Presentation on theme: "New Drug Update 2011: An LTC Approach"— Presentation transcript:
1New Drug Update 2011: An LTC Approach James W. Cooper, RPh,PhD, BCPS, CGP, FASCP, FASHP, FCP, Emeritus Professor of Pharmacy, UGa and Consultant PharmacistNOTE: Dr.J. Russell May of GHSU and UGa Clinical Professor of Pharmacy shared his 69 slides of material with us for this presentation
2Some of the Drugs Under Consideration Pitavastatin (Livalo®) and other CHD risk-affecting drugsLiraglutide (Victoza®) and other DM risk affecting drugsDalfampridine (Ampyra ®)Fingolimod (Gilenya®)Sipuleucel-T (Provenge®)Asenapine (Saphris ®) and iloperidone (Fanapt)Telavancin (Vibativ ®)Dabigatran (Pradaxa ®) apixaban and rivaroxabanBuprenorphine (Butrans) patch
3Disclosure-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.
4Other free LTC resources for MTM, PIMs and Safe Meds Please go to toDownload 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
5ObjectivesAfter 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”.
6LTC 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
7Formulary CriteriaFor 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 ClassMore EfficaciousSaferPharmacokinetic Advantage (clinically relevant)More Cost Effective
9Pitavastatin (Livalo ®) PharmacologyHMG-CoA reductase inhibitorYes… another “statin”There are now seven “statins” on the U.S. marketPitavastatin has been available in Japan since 2003Indications:Primary hyperlipidemiaMixed dyslipidemia
10Pitavastatin (Livalo®) PharmacokineticsCmax in about one hourHigh fat meal decreases Cmax by 50%AUC remains unchangedMetabolized by in the liver (CYP2C9)Substrate of OATP1B1, a hepatic drug transporterUptake is rate-limiting step in hepatobiliary clearanceHalf-life = 11 hoursMetabolites excreted in feces
11Pitavastatin (Livalo ®) EfficacyComparative efficacy (not outcome) studies published!4 mg = atorvastatin 20 mgN = 307, at months, open-label studyTotal 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 studyLDL-C lowering 39% versus 35% (n.s.)2 mg > pravastatin 10 mgTotal (28.2 % versus 14%), LDL (37.6% versus 18.4%)Hiro T et al. J Am Coll Cardiol 2009;54:293Ose L et al. Curr Med Res Opin 2009;25:2755Saito Y et al. Atherosclerosis 2002;162:373
12Pitavastatin (Livalo ®) SafetySimilar to other “statins”myalgias constipationjoint and back pain> 4 mg associated with increased risk of severe myopathyRhabdomyolysis not reported to dateDrug interactionsCyclosporine – 4.6 X increase in AUCErythromycin - ~ 2 X increase in AUCOther inhibitors of OATP1B1
13Pitavastatin (Livalo ®) Dosage and CostUsually 2 mg daily, may be increased to 4 mg after 4 weeks if neededComparative cost for 30 days (initial doses)Pitavastatin $121Atorvastatin $100Fluvastatin $103Rosuvastatin $140Simvastatin $28Lovastatin $22Pravastatin $26
15Other Newer CHD/ Apolipoprotein affecting/ Hypolipidemics Cholesterol and lipoprotein managementDarapladib (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 INTOLERANTAnacetrapib (Merck)- AAPS J Feb 23. [Epub ahead of print]- USED WITH STATINSDalcetrapib (Roche) Clin Drug Investig Mar 2 –epub- RAISE HDL
17Liraglutide (Victoza®) PharmacologyGlucagon-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 emptyingShares 97% amino acid sequence of human GLP-1 (exenatide shares 53%)Indication: adjunct to diet and exercise in adults with type 2 diabetesNot first-line therapy- NOR RECOMMENDED
18Liraglutide (Victoza®) PharmacokineticsFollowing SC administrationCmax in 8 to 12 hoursBioavailability ~ 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 hoursOnce daily
19Liraglutide (Victoza®) EfficacyApproved based on 5 published studiesMonotherapy versus glimepiride (n = 746)Greater reduction in HbA1cAdd on to metformin versus glimepiride (n = 1091)Better than placebo, = to glimepiride in HbA1c reductionAdd on to glimepiride versus glimepiride alone (n = 1041)Combo better than glimepiride alone in HbA1c reductionAdd on to metformin and glimepiride versus combo (n = 581)Three drugs better than two in HbA1c reductionAdd 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*
20Liraglutide (Victoza®) SafetyMost common side effects:Nausea (28%) vomiting (11%) diarrhea (17%)constipation (10%) headache (9%)Causes dose-dependent and treatment duration-dependent thyroid C-cell tumorsBoth genders of rats and miceUse with caution when history of pancreatitis exists
21Liraglutide (Victoza®) Dosage and Cost0.6 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 dailyCost for 30 day supply:Liraglutide 1.2 mg daily $279Exenatide 10 mcg twice daily $231Note: What about Exenatide LAR?late 2011, probably mid-2012
22Liraglutide (Victoza®) CriteriaNew Pharmacological ClassMore Efficacious ??Safer- NOT SHOWN IN OLDER ADULTSPharmacokinetic Advantage (clinically relevant) – EXCEPT FOR LOWER SERUM ALBUMINMore Cost Effective ?
23Other Diabetes drugs in works Dapagliflozen – Phase IIINew 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 diabeticsTaspoglutide – Phase IIIAnother GLP-1 agonist pulled as of Feb 2011 due to serious GI adverse effects
24Bromocriptine (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, BUTMany side effects- nausea, drowsiness, dizziness, fainting and nightmaresNever use in lactating woman as lowers breast milk production.
26Dalfampridine (Ampyra®) PharmacologyPotassium channel blockerMechanism of action UNCLEARIn animals…Increases the conduction of action potentials in demyelinated axons via inhibition of potassium channelsIndication: to improve walking in adult patients with multiple sclerosisPotential future uses:Muscle spasticity associated with spinal cord injuryGuillain-Barre syndrome
27Dalfampridine (Ampyra ®) PharmacokineticsWell absorbed after oral administrationNote: extended-release tabletMetabolized by CYP2E1Metabolites are inactiveMost eliminated unchanged through kidneysHalf-life = 5.2 – 6.5 hoursClearance 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)
28Dalfampridine (Ampyra ®) EfficacyShown in one published Phase II trialGoodman et al. Lancet 2009;373:732.Two unpublished Phase III trialsRandomized, double-blind, placebo controlledN = 540Response measured as 10%, 20%, 30% increases in walking speedDalfampridine superior to placebo in both trials34.8% versus 8.3 %42.9% versus 9.3%Does not affect exacerbations or alter the course of the disease
29Dalfampridine (Ampyra ®) SafetyContraindications:History of seizures- OR CVAModerate or severe renal impairmentUTIs occurred more frequently (compared to placebo): 12 % versus 8%Others:Insomnia 9% Asthenia 7%Dizziness 7% Back pain 5%Headache 7% Balance disorder 5%
30Dalfampridine (Ampyra ®) Dosage and Cost10 mg PO every 12 hoursDo not crush, chew, dissolve or split tabletsCost: $35.20 per day (AWP)
33Fingolimod (Gilenya®) PharmacologyInteracts with sphingosine 1- phosphate receptorsBlocks lymphocytic egress from lymph nodesReduces the number of lymphocytes in peripheral blood and the central nervous system (?)IndicationTo reduce the frequency of clinical exacerbations and delay the accumulation of physical disability in patients with relapsing forms of multiple sclerosis (MS)
34Fingolimod (Gilenya®) PharmacokineticsTmax is reached in 12 – 16 hoursBioavailability = 93%Steady state concentrations: 1 to 2 monthsMetabolized by CYP4F2Minor: 2D6, 2E1, 3A4, 4F12Only related drug interaction: ketoconazoleHalf-life = 6 to 9 days
35Fingolimod (Gilenya®) EfficacyDouble-blind randomized trial (n = 1272)Annualized relapse rateFingolimod 0.5 mg 0.18PlaceboCumulative probability of disability progressionFingolimod 0.5 mg 17.7%Placebo %Double-blind randomized trial (n = 1292)Fingolimod 0.5 mg 0.16Interferon beta-1a 0.33Kappos L et al. N Engl J Med 2010;362:387Cohen JA et al. N Engl J Med 2010;362:402
36Fingolimod (Gilenya®) SafetyMost common:Headache CoughDiarrhea Back PainIncreased risk of viral infectionsTransient bradycardiaIncluding first or second degree AV blockMacular edema (first 3 – 4 months)Dose dependent reduction in FEV1 (3.1%)
37Fingolimod (Gilenya®) Dosage and Cost0.5 mg oral once dailyCost (1 year of treatment):Interferon beta-1A $38,000Fingolimod $57,000 (estimated)
39Combination 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 DEMENTIAsADRs- diarrhea, flatulence, dizziness, cough, emesis, asthenia, peripheral edema, elevated GGT and FALLS
40Denosumab (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-
41Prolia- cont’dBeware 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?
42Risedronate (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)
44Sipuleucel-T (Provenge®) PharmacologyCellular 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
45Sipuleucel-T (Provenge®) PharmacokineticsNot 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
46Sipuleucel-T (Provenge®) Efficacy2 similar clinical trials: randomized, double-blind, placebo controlled N = 639Results were similarOverall survival in months25.8 versus 21.725.9 versus 21.4Both statistically significant(p = and p = 0.01)
47Sipuleucel-T (Provenge®) SafetySolely for autologous useMost common (>15%)Chills, fatigue, fever, back pain, nausea, joint ache, headacheOther common:Hypertension (7.5%), anorexia (6.5%)Not tested for transmissible infectious diseases…Use universal precautions
48Sipuleucel-T (Provenge®) Dosage and Cost3 doses at 2 week intervalsInfused over one hourPre-medicate with acetaminophen and diphenhydramineConfirm patient identity (patient and bag)Cost: ~$31,000 per infusion
49Sipuleucel-T (Provenge®) CriteriaNew Pharmacological ClassMore EfficaciousSaferPharmacokinetic Advantage (clinically relevant)More Cost Effective- BUT NOT IN MOST OLDER MEN IN LTC- CHECK GLEASON SCORE!
50abiraterone 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
51abiraterone 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.
52Ipilimumab (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.
53IpilimumabIpilimumab, 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.
54IpilimumabThe 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.
55Ipilimumab (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??
56peginterferon 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.
57peginterferon 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.
58peginterferon 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.
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.
61Benlysta- cont’dThose 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
62Tocilizumab (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
63Actemra- cont’d Monitor Lipids q 4-8 wks Interactions include increased infection risk with TNF inhibitors, OC s, statins, warfarin, theophylline and cyclosporineCommon ADRs include URTIs, nasopharyngitis, HA, HBP and increased ALTs and lipidsAdvantage?
65Asenapine (Saphris ®) Pharmacology Atypical antipsychotic Probable mechanism of actionDopamine (D2) antagonismSerotonin (5-HT2A) antagonismIndicationsAcute treatment of schizophrenia in adultsAcute treatment of manic or mixed episodes associated with bipolar I disorder in adultNOT INDICATED FOR DEMENTIA- SEE BLACK BOX WARNINGS!!
66Asenapine (Saphris ®) Pharmacokinetics Rapidly absorbed after sublingual administrationPeak concentration in 0.5 to 1.5 hoursBioavailability ~ 35%Intake of water within 2 – 5 minutes of dose will decrease absorptionHighly protein bound ~95% (again Lower Serum albumin in older adults!)Metabolized by CYP1A2Half-life ~ 24 hours in younger patients- NOT STUDIED IN OLDER ADULTS!
67Asenapine (Saphris ®) Efficacy Three 6 week studies for schizophrenia Randomized, placebo and active drug-controlled, double-blindStudy 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 disorderBoth studies: asenapine and olanzapine > placeboPolkin et al. J Clin Psychiatry 2007;68:1492Kane et al. J Clin Psychopharmacol 2010;30-106McIntyre et al. Bipolar Disord 2009;11:673
68Asenapine (Saphris ®) Safety Warnings similar to other atypicals Associated with increased QT intervalMost commonAkathisia 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!!
69Asenapine (Saphris ®) Dosage and Cost Schizophrenia: 5 mg SL twice dailyNo added benefit with 10 mg doseBipolar disorder: 10 mg SL twice dailyRemember DO NOT SWALLOWIf swallowed bioavailability is < 2%No food or water for 10 minutesCost: Asenapine $575Risperidone $474 NOW GENERIC and much less- 60 X1mg for $198Olanzapine $299
70Asenapine (Saphris ®) Criteria- NONE New Pharmacological Class More EfficaciousSaferPharmacokinetic Advantage (clinically relevant)More Cost Effective
71Iloperidone (Fanapt)Atypical antipsychotic-(AP)1,2,4,6,8,10 and 12 mg tabs for acute treatment of schizophrenia-NOT DEMENTIASame class as risperidone and paliperidone. NO ADVANTAGESAME ADRs as all AP s, especially tardive dyskinesias in womenReview- Arif SA, Mitchell MM, Am J Health Syst Pharm Feb 15;68(4):301-8
72Lurasidone (Latuda) The 10th oral atypical antipsychotic-no advantage Best current review- See Pharmacists Letter Feb 2011Many going generic and much lower cost with similar efficacy and safety, eg Zyprexa, Seroquel, Invega and Geodon
73Vilazodone (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.
75Telavancin (Vibativ®) PharmacologySemi-synthetic lipoglycopeptideA derivative of vancomycinMechanisms of actionInhibits cell wall synthesisBinds to bacterial membrane and disrupts membrane barrier functionIndications:For adults 18 years and olderSkin and skin structure infections caused by MSSA, MRSA, several Strep species, and Enterococcus faecalis (vancomycin sensitive only)
76Telavancin (Vibativ®) PharmacokineticsGiven by IV infusion over 1 hourProtein binding ~ 90%Half-life ~7.5 hours (note: dosed once daily)If CrCl = 10 – 29 ml/min use q48hrExcretion- Urine (76%) feces (<1%)
77Telavancin (Vibativ®) EfficacyDouble-blind, randomized trial versus vancomycin (N= 1867)Skin and skin structure infectionsSuspected or confirmed Gram positive infectionNon-inferiority provenStryjewski et al. Clin Infect Dis 2008;46:1683
81Two 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.
82Boceprevir-30MAR 11 NEJMRandomized 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.
83Boceprevir (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.
84Boceprevir (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.
85Antiinfectives … Ceftaroline fosamil (Teflaro) Forest Injectable cephalosporin with some MSRA activityTx of community-aquired bacterial pneumonia (CABP) and acute bacterial skin and soft tissue infections (ABSSSIs) including MRSASimilar to ceftriaxone (Rocephin)No drug interactions but watch for C. diff and Hx beta lactam allergy (3-10% pop.)See for full info.
86Ceftaroline fosamil (Teflaro) cont’d IV Cephalosporin for CABP and ABSSSI- similar to ceftriaxone-400 and 600mg dosesTwice the positive Coombs test (9.8 vs 4.5%) of ceftriaxone but no hemolytic anemia cases in clinical trialsAdjust dose based on CrCl<50ml/min- remember ave. CrCl of 80 yo is ml/min (Cooper JW JGDT 1991)
87Antifungals 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/
88Fidaxomicin for C. diffCurrent 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.
89Fidaxomicin cont’dSignificantly 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.
90Specific 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
92Dabigatran (Pradaxa ®) PharmacologyOral direct thrombin inhibitorInhibits both clot-bound and circulating thrombinDecreases thrombin-stimulated platelet aggregationLess variable effect than warfarinMonitoring not requiredIndication:For prevention of thromboembolic stroke in patients with non-valvular atrial fibrillation
93Dabigatran (Pradaxa ®) PharmacokineticsRapidly absorbed from GIConverted to active formTime to peak1 hour if fasting, 3 hours after high fat mealNot metabolized by hepatic enzymesEliminated renallyHalf-life = 12 to 17 hours
94Dabigatran (Pradaxa ®) EfficacyRE-LY trial: n = 18,113Fixed dose (110 mg 0r 150 mg) versus adjusted dose warfarin (INR 2 – 3)Primary outcome…strokeRates per year of stroke:Dabigatran 110 mg 1.54%Dabigatran 150 mg 1.11 %Warfarin %Patients with severe heart valve disorder excludedSJ Connelly et al. N Engl J Med 2009;361:1139SJ Connelly et al. N Engl J Med 2010;363:1875
95Dabigatran (Pradaxa ®) Safety (from studies on previous slide…)Major bleedingWarfarin %Dabigatran 110 mg 2.87%Dabigatran 150 mg 3.32%Hemorrhagic stokeWarfarin %Dabigatran %Major GI bleedingWarfarin %Dabigatran 150 mg 1.51%The MI question….higher but N.S.
96Dabigatran (Pradaxa ®) Dosage and Cost150 mg twice dailyDO NOT break, chew or empty capsulesFor CrCl 15 to 30 ml/hr: 75 mg twice dailyFor CrCl <15 ml/hr not recommendedFor conversion from warfarin or other anticoagulants…see prescribing informationCost: Pradaxa $230 / monthWarfarin $14 / month+ COST OF INR Monitoring?
97Dabigatran (Pradaxa ®) CriteriaNew Pharmacological Class-also see apixaban (NEJM Feb 11)More Efficacious-RELY-ABLE trial is LT follow-up-seeSafer in some aspects-protect GI tract in the older adult, esp. with Hx of GERD,PUD or diverticulosisPharmacokinetic Advantage(clinically relevant)More Cost Effective- in terms of total cost of care
98Dabigatran in DVT/VTEThree 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.
99Apixaban 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
100Other Anticoagulants Ticagrelor – NDA filed Competitor for clopidogrel Large international outcomes trial initiated in late 2010
101Pegloticase (Krystexx) & Febuxostat (Uloric) For treatment of gout: for patients not helped by existing drugsGiven every 2 weeks by IV infusion ( 2-hour)Use: for those who do not tolerate other hypouricemicsFebuxostat (Uloric)- xanthine oxidase inhibitor also for those who can not tolerate other XO s, eg allopurinolSee BurnsCM,Wortmann RL. Lancet Jan 8;377(9760): Epub 2010 Aug 16 for gout therapeutics review
102Topical NSAIDs- safer than oral when used sparingly! Ketorolac Nasal Spray (Sprix ®)Approved for short-term use (nmt 5 days) for moderate to moderately severe painKetorolac 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.
103COPD ExacerbationsRoflumilast –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-!!
104COPD Meds- DalirespThe 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?
105Another 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 !
106Buprenorphine (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!
107Testosterone 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/monthCareful with application process for each and watch for H/H and PSA increases
108Dexlansoprazole(Dexilant) R-isomer of lansoprazole (Prevacid)Any advantage?More costly?Covered by any plans?Any proof its better than generic omeprazole or lansoprazole?
109SummaryNew 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!
110Want a copy of these slides? Dr. May at Questions?Want a copy of these slides? Dr. May atfor original 69 or go to or for LTC modified set of 110