New Year, New Medications New Drug Update 2016

Transcription

1 New Year, New Medications New Drug Update 2016 J. Elliot Turner, PharmD, BCPS, BC-ADM Ambulatory Clinical Pharmacist Palmetto Health Disclosures I have nothing to disclose. Objectives Discuss new medications introduced to the market within the last year Discuss place in therapy of newly approved medications and dosage forms Discuss changes or updates in guidelines of therapy where appropriate regarding new medications 1

2 DIABETES 2

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6 Revisiting Metformin SCr vs. egfr As of early 2015, FDA still has not relaxed or reframed recommendations for Metformin use in patients with declining renal function Current contraindications may discourage use in patients with even mild renal impairment Revisiting Metformin egfr (ml/min per 1.73m2) Action > 60 No renal contraindication to metformin > 45 Continue use Increase monitoring of renal function (every 3-6 months) < 45 and > 30 Proceed with caution Use lower dose (e.g. 50%) Closely monitor renal function (every 3-6 months) No new starts < 30 Stop metformin Tresiba (insulin Degludec) Safety-Hypoglycemia most common adverse effect, drug was rejected from FDA in 2013 on heart safety concerns Tolerability-Hypoglycemia, allergic reactions, weight gain, injection site reactions Efficacy-The BEGIN trial was conducted comparing Tresiba to common antidiabetic orals and insulin. The results were that Tresiba showed non-inferiority. Price- 200 u/ 1 ml: $532.62; 100 u/1 ml: $ Simplicity-Patient may be apprehensive about giving themselves injections. Approved once a day basal insulin, stable at room temperature for 56 days (8 weeks) 6

7 Tresiba (insulin Degludec) Once-daily new generation basal insulin with half-life of 25 hours and duration of action of at least 42 hours For use alone or in combination with oral antidiabetic agents as well as bolus insulin Approved for Type 1 and Type 2 diabetes Will only be available in Flex Touch pens Tresiba (insulin Degludec) Dosing Type 1 (insulin naïve): 0.2 to 0.4 units/kg to calculate total daily insulin dose, then give 1/3 to 1/2 as insulin degludec dose Type 2 (insulin naïve): 10 units once daily Type 2 (already on insulin): convert unit for unit as the total daily long or intermediate acting insulin dose. Ryzodeg 70/30 (insulin Degludec and insulin Aspart) Ryzodeg 70/30 is indicated to improve glycemic control in adults with diabetes mellitus Inject Ryzodeg 70/30 subcutaneously once or twice daily with any main meal Administer a rapid-or a short-acting insulin at other meals if needed May reduce total numbers of injections for patients Same starting dose as with insulin Degludec 7

8 Toujeo (insulin glargine 300u/ml) Safety Concern for dosing errors, confusion with Gla-100 (although label colors are different for the 2 products), in general there was a tendency towards less hypoglycemia with Gla-300 (in some cases statistical significance was shown) than Gla-100 Tolerability Maximum glucose lowering effect of Gla-300 may take 5 days to fully manifest and the first dose may be insufficient to cover metabolic needs in the first 24 hours of use Efficacy The 6 month EDITION trials found glargine-300 (Gla-300) to be non-inferior to glargine-100 (Gla-100) Price $ for 3 pack of pens (1.5 ml each) Simplicity Solostar device~same as Lantus (glargine 100 u/ml); Pharmacokinetic/pharmacodynamic studies have shown that Gla-300 has a slightly longer duration of action than Gla-100 Humalog U-200 (insulin Lispro) First concentrated mealtime insulin Designed to allow patients to change their pens less frequently Approval based on bioequivalence in PK/PD studies comparing to U-100. Not available in vials day supply calculations are tricky Pens are still 3 ml in volume ~ 600 units per pen Gylxambi (empagliflozin and linagliptin) Safety risk of bone fractures and ketoacidosis with empagliflozin, pancreatitis with linagliptin Tolerability Generally well tolerated, individual components Efficacy additional lowering of HgA1c -0.4 to -0.7% with the addition of linagliptin Price $492/30 tablets Simplicity once daily tablet, first combination SGLT2 and DPP-4 combination on market 8

9 Synjardy (empagliflozin and metformin) Safety- boxed warning for lactic acidosis (metformin component). Risk increased in those who have renal disease, sepsis, excessive alcohol intake, hepatic impairment and acute HF, risk of bone fractures and ketoacidosis with empagliflozin Tolerability- Generally well tolerated, individual components Efficacy 24 week trail in 637 patients on metformin up to 1500 mg/day randomized to empagliflozin 10 or 25 mg vs. placebo % in HgA1c,-2 kg weight loss and reduction in systolic blood pressure Price $370/60 tablets Simplicity Synjardy is in tablet form, patient will take twice a day and dosed according to their current empagliflozin and metformin dose, decrease pill burden Eating Your Carbs Last May Improve Blood Sugar Levels A small, preliminary study shows that eating the protein-rich foods and non-starchy vegetables on your plate first, before starting in on starchy and sugary items, may help to raise blood glucose less than eating the exact same meal in a different order Researchers at Weill Cornell Medical College gave 11 individuals with Type 2 Diabetes an identical meal on two separate days, but instructed the participants to eat the foods in two different sequences. At the first visit, participants ate the high-carbohydrate foods first (a roll and orange juice), then waited for 15 minutes before eating the protein (grilled skinless chicken breast) and low-carb vegetables (steamed broccoli with butter and tossed salad with low-fat vinaigrette). Eating Your Carbs Last May Improve Blood Sugar Levels When individuals ate their protein and vegetables first, their blood sugars were about 29 percent lower after the first half hour, 37 percent lower after one hour, and 17 percent lower after two hours, compared to when they started with the juice and bread. It s possible that eating protein and fiber-rich vegetables first helps to slow the body s absorption of the carbohydrates that follow after, leading to a more gradual rise in blood sugar 9

10 LIPIDS Review of proteins involved in lipid metabolism and transport Lipid absorption Microsomal triglyceride transport protein (MPT) Chylomicron formation in the intestines Apolipoprotein formation in the liver Lipid transport Apolipoproteins (ApoA, ApoB, ApoC, ApoE) Ready for transport into the serum Cholesterol ester transport protein (CETP) Transports cholesteryl esters from HDL to IDL and LDL Review of proteins involved in lipid metabolism and transport Lipid metabolism Lipoprotein Lipase (LPL) Catalyzes breakdown of triglycerides Hepatic update of lipids LDL receptors (LDLR) Transports LDL into the liver or peripheral cells for storage or elimination Proprotein convertase subtilisin/kexin type 9 (PCSK9) Causes LDL receptor degradation 10

11 Familial Hypercholesterolemia (FH) Genetic basis LDL receptor Apolipoprotein B Proprotein Convertase Sutilisin Kexin-9 (PCSK9) Homozygous TC: mg/dl 1 in 1,000, fold increase in early onset CHD risk On average 40 % have MI before age 60 Heterozygous TC: mg/dl 1 in Recent approved options for FH Alirocumab (Praluent) mg SQ every other week Evolocumab (Repatha) 140 mg SQ every other week or 420 mg SQ once monthly MOA: binds to PCSK9, preventing it from binding to LDLR and preventing LDLR from being degraded Praluent (alirocumab) Safety Allergic reactions. Contraindicated if allergic. Long term safety unknown, hepatic enzyme abnormalities occurred in < 2.5% patients Tolerability Nasopharyngitis, injection site reaction, influenza Efficacy Approval based on ODYSSEY trial which has shown that Praluent as an adjunct therapy to statins reduced LDL cholesterol by 55%. Long term CV impact unknown Price-$ per dose ~ $1300 for full month supply Simplicity Patients may be apprehensive to giving themselves injections. Frequency of every two weeks may improve compliance 11

12 Praluent (alirocumab) CV Outcomes Data ODYSSEY LONG TERM Trial (n=2341) Population: (mean age = 60 with LDL >/= 70 mg/dl) HeFH (17.7%) CHD (68.9%) CHD risk equiv. (41%) (taking max tolerated statin +/- other therapies) Intervention: 150 mg SQ every 2 weeks vs. placebo X 78 weeks Primary outcome: mean % change in LDL from baseline Secondary outcomes: ADEs and major CV events (post-hoc) Praluent (alirocumab) CV Outcomes Data ODYSSEY LONG TERM Trial Results Primary efficacy outcome (% change in 24 weeks) Alirocumab (n=1553): 61% LDL decrease, 78 weeks Placebo (n=788): 0.8% LDL increase, 78 weeks p<0.001 Secondary safety outcomes Nonsignificant difference in discontinue rates, injection side reactions, ALT/AST elevations Significantly more myalgia in Praluent group Significantly less non-fatal MI and major CV events in the Praluent group (post-hoc analysis) Praluent (alirocumab) CV Outcomes Data ODYSSEY LONG TERM Trial Limitations Composite CV event endpoint in post-hoc analysis did not include all CV events: CHR requiring hospitalizations Ischemia-driven coronary revascularization When these events were included in the analysis, P=ns Total # of CV events was relatively small Outcomes trial is planning to enroll 18,000 patients and scheduled to conclude in

13 Repatha (evolocumab) Safety-Contraindicated if allergic. Long term safety unknown, hepatic enzymes abnormalities occurred in <2% patients Tolerability- nasopharyngitis, upper respiratory tract infection, back pain, injection site reaction Efficacy- Approval based on results of OSLER. Repatha plus standard therapy significantly reduced LDL by 55-60% after 3 months of therapy vs. placeob Price $1300-$1900 Simplicity Patients may be apprehensive about injecting themselves. Options to inject every 2 weeks or once a month. Repatha (evolovumab) CV Outcomes Data OSLER 1 and OSLER 2 Trials (n=4465) Population: mean age 58 average LDL of 120 mg/dl HeFH (~10%) CHD (~20%) CV Risk Factor (~70%) CVD/PAD (~9%) Intervention: 140 mg SQ every 2 weeks or 420 mg SQ monthly vs. standard therapy x 11.1 months Primary outcome: ADEs Secondary outcomes: mean % change in LDL, non-hdl, HDL, TG, TC, ApoA1, ApoB,Lp(a), and CV events Repatha (evolovumab) CV Outcomes Data OSLER 1 and OSLER 2 Trials Results Primary outcome (ADEs) really no significant difference other than injection site reaction Secondary outcomes: LDL reduction: 61% Non-HDL reduction: 52% HDL increase: 7% TG reduction: 12.6% TC: reduction 36.1% CV events: ARR 1.23% FOURIER CV outcomes study ongoing 13

14 Repatha (evolovumab) CV Outcomes Data OSLER 1 and OSLER 2 Trials Limitations Short duration (~1 year) Study subjects had a wide range of CV risk at baseline Study subjects were enrolled in OSLER 1 or OSLER 2 if they tolerated evolocumab in the 12 short-term (12 week) phase 2 trials Open label design May have influenced CV and ADE reporting Severe Hypertriglyceridemia Genetic basis for some forms of HTG Lipoprotein Lipase (LPL) APOC2 APOA5 TG> mg/dl 1 in 600 Life threatening, recurrent pancreatitis, increase in CV risk, Xanthomas Options for HTG Icosapent ethyl (Vascepa) Adminstration 2 capsules BID Efficacy Bioavailability dependent on food Omega-3 acid ethyl esters (Omtryg) 4 capsules daily or 2 BID Bioavailability dependent on food Omega- 3carbox-ylic acid (Epanova) 2-4 capsules once daily Bioavailability NOT dependent on food Lowers TG without affecting HDL or LDL Lowers TG, increases HDL (ns) and increase LDL(s) Lowers TG, increases HDL (ns) and increase LDL(s) Safety Increase LFTs Increase LFTs Increase LFTs Cost ~$250 ~$

15 New data for Zetia (ezetimibe) MOA: Neimann-Pick C1-Like 1 intestinal cholesterol transporter (NPC1L1) intestines IMPROVE-IT Trial (n=18,144) Population: age > 50, mean age 64 hospitalized for ACS in last 10 days with LDL > 50 mg/dl Max LDL = 100 mg/dl if receiving lipid lowering therapy Max LDL = 125 mg/dl if not receiving lipid lowering therapy Intervention: SIM 40 + EZE 10 daily vs. SIM 40 +PLA x 6 yrs Primary outcome: composite of CV death, non fatal MI, UA requiring hospitalization, coronary revascularization >/=30 days after randomization, or non fatal CVA New data for Zetia (ezetimibe) IMPROVE-IT Trial Resulst Primary outcome (CV death or events) SIM + EZE: 32.7% SIM + PLA: 34.7% ARR = 2% NNT = 50, p=0.016 ( ) Secondary outcomes: Significant differences in: Median time weighted average LDL Any MI Non fatal MI Ischemic CVA New data for Zetia (ezetimibe) IMPROVE-IT Trial Limitations Dose titrations to high-intensity simvastatin (80 mg) were no longer allowed after June 2011 and 80 mg doses had to be reduced if duration < 1 year Alt therapy could be substituted if LDL > 100 mg/dl Data from use of other statins would be informative 15

16 HYPERTENSION 16

17 Prestalia (perindopril arginine and amlodipine besylate) Safety-BBW: Pregnancy category D Tolerability-AE: Edema, cough, headache, and dizziness Efficacy-Approval based on the results of the PATH trial. The highest strength of Prestalia was studied in 837 patients randomized to Prestalia 14/10 mg, perindopril erbumine 16 mg, or amlodipine 10 mg once daily for 6 weeks. At week 6, Prestalia 14/10 mg produced statistically significantly greater reductions in blood pressure than each of the monotherapies. The lowest strength of Prestalia was studied in 1,581 patients randomized to Prestalia 3.5/2.5 mg, perindopril arginine 3.5 mg, perindopril arginine 5 mg, amlodipine 2.5 mg, amlodipine 5 mg, or placebo. At week 8, Prestalia 3.5/2.5 mg produced statistically significantly greater reductions in blood pressure than perindopril arginine 3.5 mg and amlodipine 2.5 mg. Prestalia (perindopril arginine and amlodipine besylate) Prices: $5.86 unit price Simplicity: Patient takes one pill a day. Additional Information: The recommended starting oral dose of Prestalia is 3.5/2.5 mg once daily. The dose may be adjusted according to blood pressure goals waiting 1 to 2 weeks between titration steps. The maximum recommended dose is 14/10 mg once daily. Administered as monotherapy, perindopril erbumine is an effective treatment for hypertension in once daily doses ranging from 4 mg to 16 mg daily but data are lacking to link these doses of perindopril erbumine to doses of Prestalia. HEART FAILURE 17

18 Statistics Heart failure is a common condition that affects approximately 5.7 million people in the U.S., about half of which have reduced left ventricular function Despite broad use of standard treatments, the prognosis for patients with heart failure is poor Projections show that by 2030, the prevalence of heart failure will increase 46 percent from 2012 estimates Corlanor (ivabradine) MOA: Corlanor blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker, which regulates heart rate. Corlanor reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If current ("funny" current) to slow the heart rate with no effect on ventricular repolarization and no effects on myocardial contractility. Dosing: The recommended starting dose of Corlanor is a 5 mg tablet twice daily with meals. After two weeks of treatment, the dose should be assessed and adjusted depending on heart rate. In patients with a history of conduction defects, or other patients in whom bradycardia could lead to hemodynamic compromise, initiate therapy at 2.5 mg twice daily before increasing the dose based on heart rate. Corlanor (ivabradine) Safety-Contraindicated in decompensated heart failure, blood pressure <90/50 mmhg, sick sinus syndrome, sinoatrial block, 3 rd degree atrioventricular block (unless pacemaker), Heart rate <60 bpm, hepatic impairment, pacemaker dependence, and concomitant use of strong CYP3A4 inhibitors Tolerability-Bradycardia, HTN, Afib, luminous phenomena Efficacy- approval based on the results of the SHIFT trial which found that Corlanor reduced the risk of hospitalization for worsening heart failure. There was not a significant effect on mortality. Price-$7.50 unit price Simplicity-Patients take medication BID with meals. 18

19 SHIFT Trial Patients received SOC, including beta blockers (89 percent), angiotensin converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARB) (91 percent), diuretics (83 percent) and anti-aldosterone agents (60 percent). Results from the Phase 3 SHIFT study showed Corlanor significantly reduced the risk of the primary composite endpoint of hospitalization or cardiovascular death for worsening heart failure, with 18 percent relative risk reduction (RRR) (p <0.0001, 4.2 percent absolute risk reduction [ARR]) versus placebo. The treatment effect reflected only a reduction in the risk of hospitalization for worsening heart failure; there was no favorable effect on the mortality component of the primary endpoint. There was a 26 percent RRR (4.7 percent ARR) in the risk of hospitalizations for worsening heart failure. Entresto (sacubitril and valsartan) Entresto, a neprilysin inhibitor/angiotensin receptor blocker (ARB), was authorized for the treatment of heart failure with reduced ejection fraction (HFrEF) in patients with New York Heart Association (NYHA) Class II or III, to reduce the incidence of cardiovascular death and heart failure hospitalization. Entresto should be administered in combination with other heart failure therapies, in place of an angiotensin-converting enzyme inhibitor (ACEi) or ARB. Recommended starting dose: 49 mg/51 mg PO BID Target maintenance dose: After 2-4 weeks, double the dose to the target maintenance dose of 97 mg/103 mg PO BID as tolerated Entresto (sacubitril and valsartan) Sacubitril blocks neprilysin and prevents the breakdown of BNP; therefore, the measured levels will be higher. This does not represent a worsening of HF Since NT-proBNP is not a substrate of neprilysin, levels will remain unaffected If you are using natriuretic peptide guided therapy, NTproBNP should be used over BNP alone 19

20 Entresto (sacubitril and valsartan) Safety-BBW for Fetal toxicity. May cause angioedema Tolerability-AE: hypotension, hyperkalemia, cough, dizziness, renal failure Efficacy-approval based on the PARADIGM-HF trial which found that Entresto reduced cardiovascular deaths, hospitalization, and overall survival. Price-$7.50 unit price Simplicity-Patients take tablets twice a day Entresto (sacubitril and valsartan) Contraindicated with concomitant use of an ACE inhibitor; if switching from an ACE inhibitor to sacubitril/valsartan, allow a washout period of 36 hr between administration of the 2 drugs Renal impairment Mild-to-moderate (egfr 30 ml/min/1.73 m²): No starting dose adjustment required Severe (egfr <30 ml/min/1.73 m²): Reduce starting dose to 24 mg/26 mg BID; double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg BID as tolerated Hepatic impairment Mild (Child-Pugh A): No starting dose adjustment required Moderate (Child-Pugh B): Reduce starting dose to 24 mg/26 mg BID; double the dose every 2-4 weeks to target maintenance dose of 97 mg/103 mg BID as tolerated Severe (Child-Pugh C): Not recommended PARADIGM-HF Trial The patient population of the PARADIGM-HF trial is reflective of the general population of HFrEF patients, and was generally well treated with guideline-recommended standard of care, but still remained at high, or relatively high, risk for cardiovascular mortality and morbidity. Key demographic and disease characteristics were well balanced between treatments. Entresto reduced the risk of the primary, pre-specified endpoint of cardiovascular death by 20% [Hazard Ratio (HR) 0.80, 1-sided p = )] and heart failure hospitalization by 21% (HR 0.79, 1-sided p = ), and to a greater extent than a standard dose of enalapril in patients with HFrEF. 20

21 PARADIGM-HF Trial Entresto also reduced the risk of all-cause death by 16% when compared to enalapril (HR 0.84, 1-sided p = ), a secondary endpoint in the study. The treatment difference was sustained during the entire duration of study. The reduction in all-cause mortality was mainly driven by the risk reduction of cardiovascular death, which accounted for 81% of allcause death in this study. PAIN FDA Strengthens Warning of Heart Attack and Stroke Risk for Non-Steroidal Anti- Inflammatory Drugs FDA is adding information in the drug label for people who already have had a heart attack. This vulnerable population is at an increased risk of having another heart attack or dying of heart attack-related causes if they re treated with NSAIDs, according to studies. But the risk is also present in people without cardiovascular disease. Everyone may be at risk even people without an underlying risk for cardiovascular disease 21

22 Vivlodex (meloxicam) Vivlodex was developed to align with recommendations from FDA and many professional medical organizations that NSAIDs be used at the lowest effective dose for the shortest possible duration Developed using proprietary SoluMatrix Fine Particle Technology, contains meloxicam as submicron particles that are approximately 10 times smaller than their original size. The reduction in particle size provides an increased surface area, leading to faster dissolution Vivlodex (meloxicam) Safety- Cardiovascular thrombotic events, Gastrointestinal ulcerations, bleeding, and perforations Tolerability- diarrhea, nausea, abdominal discomfort Efficacy-Clinical trials have shown that pain relief was achieved at lower doses than the currently available meloxicam. The VIVLODEX doses studied achieved efficacy at 33 percent lower doses than currently available meloxicam products Price-$23.76 unit price Simplicity- Patient takes 1 tablet once a day, lower dose INFECTIOUS DISEASES 22

23 Genvoya (elvitegravir, cobicistat, emtricitabine, and tenovir alafenamide) Description and indications Four-drug antiretroviral (ART) combination of elvitegravir (integrase strand transfer inhibitor [INSTI]), cobicistat (CYP3A inhibitor), and emtricitabine and tenofovir alafenamide (TAF), both nucleoside analog reverse transcriptase inhibitors (NRTIs) It is indicated as a complete treatment regimen for HIV-1 infection in adults and children aged 12 yr who are ART-naïve or to replace the current ART regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/ml) on a stable ART regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components Dosage 1 tablet PO daily with food Prior to initiation, test patients for hepatitis B infection Genvoya (elvitegravir, cobicistat, emtricitabine, and tenovir alafenamide) Safety-Lactic acidosis, severe hepatomegaly with steatosis Tolerability-nausea Efficacy-Approval was based on a study showing Genvoya to be statistically non-inferior to other HIV medications. The FDA evaluated the treatment's safety and efficacy in 3,171 patients and results showed it was effective in reducing viral loads compared to other FDA-approved treatments. Price-$ unit dose Simplicity-Patient takes one tablet a day, less toxic side effects Evotaz (atazanavir and cobicistat) Indication Evotaz is a combination human immunodeficiency virus (HIV-1) protease inhibitor and CYP3A inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection Dosage: Recommended dosage in adults: One tablet once daily, taken orally with food Must be taken with other antiretrovirals 23

24 Evotaz (atazanavir and cobicistat) Safety-Hypersensitivity Tolerability-jaundice, ocular icterus, nausea Efficacy-approval was based on Phase III trial data. Evotaz is the only protease inhibitor enhanced with cobicistat with 6% virologic failure Price- $60.58 unit price Simplicity- Take one pill daily Prezcobix (darunavir and cobicistat) Indication Prezcobix is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in treatment-nai ve and treatmentexperienced adults with no darunavir resistance-associated substitutions Dosage Prezcobix is a fixed-dose combination product containing 800 mg of darunavir and 150 mg of cobicistat. In treatment-nai ve and treatment-experienced adults with no darunavir resistance- associated substitutions, the recommended dosage of PREZCOBIX is one tablet taken once daily orally with food. Administer PREZCOBIX in conjunction with other antiretroviral agents Prezcobix (darunavir and cobicistat) Safety-liver problems Tolerability-diarrhea, nausea, headache, rash, abdominal pain Efficacy-FDA approval due to clinical trial showing the components of Prezcobix to be tolerable and efficacious. In a study, which was conducted with darunavir 800 mg and cobicistat 150 mg administered as single entities in 313 HIVinfected patients, adverse reactions evaluated through Week 24 did not differ substantially from those reported in clinical trials with darunavir co-administered with ritonavir 100 mg. Price-$ unit price Simplicity-Patient takes medication once a day 24

25 Hepatitis C It s a very exciting and hopeful time for people with Hepatitis C as treatment is rapidly changing for the better. We now have higher cure rates, shorter treatment times, and all-oral treatment regimens for most people with HCV infection This decision will depend upon a number of factors including: Hepatitis C virus (HCV) genotype cirrhosis, and if it s mild (compensated) or severe (decompensated) Previous treatment Awaiting transplant or previous transplant Other conditions Treatment regimens are usually 12 or 24 weeks, but sometimes longer, depending on your particular circumstances. About 75% of the people with HCV in the U.S. have either genotype 1a or 1b. Between 10% 20% of people with HCV in the U.S. have either genotype 2 or 3 Technivie (ombitasvir/paritaprevir/ritonav ir) Technivie was approved for use in combination with ribavirin for the treatment of HCV genotype 4 in patients without scarring and cirrhosis. This is the first treatment option for people with genotype 4 that does not require co-administration of interferon. The three drugs included in Technivie are also included in Viekira Pak, previously approved for the treatment of HCV genotype 1. In clinical trials, once daily doses of Technivie with ribavirin for 12 weeks cured 100% of the people with HCV genotype 4 without cirrhosis. The most common side effects of Technivie plus ribavirin were fatigue, weakness, nausea, insomnia, itching (pruritis), and other skin reactions. Elevation of liver enzymes to greater than five times the upper limit of normal occurred in approximately 1% of clinical trial participants. This occurred more frequently in women taking contraceptives containing ethinyl estradiol. Contraceptives that contain this must be discontinued prior to starting Technivie. It s recommended that liver enzyme testing be performed during the first four weeks of treatment, and as clinically indicated thereafter. Daklinza (daclatasvir) Part of the class of drugs called direct acting anitvirals or DAAs was approved for use with sofosbuvir (Sovaldi) to treat HCV genotype 3 infections. Daklinza is the first drug that demonstrated safety and efficacy in treating HCV genotype 3 without the need for coadministration of interferon or ribavirin In clinical trials, 152 treatment-naïve (people who haven t previously received HCV treatment) and treatment-experienced (people who have previously received HCV treatment) adults received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks. At 12 weeks post-treatment, their blood was tested to see if the hepatitis C virus was no longer detectable, indicating they achieved a sustained virologic response (SVR 12), or cure. The results were as follows: Treatment-naïve patients with no cirrhosis: 98% achieved SVR Treatment-naïve patients with cirrhosis: 58% achieved SVR Treatment-experienced patients with no cirrhosis: 92% achieved SVR Treatment-experienced patients with cirrhosis: 69% achieved SVR 25

26 Daklinza (daclatasvir) Daklinza labeling carries a statement informing prescribers that SVR rates are reduced in patients with HCV genotype 3 infected patients with cirrhosis. The most common side effects of Daklinza with sofosbuvir were fatigue and headache. Daklinza carries a warning that serious slowing of the heart rate (symptomatic bradycardia) and cases requiring pacemaker intervention have been reported when amiodarone (brand names Cordarone, Pacerone) is co-administered with sofosbuvir in combination with another HCV direct-acting antiviral, including daclatasvir. Co-administration of amiodarone with sofosbuvir in combination with Daklinza, is not recommended. Genotype 1 Options Harvoni (ledipasvir/sofosbuvir) Recommended dosage: One tablet (ledipasvir 90 mg/sofosbuvir 400 mg) taken orally once daily with or without food. In clinical trials, the most common side effects observed with treatment for 8, 12, or 24 weeks were fatigue and headache. Olysio (simprevir) plus Sovaldi (sofosbuvir); sometimes given with ribavirin. Recommended dosage of simeprevir: One 150-mg capsule once a day with food. Recommended dosage of sofosbuvir: One 400-mg tablet once a day with or without food. In clinical trials, the most common side effects observed during 12 weeks of treatment with simprevir/sofosbuvir combination therapy were fatigue, headache, nausea, insomnia, itching, rash and photosensitivity. During 24 weeks of treatment, dizziness and diarrhea were also observed. Genotype 1 Options Viekira Pak (ombitasvir/paritaprevir/ritonavir tablets; dasabuvir tablets); sometimes given with ribavirin. Recommended dosage: Two ombitasvir 12.5 mg/paritaprevir 75 mg/ritonavir 50 mg tablets once daily (in the morning) and one dasabuvir 250 mg tablet twice daily (morning and evening) with a meal. Length of treatment is usually 12 or 24 weeks. The common side effects for Viekira Pak without ribavirin include nausea, itching, and sleep problems. If taken with ribavirin side effects include tiredness, nausea, itching, sleep problems, feeling weak and skin reactions such as redness or rash 26

27 Genotype 2 Options Sovaldi (sofosbuvir) plus ribavirin Recommended dosage of sofosbuvir: One 400-mg tablet once a day with or without food. Ribavirin is a pill taken by mouth with food. The dose is individualized based on your weight. Length of treatment is usually 12 or 16 weeks. The most common side effects for sofosbuvir/ribavirin combination therapy are fatigue and headache. Genotype 3 Options Sovaldi (sofosbuvir) plus ribavirin Recommended dosage of sofosbuvir: One 400-mg tablet once a day with or without food. Ribavirin is a pill taken by mouth with food. The dose is individualized based on your weight. Length of treatment with sofosbuvir/ribavirin combination therapy is usually 24 weeks. The most common side effects for sofosbuvir/ribavirin combination therapy are fatigue and headache. Daklinza (daclatasvir) with Sovaldi (sofosbuvir) Recommended dosage: Daclatasvir 60 mg with sofosbuvir 400 mg once a day. Length of treatment is 12 weeks. The most common side effects are fatigue and headache. Genotype 4 Options Harvoni (ledipasvir/sofosbuvir) Recommended dosage: One tablet (ledipasvir 90 mg/sofosbuvir 400 mg) taken orally once daily with or without food. Length of treatment is usually 12 weeks. The most common side effects are fatigue and headache. Sovaldi (sofosbuvir) plus ribavirin Recommended dosage of sofosbuvir: One 400-mg tablet once a day with or without food. Ribavirin is a pill taken by mouth with food. The dose is individualized based on your weight. Length of treatment is usually 24 weeks. The most common side effects for sofosbuvir/ribavirin combination therapy are fatigue and headache. 27

28 Genotype 4 Options Technivie (ombitasvir/paritaprevir/ritonavir) plus ribavarin Recommended dosage of Technivie: One tablet once daily with a meal. Ribavarin is a pill taken by mouth with food. The dose is individualized based on your weight. Length of treatment is 12 weeks. The common side effects for Technivie with ribavirin include fatigue, nausea, sleep problems, feeling weak, itching and other skin reactions such as redness or rash. Genotype 5 Options Sovaldi (sofosbuvir) plus ribavirin plus peg-interferon Recommended dosage of sofosbuvir: One 400-mg tablet once a day with or without food. Ribavirin is a pill taken by mouth with food. The dose is individualized based on your weight. Length of treatment with sofosbuvir/ribavirin/ peginterferon combination therapy is usually12 weeks. The most common side effects for sofosbuvir/ribavirin/peg-interferon combination therapy are fatigue, headache, nausea, insomnia and anemia. Genotype 6 Options Harvoni (ledipasvir/sofosbuvir) Recommended dosage: One tablet (ledipasvir 90 mg/sofosbuvir 400 mg) taken orally once daily with or without food. Length of treatment is usually 12 weeks. The most common side effects are fatigue and headache. 28

29 GOUT 29

30 Zurampic (lesinurad) Indication Indicated to treat hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor, when treatment with a xanthine oxidase inhibitor alone fails to adequately control hyperuricemia Dosage 200 mg PO daily in combination with a xanthine oxidase inhibitor. Administer in the morning with food and water. Considerations not recommended for the treatment of asymptomatic hyperuricemia should not be used as monotherapy Zurampic (lesinurad) Safety Major cardiac events (eg, cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) have occurred, though causality has not been established. Adverse renal events, including acute renal failure, have been reported, usually when used at higher than recommended doses or when used as monotherapy Tolerability - headache, increased blood creatinine levels, GERD, and influenza Efficacy discussed in the next slides Price - n/a Simplicity - once daily administration Zurampic (lesinurad) The efficacy of ZURAMPIC 200 mg and 400 mg once daily was studied in 3 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with hyperuricemia and gout in combination with a xanthine oxidase inhibitor, allopurinol or febuxostat. All studies were of 12 months duration and patients received prophylaxis for gout flares with colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs) during the first 5 months of ZURAMPIC treatment. Although other doses have been studied, the recommended dose of ZURAMPIC is 200 mg once daily in combination with a xanthine oxidase inhibitor. 30

31 Zurampic (lesinurad) Study 1 and Study 2 enrolled patients with gout who were on a stable dose of allopurinol of at least 300 mg (or 200 mg for moderate renal impairment) that had a serum uric acid > 6.5 mg/dl and reported at least 2 gout flares in the prior 12 months. Mean years since gout diagnosis were 12 years. More than half of the patients (61%) had mild or moderate renal impairment and 19% of the patients had tophi. Patients continued their allopurinol dose and were randomized 1:1:1 to receive Zurampic 200 mg, Zurampic 400 mg, or placebo once daily. The average dose of allopurinol in the studies was 310 mg (range: mg). Zurampic 200 mg in combination with allopurinol was superior to allopurinol alone in lowering serum uric acid to less than 6 mg/dl at Month 6. Zurampic (lesinurad) Study 3 enrolled gout patients with measurable tophi. Patients received febuxostat 80 mg once daily for 3 weeks and then were randomized 1:1:1 to once daily doses of Zurampic 200 mg, Zurampic 400 mg, or placebo in combination with febuxostat. A total of 66% of patients had mild or moderate renal impairment. Fifty percent of patients did not reach target serum uric acid < 5.0 mg/dl at Baseline after 3 weeks of febuxostat treatment. As shown in Table 6, there was not statistical evidence of a difference in the proportion of patients treated with Zurampic 200 mg in combination with febuxostat achieving a serum uric acid < 5 mg/dl by Month 6, compared with patients receiving febuxostat alone. However, the average decrease in serum uric acid with Zurampic 200 mg in Study 3 was similar to that seen in Study 1 and Study 2 PSYCH 31

32 Aristada (aripiprazole lauroxi) Indication an atypical antipsychotic and is a prodrug of aripiprazole; for schizophrenia Dosage Initial dose of 441, 662, or 882 mg IM monthly or 882 mg IM q 6 wks. Administer oral aripiprazole for 21 days along with intital IM injection. Maintenance dose 441 mg (1.6 ml) IM inj. to deltoid or gluteal muscle Light blue label 662 mg (2.4 ml) IM inj. to Gluteal muscle green label 882 mg (3.2 ml) IM inj. to Gluteal muscle burgundy label Aristada (aripiprazole lauroxi) Safety Tardive dyskinesia, neuroleptic malignant syndrome, hyperglycemia, dyslipidemia, weight gain, orthostatic hypotension, and leukopenia/neutropenia/agranulocytosis may occur and monitoring is recommended Tolerability Reported adverse events includes injection-site pain, and extrapyramidal symptoms including akathisia and restlessness Effectiveness The efficacy of Aristada was demonstrated in part by a 12-week clinical trial in 622 participants. In participants with acute schizophrenia who had been stabilized with oral aripiprazole, Aristada was found to maintain the treatment effect compared to a placebo. Price 441 mg = $ 1266; 662 mg = $ ; 882 mg = $ Simplicity No renal or hepatic dose adjustments Administer oral aripiprazole for 21 days along with intital IM injection. Therapeutic levels is reached within 4 days with the addition of oral aripiprazole supplementation for 21 days Rexulti (brexpiprazole) Indication Indicated in adults for adjunctive treatments of major depressive disorder (MDD) and for the treatment of schizophrenia Dosage MDD mg orally once daily; titrate at weekly intervals based on response and tolerability to 1 mg orally once daily and then to target dosage of 2 mg orally once daily; MAX 3 mg orally once daily; periodically reassess dosage and need for treatment Schizophrenia 1 mg orally once daily on days 1-4; titrate to 2 mg orally once daily on days 5-7, then to target dosage of 4 mg orally once daily beginning on day 8, based on response and tolerability; MAX 4 mg orally once daily; periodically reassess dosage and need for treatment 32

33 Rexulti (brexpiprazole) Safety Commonly reported adverse events include akathisia, dyspepsia, headache, somnolence and weight gain Tolerability Neonates with fetal exposure during the third trimester are at risk of extrapyramidal and withdrawal symptoms High fat meal has no significant effect on exposure May increase risk of suicidal thoughts and behaviors in patients 24 years of age or younger Effectiveness Rexulti superior to placebo for MDD and Schizophrenia Price $34.62/tablet 30 tabs = $ Simplicity Dosage adjustments are needed for moderate to severe hepatic impairment, moderate to severe renal impairment, ESRD, in poor CYP2D6 metabolizers, when used concomitantly with strong or moderate CYP2D6 inhibitors, strong or moderate CYP3A4 inhibitors, or strong CYP3A4 inducers. Start at the low end of dosing in geriatric patients.substrate of CYP3A4 and CYP2D6 Vraylar (cariprazine) Indication Indicated in adults for the treatment of schizophrenia or the acute treatment of manic or mixed bipolar I episodes Dosage Schizophrenia & Bipolar disorder Initial dose: 1.5 mg orally once daily on day 1. Increase to 3 mg/day may be made on day 2 with further increases as needed and tolerated. For either indication, titrate in 1.5- or 3-mg increments with a maximum dose of 6 mg/day. Vraylar (cariprazine) Safety Commonly reported adverse reactions included extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness Tolerability Tardive dyskinesia or metabolic changes such as hyperglycemia, diabetes mellitus, dyslipidemia, or weight gain may occur Effectiveness The efficacy of Vraylar for the treatment of schizophrenia was established in three, 6-week, randomized, double-blind, placebo-controlled trials in patients (aged 18 to 60 years) who met DSM-IV-TR criteria for schizophrenia. An active control arm (risperidone or aripiprazole) was included in two trials to assess assay sensitivity. In all three trials, Vraylar was superior to placebo The efficacy of Vraylar in the acute treatment of bipolar mania was established in three, 3-week placebocontrolled trials in patients (mean age of 39 years, range 18 to 65 years) who met DSM-IV-TR criteria for bipolar 1 disorder with manic or mixed episodes with or without psychotic features. In all three trials, Vraylar was superior to placebo Price N/A Simplicity Once daily dosing 33

34 Invega Trinza (palperidone palmitate) Indication Indicated for the treatment of schizophrenia in adults after they have been adequately treated with paliperidone palmitate 1-month extendedrelease injection for at least 4 months Dosage Initiate when the next 1-month paliperidone palmitate dose is scheduled, giving 3.5 times the 1-month dose: Three-month IM paliperidone may be administered up to 7 days before or after the next monthly dose date. 78 mg IM qmonth (Invega Sustenna) Invega Trinza 273 mg q3 mos. 117 mg IM qmonth (Invega Sustenna Invega Trinza 410 mg IM q3 months; 156 mg IM qmonth (Invega Sustenna) Invega Trinza 546 mg IM q3 months; 234 mg IM qmonth (Invega Sustenna Invega Trinza 819 mg IM q3months Patients may be given the injection up to 2 weeks before or after the 3- month time point. Requires renal dose adjustments Invega Trinza (palperidone palmitate) Safety Injection site reactions, weight gain, upper respiratory tract infection, akathisia, and parkinsonism. Tolerability Avoid use with any drug known to prolong QTc interval, and in patients with risk factors for prolonged QT interval Metabolic changes may occur and increase cardiovascular and cerebrovascular risk; monitor weight gain in all patients, and blood sugars in diabetic patients and patients at risk for diabetes. Use cautiously in patients with seizures, conditions that lower seizure threshold, cardiovascular or cerebrovascular disease, and patients predisposed to hypotension. Effectiveness Paliperidone palmitate is hydrolyzed to paliperidone, the major active metabolite of risperidone Inducers of CYP3A4 (Strong) and P-glycoprotein: May decrease the serum concentration of Paliperidone. Management: Avoid using the 3-month extended-release injectable suspension (Invega Trinza) with inducers of both CYP3A4 and P-glycoprotein during the 3- month dosing interval if possible. If combination is necessary, consider using extendedrelease tablets. Risk D: Consider therapy modification Invega Trinza (palperidone palmitate) Price 273 mg/0.875 ml = $2,529.56; 410 mg/1.315ml = $3, ; 546 mg/1.75 ml = $5,059.27; 819 mg/2.625 ml = $ Simplicity Extended-release 3-month injection Three-month IM paliperidone is to be used only after monthly IM paliperidone (Invega Sustenna) has been established as adequate treatment for at least 4 months. Must be administered using only the thin wall needles that are provided in the pack. Do not use needles from monthly IM paliperidone or other commercially-available needles to reduce the risk of blockage. In the event of an incompletely administered dose, do not re-inject the dose remaining in the syringe and do not administer another dose. Closely monitor and treat the patient with oral supplementation as clinically appropriate until the next scheduled 3-month injection. Extensize dosing regimens!! Requires refrigeration 34

35 IMMUNIZATIONS Bexsero (meningococcal group B vaccine) Indication Meningococcal group B vaccine is indicated in subjects years to prevent invasive disease caused by Neisseria meningitidis serogroup B. Dosage 0.5 ml IM (only to deltoid muscle) 2-dose series at least 1 month apart Bexsero (meningococcal group B vaccine) Safety Injection site pain, myalgia, erythema, fatigue, headache, induration, nausea, and arthralgia Tolerability May contain latex. Use is contraindicated if a severe allergic reaction has occurred following a previous meningococcal vaccine dose. Acute anaphylaxis or syncope may occur. Immunocompromised individuals may have a reduced immune response Effectiveness Efficacy of the 2-dose vaccination series was evaluated during clinical trials involving pediatric and young adult patients, ages 11 to 24 years. Serum bactericidal antibodies were measured with hsba assays using 3 strains selected to measure responses to 1 of 3 vaccine antigens, either fhbp, NadA, or PorA P1.4, prevalent among strains in the U.S. The primary endpoints were the percentage of subjects with >= 4-fold rise in hsba titers for each of the 3 test strains, and the percentage of subjects who achieved titers >= the lower limit of quantitation (LLOQ) for all 3 strains (composite response). At one month after the second dose, a >= 4-fold rise in hsba titers was observed in 78 98% for strain fhbp, 94 99% for strain NadA, and 39 67% for strain PorA P1.4; 63 88% of vaccine recipients achieved the composite response of titers >= LLOQ for all 3 strains 35

36 Bexsero (meningococcal group B vaccine) Price $192.75/vial Simplicity Bexsero is the 2 nd meningococcal group B vaccine that is FDA-approved to prevent invasive disease caused by Neisseria meningitidis serogroup B 2-dose series Fluad (adjuvanted trivalent, inactivated influenza vaccine) Indication For adults >/= 65 years for immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine Dosage Single 0.5 ml IM injection Fluad (adjuvanted trivalent, inactivated influenza vaccine) Safety Injection site pain and tenderness, myalgia, headache, fatigue, and arthralgia. Tolerability Syncope Effectiveness Fluad was first approved for use in Italy in 1997 and is currently approved in 38 countries, including Canada and 15 European countries In the case of Fluad, the antibody response to the vaccine provided this evidence to reach accelerated approval. Under the accelerated approval requirements, a confirmatory study is required to verify and describe the clinical benefit of Fluad. Price n/a Simplicity Only for pts > 65 years Pre-filled syringes contain latex tip caps 36

37 2016 Adult Immunization Schedule Updates Use of 9-Valent Human Papillomavirus (HPV) Vaccine: Updated HPV Vaccination Recommendations of the Advisory Committee on Immunization Practices Use of Serogroup B M eningococcal Vaccines in Persons Aged 10 Years at Increased Risk for Serogroup B Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices Intervals Between PCV13 and PPSV23 Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) Updates for HPV Vaccination Available HPV vaccines 3 for females:2vhpv,4vhpv,9vhpv 2 for males:4vhpv,9vhpv For females aged years, 3-dose series of 2vHPV, 4vHPV, or 9vHPV is recommended For males aged years, 3-dose series of 4vHPV or 9vHPV is recommended For MSM and immunocompromised men (including those with HIV infection) through age 26 years,3-dose series of 4vHPV or 9vHPV is recommended HPV vaccination replaces HPV4 or HPV2 Updates to Pneumococcal Vaccination Intervals between PCV13 and PPSV23 PCV13 PPSV23 interval is at least 1 year for immunocompetent adultsaged 65 years (for adults with immunocompromising conditions, asplenia, or CSF leak or cochlear implant, the interval is at least 8 weeks) Correction of errata Adults aged 19 years with immunocompromising conditions replaces adults aged 19 through 64 years with immunocompromising conditions Adults aged 19 through 64 years who smoke cigarettes or reside in nursing home or long-term care facilities: Administer PPSV23 removed Adults aged 19 through 64 years who reside in a nursing home removed from list of adults recommended for PPSV23 Adults aged 19 through 64 years who smoke cigarettes remains indication for PPSV23 37

38 Updates to Meningococcal Vaccination Listed separately in figures in schedule MenACWY/MPSV MenB Recommendation for either 2-dose series MenB-4C (Bexsero) or 3- dose series MenB-FHbp (Trumenba) Asplenia or complement deficiencies, microbiologists, outbreak settings MenB not recommended for travelers No recommendation for MenB revaccination MenB for adults with asplenia and complement deficiencies is yellow (recommended for all),other groups are purple (recommended if risk factor) Updates to Meningococcal Vaccination Young adults aged years (prefered age years) may be vaccinated to provide short-term protection against most strains of MenB disease. Additional notes HIV infection is not indication for routine vaccination with MenACWY or MenB vaccine. MenB-4Cor MenB-FHbp vaccine may be administered concomitantly with MenACWY vaccine, but at a different anatomic site if feasible The two MenB vaccines are not interchangeable; the same vaccine product must be used for all doses MenB added to Contraindications and Precautions Table Contraindications: Severe allergic reaction (e.g.,anaphylaxis) after a previous dose or to a vaccine component Precautions: Moderate or severe acute illness with or without fever 38

39 OBESITY Saxenda (liraglutide) Indication Indicated as an adjunct to non-pharmacologic therapy for chronic weight management in adults who have initial BMI 30 or 27 or greater with at least one weight-related comorbid condition, such as HTN, type 2 DM or dyslipidemia. Saxenda is not indicated for type 2 diabetes mellitus treatment Dosage Chronic weight management: Initial: 0.6 mg once daily x 1 week; increase by 0.6 mg daily at weekly intervals to a target dose of 3 mg once daily. If the patient cannot tolerate an increased dose during dose escalation, consider delaying dose escalation for one week. If the 3 mg daily dose is not tolerated, discontinue use as efficacy has not been established at lower doses. Saxenda (liraglutide) Safety Nausea (39%), diarrhea (21%), increased HR (> 10 bpm from baseline (34%); > 20 bpm (5%), Headache (14%) Pregnancy Risk Factor: X( (weight lost not recommended for pregnant women) Tolerability Serious adverse reactions include risk of thyroid C-cell tumors, acute pancreatitis, acute gallbladder disease, and suicidal behaviors. Black Box Warning: Liraglutide causes dose-dependent and treatment duration dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, because the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined REMS Components Communication Plan Effectiveness Higher dose used than what s used to treat DM-II Cholelithiasis and cholecystitis have been reported in patients treated with liraglutide for obesity Saxenda should be promptly discontinued if pancreatitis is suspected and should not be restarted if it is confirmed 39