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New Drug Update 2011: An LTC Approach

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1 New Drug Update 2011: An LTC Approach
James W. Cooper, RPh,PhD, BCPS, CGP, FASCP, FASHP, FCP, Emeritus Professor of Pharmacy, UGa and Consultant Pharmacist NOTE: Dr.J. Russell May of GHSU and UGa Clinical Professor of Pharmacy shared his 69 slides of material with us for this presentation

2 Some of the Drugs Under Consideration
Pitavastatin (Livalo®) and other CHD risk-affecting drugs Liraglutide (Victoza®) and other DM risk affecting drugs Dalfampridine (Ampyra ®) Fingolimod (Gilenya®) Sipuleucel-T (Provenge®) Asenapine (Saphris ®) and iloperidone (Fanapt) Telavancin (Vibativ ®) Dabigatran (Pradaxa ®) apixaban and rivaroxaban Buprenorphine (Butrans) patch

3 Disclosure-Dr. Cooper has served on numerous speakers bureaus and as an advisor or clinical researcher for many of the companies whose products are discussed herein- a * is placed by those companies for whom he currently serves :These companies have included (before mergers not guaranteed to be current titles) Abbott, AstraZeneca, Aventis, Bayer, Boehringer-Ingleheim*, Bristol-Myers Squibb, Ciba-Geigy, Marion-Merrell-Dow, Merck, Janssen, Glaxo-SKB, Lederle, Pfizer-Roerig*, Proctor and Gamble, Ortho-McNeil, Purdue-Pharma, Pfizer-Roerig, Lilly-Dista, Merck, Organon, Roxane, Forest *, Upjohn-Pharmacia Watson Labs and Novartis.

4 Other free LTC resources for MTM, PIMs and Safe Meds
Please go to to Download four free slide sets on MTM (164), PIMs (84) and Safe med use in the older adult (48) for use in your practice– as well as this set of 110 presentation slides. May also download presentation at

5 Objectives After attending the lecture and discussion, the attendee should be able to: > Compare and contrast newly approved drugs with older agents regarding their pharmacology, pharmacokinetics, efficacy, safety, dosage and cost. > Describe and apply the “LTC formulary approach” to evaluating new drugs. > Describe the place of the newer agents in current pharmacotherapeutic “hierarchy”.

6 LTC Formulary Approach
A finite list of therapeutic agents Established value in light of current medical opinion Sufficiently broad to meet the usual clinical problems Avoids duplication of clinical effect Subject to continuing revision based on new therapeutic knowledge

7 Formulary Criteria For a drug to be recommended for addition to the LTC Formulary of most PDPs (prescription drug plans), it must meet at least one of the following: New Pharmacological Class More Efficacious Safer Pharmacokinetic Advantage (clinically relevant) More Cost Effective


9 Pitavastatin (Livalo ®)
Pharmacology HMG-CoA reductase inhibitor Yes… another “statin” There are now seven “statins” on the U.S. market Pitavastatin has been available in Japan since 2003 Indications: Primary hyperlipidemia Mixed dyslipidemia

10 Pitavastatin (Livalo®)
Pharmacokinetics Cmax in about one hour High fat meal decreases Cmax by 50% AUC remains unchanged Metabolized by in the liver (CYP2C9) Substrate of OATP1B1, a hepatic drug transporter Uptake is rate-limiting step in hepatobiliary clearance Half-life = 11 hours Metabolites excreted in feces

11 Pitavastatin (Livalo ®)
Efficacy Comparative efficacy (not outcome) studies published! 4 mg = atorvastatin 20 mg N = 307, at months, open-label study Total C lowering: 21.9% versus 21.9% LDL-C lowering: % versus 35.8% HDL-C increased: 9.9% versus 8.0% 2 mg = simvastatin 20 mg (also 4 mg = 40 mg) N = 857, 12 weeks, randomized, double-blind study LDL-C lowering 39% versus 35% (n.s.) 2 mg > pravastatin 10 mg Total (28.2 % versus 14%), LDL (37.6% versus 18.4%) Hiro T et al. J Am Coll Cardiol 2009;54:293 Ose L et al. Curr Med Res Opin 2009;25:2755 Saito Y et al. Atherosclerosis 2002;162:373

12 Pitavastatin (Livalo ®)
Safety Similar to other “statins” myalgias constipation joint and back pain > 4 mg associated with increased risk of severe myopathy Rhabdomyolysis not reported to date Drug interactions Cyclosporine – 4.6 X increase in AUC Erythromycin - ~ 2 X increase in AUC Other inhibitors of OATP1B1

13 Pitavastatin (Livalo ®)
Dosage and Cost Usually 2 mg daily, may be increased to 4 mg after 4 weeks if needed Comparative cost for 30 days (initial doses) Pitavastatin $121 Atorvastatin $100 Fluvastatin $103 Rosuvastatin $140 Simvastatin $28 Lovastatin $22 Pravastatin $26

14 Pitavastatin (Livalo ®)
Criteria Met? New Pharmacological Class More Efficacious Safer Pharmacokinetic Advantage (clinically relevant) More Cost Effective

15 Other Newer CHD/ Apolipoprotein affecting/ Hypolipidemics
Cholesterol and lipoprotein management Darapladib (GlaxoSmith-Kline)- White H Am Heart J 2010; 160(4): Mipomersen (Genzyme)- Expert Opin Investig Drugs Feb;20(2): Epub 2011 Jan 6 FOR STATIN INTOLERANT Anacetrapib (Merck)- AAPS J Feb 23. [Epub ahead of print]- USED WITH STATINS Dalcetrapib (Roche) Clin Drug Investig Mar 2 –epub- RAISE HDL


17 Liraglutide (Victoza®)
Pharmacology Glucagon-like peptide-1 (GLP-1) receptor agonist (like exenatide - Byetta® ) GLP-1: incretin hormone that stimulates the pancreas to release insulin (when serum glucose is elevated) Decreases glucagon secretion and slows gastric emptying Shares 97% amino acid sequence of human GLP-1 (exenatide shares 53%) Indication: adjunct to diet and exercise in adults with type 2 diabetes Not first-line therapy- NOR RECOMMENDED

18 Liraglutide (Victoza®)
Pharmacokinetics Following SC administration Cmax in 8 to 12 hours Bioavailability ~ 55% Highly protein bound ~98%- beware of lower serum albumin ( average 3.0 in LTC pts. Cooper and Cobb Nutr Supp Serv 1988) Endogenously metabolized (similarly to large proteins) Half-life ~ 13 hours Once daily

19 Liraglutide (Victoza®)
Efficacy Approved based on 5 published studies Monotherapy versus glimepiride (n = 746) Greater reduction in HbA1c Add on to metformin versus glimepiride (n = 1091) Better than placebo, = to glimepiride in HbA1c reduction Add on to glimepiride versus glimepiride alone (n = 1041) Combo better than glimepiride alone in HbA1c reduction Add on to metformin and glimepiride versus combo (n = 581) Three drugs better than two in HbA1c reduction Add on to metformin and rosigliazone versus combo (n = 533) Versus exenatide? Yes* ADEQUATELY STUDIED IN OLDER ADULTS- NO! Diabet Med 2009;26:268. Diabetes Care 2009;32:84. Lancet 2009;373:473. Diabetes Care 2009;32: Diabetologia 2009;52: Lancet 2009;374:39*

20 Liraglutide (Victoza®)
Safety Most common side effects: Nausea (28%) vomiting (11%) diarrhea (17%) constipation (10%) headache (9%) Causes dose-dependent and treatment duration-dependent thyroid C-cell tumors Both genders of rats and mice Use with caution when history of pancreatitis exists

21 Liraglutide (Victoza®)
Dosage and Cost 0.6 mg sc daily for 1 week (to reduce GI side effects…not an efficacious dose) 1.2 mg sc daily up to 1.8 mg daily Cost for 30 day supply: Liraglutide 1.2 mg daily $279 Exenatide 10 mcg twice daily $231 Note: What about Exenatide LAR? late 2011, probably mid-2012

22 Liraglutide (Victoza®)
Criteria New Pharmacological Class More Efficacious ?? Safer- NOT SHOWN IN OLDER ADULTS Pharmacokinetic Advantage (clinically relevant) – EXCEPT FOR LOWER SERUM ALBUMIN More Cost Effective ?

23 Other Diabetes drugs in works
Dapagliflozen – Phase III New class: “subtype 2 sodium glucose co-transport protein inhibitor- will be the first in a new class that seeks to block the reabsorption of glucose to lower elevated blood glucose levels in diabetics Taspoglutide – Phase III Another GLP-1 agonist pulled as of Feb 2011 due to serious GI adverse effects

24 Bromocriptine (Cycloset)
Lowers blood glucose only slightly (A1c by ~0.5% at $ /month cost! Dopamine agonist for Parkinson’s with little risk for weight gain or hypoglycemia, BUT Many side effects- nausea, drowsiness, dizziness, fainting and nightmares Never use in lactating woman as lowers breast milk production.


26 Dalfampridine (Ampyra®)
Pharmacology Potassium channel blocker Mechanism of action UNCLEAR In animals… Increases the conduction of action potentials in demyelinated axons via inhibition of potassium channels Indication: to improve walking in adult patients with multiple sclerosis Potential future uses: Muscle spasticity associated with spinal cord injury Guillain-Barre syndrome

27 Dalfampridine (Ampyra ®)
Pharmacokinetics Well absorbed after oral administration Note: extended-release tablet Metabolized by CYP2E1 Metabolites are inactive Most eliminated unchanged through kidneys Half-life = 5.2 – 6.5 hours Clearance is decreased by 75% with CrCl <30 (half-life 3.3 X longer)- Average CrCl of LTC older adults is 35ml/min or lower Cooper et al JGDT 1991 and Marasco R et al TCP 2005)

28 Dalfampridine (Ampyra ®)
Efficacy Shown in one published Phase II trial Goodman et al. Lancet 2009;373:732. Two unpublished Phase III trials Randomized, double-blind, placebo controlled N = 540 Response measured as 10%, 20%, 30% increases in walking speed Dalfampridine superior to placebo in both trials 34.8% versus 8.3 % 42.9% versus 9.3% Does not affect exacerbations or alter the course of the disease

29 Dalfampridine (Ampyra ®)
Safety Contraindications: History of seizures- OR CVA Moderate or severe renal impairment UTIs occurred more frequently (compared to placebo): 12 % versus 8% Others: Insomnia 9% Asthenia 7% Dizziness 7% Back pain 5% Headache 7% Balance disorder 5%

30 Dalfampridine (Ampyra ®)
Dosage and Cost 10 mg PO every 12 hours Do not crush, chew, dissolve or split tablets Cost: $35.20 per day (AWP)

31 Dalfampridine (Ampyra ®)
Criteria New Pharmacological Class More Efficacious Safer Pharmacokinetic Advantage (clinically relevant) More Cost Effective


33 Fingolimod (Gilenya®)
Pharmacology Interacts with sphingosine 1- phosphate receptors Blocks lymphocytic egress from lymph nodes Reduces the number of lymphocytes in peripheral blood and the central nervous system (?) Indication To reduce the frequency of clinical exacerbations and delay the accumulation of physical disability in patients with relapsing forms of multiple sclerosis (MS)

34 Fingolimod (Gilenya®)
Pharmacokinetics Tmax is reached in 12 – 16 hours Bioavailability = 93% Steady state concentrations: 1 to 2 months Metabolized by CYP4F2 Minor: 2D6, 2E1, 3A4, 4F12 Only related drug interaction: ketoconazole Half-life = 6 to 9 days

35 Fingolimod (Gilenya®)
Efficacy Double-blind randomized trial (n = 1272) Annualized relapse rate Fingolimod 0.5 mg 0.18 Placebo Cumulative probability of disability progression Fingolimod 0.5 mg 17.7% Placebo % Double-blind randomized trial (n = 1292) Fingolimod 0.5 mg 0.16 Interferon beta-1a 0.33 Kappos L et al. N Engl J Med 2010;362:387 Cohen JA et al. N Engl J Med 2010;362:402

36 Fingolimod (Gilenya®)
Safety Most common: Headache Cough Diarrhea Back Pain Increased risk of viral infections Transient bradycardia Including first or second degree AV block Macular edema (first 3 – 4 months) Dose dependent reduction in FEV1 (3.1%)

37 Fingolimod (Gilenya®)
Dosage and Cost 0.5 mg oral once daily Cost (1 year of treatment): Interferon beta-1A $38,000 Fingolimod $57,000 (estimated)

38 Fingolimod (Gilenya®)
Criteria New Pharmacological Class More Efficacious Safer Pharmacokinetic Advantage (clinically relevant) More Cost Effective

39 Combination for Pseudobulbar Affect (PBA)
Dextromethorphan HBr 20mg and quinidine SO4 10mg as metabolic inhibitor to boost DM levels(Neudexta) to improve emotional lability and decrease laughing and crying episodes. NMT 2 caps/24 hrs! Caution with QT, CYP2D6 DI s and MAOIs and NOT FOR DEMENTIAs ADRs- diarrhea, flatulence, dizziness, cough, emesis, asthenia, peripheral edema, elevated GGT and FALLS

40 Denosumab (Prolia) Human mononclonal antibody that targets and binds to RANK ligand, inhibiting osteoclast formation, function and survival. Given q 6 months. Intended for those with high Fx risk osteoporosis (OP) or those who have failed or intolerant to other OP therapies (BPs, teriparitide, miacalcin) Reduces veterbral, hip and non-vertebral Fxs-

41 Prolia- cont’d Beware of higher serious infection rate with denosumab- esp. if on other immunosuppresant agents. Also higher risk of skin reactions, eg dermatitis, eczema and rashes . Osteonecrosis of the Jaw (ONJ) with tooth extraction and/or local infection with delayed healing is seen. Place in therapeutic hierarchy? Ca/Vit D, BPs, Forteo and Miacalcin?

42 Risedronate (Atelvia)
Delayed-release similar to Actonel, except its meant to be taken AFTER meals rather than minutes before like other bisphosphonates-may reduce malabsorption of calcium and iron. Still need to take with plenty of water and sit upright for minutes afterward. No H-2B nor PPIs!-Interfere with release-About $135/month- same as Actonel, but risedronate is going generic in 2014 and weekly alendronate is as little as 4$/month (Rx Letter Feb 2011)


44 Sipuleucel-T (Provenge®)
Pharmacology Cellular immunotherapy designed to induce an immune response targeted against prostatic acid phosphatase (an antigen expressed in most prostate cancers. Classified as “autologous cellular immunotherapy: Indication: treatment of asymptomatic or minimally symptomatic, metastatic, castrate resistant (hormone refractory) prostate cancer

45 Sipuleucel-T (Provenge®)
Pharmacokinetics Not one word in prescribing information therefore we will re- label this slide: What is “autologous cellular immunotherapy”? Patient’s immune cells combined with a recombinant antigen containing prostatic acid phosphatase and GM-CSF

46 Sipuleucel-T (Provenge®)
Efficacy 2 similar clinical trials: randomized, double-blind, placebo controlled N = 639 Results were similar Overall survival in months 25.8 versus 21.7 25.9 versus 21.4 Both statistically significant (p = and p = 0.01)

47 Sipuleucel-T (Provenge®)
Safety Solely for autologous use Most common (>15%) Chills, fatigue, fever, back pain, nausea, joint ache, headache Other common: Hypertension (7.5%), anorexia (6.5%) Not tested for transmissible infectious diseases…Use universal precautions

48 Sipuleucel-T (Provenge®)
Dosage and Cost 3 doses at 2 week intervals Infused over one hour Pre-medicate with acetaminophen and diphenhydramine Confirm patient identity (patient and bag) Cost: ~$31,000 per infusion

49 Sipuleucel-T (Provenge®)
Criteria New Pharmacological Class More Efficacious Safer Pharmacokinetic Advantage (clinically relevant) More Cost Effective- BUT NOT IN MOST OLDER MEN IN LTC- CHECK GLEASON SCORE!

50 abiraterone acetate (Zytiga)
FDA approved abiraterone acetate (Zytiga) on 4/29/11 for treatment of late-stage, castration-resistant prostate cancer as a combination therapy with prednisone in patients who have received prior chemotherapy with docetaxel. Abiraterone decreases the production of the protein cytochrome P450 17A1 -- which the body uses in the production of testosterone & curbs cancer cell growth

51 abiraterone acetate (Zytiga)
Approval was based on a clinical trial of 1,195 patients with late- stage, castration-resistant prostate cancer who had undergone prior docetaxel chemotherapy. Patients were randomized to abiraterone once a day and prednisone twice daily, or to both placebo and prednisone twice daily. Those in the active treatment group had a median overall survival of months, versus 10.9 months for those in the placebo group. Adverse events include joint swelling and discomfort, low levels of blood potassium, fluid retention, muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, hypertension, heartbeat disorders, urinary frequency, increased nocturnal urination, upset stomach, and upper respiratory tract infection.

52 Ipilimumab (Yervoy) The FDA approved on 3/25/11 the use of the monoclonal antibody ipilimumab for the treatment of previously treated metastatic melanoma. It is the first drug approved for metastatic, or advanced, melanoma in more than a decade-. Patients receiving ipilimumab plus a peptide vaccine (glycoprotein 100) had a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone (P < .001). Patients receiving ipilimumab alone had a nearly identical median survival months -- in the 3-group clinical triaI(P < .003). It only worked in a small percentage of patients.

53 Ipilimumab Ipilimumab, developed by BMS and Medarex, is a monoclonal antibody that consists of millions of copies of a human antibody that binds to CTLA-4 protein molecule on T cells — white blood cells that patrol the body for signs of illness. CTLA-4 serves as a control switch for the immune system’s response to disease. With no antibody attached, CTLA-4 suppresses the immune response. Ipilimumab reverses that condition, unleashing the immune attack on abnormal cells, including cancer cells.

54 Ipilimumab The median survival period for patients receiving ipilimumab plus gp100 was 10 months, compared with 6.4 months for those receiving gp100 alone. The median survival for participants receiving ipilimumab alone was 10.1 months. In the ipilimumab-alone group, nine of 15 patients continued to benefit from the therapy for at least two years, as did four of 23 patients in the combination therapy group. About 60 percent of the patients treated with ipilimumab experienced adverse side effects to the therapy, as did 32 percent of the patients treated with gp100. The complications were generally immune system-related and most often affected the skin and gastrointestinal tract. The most common included diarrhea, nausea, constipation, fatigue, decreased appetite, and rash. While the adverse effects could be severe and long-lasting, most of them were reversible with appropriate treatment.

55 Ipilimumab (Yervoy) However, about 13 percent of users suffered severe-to-fatal autoimmune reactions. As a result, REMS guides will be distributed with the drug, informing doctors and patients of the medication's potential risks, per the FDA 6 Apr 11.      Yervoy will cost $30,000 a dose, or $120,000 for a four- dose course of treatment. Coverage? Benefit to risk??

56 peginterferon alfa-2b (Sylatron)
to prevent melanoma recurrence following definitive surgical resection in patients with microscopic or gross nodal involvement approved by FDA 4/1/11. By Merck's Schering unit-Recommended dose of 6 mcg/kg/week subcutaneously for eight doses, followed by 3 mcg/kg/week subcutaneously for up to five years. Treatment should begin within 12 weeks of resection. In the sole trial submitted in support of the approval, EORTC , the drug extended relapse-free survival by about nine months compared with an observation-only arm (34.8 months versus 25.5 months), according to an FDA statement.

57 peginterferon alfa-2b (Sylatron)
However, overall survival was not improved with peginterferon alfa-2b in the five-year trial, which had enrolled 1,256 patients and had relapse-free survival as the primary endpoint. Among the 33 patients who discontinued the drug because of adverse effects, the most common were fatigue, depression, anorexia, increased transaminases, myalgia, nausea, headache, and pyrexia.

58 peginterferon alfa-2b (Sylatron)
Five deaths were reported within 30 days of the last drug dose. Two were attributed to recurrent disease, two to cardiovascular disease possibly related to the treatment, and one to an accident. Overall, the following were seen in more than 60% of patients receiving the drug: fatigue, elevated transaminases, fever, headache, anorexia, myalgia, nausea, chills, and injection-site reactions.

59 peginterferon alfa-2b (Sylatron)
Overall ? Benefit? Costs? Acceptance? Severe adverse reactions? YES

60        Benlysta (belimumab), First new drug for lupus in half century-reduces the disease's level of activity by inhibiting a bodily protein called the B- lymphocyte stimulator- Steroid sparing benefit, but only works in 35% of pts. Not recommended for African-Americans nor patients whose disease is severely damaging their kidneys or central nervous systems because it was not beneficial nor tested on those patients. Most common ADRs in clinical trials were nausea, diarrhea and fever.

61 Benlysta- cont’d Those receiving Benlysta during clinical studies reported more deaths and serious infections compared with placebo. The drug should not be administered with live vaccines. The manufacturer is required to provide a Medication Guide to inform patients of the risks associated with Benlysta. The most common side effects in the studies included nausea, diarrhea, and fever (pyrexia). Patients also commonly experienced infusion reactions, so pre- treatment with an antihistamine should be considered

62 Tocilizumab (Actemra)
IL-6 inhibitor for IV use q 4 wks. in those pts.with moderate to severe RA who have had an inadequate response to one or more TNFs. May be used with MTX or DEMARDs. Higher infection risk- watch ANC, platelets, AST/ALT and LFTs-MUST check q 4-8 wks. Avoid live vaccines- check for latent TB before starting Tx

63 Actemra- cont’d Monitor Lipids q 4-8 wks
Interactions include increased infection risk with TNF inhibitors, OC s, statins, warfarin, theophylline and cyclosporine Common ADRs include URTIs, nasopharyngitis, HA, HBP and increased ALTs and lipids Advantage?


65 Asenapine (Saphris ®) Pharmacology Atypical antipsychotic
Probable mechanism of action Dopamine (D2) antagonism Serotonin (5-HT2A) antagonism Indications Acute treatment of schizophrenia in adults Acute treatment of manic or mixed episodes associated with bipolar I disorder in adult NOT INDICATED FOR DEMENTIA- SEE BLACK BOX WARNINGS!!

66 Asenapine (Saphris ®) Pharmacokinetics
Rapidly absorbed after sublingual administration Peak concentration in 0.5 to 1.5 hours Bioavailability ~ 35% Intake of water within 2 – 5 minutes of dose will decrease absorption Highly protein bound ~95% (again Lower Serum albumin in older adults!) Metabolized by CYP1A2 Half-life ~ 24 hours in younger patients- NOT STUDIED IN OLDER ADULTS!

67 Asenapine (Saphris ®) Efficacy Three 6 week studies for schizophrenia
Randomized, placebo and active drug-controlled, double-blind Study 1 – both asenapine and risperidone > placebo (n = 174) Study 2 - both asenapine and haloperidol > placebo (n = 458) Study 3 – olanzapine > placebo and asenapine = placebo (data on file only) Two 3 week studies for bipolar disorder Both studies: asenapine and olanzapine > placebo Polkin et al. J Clin Psychiatry 2007;68:1492 Kane et al. J Clin Psychopharmacol 2010;30-106 McIntyre et al. Bipolar Disord 2009;11:673

68 Asenapine (Saphris ®) Safety Warnings similar to other atypicals
Associated with increased QT interval Most common Akathisia 11% (with 10 mg dose) Somnolence 16% – 24% Dizziness 11% Increased weight 5% FALLS proportional to total psychoactive drug “load” ( Cooper J et all TCP 2007) with ALL antipsychotics!!

69 Asenapine (Saphris ®) Dosage and Cost
Schizophrenia: 5 mg SL twice daily No added benefit with 10 mg dose Bipolar disorder: 10 mg SL twice daily Remember DO NOT SWALLOW If swallowed bioavailability is < 2% No food or water for 10 minutes Cost: Asenapine $575 Risperidone $474 NOW GENERIC and much less- 60 X1mg for $198 Olanzapine $299

70 Asenapine (Saphris ®) Criteria- NONE New Pharmacological Class
More Efficacious Safer Pharmacokinetic Advantage (clinically relevant) More Cost Effective

71 Iloperidone (Fanapt) Atypical antipsychotic-(AP)1,2,4,6,8,10 and 12 mg tabs for acute treatment of schizophrenia-NOT DEMENTIA Same class as risperidone and paliperidone. NO ADVANTAGE SAME ADRs as all AP s, especially tardive dyskinesias in women Review- Arif SA, Mitchell MM, Am J Health Syst Pharm Feb 15;68(4):301-8

72 Lurasidone (Latuda) The 10th oral atypical antipsychotic-no advantage
Best current review- See Pharmacists Letter Feb 2011 Many going generic and much lower cost with similar efficacy and safety, eg Zyprexa, Seroquel, Invega and Geodon

73 Vilazodone (Viibryd) Vilazodone is a dual-acting antidepressant drug, with a primary mechanism of action of blocking the serotonin reuptake transporter together with acting as a 5-HT1A receptor partial agonist. The antidepressant efficacy of vilazodone was established in two 8-week placebo-controlled studies. One long-term (52-week) open-label study has been conducted. The most common side effects are diarrhea, nausea, and headache. The drug has not been studied in pediatric patients or well studied in patients older than 65. Vilazodone is efficacious, safe, and well tolerated, but does not appear to have major efficacy advantages compared with other antidepressant drugs- simply a newer trazodone or nefazodone? RH Howland J Psychosoc Nurs Ment Health Serv Mar;49(3): Epub 2011 Feb 16.


75 Telavancin (Vibativ®)
Pharmacology Semi-synthetic lipoglycopeptide A derivative of vancomycin Mechanisms of action Inhibits cell wall synthesis Binds to bacterial membrane and disrupts membrane barrier function Indications: For adults 18 years and older Skin and skin structure infections caused by MSSA, MRSA, several Strep species, and Enterococcus faecalis (vancomycin sensitive only)

76 Telavancin (Vibativ®)
Pharmacokinetics Given by IV infusion over 1 hour Protein binding ~ 90% Half-life ~7.5 hours (note: dosed once daily) If CrCl = 10 – 29 ml/min use q48hr Excretion- Urine (76%) feces (<1%)

77 Telavancin (Vibativ®)
Efficacy Double-blind, randomized trial versus vancomycin (N= 1867) Skin and skin structure infections Suspected or confirmed Gram positive infection Non-inferiority proven Stryjewski et al. Clin Infect Dis 2008;46:1683

78 Telavancin (Vibativ®)
Safety Differences in adverse effects Telavancin Vancomycin (N = 929) (N = 938) Nausea 27% 15% Vomiting 14% 7% Taste disturbance 33% 7% Foamy urine 13% 3% Pruritis 6% 13%

79 Telavancin (Vibativ®)
Dosage and Cost 10 mg/kg IV daily over one hour For CrCl ml/min: 7.5 mg/kg daily For CrCl ml/min: 10 mg/kg q48hr Insufficient data for < 10 ml/min Cost: Vancomycin $4.49 / 1 gm Telavancin $44.96 / 250 mg

80 Telavancin (Vibativ®)
Criteria- NONE New Pharmacological Class More Efficacious Safer Pharmacokinetic Advantage (clinically relevant) ? More Cost Effective

81 Two Hep C PIs-boceprevir and telaprevir-Med Page 29 Apr 11
Dosing-750 mg of telaprevir (VX-950) three times daily for 12 weeks, combined with peginterferon and ribavirin at standard doses for 24 or 48 weeks, depending on virologic response. ADRs-increased incidence of serious and life- threatening skin reactions, including three cases of Stevens- Johnson Syndrome in patients who took telaprevir. More than half of patients receiving the drug reported rash or pruritus, with 6% discontinuing treatment as a result.

82 Boceprevir-30MAR 11 NEJM Randomized 403 patients with HCV genotype 1 infection who had either a nonresponse to treatment or who suffered a relapse following treatment with peginterferon–ribavirin to one of three treatment groups. In all three groups, patients received peginterferon alfa-2b and ribavirin for 4 weeks. Following this therapy, group 1 received a placebo plus peginterferon–ribavirin for 44 weeks. Group 2 received boceprevir plus peginterferon–ribavirin for 32 weeks, and then only those patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon–ribavirin for an additional 12 weeks. Group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks.

83 Boceprevir (Victrelis)
The rate of sustained virologic response was about three times higher in the two groups of patients who received boceprevir, compared with the group that did not. Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy.

84 Boceprevir (Victrelis)
Among the 102 patients in whom HCV RNA dropped below 1 log10 IU per milliliter at treatment week 4, virologic response was 0% in those who did not receive boceprevir, compared with 33% and 34% in the two groups that did receive the drug. Chief use of both boceprevir and teleprevir is for those who do not respond to interferon plus ribavirin and/or relapse after Tx.

85 Antiinfectives … Ceftaroline fosamil (Teflaro) Forest
Injectable cephalosporin with some MSRA activity Tx of community-aquired bacterial pneumonia (CABP) and acute bacterial skin and soft tissue infections (ABSSSIs) including MRSA Similar to ceftriaxone (Rocephin) No drug interactions but watch for C. diff and Hx beta lactam allergy (3-10% pop.) See for full info.

86 Ceftaroline fosamil (Teflaro) cont’d
IV Cephalosporin for CABP and ABSSSI- similar to ceftriaxone-400 and 600mg doses Twice the positive Coombs test (9.8 vs 4.5%) of ceftriaxone but no hemolytic anemia cases in clinical trials Adjust dose based on CrCl<50ml/min- remember ave. CrCl of 80 yo is ml/min (Cooper JW JGDT 1991)

87 Antifungals Isavuconazole (Basilia)
Antifungal IV/PO-in phase III studies.The primary goal of this phase III study is to demonstrate statistical non-inferiority of isavuconazole versus the comparator, current standard-of-care voriconazole in the treatment of invasive Aspergillus infections. For more on antifungals and all antiinfectives and 12 hours ID course-ID Overview, Cooper JW education/consultant-course-descriptions/

88 Fidaxomicin for C. diff Current study found fidaxomicin- a macrocyclic antibiotic that is more active in vitro than vancomycin in clinical isolates of C difficile, including the NAP1/BI/027 strain. Recurrence of infection occurred in significantly fewer patients taking fidaxomicin vs vancomycin in both the modified intent-to-treat analysis (15.4% vs 25.3%; P = .005) and the per-protocol analysis (13.3% vs 24.0%; P = .004). In addition, the lower rate of recurrence was seen in patients with non–North American Pulsed Field type 1 strains. The current study included 629 adults with acute symptoms of C difficile infection, with a positive result on a stool toxin test. Patients were randomly assigned to receive fidaxomicin at a dose of 200 mg twice daily or vancomycin at a dose of 125 mg 4 times daily. Both medicines were taken orally for 10 days.The 2 treatments appeared to be mostly comparable with respect to adverse events.

89 Fidaxomicin cont’d Significantly more serious adverse events related to laboratory test results occurred in the fidaxomicin group vs the vancomycin group (4.7% vs 1.2%; P = .01), although no participants discontinued the study because of allergy or intolerance. Potentially treatment-related adverse events included mild gastrointestinal tract and nonspecific symptoms, which occurred at a similar rate between the 2 groups. NEJM 3 Feb 11.

90 Specific antimicrobial therapy
Clostridium difficle monoclonal antibody (Medarex) for CDAD N Engl J Med Jan 21;362(3): Treatment with monoclonal antibodies (mca) against Clostridium difficile toxins and recurrence rate was lower with mca when added to metronidazole or vancomycin antiinfectives


92 Dabigatran (Pradaxa ®)
Pharmacology Oral direct thrombin inhibitor Inhibits both clot-bound and circulating thrombin Decreases thrombin-stimulated platelet aggregation Less variable effect than warfarin Monitoring not required Indication: For prevention of thromboembolic stroke in patients with non-valvular atrial fibrillation

93 Dabigatran (Pradaxa ®)
Pharmacokinetics Rapidly absorbed from GI Converted to active form Time to peak 1 hour if fasting, 3 hours after high fat meal Not metabolized by hepatic enzymes Eliminated renally Half-life = 12 to 17 hours

94 Dabigatran (Pradaxa ®)
Efficacy RE-LY trial: n = 18,113 Fixed dose (110 mg 0r 150 mg) versus adjusted dose warfarin (INR 2 – 3) Primary outcome…stroke Rates per year of stroke: Dabigatran 110 mg 1.54% Dabigatran 150 mg 1.11 % Warfarin % Patients with severe heart valve disorder excluded SJ Connelly et al. N Engl J Med 2009;361:1139 SJ Connelly et al. N Engl J Med 2010;363:1875

95 Dabigatran (Pradaxa ®)
Safety (from studies on previous slide…) Major bleeding Warfarin % Dabigatran 110 mg 2.87% Dabigatran 150 mg 3.32% Hemorrhagic stoke Warfarin % Dabigatran % Major GI bleeding Warfarin % Dabigatran 150 mg 1.51% The MI question….higher but N.S.

96 Dabigatran (Pradaxa ®)
Dosage and Cost 150 mg twice daily DO NOT break, chew or empty capsules For CrCl 15 to 30 ml/hr: 75 mg twice daily For CrCl <15 ml/hr not recommended For conversion from warfarin or other anticoagulants…see prescribing information Cost: Pradaxa $230 / month Warfarin $14 / month+ COST OF INR Monitoring?

97 Dabigatran (Pradaxa ®)
Criteria New Pharmacological Class-also see apixaban (NEJM Feb 11) More Efficacious-RELY-ABLE trial is LT follow-up-see Safer in some aspects-protect GI tract in the older adult, esp. with Hx of GERD,PUD or diverticulosis Pharmacokinetic Advantage(clinically relevant) More Cost Effective- in terms of total cost of care

98 Dabigatran in DVT/VTE Three large phase III studies have looked at dabigitran vs. enoxaparin in VTE prevention after orthopedic surgery- RE- NOVATE, RE-MODEL and RE-MOBILIZE trials found similar results with both agents. The RE-COVER trial found dabigatran to be as effective/safe as warfarin for treatment of acute VTE.

99 Apixaban and Rivaroxaban
Apixaban was used only for those who could not take a vitamin K antagonist (VKA) see NEJM 10 Feb 11- NOT compared to warfarin, but was compared to low-dose ASA (RR=0.45 compared to ASA) but with higher bleeding risk compared to ASA. Rivaroxaban was not approved to date

100 Other Anticoagulants Ticagrelor – NDA filed Competitor for clopidogrel
Large international outcomes trial initiated in late 2010

101 Pegloticase (Krystexx) & Febuxostat (Uloric)
For treatment of gout: for patients not helped by existing drugs Given every 2 weeks by IV infusion ( 2-hour) Use: for those who do not tolerate other hypouricemics Febuxostat (Uloric)- xanthine oxidase inhibitor also for those who can not tolerate other XO s, eg allopurinol See BurnsCM,Wortmann RL. Lancet Jan 8;377(9760): Epub 2010 Aug 16 for gout therapeutics review

102 Topical NSAIDs- safer than oral when used sparingly!
Ketorolac Nasal Spray (Sprix ®) Approved for short-term use (nmt 5 days) for moderate to moderately severe pain Ketorolac gel (Voltaren) is approved for OA pain other than shoulder, hips and spine up to 32 g/day. Watch liver function and fluid retention as with oral NSAIDs! Another topical NSAID that is compounded is 5% ketoprofen gel. Apply sparingly to FOCAL not diffuse pain 2 to 3 times a day.

103 COPD Exacerbations Roflumilast – First in a new class and first oral treatment for COPD exacerbations. Also being studied for asthma. Phospho-diesterase-4 enzyme inhibitor. *See Cannon CP et al. N Engl Med 2010;363: Also see updates on tiotropium, inhaled steroids and longer-acting beta agonists. See EJ Mill et al Clin Epidem-25 Mar 11 Issue- Pharmacotherapies for chronic obstructive pulmonary disease: a multiple treatment and comparison meta- analysis- BEST Review of COPD Tx to date- and FREE! AVOID THEOPHYLLINE IN COPD-!!

104 COPD Meds- Daliresp The Food and Drug Administration has approved roflumilast (Daliresp®) as a treatment for chronic obstructive pulmonary disease.  It is an oral medication taken daily to reduce the frequency of flare-ups of the disease.  Roflumilast is the first in a new class of medications for COPD, an inhibitor of an enzyme called phosphodiesterase type 4 (PDE-4).  How does this fit with oral and inhaled anticholinergics, beta agonists, theophylline and steroids?

105 Another LA Beta Agonist-Indacterol (Arcapta)
An FDA advisory panel has voted 13-4 that a 75 mcg once- daily dose of indacaterol (Arcapta Neohaler), an investigational long-acting beta-adrenergic agonist is safe and effective at treating airflow obstruction in patients with COPD. Never use a LABA WITHOUT a baseline Spiriva, inhaled corticosteroid if asthmatic or short-acting beta agonist !

106 Buprenorphine (Butrans) Patch
Buprenorphine 5,10 and 20mcg/hr, 7-day patch for opioid- naïve & tolerant pts. With moderate to severe pain-->3 most recent studies- AAPM Sep 10 meeting; abstracts #27,28 and 29. Three key findings - equally effective in those < and > 65yo in opioid-tolerant pts. (30-80mgMS/day), BUT NOT Effective if pt. already getting MORE than 80mgMS/day or equivalent dose. Improved sleep and pain scores in opioid- naïve patients. Watch respiratory depression, QT,CNS depression.& hypotensive effects. DO NOT COVER NOR USE WITH EXTERNAL HEAT SOURCES. Rotate Sites- do not reapply to same site earlier than 21 days after removal!

107 Testosterone replacement therapy ( Rx letter March 2011)
Fortesta and Axiron gels. Testosterone for older men is controversial-mixed blessings! May increase BPH, prostate cancer risk and melanomas, edema, sleep apnea and gynecomastia. Cost-$300/month Careful with application process for each and watch for H/H and PSA increases

108 Dexlansoprazole(Dexilant)
R-isomer of lansoprazole (Prevacid) Any advantage? More costly? Covered by any plans? Any proof its better than generic omeprazole or lansoprazole?

109 Summary New drugs for LTC pts. Have some advantages but few have been adequately evaluated in older adults. The real question is whether or not any of these meds are safer and/or more cost effective than existing agents. Most of these newer agents are more toxic in the older adult and should be used with caution if at all!

110 Want a copy of these slides? Dr. May at
Questions? Want a copy of these slides? Dr. May at for original 69 or go to or for LTC modified set of 110

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