1. Matthew Lacroix Pharm.D BCPS Assistant Professor University of New England College of Pharmacy April 26, 2014

2. Objectives Pharmacists objectives 1. Discuss the basic pharmacology of the new drugs presented and how the pharmacologic actions relate to both therapeutic and adverse effects. 2. Discuss clinically significant adverse effects and drug interactions, and the appropriate dosing and monitoring of the new drugs presented. 3. Discuss the therapeutic role of the new drugs presented as compared to agents already marketed. Technician objectives 1. List the new drugs presented. 2. Describe clinically significant adverse effects and drug interactions, and the appropriate dosing and monitoring of the new drugs presented.

3. Conflicts of Interest  Dr. Lacroix has no conflicts to report

4. Best resource for new drug release  Pharmacist Letter  http://pharmacistsletter.therapeuticresearch.com/ pl/NewDrugs.aspx?cs=&s=PL&pt=20&yr=2013 http://pharmacistsletter.therapeuticresearch.com/ pl/NewDrugs.aspx?cs=&s=PL&pt=20&yr=2013  Tend to highlight most important new agents, new formulations, and new biologics

5. How this presentation was developed  There have been about 50 new agents since May 2013  Using the most scientific polling source I could find (Facebook) I asked about what new medications people most wanted to spend some time on  That list was cross referenced with New Entities list from Pharmacist Letter©  Drugs are introduced in two ways  Quick hits  1 slide on the medication as it may be rarer to see in practice  Topic reviews  4-5 slides on the medication, focusing on what is unique about the drug, key elements in patient counseling and monitoring, and the product that is currently the most similar to it on the market

6. Q1) Lurasidone has FDA indications for which of the following 1) bipolar I; Schizophrenia 2)bipolar II; Schizophrenia 3) Bipolar I; Depression 4) Bipolar II; Depression

7. Lurasidone (Latuda©)  Class: Atypical Antipsychotic  Uses  Depressive phase of bipolar  Schizophrenia  MOA  high affinity for D 2, 5-HT 2A, and 5-HT 7 receptors; moderate affinity for alpha 2C -adrenergic receptors; and is a partial agonist for 5-HT 1A receptors  No affinity for muscarinic M 1 and histamine H 1 receptors

8. Lurasidone (Latuda©)  Adverse effects >10%  Central nervous system:  Drowsiness  extrapyramidal reaction  Akathisia  parkinsonian-like syndrome  Endocrine & metabolic:  Increased serum triglycerides  increased serum glucose  increased serum cholesterol  Gastrointestinal:  Nausea

9. Lurasidone (Latuda©)  Renal Dosing  At CrCl of 50ml/min reduce dose by 50%  Drug-Drug interactions  CYP 450 3A4 substrate  Watch out for strong inhibitors and inducers  Moderate inhibitors (verapamil) PI indicates 50% dose  Pregnancy rating-B  Still risk, particularly in 3 rd trimester

10. Lurasidone (Latuda©)  Key counseling points  Patients do experience orthostatic hypertension  Food should be taken with med to reduce symptoms  Clear fluids; preferable non-caffeinated  Available as  20,40,60,80,100, 120 mg tablets  Average cost about $800 for 30 days

11. Q2) Estrogens (conjugated/equine) and Bazedoxifene is a combination of what two classes of medications? 1) estrogen derivatives and SERM 2) estrogen and progestogen 3) estrogen and SSRI 4) estrogen and SNRI

12. Estrogens (conjugated/equine) and Bazedoxifene (Duavee©)  Class: Estrogen Derivative; Selective Estrogen Receptor Modulator (SERM)  Primary uses  Postmenopausal osteoporosis prophylaxis  Vasomotor symptoms  MOA  Conjugated estrogens act as an estrogen agonist and bazedoxifene acts as an estrogen agonist/antagonist depending on the specific tissue.

13. Estrogens (conjugated/equine) and Bazedoxifene (Duavee©)  Vasomotor symptoms  Most common 12-24 months after last Menses  Most common reason treatment is sought  May interrupt sleep and cause insomnia  Occur in 75%–85% of women, usually within 12–24 months after the last menstrual period  May cause increased skin temperature, nausea, dizziness, headache, palpitations, diaphoresis, and night sweats

14. Estrogens (conjugated/equine) and Bazedoxifene (Duavee©)  Adverse effects  Dizziness  Gastrointestinal  Diarrhea  Nausea  Dyspepsia  upper abdominal pain  Neuromuscular  Muscle spasm  neck pain  Respiratory:  Oropharyngeal pain

15. Estrogens (conjugated/equine) and Bazedoxifene (Duavee©)  Renal dosing  Not studied- no official recommendation  May consider stopping at 30ml/min  Drug-Drug interactions  Anticoagulants  Reduce efficacy- consider different therapy  CYP 450 3A4  Estrogen is a substrate so be aware!  Pregnancy category X

16. Estrogens (conjugated/equine) and Bazedoxifene (Duavee©)  Key counseling points  Swallow tablet whole  Any abnormal bleeding should be report to PCP  Any signs of chest pain, stroke like symptoms  Take at same time every day  Available as  0.45-20mg tablet  $133.03 for 30  Most like  Prempro  Replaces the progestin with the SERM

17. Ospemifene (Osphena)  Class: SERM  Indication: use for Dyspareunia  60 mg once daily  Not indicated for use for vasomotor symptoms  CYP 3A4, 2C9 drug drug interactions

18. Q3)Fluticasone/vilanterol inhalers most resemble which current inhaler on the market? 1) Advair HFA 2) Advair DPI 3) Serevent diskus 4) Proair HFA

19. Fluticasone and Vilanterol (Breo Ellipta©)  Class: Combo long acting B2 agonist; inhaled corticosteroid  Primary Use  COPD exacerbation reduction  MOA  Fluticasone is a corticosteroid with anti-inflammatory activity, immunosuppressive properties, and antiproliferative actions.  Vilanterol, a long-acting beta 2 -agonist, relaxes bronchial smooth muscle by selective action on beta 2 - receptors with little effect on heart rate.

20. Fluticasone and Vilanterol (Breo Ellipta©)  Adverse effects  Cardiovascular:  Hypertension  peripheral edema  Central nervous system:  Headache  Gastrointestinal:  Oropharyngeal candidiasis  Diarrhea  Neuromuscular  Arthralgia  back pain  bone fracture  Respiratory  Nasopharyngitis  upper respiratory tract infection  Pneumonia

21. Fluticasone and Vilanterol (Breo Ellipta©)  Renal dosing  Inhaled-no adjustment needed  Drug-Drug interactions  The same as all other combo inhalers  Pregnancy class C

22. Fluticasone and Vilanterol (Breo Ellipta©)  Counseling points  Unique inhaler delivery system  http://youtu.be/Cq8uQi_ETls http://youtu.be/Cq8uQi_ETls  Other key points are similar to other combo products (Advair)  Available as 100/25mcg inhaler  Cost of ~$121 for 30 day supply  (slightly cheaper)

23. Umeclidinium/vilanterol (Anoro Ellipta©)  Long acting anticholinergic/Beta-agonist for COPD  Avoid other anticholinergics  Potassium needs to be monitored, supplemental potassium held until patient is stabilized on medication  Dosing: once daily (14 doses per inhaler)

24. Q4) dapagliflozin reduces A1C by what percent? 1) 0.5% 2) 1% 3) 1.5% 4) 2%

25. Dapagliflozin (Farxiga©)  Class: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor  Use  Treatment of type 2 DM  MOA  inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules,  reduces reabsorption of filtered glucose from the tubular lumen  SGLT2 is the main site of filtered glucose reabsorption  reduction of filtered glucose reabsorption and lowering of RT G result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

26. Dapagliflozin (Farxiga©)  Adverse effects  Endocrine  Mild hypoglycemia  Dyslipidemia  Gastrointestinal  Nausea  Constipation  Hematologic  Increased hematocrit (1%, hematocrit >55%)  Infection  Influenza  Neuromuscular  Back pain  Respiratory  Nasopharyngitis  Genitourinary:  Fungal vaginosis  urinary tract infection  increased urine output  genitourinary fungal infections  dysuria

27. Dapagliflozin (Farxiga©)  Renal dosing  eGFR <60 mL/minute/1.73 m 2 :  Initial: Use not recommended.  persistent decrease in eGFR to <60 mL/minute/1.73 m 2, dapagliflozin should be discontinued.  Drug-Drug Interactions  No significant CYP450 interactions  Caution in concurrent steroid use  Pregancy Category: C  Advise discontinuation in 2 nd and 3 rd trimesters

28. Dapagliflozin (Farxiga©)  Counseling points  Make sure to report soreness in genitals to PCP  High risk of infection secondary to medication  You may initially need to void more frequently  You may feel dizziness with this medication, check BG. If normal consider checking BP, consult with PCP  Available as 5 and 10mg capsule  Cost ~$347 for 30 day supply

29. Alogliptin/metformin (Kazano©) Alogliptin/pioglitazone (Oseni©)  Combo DPP-4 and biguanide  Combo DPP-4 and Thiazolidinedione

30. Q5) Qudexy XR an extended release formulation for what currently available anticonvulsant? 1) Topiramate 2) Phenytoin 3) Carbamazipine 4) Ethosuximide

31. Topiramate (Qudexy XR ©; Trokendi XR©)  Class: Anticonvulsant  Use:  Extended release formulations for epilepsy as mono- or adjunctive therapy  Both are new extended release formulations  Qudexy XR is indicated for age 2 or greater  Trokendi XR is indicated for age 6 or greater  NOT BIOEQUVALANTS  MOA  Not fully described (AKA we don’t know but think something from below is involved)  Blocks neuronal voltage-dependent sodium channels  enhances GABA(A) activity  antagonizes AMPA/kainate glutamate receptors  weakly inhibits carbonic anhydrase

32. Topiramate (Qudexy XR ©; Trokendi XR©)  Adverse Effects >10%  Central nervous system:  Paresthesia  Drowsiness  Dizziness  Nervousness  Fatigue  Ataxia  psychomotor retardation  impaired speech  memory impairment  abnormal behavior  confusion  Endocrine  Decreased serum bicarbonate  Gastrointestinal  Anorexia  Nausea  Ophthalmic  Visual disturbance  Renal  Increased serum creatinine

33. Topiramate (Qudexy XR ©; Trokendi XR©)  Renal dosing  CrCL <70 ml/min reduce dose by 50%  Drug-Drug interactions  Oral contraceptives  Anything that causes sleepiness;fatigue  Pregnancy category: D

34. Topiramate (Qudexy XR ©; Trokendi XR©)  Counseling points  Same as topiramate noting side effects may last longer as the half life is about 5 times as long as IR topiramate  Avoid beer, wine, or mixed drinks within 6 hours before or 6 hours after taking this drug.  Available as 25, 50, 100, 200 mg (Tokendi XR)  Price range from ~$200 to ~$700 depending on strength for 30 tablets  Qudexy XR approved March 2014, expected shortly on shelves

35. Vortioxetine (Brintellix©)  Class: SSRI  Initial indication for Major depressive disorder  Major substrate of CYP 2D6  Major side effect  sexual disorder  Up to 30% of both men and women  GI  Up to 30% dose dependent, tolerance can build

36. Q6) Simeprevir and and sofosbuvir are new medications introduced for the treatment of what disease at the end of 2013? 1) COPD 2) Menopause 3) Hepatitis C 4) bipolar disorder

37. Hepatitis C  Simeprevir (Olysio)  Oral: 150 mg once daily (in combination with peginterferon alfa and ribavirin). Treatment duration is indication and response-specific.  Focus on HCV-RNA detection/undectable  Cost: 150 mg (28): $26544.00  Sofosbuvir (Sovaldi)  Oral: 400 mg daily with concomitant ribavirin and with or without peginterferon alfa (maximum: 400 mg daily).  Genotype specific for duration requirements  Costs : 400 mg (28): $33600.00

38. Hydrocodone (Zohydro ER)  New stand alone product  Highly controversial  Starting dose is 10mg in opioid naïve patients and titrated up q3-7 days  Side effects are similar to hydrocodone/APAP with less liver side effects  C-II

39. Hydrocodone (Zohydro ER)  Conversion from transdermal fentanyl: Treatment with hydrocodone ER may be started 18 hours after the removal of the fentanyl transdermal patch. For every fentanyl 25 mcg per hour transdermal patch, initially substitute hydrocodone ER 10 mg every 12 hours. Monitor the patient closely. Previous Oral Opioid Oral Dosage Approximate Oral Conversion Factor 2 Hydrocodone10 mg1 Oxycodone10 mg1 Methadone 3 10 mg1 Oxymorphone5 mg2 Hydromorphone3.75 mg2.67 Morphine15 mg0.67 Codeine100 mg0.1 1 Approximate equivalent doses for conversion from current opioid therapy to hydrocodone ER. 2 Ratio for converting oral opioid dose to approximate hydrocodone ER equivalent dose. 3 Monitor closely; ratio between methadone and other opioid agonists may vary widely as a function of previous drug exposure. Methadone has a long half-life and may accumulate in the plasma.

40. Questions?