95% CI ; p<0.0001) Cardiovascular deaths & all cause deaths were not significantly reduced in the ivabradine group (p=0.128) but deaths due to HF (3% ivabradine vs. 5% placebo; p=0.014) & hospital admissions for worsening heart failure decreased significantly (16% ivabradine vs. 21% placebo; p<0.0001) Ivabradine was associated with fewer serious adverse events in the ivabradine group (45% ivabradine vs. 48% placebo; p=0.025) Lancet Sep 11; 376(9744): Lancet Sep 11; 376(9744): ACE/ARB Stepwise Approach to Treatment of Heart Failure Beta blocker Aldosterone Antagonist If heart rate > 70 bpm consider addition of Ivabradine Sacubitril/Valsartan (Entresto ) FDA Approved July, 2015 Indications To reduce the risk of hospitalization and cardiovascular death in patients with chronic heart failure (NYHA Class II IV) and reduced ejection fraction Useful in patients who have progressed in heart failure severity despite the use of ACEinhibitor therapy Entresto package insert, Novartis, 2015 Sacubitril/Valsartan PARADIGM Study Study Design Intervention Results: Efficacy Results: Safety Mechanism of action due to combination neprilysin inhibiton (sacubitril) + ARB Cardiovascular effects Enhanced levels of peptides due to inhibition of peptide degradation Vasodilation Sodium loss Decrease in cardiac and vascular remodeling Inhibition of the effects of angiotensin II Vasodilation Inhibits aldosterone release Entresto package insert, Novartis, 2015 Randomized, double blind, phase 3 trial comparing Entresto to enalapril in patients with chronic heart failure with a reduced ejection fraction currently on a beta blocker and ACE inhibitor therapy Patients were randomized to Entresto 200 mg vs. enalapril 10 mg BID Patients who were randomized to Entresto had a significant reduction n the incidence of death from cardiovascular causes, hospitalization due to heart failure, and death from any cause Entresto was associated with an increased incidence of hypotension, although enalapril was associated with an increased incidence of hyperkalemia, and serum creatinine increase N Engl J Med 2014; 371:

8 Dosing and Monitoring Initial Doses Target Dose Dosage Adjustments Previous ACE I or ARB 49/51 mg bid No ACE I or ARB or low doses 24/26 mg bid Titrate after 2 4 weeks to 97/103 mg bid as tolerated by the patient Dosage adjustments are required in severe renal and moderate hepatic impairment Use is not recommended in severe hepatic impairment If switching from another ACE/ARB therapy, 36 hour washout period is recommended Efficacy monitoring: Blood pressure Safety monitoring: Serum creatinine, Electrolytes What is the Mechanism of Action of Ivabradine? A. Improves glycemic control in adults with diabetes mellitus B. Inhibits the cardiac placement current within the SA node that regulates heart rate C. Reduces LDLR degradation and increases LDLR reutilization D. Binds to dabigatran neutralizing its anticoagulant effects Entresto package insert, Novartis, 2015 Monoclonal Antibodies for Asthma Mechanism of action Asthma Monoclonal Antibodies Omalizumab (Xolair ) IgE antibody Resilizumab (Cinquair ) (March 2016) Interleukin 5 antagonist monoclonal antibody (IgG1 kappa) Mepolizumab (Nucala ) (November 2015) Interleukin 5 antagonist monoclonal antibody (IgG1 kappa) Three hallmark signs of asthma 1) Airway inflammation 2) Airway hyperresponsiveness 3) Reversible airway obstruction ERJ Open Research : Indications Dosing Adverse effects Moderate to severe persistent asthma in patients 6 years of age and older with a positive skin test to aeroallgen inadequately controlled on ICS 75 to 375 mg SC every 2 or 4 weeks (dependent on IgE level and weight) Arthralagias, myalgias, headache, viral infections, injection site reactions Add on maintenance treatment of patients with severe asthma aged 18 years with an eosinophilic phenotype 3 mg/kg IV q4wk infused over minutes Myalgias, elevated CPK, oropharyngeal pain Anaphylaxis reactions are possible, and have occurred with all of the above!!! Add on maintenance treatment of patients with severe asthma > 12 years 100 mg SQ q 4 weeks Headache, injection site reactions, back pain, and fatigue Nucala pacakge insert. Glasko Smith Klein, Omalizumab pacakge insert, Novartis, Cinquair pacakge insert, Teva Pharmaceuticals, Which of the Following Agents Requires Monitoring in a Physician s Office After Administration Due to Anaphylaxis Concerns? A. Xolair B. Nucalla C. Cinquair D. All of the above Indications Novel Approaches to Hepatitis C Virus (HCV) Epclusa (sofosbuvir/velpatasvir) (June 2016) Indicated for adults with HCV infection genotypes 1, 2, 3, 4, 5, and 6 with and without cirrhosis Zepatier (Elbasvir grazoprevir) (January 2016) Indicated for adults with HCV with or without ribavirin for treatment of chronic HCV genotypes 1 or 4 infection in adults Daklinza (Daclatasvir) (July 2016) Indicated for adults with HCV genotypes 1 or 3 Concomitant therapy Approved for use in combination Does not need to be administered with Must be taken with sofosbuvir, or with the drug ribavirin interferon and ribavirin with sofosbuvir + ribavirin Adverse Effects Headache, fatigue Fatigue, headache, nausea, anemia* Headache, fatigue,nausea, anemia Dosing Clinical Pearls One tablet (400 mg of sofosbuvir and 100 mg of velpatasvir) taken orally once daily with or without food First drug available that treats all major genotypes of HCV Bradycardia is a concern; Epcusa should not be used with amiodarone One tablet taken orally once daily with or without food (Tablets: 50 mg elbasvir and 100 mg grazoprevir) Breakthrough therapy for patients with hepatitis C genotype 1 disease who have ESRD or HD, and for patients with hepatitis C genotype 4 60 mg once daily Dose adjustments necessary for CYP3A medications Daklinza package insert, BMS, Epclusa package insert, Gilead Sciences, Zapatier package insert, Merck,

9 Which of the Following Agents Can be Administered Without Ribavirin for Treatment of HCV? A) Epclusa B) Daklinza C) Zepatier D) All must be administered with ribavirin Other Notable New Agents Drug Name Generic Approval Date Indication Xlidra lifitegrast ophthalmic 7/11/16 Dry eye disease solution Zinbryta Daciluzumab 5/27/16 Multiple sclerosis Nuplazid Pimavanserin 4/29/16 Hallucinations/delusions associated with Parkinson s Disease Defitelio defibrotide sodium 3/30/16 Hepatic veno occlusive disease s/p stem cell transplant Taltz ixekizumab 3/22/16 Plaque psoriasis Anthim obiltoxaximab 3/18/16 Inhalational anthrax Briviact brivaracetam 2/18/16 Partial onset seizures Uptravi Selexipag 12/22/15 Pulmonary arterial hypertension Kanuma Sebelipase alfa 12/8/15 Lysosomal acid lipase (LAL) deficiency Veltassa Patiromer 10/21/15 Hyperkalemia Vraylar Cariprazine 9/17/15 Schizophrenia/bipolar disorder Summary Several groundbreaking new drugs for chronic disease states over the past year Questions? Most clinic guidelines not updated yet to reflect new drug choices Knowledge of new agents and clinical judgment is essential when treating patients Lalita Prasad Reddy, PharmD, MS, BCACP, BCPS, CDE lprasad@csu.edu Diana Isaacs, Pharm.D., BCPS, BC ADM, CDE isaacsd@ccf.org 9