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New Drug Update Stephanie Ha+oy, PharmD, BCPS, CGP Chris7ne Eisenhower, PharmD, BCPS Schwar7ng-‐Senior Symposium March 17, 2015 1 Faculty Disclosures Drs. Ha(oy and Eisenhower have no actual or poten8al conﬂicts of interest associated with this presenta8on. 2 Objec7ves A<er this presenta8on, audience members should be able to: 1.  List indica7ons, mechanisms of ac7on, dosing, and adverse/side eﬀects of new drug products. 2.  Describe the poten7al place in therapy for each of the new drugs discussed. 3.  Discuss the poten7al social or economic implica7ons associated with each of the new drugs discussed. 3 New Drug Index 2014 1. 
Akynzeo® (netupitant/palonosetron) 10.  Saxenda® (liraglu7de) 2. 
Belsomra® (suvorexant) 11.  Afrezza® (insulin human) 3. 
Jardiance® (empagliﬂozin) 12.  Jublia® (eﬁnaconazole) 4. 
Movan7k™ (naloxegol) 5. 
Striverdi® Respimat® (olodaterol) 14.  Dalvance™ (dalbavancin) 6. 
Zon7vity™ (vorapaxar) 15.  Plegridy™ (peginterferon beta-‐1a) 7. 
Entyvio® (vedolizumab) 16.  Lemtrada™ (alemtuzumab) 8. 
Tanzeum™ (albiglu7de) 17.  Harvoni™ (ledipasvir/sofosbuvir) 9. 
Trulicity™ (dulaglu7de) 18.  Viekira Pak™ (ombitasvir/paritaprevir/
13.  Rapivab™ (peramivir) ritonavir with dasabuvir) 4 AKYNZEO® (NETUPITANT/PALONOSETRON) SELECTIVE 5-‐HT3 RECEPTOR ANTAGONIST/
SUBSTANCE P/NEUROKININ-‐1 RECEPTOR ANTAGONIST 5 Akynzeo® (netupitant/palonosetron) •  Manufacturer: Eisai •  ClassiﬁcaHon: Substance P neurokinin-‐1 (NK1) and serotonin (5-‐HT3) antagonist •  IndicaHon: Preven7on of chemotherapy induced nausea/vomi7ng 6 Akynzeo® (netupitant/palonosetron) Dosage Form Strength Package Size AWP Capsule 300mg/0.5mg 1 $571.20 •  300 mg/0.5 mg capsule –  1 capsule in each carton –  White/Brown –  Imprint: “HE1” 7 Pharmacology •  Mechanism of AcHon: –  Both agents target cri7cal signaling pathways associated with inducing CINV •  Netupitant – NK1 receptor antagonist; prevents CINV during acute and delayed phase •  Palonosetron – 5-‐HT3 receptor antagonist; prevents acute phase (within 24 hours) CINV Akynzeo® (netupitant/palonosetron) 8 Dosing •  1 capsule orally 60 minutes prior to chemotherapy •  Renal impairment –  No dosage adjustment in mild or moderate impairment –  Avoid use in severe impairment or ESRD •  Hepa7c impairment –  Mild (Child-‐Pugh score 5-‐8) = no adjustment –  Severe (Child-‐Pugh score >9) = avoid use 9 Akynzeo® (netupitant/palonosetron) Safety Common Side Eﬀects >10 % None 1 to 10% Headache, fa7gue, dyspepsia, cons7pa7on, erythema, weakness Serious/Rare Side Eﬀects None ContraindicaHons Hypersensi7vity to 5-‐HT3 antagonists Warnings/PrecauHons Serotonin syndrome Avoid use with strong CYP3A4 inducers (e.g., rifampin) Akynzeo® (netupitant/palonosetron) 10 Clinical Pearls •  Store in a closed container at room temperature, away from heat, moisture, and direct light •  Take with or without food •  Review instruc7ons for opening package to assist with administra7on Akynzeo® (netupitant/palonosetron) 11 Comparison to Other Drugs •  Combina7on was more eﬀec7ve at preven7ng CINV than palonosetron alone –  Pa7ents experiencing no vomi7ng or rescue medica7on for nausea 98.5% vs. 89.7% –  Delayed phase 90.4% vs. 80.1% –  Overall 89.6% vs. 76.5% •  Netupitant is an alterna7ve to aprepitant –  Aprepitant is a CYP2C9 inducer Akynzeo® (netupitant/palonosetron) 12 Place in Therapy •  Highly emetogenic chemotherapy (e.g., cispla7n) managed with three medica7ons –  Akynzeo® + dexamethasone •  Moderate emetogenic chemotherapy (e.g., oxalipla7n) managed with two medica7ons –  5-‐HT3 antagonist + dexamethasone Akynzeo® (netupitant/palonosetron) 13 BELSOMRA® (SUVOREXANT) OREXIN RECEPTOR ANTAGONIST 14 Belsomra® (suvorexant) •  Manufacturer: Merck •  ClassiﬁcaHon: Orexin receptor antagonist (controlled substance – CIV) •  IndicaHon: Insomnia characterized by diﬃcul7es with sleep onset and/or disturbance 15 Belsomra® (suvorexant) Dosage Form Strength Package Size AWP Tablet 5 mg, 10mg, 15mg, 20mg 30 Not available 16 Pharmacology •  Mechanism of AcHon: –  Selec7ve antagonist for orexin receptors •  Alters the signaling of neurotransmi+ers that are responsible for regula7ng the sleep-‐wake cycle •  Blocks orexin A and B that promote wakefulness by ac7ng on orexin receptors OX1R and OX2R •  Drive to wake is suppressed 17 Belsomra® (suvorexant) Dosing •  10 mg orally taken no more than once a night, within 30 minutes of bed7me and with at least 7 hours available prior to awakening –  Pa7ents should use lowest eﬀec7ve dose –  Maximum: 20 mg •  No renal dose adjustment necessary •  Not recommended in severe hepa7c impairment Belsomra® (suvorexant) 18 Safety Common Side Eﬀects >10 % Drowsiness (dose-‐dependent, more common in females) 1 to 10% Headache, diarrhea, cough (more common in females), xerostomia (more common in females) Serious/Rare Side Eﬀects Suicidal idea7on, sleep paralysis (undeﬁned incidence) ContraindicaHons History of narcolepsy Warnings/PrecauHons Abnormal thinking/behavioral changes, CNS depression, sleep-‐
related ac7vi7es Use with cau7on if history of depression and suicidal idea7on 19 or drug abuse Belsomra® (suvorexant) Clinical Pearls •  Pa7ents should not take this medicine if they are not able to sleep or rest for at least 7 hours before they need to be ac7ve again •  Take on an empty stomach (7me to eﬀect may be delayed if taken aver a meal) •  Concomitant use with strong inhibitors of CYP3A (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir) requires does reduc7on Belsomra® (suvorexant) 20 Comparison to Other Drugs •  New mechanism of ac7on, only one in its class •  Similar adverse eﬀect proﬁle when compared to other hypno7c agents Belsomra® (suvorexant) 21 JARDIANCE® (EMPAGLIFLOZIN) SODIUM-‐GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR 22 Jardiance® (empagliﬂozin) •  Manufacturer: Boehringer Ingelheim •  ClassiﬁcaHon: Sodium-‐glucose cotransporter 2 (SGLT2) inhibitor •  IndicaHon: Treatment of type 2 diabetes mellitus in combina7on with diet and exercise 23 Jardiance® (empagliﬂozin) Dosage Form Strength Package Size AWP Tablet 10 mg 30 $361.06 90 $1083.08 30 $361.06 90 $1083.08 25 mg •  10 mg tablets –  Pale yellow, round, ﬁlm-‐coated –  Imprint: “S 10” •  25 mg tablets –  Pale yellow, oval, ﬁlm-‐coated –  Imprint: “S 25” 24 Pharmacology •  Mechanism of AcHon: –  Inhibits reabsorp7on of ﬁltered glucose in the proximal renal tubules –  Lowers renal threshold for glucose thus increasing urinary glucose excre7on Jardiance® (empagliﬂozin) Dosing •  10 mg once daily in the morning –  Maximum: 25 mg daily •  Renal dose adjustments –  eGFR ≥ 45 mL/minute/1.73m2 = no adjustment –  eGFR < 45 mL/minute/1.73m2 = do not ini7ate therapy, discon7nue if eGFR remains < 45 –  eGFR < 30 mL/minute/1.73m2, ESRD or dialysis = contraindicated •  No adjustment for hepa7c impairment Jardiance® (empagliﬂozin) 26 Safety Common Side Eﬀects >10 % Hypoglycemia, UTI/cys77s 1 to 10% Increased LDL, dyslipidemia, increased thirst, respiratory infec7ons Serious/Rare Side Eﬀects Decreased eGFR, hypotension, increased SCr, hypovolemia ContraindicaHons Hypersensi7vity to empaglifozin, severe renal impairment (eGFR < 30 mL/min/1.73m2), ESRD, or dialysis Warnings/PrecauHons Genital mycoc7c infec7ons, symptoma7c hypotension, lipid abnormali7es, renal eﬀects, UTIs Do not use in pa7ents with diabe7c ketoacidosis or type 1 27 diabetes. Jardiance® (empagliﬂozin) Clinical Pearls •  Indicated for use as monotherapy or in combina7on with other an7diabe7cs •  Take in the morning, with or without food •  Renal dose adjustment based on eGFR, not on crea7nine clearance (CrCl) Jardiance® (empagliﬂozin) 28 Comparison to Other Drugs •  Comparable to other SGLT2 inhibitors canaglifozin and dapaglifozin –  Advantages: •  Similar renal dosing to canagliﬂozin •  Less restric7ve renal dosing and less risk of bladder cancer than dapagliﬂozin –  Disadvantages: •  Addi7ve beneﬁt when used in combina7on with mezormin is s7ll being inves7gated •  Causes 1 more yeast infec7on for every 26 women and 38 men treated for 6 months 29 Jardiance® (empagliﬂozin) Place in Therapy •  Generally thought to be second-‐ or third-‐line op7on •  SGLT2 inhibitors: –  Decrease HgbA1c by 0.7-‐1% –  Average weight loss of 4 to 7 pounds –  Lower systolic blood pressure by 3 to 5 mmHg –  May raise LDL concentra7ons Jardiance® (empagliﬂozin) 30 MOVANTIK™ (NALOXEGOL) OPIOID ANTAGONIST 31 Movan7k™ (naloxegol) •  Manufacturer: AstraZeneca •  ClassiﬁcaHon: Peripherally ac7ng opioid antagonist (controlled substance – CII) •  IndicaHon: Opioid-‐induced cons7pa7on (OIC) for adults with chronic non-‐cancer related pain 32 Movan7k™ (naloxegol) Dosage Form Strength Package Size AWP Tablet 12.5 mg Not available Not available 25 mg Not available Not available 33 Pharmacology •  Mechanism of AcHon: –  μ-‐opioid receptor antagonist –  Speciﬁc to peripheral 7ssues (e.g., gastrointes7nal tract) due to pegyla7on that decreases passive permeability and CNS penetra7on at recommended dosages –  Limited interference with centrally mediated analgesia Movan7k™ (naloxegol) 34 Dosing •  25 mg once daily in the morning on an empty stomach –  12.5 mg once daily if not tolerated –  Discon7nue all maintenance laxa7ve therapy prior to use –  Concomitant use with moderate CYP3A4 inhibitors should be avoided if possible (if necessary, use 12.5 mg once daily) •  Renal Impairment: –  CrCl < 60 mL/min, start at 12.5 mg once daily; if tolerated, may increase to 25 mg daily •  Avoid use in severe hepa7c impairment 35 Movan7k™ (naloxegol) Safety Common Side Eﬀects >10 % Abdominal pain 1 to 10% Headache, hyperhidrosis, diarrhea, nausea, ﬂatulence, vomi7ng Serious/Rare Side Eﬀects Gastrointes7nal (GI) perfora7on, joint pain, yawning ContraindicaHons History of serious or severe hypersensi7vity reac7on to naloxegol or any components of formula7on, known or suspected GI perfora7on or increased risk of recurrent obstruc7on, concomitant use of strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole) Warnings/PrecauHons GI perfora7on, opioid withdrawal symptoms Movan7k™ (naloxegol) 36 Clinical Pearls •  Shown to be eﬀec7ve in pa7ents on opioids for at least 4 weeks •  Naloxegol should be taken on empty stomach at least 1 hour prior or 2 hours aver the ﬁrst meal of the day •  Do not cut, crush or chew tablet •  May reintroduce laxa7ves as needed if subop7mal response to naloxegol aver 3 days •  Discon7nue if opioid analgesic is discon7nued Movan7k™ (naloxegol) 37 Comparison to Other Drugs •  First medica7on in this class to be available in an oral formula7on –  Methylnaltrexone is in the same class, but is only available as a subcutaneous injec7on •  Lubiprostone was approved for OIC last year and acts on CIC-‐2 chloride channels, bypassing an7secretory ac7on of opiates Movan7k™ (naloxegol) 38 Assessment Ques7on #1 Which of the following new drugs is the ﬁrst in its class, selec7vely inhibi7ng orexin receptors responsible for suppressing the drive to wake? a. 
b. 
c. 
d. 
Akynzeo® (netupitant/palonosetron) Belsomra® (suvorexant) Jardiance® (empagliﬂozin) Movan7k™ (naloxegol) 39 STRIVERDI® RESPIMAT® (OLODATEROL) LONG ACTING BETA-‐2 AGONIST (LABA) 40 Striverdi® Respimat® (olodaterol) •  Manufacturer: Boehringer Ingelheim •  ClassiﬁcaHon: Long-‐ac7ng β-‐2 agonist (LABA) •  IndicaHon: Maintenance treatment of chronic obstruc7ve pulmonary disease (COPD) (e.g., chronic bronchi7s and/or emphysema) 41 Striverdi® Respimat® (olodaterol) Dosage Form Strength Package Size AWP Aersosol solu7on for inhala7on 2.5 mcg/actua7on (4 g) 28 actua7ons $87.19 60 actua7ons $186.84 42 Pharmacology •  Mechanism of AcHon: –  Ac7vates β-‐2 airway receptors, resul7ng in the increased ac7vity of adenyl cyclase and a subsequent increase in cAMP synthesis –  Induce bronchodila7on by relaxa7on of airway smooth muscle cells –  Greater aﬃnity for β-‐2 receptors than for other β receptors 43 Striverdi® Respimat® (olodaterol) Dosing •  Two inhala7ons once daily –  Maximum: 2 inhala7ons (5 mcg) per day •  No hepa7c or renal dose adjustments necessary Striverdi® Respimat® (olodaterol) 44 Safety Black Box Warning: Use of LABAs increases the risk of asthma-‐related death. Common Side Eﬀects >10 % Nasopharyngi7s 1 to 10% Skin rash, arthralgia, bronchi7s, URI, UTI, cough, back pain, dizziness, diarrhea, cons7pa7on Serious/Rare Side Eﬀects Pneumonia, ECG abnormali7es, transient hypokalemia, increased blood pressure and heart rate, hyperglycemia, lung malignancies ContraindicaHons Monotherapy in treatment of asthma, possible risk of allergenic cross-‐sensi7vity for sympathomime7cs Warnings/PrecauHons Asthma-‐related death, bronchospasm, hypersensi7vity Striverdi® Respimat® (olodaterol) reac7ons Use with cau7on in pa7ents with cardiovascular disease, diabetes, hyperthyroidism, hypokalemia, and epilepsy Clinical Pearls •  Inhaler priming: –  First 7me = actuate the inhaler toward the ground un7l aerosol cloud is visible, then actuate three more 7mes –  No use in > 3 days = actuate once to prime –  No use in > 21 days = repeat ﬁrst 7me priming procedure •  Pneumonic “TOP” to help remember steps: –  Turn the clear base –  Open the cap and close lips around mouthpiece –  Press the dose-‐release bu+on and inhale •  Do not use as rescue therapy to treat acute bronchospasm or pa7ent with acutely decompensa7ng COPD Striverdi® Respimat® (olodaterol) 46 Comparison to Other Drugs •  Clinical studies showed improvement in lung func7on with olodaterol were comparable to 7otropium (LAMA) and formoterol (LABA) •  Once daily administra7on similar to indacaterol, but no capsule for administra7on •  Formoterol and salmeterol (both twice daily) are indicated for maintenance treatment of asthma 47 Striverdi® Respimat® (olodaterol) Place in Therapy •  LABAs and LAMAs are considered ﬁrst-‐line therapy op7ons for mild to moderate COPD •  Pa7ents familiar with Respimat® products may minimize device confusion •  LABA therapy should be selected based on cost, availability, and pa7ent response Striverdi® Respimat® (olodaterol) 48 ZONTIVITY™ (VORAPAXAR) PROTEASE-‐ACTIVATED RECEPTOR-‐1 (PAR-‐1) ANTAGONIST 49 Zon7vity™ (vorapaxar) •  Manufacturer: Merck •  ClassiﬁcaHon: Protease-‐ac7vated receptor-‐1 (PAR-‐1) antagonist •  IndicaHon: Secondary prophylaxis for myocardial infarc7on, stroke, and thrombosis in pa7ents with history of myocardial infarc7on or with peripheral vascular disease 50 Zon7vity™ (vorapaxar) Dosage Form Strength Package Size AWP Tablet 2.08 mg 30 $320.76 90 $962.28 100 (10x10 blister) $1069.20 51 Pharmacology •  Mechanism of AcHon: –  Compe77ve antagonist of the PAR-‐1 expressed on platelets •  Inhibits thrombin-‐
induced and thrombin receptor agonist pep7de (TRAP)-‐induced platelet aggrega7on Zon7vity™ (vorapaxar) 52 Dosing •  2.08 mg once daily in combina7on with low dose aspirin and/or clopidogrel –  There is no clinical data regarding the use of vorapaxar as monotherapy or with an7platelet agents other than aspirin and clopidogrel •  Use not recommended in severe hepa7c impairment •  No dose adjustments in renal impairment 53 Zon7vity™ (vorapaxar) Safety Black Box Warning: Do not use in pa7ents with ac7ve pathological bleeding, history of stroke, TIA, or intracranial bleeding Common Side Eﬀects >10 % Bleeding and hemorrhage 1 to 10% Depression, anemia, iron deﬁciency, skin rash, re7nopathy Serious/Rare Side Eﬀects Hemorrhagic death, intracranial hemorrhage (ICH) ContraindicaHons History of stroke, TIA, or ICH; ac7ve pathological bleeding Warnings/PrecauHons Increased risk of bleeding (including ICH and fatal bleeding) Use not recommended in severe hepa7c impairment Zon7vity™ (vorapaxar) 54 Clinical Pearls •  Administer with or without regard to food •  Monitor for signs of bleeding -  Do not use in combina7on with prasugrel or 7cagrelor -  Long half-‐life (approximately 4 weeks) -  No an7dote available •  Drug interac7ons with strong CYP3A4 inhibitors (e.g., clarithromycin) or inducers (e.g., phenytoin) 55 Zon7vity™ (vorapaxar) Place in Therapy •  First-‐in-‐class an7platelet –  Vorapaxar has a unique mechanism of ac7on compared to P2Y12 adenosine diphosphaste receptor inhibitors (prasugrel, 7cagrelor) •  Beneﬁt for pa7ents at very high cardiovascular risk should outweigh risk of bleeding Zon7vity™ (vorapaxar) 56 ENTYVIO® (VEDOLIZUMAB) SELECTIVE ADHESION-‐MOLECULE INHIBITOR 57 Entyvio® (vedolizumab) •  Manufacturer: Takeda Pharmaceu7cals •  ClassiﬁcaHon: Selec7ve adhesion-‐molecule inhibitor •  IndicaHon: Treatment of moderately to severely ac7ve Crohn’s disease or ulcera7ve coli7s in pa7ents who have had an inadequate response with conven7onal therapy (e.g., cor7costeroids, immunomodulators, TNF-‐α inhibitors) 58 Entyvio® (vedolizumab) Dosage Form Strength Package Size AWP Powder for injec7on 300 mg 1 $5,782.80 59 Pharmacology •  Mechanism of AcHon: –  Binds to α-‐4-‐β-‐7 integrin blocking its interac7on with mucosal addressin cell adhesion molecule-‐1 (MAdCAM-‐1) reducing the inﬂammatory process –  Inhibits the migra7on of memory T-‐lymphocytes across the endothelium into inﬂamed gastrointes7nal parenchymal 7ssue Entyvio™ (vedolizumab) 60 Dosing •  300 mg IV infusion over 30 minutes –  Given at weeks 0, 2, and 6 –  Maintenance regimen every 8 weeks –  Discon7nue therapy in pa7ents who show no evidence of therapeu7c beneﬁt by week 14 •  Hepa7c: reports of hepa77s, elevated transaminase and/or bilirubin •  No renal dose adjustment 61 Entyvio™ (vedolizumab) Safety Common Side Eﬀects >10 % Headache, an7body development, arthralgia, nasopharyngi7s 1 to 10% Fa7gue, pruritus, skin rash, nausea, elevated LFTs, URTIs Serious/Rare Side Eﬀects Hepa77s, hypersensi7vity reac7ons, infec7ons, malignant neoplasm ContraindicaHons Serious or severe hypersensi7vity to vedolizumab or any component of the formula7on Warnings/PrecauHons Hypersensi7vity reac7ons, infec7ons, liver injury, progressive mul7focal leukoencephalopathy Entyvio™ (vedolizumab) 62 Clinical Pearls •  Use in cau7on if history of PML when treated with another integrin receptor antagonist •  Do not administer live or live a+enuated vaccines Entyvio™ (vedolizumab) 63 Comparison to Other Drugs •  Pa7ents in clinical trials did not experience PML -  FDA warning with natalizumab prompted by PML occurring in 1 in 1000 pa7ents -  Natalizumab blocks α-‐4 in the brain compared to α-‐4-‐
β-‐7 which is not expressed in the blood-‐brain barrier •  Has the poten7al to be a ﬁrst-‐line treatment based on ﬁndings demonstra7ng steroid-‐free clinical remission and maintenance of clinical response and remission Entyvio™ (vedolizumab) 64 TANZEUM™ (ALBIGLUTIDE) GLUCAGON-‐LIKE PEPTIDE-‐1 (GLP-‐1) RECEPTOR AGONIST 65 Tanzeum™ (albiglu7de) •  Manufacturer: GlaxoSmithKline •  ClassiﬁcaHon: Glucagon-‐like pep7de-‐1 (GLP-‐1) receptor agonist (incre7n mime7c) •  IndicaHon: Treatment of type 2 diabetes mellitus in combina7on with diet and exercise 66 Tanzeum™ (albiglu7de) Dosage Form Strength Package Size AWP Pen-‐injector, Subcutaneous 30 mg 1 pen $391.15 50 mg $391.15 67 Pharmacology •  Mechanism of AcHon: –  GLP-‐1 released aver inges7on of carbohydrates or fats –  Augments glucose dependent insulin synthesis and secre7on –  Slows gastric emptying Tanzeum™ (albiglu7de) 68 Dosing •  30 mg subcutaneously once weekly –  May increase to 50 mg once weekly if inadequate glycemic response •  No hepa7c or renal dose adjustments –  Increase in gastrointes7nal events with reduced renal clearance –  Use cau7on when ini7a7ng or escala7ng doses when used in combina7on with other an7diabe7cs 69 Tanzeum™ (albiglu7de) Safety Black Box Warning: Development of thyroid C-‐cell tumors in animal studies.* Common Side Eﬀects >10 % Diarrhea, nausea , hypoglycemia, local injec7on site reac7on, URTI 1 to 10% Atrial ﬁbrilla7on, GERD, vomi7ng, an7body development Serious/Rare Side Eﬀects Appendici7s, increased serum ALT and bilirubin, pancrea77s ContraindicaHons Severe hypersensi7vity to albiglu7de or any component of the formula7on, personal or family history of medullary thyroid carcinoma (MTC)*, history of mul7ple endocrine neoplasia syndrome type 2 (MEN2)* Warnings/PrecauHons Hypersensi7vity reac7ons, pancrea77s May aﬀect rate/extent of absorp7on of oral medica7ons Use not recommended in pa7ents with pre-‐exis7ng severe GI 70 disease, use with cau7on in renal impairment Tanzeum™ (albiglu7de) Clinical Pearls •  Administered any 7me of the day, with or without meals •  Powder needs to be recons7tuted -  Do not shake the pen to reduce foaming -  Must wait 15 minutes or 30 minutes before injec7ng for the 30-‐mg pen and 50-‐mg pen, respec7vely -  Wait 10 minutes if in a health care environment -  Use within 8 hours of recons7tu7on •  Causes less nausea than exena7de, dulaglu7de, and liraglu7de Tanzeum™ (albiglu7de) 71 TRULICITY™ (DULAGLUTIDE) GLUCAGON-‐LIKE PEPTIDE-‐1 (GLP-‐1) RECEPTOR AGONIST 72 Trulicity™ (dulaglu7de) •  Manufacturer: Lilly •  ClassiﬁcaHon: Glucagon-‐like pep7de-‐1 (GLP-‐1) receptor agonist (incre7n mime7c) •  IndicaHon: Treatment of type 2 diabetes mellitus in combina7on with diet and exercise 73 Trulicity™ (dulaglu7de) Dosage Form Strength Package Size AWP Solu7on for injec7on 0.75 mg/0.5 mL 4 pens (1 pen = 0.5ml) $585.98 1.5 mg/0.5 mL 74 Pharmacology •  Mechanism of AcHon: –  GLP-‐1 released aver inges7on of carbohydrates or fats –  Augments glucose dependent insulin synthesis and secre7on –  Slows gastric emptying 75 Trulicity™ (dulaglu7de) Dosing •  0.75 mg subcutaneously once weekly –  May increase to 1.5 mg once weekly if inadequate glycemic response –  Maximum: 1.5 mg once weekly •  No hepa7c or renal dose adjustments - Use cau7on when ini7a7ng or escala7ng doses when used in combina7on with other an7diabe7cs Trulicity™ (dulaglu7de) 76 Safety Black Box Warning: Development of thyroid C-‐cell tumors in animal studies.* Common Side Eﬀects >10 % Nausea, diarrhea, vomi7ng, abdominal pain 1 to 10% Sinus tachycardia, fa7gue, hypoglycemia, prolonged PR interval, ﬁrst degree heart block Serious/Rare Side Eﬀects Acute renal failure, chronic renal failure, increased serum amylase and lipase, pancrea77s ContraindicaHons Serious hypersensi7vity to dulaglu7de or any component of the formula7on, personal or family history of medullary thyroid carcinoma (MTC)*, history of mul7ple endocrine neoplasia syndrome type 2 (MEN2)* Warnings/PrecauHons Hypersensi7vity reac7ons, pancrea77s Avoid use in pa7ents with pre-‐exis7ng severe GI disease, use with cau7on in hepa7c or renal impairment Not for use in type 1 diabetes, diabe7c ketoacidosis, or severe 77 abdominal or intes7nal problems Trulicity™ (dulaglu7de) Clinical Pearls •  Can be administered any 7me of day with or without meals •  Inject subcutaneously into the upper arm, thigh, or abdomen using a diﬀerent injec7on site each week •  Pens can be kept at room temperature for up to 14 days •  Drug-‐drug interac7on with cor7costeroids and thiazide diure7cs (cor7costeroids and thiazides may diminish the eﬀect of dulaglu7de) •  Risk of severe hypoglycemia is higher in elderly pa7ents Trulicity™ (dulaglu7de) 78 Comparison to Other Drugs •  Other GLP-‐1 agonists include exena7de, exena7de ER, albiglu7de, and liraglu7de -  More weight loss and HgbA1c lowering with dulaglu7de compared to exena7de and albiglu7de -  Once weekly administra7on compared to exena7de (twice daily) and liraglu7de (once daily) -  Administra7on does not require recons7tu7on by pa7ent (albiglu7de, exena7de ER) •  AWARD-‐1 placebo controlled, phase 3 trial -  At 26-‐weeks, mean HgbA1c reduc7on 1.5% with dulaglu7de vs. 1.0% with exena7de vs. 0.5% with placebo –  At 52 weeks, 57% of the dulaglu7de group achieved target HgbA1c of ≤ 6.5% vs. 35% in the exena7de group 79 Trulicity™ (dulaglu7de) Place in Therapy •  Not recommended for ﬁrst-‐line therapy in pa7ents inadequately controlled on diet and exercise alone •  Possible adjunct to mezormin •  Selec7on based on preference of pen devices, pa7ent tolerance, and cost Trulicity™ (dulaglu7de) 80 Assessment Ques7on #2 Which of the follow describes the mechanism of ac7on of Zon7vity™ (vorapaxar)? a.  GLP-‐1 inhibitor b.  Long-‐ac7ng β-‐2 agonist c.  α-‐4-‐β-‐7 integrin inhibitor d.  PAR-‐1 antagonist 81 82 SAXENDA® (LIRAGLUTIDE) GLUCAGON-‐LIKE PEPTIDE-‐1 (GLP-‐1) RECEPTOR AGONIST 83 Saxenda® (liraglu7de) •  Manufacturer: Novo Nordisk •  ClassiﬁcaHon: GLP-‐1 receptor agonist •  IndicaHon: Adjunct to reduced-‐calorie diet and increased physical ac7vity for chronic weight management in adults with: –  BMI > 30 kg/m2 –  BMI > 27 kg/m2 and at least one weight-‐related co-‐morbid condi7on (hypertension, type 2 diabetes, or dyslipidemia) 84 Saxenda® (liraglu7de) Dosage Form Strength Package Size AWP Pen-‐injector, subcutaneous 6 mg/mL 3 x 3 mL pens Not yet available 6 mg/mL 5 x 3 mL pens Not yet available •  Disposable •  Pre-‐ﬁlled •  Mul7-‐dose 85 Pharmacology •  Mechanism of AcHon: –  Binds to and ac7vates GLP-‐1 receptor •  GLP-‐1: regulator of appe7te and calorie intake –  S7mulates insulin secre7on and reduces glucagon secre7on in glucose-‐dependent manner •  Can lead to reduc7on of blood glucose –  Lowers body weight through decreased calorie intake –  Does not increase 24-‐hour energy expenditure –  Slows gastric emptying Saxenda® (liraglu7de) 86 Dosing •  Once daily without regard to meals •  Not studied in renal or hepa7c impairment; use with cau7on •  Use dose escala7on schedule to reduce GI side eﬀects (below) Week 1 2 3 4 5 and onward Daily Dose 0.6 mg 1.2 mg 1.8 mg 2.4 mg 3 mg Saxenda® (liraglu7de) 87 Administra7on •  Check medica7on ﬂow before ﬁrst injec7on with each new pen –  Turn dose selector un7l the dose counter shows ﬂow check symbol –  Press and hold un7l dose counter reads “0” Source: Saxenda® (liraglu7de) Medica7on Guide Saxenda® (liraglu7de) 88 Clinical Trials Source: Saxenda® (liraglu7de) Prescribing Informa7on Baseline mean weight (SD) (kg) Study 1 (Obese/overweight with co-‐morbidity) Study 2 (Type 2 diabetes and obese/overweight) Study 3 (Obese/overweight with co-‐
morbidity following at least 5% weight loss with diet) Saxenda® (liraglu7de) N=2487 Placebo N=1244 Saxenda® (liraglu7de) N=423 Placebo N=212 Saxenda® (liraglu7de) N=212 Placebo N=210 106.2 (21.2) 106.2 (21.7) 105.7 (21.9) 106.5 (21.3) 100.4 (20.8) 98.7 (21.2) -‐3.0 -‐1.7 -‐4.9 0.3 % change from -‐7.4 baseline (LSMean) Diﬀerence v. placebo (LSMean; 95% CI) -‐4.5* (-‐5.2 to -‐3.8) % pa7ents losing ≥ 62.3% 5% body weight Diﬀerence v. placebo (LSMean; 95% CI) Diﬀerence from placebo (LSMean, 95% CI) -‐3.7* (-‐4.7 to -‐2.7) 34.4% 27.9%* (23.9 to 31.9) % pa7ents losing > 33.9% 10% body weight 49.0% -‐5.2* (-‐6.8 to -‐3.5) 16.4% 32.6* (25.1 to 40.1) 15.4% 18.5* (15.2 to 21.7) -‐5.4 22.4% 44.2% 21.7% 22.6* (13.9 to 31.3) 5.5% 16.9* (11.7 to 22.1) 25.4% 18.5* (11.7 to 25.3) 6.9% 89 Safety Black Box Warning: Development of thyroid C-‐cell tumors in animal studies.* Common Side Eﬀects ≥ 2% and more Nausea, diarrhea, vomi7ng, dyspepsia, hypoglycemia, frequently than headache, fa7gue, dizziness, decreased appe7te placebo Serious/Rare Side Eﬀects Pancrea77s, cholecys77s ContraindicaHons History of hypersensi7vity to liraglu7de or any component of the formula7on, personal or family history of medullary thyroid carcinoma (MTC)* or history of mul7ple endocrine neoplasia syndrome type 2 (MEN2)* Warnings/PrecauHons Acute pancrea77s, acute gallbladder disease, hypoglycemia, tachycardia Use with cau7on in renal impairment, avoid use in pa7ents 90 with history of suicidal a+empts or idea7on Saxenda® (liraglu7de) Clinical Pearls •  Discon7nue if pa7ent has not lost at least 4% of baseline body weight aver 16 weeks •  Consider reducing dose of concomitant insulin secretagogues by 50% •  If more than three days have elapsed since last dose, reini7ate at 0.6 mg daily and follow dose escala7on schedule •  Pen should be used with NovoFine® or NovoTwist® disposable needles •  Store in refrigerator prior to ﬁrst use; aver opening, may store at room temperature or refrigerator for 30 days 91 Saxenda® (liraglu7de) Place in Therapy •  Only GLP-‐1 receptor agonist indicated for chronic weight loss management •  Studies did include older adults who were obese or overweight: –  Total of 232 (6.9%) of pa7ents were 65 years or older –  17 (0.5%) of pa7ents were 75 years or older •  Use may lead to hypoglycemia in paHents with diabetes type 2 taking concomitant anH-‐diabeHc agents •  Has not been compared to other medica7ons approved for weight loss (i.e. orlistat, lorcaserin) •  Eﬀects on morbidity and mortality have not been studied Saxenda® (liraglu7de) 92 AFREEZA® (INSULIN HUMAN) RAPID ACTING INHALED INSULIN 93 Afrezza® (insulin human) •  Manufacturer: MannKind Corpora7on (patented device) •  ClassiﬁcaHon: Rapid ac7ng inhaled insulin •  IndicaHon: Glycemic control in adults with diabetes mellitus 94 Afrezza® (insulin human) Dosage Form Strength Package Size AWP Inhala7on powder and single-‐use cartridges 4 unit cartridge 60 – 4 unit or 8 unit cartridges plus 2 inhalers 90 – 4 unit or 8 unit cartridges Not available • 
• 
• 
• 
8 unit cartridge Not available May store unopened packages at refrigerated temperatures un7l expira7on date Must use unopened blister cards and strips stored at room temperature within 10 days Opened strips must be used within 3 days Cartridges should be at room temperature for 10 minutes before use 95 Afrezza® (insulin human) 96 Pharmacology •  Mechanism of AcHon: –  S7mulates peripheral glucose uptake by muscle and fat –  Inhibits hepa7c glucose produc7on, lipolysis in adipocytes, proteolysis –  Enhances protein synthesis –  Lowers blood glucose! 97 Afreeza® (human insulin) Pharmacokine7cs •  Maximum serum insulin serum concentra7on reached 12-‐15 minutes aver inhala7on of 8 units •  Concentra7on declines to baseline aver 180 minutes •  Median terminal half-‐life aver inhala7on of 4 and 32 units is 28 to 39 minutes versus 145 minutes aver subcutaneous injec7on of 15 units Afreeza® (human insulin) 98 Pharmacokine7cs (con7nued) Afreeza® (human insulin) 99 Dosing and Administra7on •  1 inhala7on (1 cartridge) before beginning of meal •  Has not been studied in pa7ents with renal impairment or hepa7c impairment Afreeza® (human insulin) 100 Safety Black Box Warning: Acute bronchospasm has been observed with use. Contraindicated in pa7ents with chronic lung disease. Evalua7on for lung disease should be performed before ini7a7on of Afrezza® (human insulin). Common Side Eﬀects >10 % Hypoglycemia, cough 1 to 10% Throat pain or irrita7on, headache, fa7gue, bronchi7s Serious/Rare Side Eﬀects Diabe7c ketoacidosis, hypersensi7vity reac7on ContraindicaHons Do not use if hypoglycemic History of chronic lung disease (i.e. asthma, COPD) Hypersensi7vity to regular human insulin or any of Afrezza® excipients Warnings/PrecauHons Acute bronchospasm, life-‐threatening hypoglycemia, decline in pulmonary func7on, diabe7c ketoacidosis, life-‐threatening hypokalemia, ﬂuid reten7on and heart failure if taking concomitant thiazolidinediones 101 Do not use in pa7ents with ac7ve lung cancer Afreeza® (human insulin) Clinical Pearls •  Pa7ents with type 1 diabetes must use with long-‐ac7ng insulin •  Signs and symptoms of hypoglycemia may be masked by concomitant use of an7-‐adrenergics •  Safety and eﬃcacy in pa7ents who smoke is unknown Afreeza® (human insulin) 102 Place in Therapy •  Eﬃcacy compared versus injec7on in type 1 diabetes –  24-‐week trial showed that Afrezza® (insulin human) did not lower A1c as much as insulin aspart (sta7s7cally signiﬁcant diﬀerence) in pa7ents with stable basal insulin regimen •  Afrezza® (inslulin human) only compared to placebo in type 2 diabetes in pa7ents taking oral an7-‐diabe7c agents •  MannKind™ partnered with Sanoﬁ® for supply of insulin and marke7ng of product – this will determine cost •  Clinical studies included 381 pa7ents who were 65 years or older –  20 of these pa7ents were 75 years or older –  No overall diﬀerences observed for safety and eﬃcacy Afreeza® (human insulin) 103 JUBLIA® (EFINACONAZOLE INSULIN) AZOLE ANTIFUNGAL 104 Jublia® (eﬁnaconazole) •  Manufacturer: Valeant Pharmaceu7cals North America LLC •  ClassiﬁcaHon: Azole an7fungal •  IndicaHon: Onychomycosis of the toenails due to Trichophyton rubrum and Trichophyton mentagrophytes 105 Jublia® (eﬁnaconazole) Dosage Form Strength Package Size AWP Topical solu7on 10% 1 (4 mL) $538.80 106 Pharmacology •  Mechanism of acHon: –  Inhibits fungal lanosterol 14α-‐demethylase involved in biosynthesis of ergosterol –  Results in cell death –  Exhibits in vitro MICs of 0.06 μg/mL or less against ≥ 90% isolates of Trichophyton rubrum and Trichophyton mentagrophytes 107 Jublia® (eﬁnaconazole) Dosing and Administra7on •  Apply to aﬀected toenails once daily for 48 weeks using the integrated ﬂow-‐through brush applicator •  Aﬀected toenail(s) should be clean and dry •  Squeeze bo+le and apply one drop onto the toenail –  Apply two drops if great toe is aﬀected •  Gently spread solu7on completely around toenail with a+ached applicator brush and let dry thoroughly •  Wash hands with soap and water aver use Jublia® (eﬁnaconazole) 108 Clinical Trials •  Two, 52-‐week prospec7ve, mul7-‐center, randomized, double-‐
blind clinical trials – Included pa7ents 18 to 70 years of age with 20% to 50% clinical involvement of the target toenail, without dermatophytomas or lunula involvement – Jublia® (eﬁnaconazole) or vehicle applied for 48 weeks •  Cure rates assessed at Week 52: – Complete cure: 0% clinical involvement of target toenail plus nega7ve potassium hydroxide (KOH) and nega7ve culture – Complete or Almost Complete Cure: ≤ 5% involvement of target toenail and nega7ve KOH and culture – Mycologic Cure: nega7ve KOH and nega7ve culture 109 Jublia® (eﬁnaconazole) Clinical Trials (con7nued) Trial 1 Jublia® Vehicle (eﬁnaconazole) N=214 N=256 Trial 2 Jublia® Vehicle (eﬁnaconazole) N=201 N=580 Complete Cure 117 17.8% 7 3.3% 88 15.2% 11 5.5% Complete or Almost Complete Cure 173 26.4% 15 7% 136 23.4% 15 7.5% Mycologic Cure 362 55.2% 36 16.8% 310 53.4% 34 16.9% Jublia® (eﬁnaconazole) 110 Safety Common Side Eﬀects > 10 % None 1 to 10 % Ingrown toenail, applica7on site derma77s/vesicles/pain Serious/Rare Side Eﬀects None at this 7me ContraindicaHons None Warnings/PrecauHons Local irrita7on For topical use only on the toenails and surrounding skin 111 Jublia® (eﬁnaconazole) Clinical Pearls •  Pa7ent should avoid pedicures, use of nail polish, or cosme7c nail products while using solu7on •  Flammable; avoid use around heat and ﬂame •  In vitro studies have shown that at therapeu7c concentra7ons, JUBLIA® (eﬁnaconazole) neither inhibits nor induces CYP450 enzymes Jublia® (eﬁnaconazole) 112 Place in Therapy •  Same cost and dura7on of therapy as topical Kerydin® (tavaborole) for onychomycosis •  Has not been studied versus tavaborole •  Studies included pa7ents ages 18 to 70 (N=1227) –  137 (11.3%) paHents were 65 to 74 years old –  No overall diﬀerences in safety and eﬃcacy –  Some older individuals could be more sensi7ve to eﬀects of medica7on Jublia® (eﬁnaconazole) 113 RAPIVAB® (PERANMIVIR) NEURAMINIDASE INHIBITOR 114 Rapivab™ (peramivir) •  Manufacturer: BioCryst •  ClassiﬁcaHon: Neuraminidase inhibitor •  IndicaHon: Treatment of acute, uncomplicated inﬂuenza in adults who have been symptoma7c for ≤ two days 115 Rapivab™ (peramivir) Dosage Form Strength Package Size AWP Solu7on, Intravenous 10 mg/mL 1 (20 mL) $380.00 116 Pharmacology •  Mechanism of AcHon: –  Selec7vely inhibits inﬂuenza virus neuraminidase enzyme –  Prevents release of viral par7cles from infected cells 117 Rapivab™ (peramivir) Dosing •  600 mg IV as a single dose •  Renal dose adjustment –  CrCl 30-‐49 mL/min: 200 mg IV as a single dose –  CrCl < 29 mL/min: 100 mg IV as a single dose •  No hepa7c dosage adjustment recommended Rapivab™ (peramivir) 118 Safety Common Side Eﬀects Diarrhea, increased ALT, increased serum glucose, decreased neutrophil count Serious/Rare Side Eﬀects Skin reac7ons (erythema mul7forme, Stevens-‐Johnson Syndrome) ContraindicaHons None Warnings/PrecauHons Hypersensi7vity reac7ons, neuropsychiatric events Use cau7on in renal impairment 119 Rapivab™ (peramivir) Clinical Pearls •  Administer to pa7ents who have had symptoms of inﬂuenza for less than two days •  Administered over 15 to 30 minutes •  Avoid an7virals 48 hours prior to and 2 weeks aver receiving the inﬂuenza vaccine Rapivab™ (peramivir) 120 Comparison to Other Drugs •  Two placebo-‐controlled trials demonstrated safety and tolerability of single-‐dose peramivir and reduc7on in dura7on of clinical symptoms and viral shedding –  Median 7me to allevia7on of symptoms was 113.2 hours with peramivir vs. 134.8 hours with placebo –  Median resolu7on of fever was reduced by 24 hours aver treatment with peramivir 121 Rapivab™ (peramivir) Place in Therapy •  Advantage over other an7virals: single dose, non-‐
oral route beneﬁcial for pa7ents with nausea/
vomi7ng •  Disadvantages: invasive route of administra7on; more expensive than oral agents •  Studied in older adults? Rapivab™ (peramivir) 122 DALVANCE® (DALBAVANCIN) GLYCOPEPTIDE ANTIBIOTIC 123 Dalvance™ (dalbavancin) •  Manufacturer: Durata Therapeu7cs •  ClassiﬁcaHon: Glycopep7de •  IndicaHon: Acute bacterial skin and skin structure infec7ons 124 Dalvance™ (dalbavancin) Dosage Form Strength Package Size AWP Recons7tuted intravenous solu7on, preserva7ve free 500 mg per vial 1 vial $1788.00* *Treatment course for adult with normal renal func7on requires 3 vials: $5364.00 125 Pharmacology •  Mechanism of AcHon: –  Lipoglycopep7de that binds to D-‐alanyl D-‐alanine terminus of stem pentapep7de in nascent cell wall pep7doglycan –  Prevents cross-‐linking and interferes with cell wall synthesis –  Bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes Dalvance™ (dalbavancin) 126 Dosing and Administra7on •  Infused over 30 minutes •  1000 mg IV as a single dose ini7ally –  Followed by 500 mg IV as a single dose one week later •  CrCl < 30 mL/min: 750 mg IV as single, ini7al dose –  Followed by 375 mg IV as a single dose 1 week later •  ESRD receiving intermi+ent hemodialysis: no dosage adjustment necessary •  No dose adjustment recommended for hepa7c impairment –  Use with cau7on in moderate or severe impairment 127 Dalvance™ (dalbavancin) Safety Common Side Eﬀects > 10% None 1 to 10% Flushing, phlebi7s, headache, dizziness, skin rash, nausea, vomi7ng, diarrhea, abdominal pain, oral candidiasis, anemia, hepatotoxicity, infusion-‐related reac7on Serious/Rare Side Eﬀects Hypersensi7vity reac7on, increased serum ALT ContraindicaHons Hypersensi7vity to dalbavancin or to any component of the formula7on Warnings/PrecauHons Hypersensi7vity reac7ons, hepa7c eﬀects, infusion reac7ons (may resemble Red Man Syndrome), fungal or bacterial superinfec7on Dalvance™ (dalbavancin) 128 Clinical Pearls •  Total 7me from recons7tu7on to dilu7on to administra7on should be < 48 hours •  IV line should be ﬂushed before and aver each infusion with D5W, if needed for other drugs •  Obtain baseline BUN, SCr, and LFTs Dalvance™ (dalbavancin) 129 Comparison to Other Drugs •  Two trials included 1312 par7cipants and compared Dalvance® (dalbavancin) to vancomycin/linezolid for acute bacterial skin and skin structure infec7ons –  Trial 1 clinical response rates aver 48-‐72 hours: 83.3% for Dalvance® (dalbavancin) vs. 81.8% for vancomycin/linezolid –  Trial 2 clinical response rate: 76.8% for Dalvance® (dalbavancin) vs. 78.3% for vancomycin/linezolid –  Similar results between Dalvance® (dalbavancin) and vancomycin/linezolid for reduc7on in lesion size of 20% or greater aver 48-‐72 hours and clinical success rates at follow-‐up (Days 26 to 30) Dalvance™ (dalbavancin) 130 Place in Therapy •  Advantages: another treatment op7on for gram posi7ve infec7ons, infrequent dosing •  Disadvantages: pa7ents need to return for 2nd dose if outpa7ent, expensive •  313 (17.7%) of pa7ents in phase 2 and 3 trials were 65 years or older –  Eﬃcacy and tolerability similar to younger pa7ents –  Pharmacokine7cs not signiﬁcantly altered with age –  Use cau7on due to renal clearance Dalvance™ (dalbavancin) 131 PLEGRIDY™ (PEGINTERFERON β-‐1A) BIOLOGICAL RESPONSE MODULATOR 132 Plegridy™ (peginterferon β-‐1a) •  Manufacturer: Biogen Idec. •  ClassiﬁcaHon: Biological response modulator; interferon •  IndicaHon: Relapsing forms of mul7ple sclerosis (MS) 133 Plegridy™ (peginterferon β-‐1a) Dosage Form Strength Package Size AWP 2 $2863.2 Starter Pack: Dose 1: 63 mcg/0.5 mL Dose 2: 94 mcg/0.5 mL 2 $5726.4 125 mcg/0.5 mL 2 $2863.2 Starter Pack: Dose 1: 63 mcg/0.5 mL Dose 2: 94 mcg/0.5 mL 2 $5726.4 Single-‐dose preﬁlled pen 125 mcg/0.5 mL Single-‐dose preﬁlled syringe 134 Pharmacology •  Mechanism of acHon: –  Unknown –  Interferon beta diﬀers from naturally occurring human protein by one amino acid subs7tu7on and lack of carbohydrate side chains –  Alters expression and response to surface an7gens –  Can enhance immune cell ac7vi7es –  Proper7es of interferon beta that modify biologic responses are mediated by cell surface receptor interac7ons 135 Plegridy™ (peginterferon β-‐1a) Dosing OR Plegridy™ (peginterferon β-‐1a) 136 Clinical Trial •  Randomized, double-‐blind, placebo controlled trial –  Compared clinical outcomes and MRI results at 48 weeks –  Pa7ents received Plegridy® (peginterferon β-‐1a)125 mcg (n=512) or placebo (n=500) every 14 days •  Inclusion criteria: baseline Expanded Disability Status Scale (EDSS) score from 0 to 5, at least 2 relapses within previous three years, & at least 1 relapse in previous year •  Average baseline characteris7cs: 37 years old, disease dura7on of 3.6 years, EDSS score of 2.46, 71% female •  Results: •  Annualized relapse rate was reduced by 35.6% •  New lesions on MRI scans were reduced by 67% •  Risk of disability progression (as measured by EDSS) reduced by 38% 137 Plegridy™ (peginterferon β-‐1a) Safety Common Side Eﬀects > 10 % 1 to 10 % Headache, chills, injec7on site erythema and pain, myalgia, weakness, arthralgia, ﬂu-‐like illness, fever Increased body temperature, pain, hyperthermia, N/V Serious/Rare Side Eﬀects Angioedema, hepa7c disease, severe neutropenia or thrombocytopenia, 7ssue necrosis at injec7on site, ur7caria ContraindicaHons Hypersensi7vity to inferferon beta or peginterferon or any component of the formula7on, possible risk of allergenic cross-‐reac7vity among interferons Warnings/PrecauHons Autoimmune disorders, bone marrow suppression, hepa7c Plegridy™ (peginterferon β-‐1a) eﬀects, hypersensi7vity, injec7on site reac7ons, neuropsychiatric disorders, cardiovascular disease Use with cau7on with renal impairment and in epilepsy 138 Clinical Pearls •  Prophylac7c and concurrent use of analgesics and/or an7pyre7cs may prevent or ameliorate ﬂu-‐like symptoms •  Store in refrigerator and allow to warm to room temperature (about 30 minutes) prior to injec7on •  Monitor for hepa7c injury, severe injec7on site reac7ons, worsening cardiac condi7ons, new or worsening depression or psychiatric illness •  Monitor CBC with diﬀeren7al throughout treatment 139 Plegridy™ (peginterferon β-‐1a) Place in Therapy •  Plegridy® (peginterferon β-‐1a)has not been compared to other agents for relapsing forms of MS •  Interferon β-‐1a, β-‐1b also available •  Less frequent injec7on schedule may be more convenient •  Mean age in study was 37 years –  Safety and eﬃcacy in older adults has not been established Plegridy™ (peginterferon β-‐1a) 140 LEMTRADA™ (ALEMTUZUMAB) MONOCLONAL ANTIBODY 141 Lemtrada™ (alemtuzumab) •  Manufacturer: Genzyme •  ClassiﬁcaHon: Monoclonal an7body •  IndicaHon: Relapsing forms of mul7ple sclerosis (MS), generally aver inadequate response with two or more medica7ons; not indicated for stable or inac7ve MS 142 Lemtrada™ (alemtuzumab) Dosage Form Strength Package Size AWP Intravenous solu7on 12 mg/ 1.2 mL 1 (1.2 mL) $23,700.00 143 Pharmacology •  Mechanism of AcHon: –  Immunomodulatory eﬀects may include altera7on in number, propor7ons, and proper7es of some lymphocyte subsets Lemtrada™ (alemtuzumab) 144 Dosing •  12 mg daily IV for 5 consecu7ve days –  Followed by 12 mg daily IV for 3 consecu7ve days 12 months later •  No renal or hepa7c dosage adjustments recommended 145 Lemtrada™ (alemtuzumab) Safety Black Box Warning: Autoimmune condi7ons, infusion reac7ons, and malignancy may develop. Must obtain Lemtrada® (alemtuzumab) through REMS program. Common Side Eﬀects > 10% 1 to 10% Headache, fa7gue, insomnia, paresthesia, skin rash, ur7caria, pruritus, nausea, diarrhea, UTI, oral or vulvovaginal candidiasis, arthralgia, back/
limb pain, nasopharyngi7s, URTI, fever Flushing, tachycardia, chills, dizziness, drowsiness, thyroid disorder, vomi7ng, inﬂuenza, myalgia, weakness Serious/Rare Side Eﬀects Abnormal LFTs, autoimmune thrombocytopenia, candidiasis, cardiac failure, decreased Hgb/Hct [see Prescribing Informa7on for more serious/rare eﬀects] ContraindicaHons History of HIV (due to prolonged reduc7on in CD4 lymphocytes) Warnings/PrecauHons Autoimmune condi7ons such as immune thrombocytopenia and an7glomerular basement membrane disease, gastrointes7nal toxicity, infusion reac7ons, malignancy, pneumoni7s, progressive mul7focal leukoencephalopathy, thyroid disorders Has not been studied in pa7ents with HBV or HCV infec7on Lemtrada™ (alemtuzumab) 146 Clinical Pearls •  Administer over four hours and do not infuse other medica7ons into the same IV line –  Pre-‐medicate with cor7costeroids (methylprednisolone 1000 mg or equivalent) for ﬁrst three days of each treatment course –  Monitor vital signs prior to, during, and aver infusion •  Monitoring for adverse eﬀects –  CBC with diﬀeren7al prior to ini7a7on and monthly un7l 48 months aver last infusion –  SCr, TSH, ECG, urinalysis, signs/symptoms of PML and melanoma •  Pa7ents should not receive live, viral vaccines during treatment or immediately aver –  If history of chickenpox or VZV vaccina7on is unknown, check VZV an7bodies prior to ini7a7ng treatment 147 Lemtrada™ (alemtuzumab) Comparison with Other Drugs •  Two studies compared alemtuzumab to interferon β-‐1a –  Annualized relapse rate was signiﬁcantly lower in pa7ents treated with alemtuzumab •  Rela7ve reduc7on in annual relapse rates –  Trial 1: 0.26 for alemtuzumab vs. 0.52 for placebo –  Trial 2: 0.19 for alemtuzumab vs. 0.39 for interferon beta-‐1a Lemtrada™ (alemtuzumab) 148 Place in Therapy •  Advantages: has been compared to interferon β-‐1a with greater reduc7on in relapse rate •  Disadvantages: very expensive, must be infused over four hours •  Manufacturer states insuﬃcient number of pa7ents age 65 or older in trials to determine whether response rates diﬀer from younger pa7ents Lemtrada™ (alemtuzumab) 149 HARVONI™ (LEDIPASVIR/SOFOSBUVIR) HEPATITIS C VIRUS (HCV) NS5A INHIBITOR/HCV NUCLEOTIDE ANALOG NS5B POLYMERASE INHIBITOR 150 Harvoni™ (ledipasvir/sofosbuvir) •  Manufacturer: Gilead Sciences •  ClassiﬁcaHon: Hepa77s C virus (HCV) NS5A inhibitor and HCV nucleo7de analog NS5B polymerase inhibitor •  IndicaHon: Treatment of chronic hepa77s C (CHC) genotype 1 infec7on in adults 151 Harvoni™ (ledipasvir/sofosbuvir) Dosage Form Strength Package Size AWP Oral tablets 90 mg/400 mg 28 tablets $37,800.00* *12-‐week treatment course = $113,400.00; 24-‐week treatment course = $226,800.00 •  Orange, diamond-‐shaped, ﬁlm-‐coated tablets •  Imprint: “GSI” and “7985” 152 Pharmacology •  Mechanism of AcHon: –  HCV NS5A protein and NS5B RNA-‐dependent RNA polymerase are necessary for viral replica7on –  Ledipasvir inhibits HCV NS5A protein –  Sofosbuvir is converted to GS-‐461203 and inhibits NS5B RNA-‐dependent RNA polymerase and acts as a chain terminator 153 Harvoni™ (ledipasvir/sofosbuvir) Dosing •  1 tablet once daily with or without food –  Treatment-‐naïve with or without cirrhosis: 12 weeks –  Treatment-‐experienced without cirrhosis: 12 weeks –  Treatment-‐experienced with cirrhosis: 24 weeks •  Renal impairment –  No recommenda7on for CrCl ≤ 30 mL/min or ESRD (including intermi+ent hemodialysis) –  Predominant metabolite of sofosbuvir may accumulate up to 20-‐fold •  Hepa7c impairment –  Child-‐Pugh class A, B, C: no dose adjustment needed –  Decompensated cirrhosis: use has not been studied Harvoni™ (ledipasvir/sofosbuvir) 154 Safety Common Side Eﬀects >10 % Fa7gue, headache 1 to 10% Insomnia, nausea, diarrhea, increased serum lipase and hyperbilirubinemia Serious/Rare Side Eﬀects None at this 7me ContraindicaHons None Warnings/PrecauHons Drug-‐drug interac7ons with potent P-‐gp inducers (i.e. rifampin, Harvoni™ (ledipasvir/sofosbuvir) St. John’s wort) Use cau7on in pa7ents with history of galactose intolerance as tablet may contain lactose Treatment should be ini7ated by experienced physician 155 Clinical Pearls •  Based on clinical studies, treatment dura7on of 8 weeks could be considered for treatment-‐naïve pa7ents without cirrhosis and pre-‐treatment HCV RNA < 6 million IU/mL •  Discon7nua7on rates in studies due to adverse eﬀects were 0% (8 weeks), < 1% (12 weeks), and 1% (24 weeks) •  Monitor serum HCV RNA at baseline, during treatment, end of treatment, and treatment follow-‐up •  Other poten7al drug-‐drug interac7ons include acid reducing agents, digoxin, an7convulsants, rosuvasta7n, an7mycobacterials, HIV an7retrovirals, and simeprevir Harvoni™ (ledipasvir/sofosbuvir) 156 Place in Therapy •  AASLD/IDSA guidelines recommend Harvoni® (ledipasvir/
sofosbuvir) as a ﬁrst line (Class 1, Level A) op7on for treatment-‐naïve and treatment-‐experienced pa7ents with genotype 1 –  Guidelines available at: h+p://www.hcvguidelines.org/full-‐report-‐view (updated 19 December 2014) •  Very expensive but all Class 1 Level A op7ons are > $80,000 –  Co-‐pay coupon program: h+ps://www.harvoni.com/co-‐pay-‐coupon-‐registra7on?
evo_source=MYSUPPORTPATH&_ga=1.1161592.811861338.14220206
53 –  Sofosbuvir covered by Medicare Part D – ledipasvir? •  Clinical trials included 117 pa7ents age 65 or older –  No overall diﬀerences found in safety and eﬃcacy vs. younger pa7ents –  Greater sensi7vity to the drug s7ll possible in certain individuals Harvoni™ (ledipasvir/sofosbuvir) 157 VIEKIRA PAK™ (OMBITASVIR/PARITAPREVIR/
ROTONAVIR WITH DASABUVIR) HEPATITIS C VIRUS (HCV) NS5A INHIBITOR, HCV NS3/4A PROTEASE INHIBITOR, CYP3A4 INHIBITOR WITH NS5B PALM POLYMERASE INHIBITOR 158 Viekira Pak™ (ombitasvir/paritaprevir/ ritonavir with dasabuvir) •  Manufacturer: AbbVie Inc. •  ClassiﬁcaHon: Combina7on of hepa77s C virus (HCV) NS5A inhibitor, HCV NS3/4A protease inhibitor, CYP3A4 inhibitor and HCV NS5B palm polymerase inhibitor •  IndicaHon: Treatment of hepa77s C virus (HCV) genotype 1 including pa7ents with compensated cirrhosis 159 Viekira Pak™ (ombitasvir/paritaprevir/ ritonavir with dasabuvir) Dosage Form Strength Package Size Ombitasvir/paritaprevir/ritonavir 12.5/75/50 mg 1 carton (28 tablet day supply) Dasabuvir tablet 250 mg AWP* $83,320 for 12 weeks (not yet available) *Must consider addi7onal cost of ribavirin – es7mated $2500 for 12 weeks or $5000 for 24 weeks. •  Ombitasvir/paritaprevir/
ritonavir tablet –  Pink, ﬁlm-‐coated, oblong biconvex tablet –  Imprint: “AVI” •  Dasabuvir tablet –  Beige, ﬁlm-‐coated, oval –  Imprint: “AV2” 160 Pharmacology •  Mechanism of AcHon: –  HCV NS5A protein, NS5B RNA-‐dependent RNA polymerase, and NS3/4A protease are necessary for viral replica7on –  Ombitasvir inhibits HCV NS5A –  Paritaprevir inhibits HCV NS3/4A protease •  Ritonavir increases peak and trough plasma drug concentra7ons of paritaprevir –  Dasabuvir inhibits HCV NS5B RNA-‐dependent RNA polymerase Viekira Pak™ (ombitasvir/paritaprevir/ritonavir with dasabuvir) 161 Dosing and Administra7on •  Two tablets of ombitasvir/paritaprevir/ritonavir daily and one tablet of dasabuvir twice daily –  Take with meal without regard to fat or calorie content •  Treatment regimen and dura7on: –  Genotype 1a without cirrhosis: 12 weeks with ribavirin –  Genotype 1a with cirrhosis: 24 weeks with ribavirin –  Genotype 1b without cirrhosis: 12 weeks –  Genotype 1b with cirrhosis: 12 weeks with ribavirin •  Renal impairment: no adjustment needed; not studied in dialysis •  Hepa7c impairment: not studied in decompensated cirrhosis Viekira Pak™ (ombitasvir/paritaprevir/ritonavir with dasabuvir) 162 Viekira Pak™ (ombitasvir/paritaprevir/ritonavir with dasabuvir) 163 Safety (including ribavirin risks) Common Side Eﬀects >/= 5% versus Fa7gue, nausea, pruritus, skin reac7ons, insomnia, asthenia placebo Serious/Rare Side Eﬀects Hypersensi7vity and skin reac7ons ContraindicaHons Consider contraindica7ons to use of ribavirin Pa7ents with severe hepa7c impairment; concomitant use of drugs dependent on CYP3A4 clearance, strong inducers of CYP3A4 or CYP2C8, strong inhibitors of CYP2C8; known hypersensi7vity to ritonavir Warnings/PrecauHons Eleva7on in ALT – discon7nue medica7ons containing ethinyl estradiol prior to ini7a7on Viekira Pak™ (ombitasvir/paritaprevir/ritonavir with dasabuvir) 164 Clinical Pearls •  92% of pa7ents who received Viekira Pak™ with or without ribavirin achieved sustained viral response (SVR) at 12 weeks –  99% of these pa7ents maintained SVR at 48 weeks post-‐
treatment •  Consider 12-‐week treatment for some pa7ents with genotype 1a and cirrhosis •  Pa7ents should inform their clinicians of any prescrip7on and OTC medica7ons they are taking due to high risk of DDIs •  Missed dose of ombitasvir/paritaprevir/ritonavir can be taken with 12 hours; missed dose of dasabuvir can be taken within 6 hours Viekira Pak™ (ombitasvir/paritaprevir/ritonavir with dasabuvir) 165 Place in Therapy •  AASLD/IDSA guidelines recommend use of Viekira Pak™ as Class 1 Level A op7on for treatment-‐naïve or treatment-‐experienced pa7ents with HCV genotype 1 –  URL: h+p://www.hcvguidelines.org/full-‐report-‐view •  Insurance coverage –  CVS Health: does not cover Viekira Pak™ over others unless medical excep7on or prior authoriza7on –  Express Scripts: gave Viekira Pak™ preferred formulary status in exchange for discount from AbbVie •  No dosage adjustment needed for older adults –  174/2053 (8.5%) of pa7ents in studies were 65 or older –  No overall diﬀerences observed in safety and eﬃcacy Viekira Pak™ (ombitasvir/paritaprevir/ritonavir with dasabuvir) 166 Assessment Ques7on #3 Your 62 y/o pa7ent reports that she received an infusion of alemtuzumab (Lemtrada®) for relapsing-‐
remiŠng MS earlier this week. Which one of the following vaccines should NOT be administered at today’s visit? a. 
b. 
c. 
d. 
Pneumoccoal (Pneumovax) Herpes zoster (Zostavax) Tetanus/diphtheria/pertussis (Tdap) Inﬂuenza (Fluarix) 167 Assessment Ques7on #4 Which one of the following statements describes a pa7ent who should receive ledipasvir/sofosbuvir (Harvoni®) for 24 weeks? a. 
b. 
c. 
d. 
Treatment-‐naïve, with cirrhosis Treatment-‐naïve, without cirrhosis Treatment-‐experienced, with cirrhosis Treatment-‐experienced, without cirrhosis 168 References •  Akynzeo® (netupitant/palonosetron) [package insert]. Eisai Inc; 2014. •  Belsomra® (suvorexant) [package insert]. Merck & Co., Inc; 2014. •  Jardiance® (empagliﬂozin) [package insert]. Boehringer Ingelheim Pharmaceu7cals, Inc; 2014. •  Movan7k™ (naloxegol) [package insert]. AstraZeneca Pharmaceu7cals LP; 2014. •  Striverdi® Respimat® (olodaterol) [package insert]. Boehringer Ingelheim Pharmaceu7cals, Inc; 2014. •  Zon7vity™ (vorapaxar) [package insert]. Merck & Co., Inc; 2013. •  Entyvio® (vedolizumab) [package insert]. Takeda Pharmaceu7cals America, Inc; 2014. •  Tanzeum™ (albiglu7de) [package insert]. GlaxoSmithKline LLC; 2014. •  Trulicity™ (dulaglu7de) [package insert]. Eli Lilly and Company; 2014. 169 References (con7nued) •  Saxenda® (liraglu7de) [package insert]. Novo Nordisk; 2014. •  Afrezza® (insulin human) [package insert]. MannKind Corpora7on; 2014. •  Jublia® (eﬁnaconazole) [package insert]. Valeant Pharmaceu7cals North America LLC; 2014. •  Rapivab™ (peramivir) [package insert]. BioCryst; 2014. •  Dalvance™ (dalbavancin) [package insert]. Durata Therapeu7cs Inc; 2014. •  Plegridy™ (peginterferon beta-‐1a) [package insert]. Biogen Idec Inc; 2014 •  Lemtrada™ (alemtuzumab) [package insert]. Genzyme Corpora7on; 2014. •  Harvoni™ (ledipasvir/sofosbuvir) [package insert]. Gilead Sciences; 2014. •  Viekira Pak™ (ombitasvir/paritaprevir/ritonavir with dasabuvir) [package insert]. AbbVie Inc.; 2014. 170 Thank you for your a+en7on! QUESTIONS? 171 Acknowledgments University of Saint Joseph, PharmD students: Sylvia Narciso and Mamta Samtani University of Rhode Island, PharmD students: Nick LaBier and Danielle Longo 172 Contact Informa7on Stephanie Ha+oy, PharmD, BCPS, CGP Assistant Professor University of Saint Joseph, School of Pharmacy Email: sha+oy@usj.edu Chris7ne Eisenhower, PharmD, BCPS Clinical Assistant Professor University of Rhode Island, College of Pharmacy Email: ceisenhower@uri.edu 173