james w. cooper, rph,phd, bcps, cgp, fascp, fashp, fcp, emeritus professor of pharmacy, uga and...

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

New Drug Update 2011: An LTC Approach

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

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.

Other free LTC resources for MTM, PIMs and Safe MedsPlease go to

www.cooperconsultantpress.com 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 www.ghca.org

ObjectivesAfter 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”.

LTC Formulary Approach

A finite list of therapeutic agentsEstablished value in light of current medical

opinionSufficiently broad to meet the usual clinical

problemsAvoids duplication of clinical effectSubject to continuing revision based on new

therapeutic knowledge

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 ClassMore Efficacious SaferPharmacokinetic Advantage (clinically relevant)More Cost Effective

Pitavastatin (Livalo ®)

PharmacologyHMG-CoA reductase inhibitor

Yes… another “statin”There are now seven “statins” on the U.S.

marketPitavastatin has been available in Japan since 2003

Indications:Primary hyperlipidemiaMixed dyslipidemia

Pitavastatin (Livalo®)Pharmacokinetics

Cmax 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

Pitavastatin (Livalo ®)Efficacy

Comparative efficacy (not outcome) studies published!4 mg = atorvastatin 20 mg

N = 307, at 8 -12 months, open-label studyTotal C lowering: 21.9% versus 21.9%LDL-C lowering: 36.2% 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;54:293 Ose L et al. Curr Med Res Opin 2009;25:2755 Saito Y et al. Atherosclerosis 2002;162:373

Pitavastatin (Livalo ®)Safety

Similar to other “statins”myalgias constipationjoint and back pain

> 4 mg associated with increased risk of severe myopathy

Rhabdomyolysis not reported to dateDrug interactions

Cyclosporine – 4.6 X increase in AUCErythromycin - ~ 2 X increase in AUCOther inhibitors of OATP1B1

Pitavastatin (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

Pitavastatin (Livalo ®)Criteria Met?

New Pharmacological ClassMore Efficacious Safer Pharmacokinetic Advantage (clinically

relevant) More Cost Effective

Other Newer CHD/ Apolipoprotein affecting/ Hypolipidemics

Cholesterol and lipoprotein managementDarapladib (GlaxoSmith-Kline)- White H Am

Heart J 2010; 160(4): 661-5.Mipomersen (Genzyme)- Expert Opin Investig

Drugs. 2011 Feb;20(2):265-72. Epub 2011 Jan 6 FOR STATIN INTOLERANT

Anacetrapib (Merck)- AAPS J. 2011 Feb 23. [Epub ahead of print]- USED WITH STATINS

Dalcetrapib (Roche) Clin Drug Investig. 2011 Mar 2 –epub- RAISE HDL

Liraglutide (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 emptying

Shares 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


PharmacokineticsFollowing SC administration

Cmax 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

Liraglutide (Victoza®)Efficacy

Approved based on 5 published studies Monotherapy 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)

Three drugs better than two in HbA1c reductionVersus 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;32:1224. Diabetologia 2009;52:2046. Lancet 2009;374:39*


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 mice

Use with caution when history of pancreatitis exists


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 $231

Note: What about Exenatide LAR?late 2011, probably mid-2012

Liraglutide (Victoza®)Criteria

New Pharmacological ClassMore Efficacious ??Safer- NOT SHOWN IN OLDER ADULTS Pharmacokinetic Advantage

(clinically relevant) – EXCEPT FOR LOWER SERUM ALBUMIN

More Cost Effective ?

Other Diabetes drugs in works

DiabetesDapagliflozen – 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 IIIAnother GLP-1 agonist pulled as of Feb 2011 due to

serious GI adverse effects

Bromocriptine (Cycloset)Lowers blood glucose only slightly (A1c by

~0.5% at $120-360/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.

Dalfampridine (Ampyra®)

PharmacologyPotassium channel blockerMechanism of action UNCLEARIn 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 injuryGuillain-Barre syndrome

Dalfampridine (Ampyra ®)Pharmacokinetics

Well 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)

Dalfampridine (Ampyra ®)Efficacy

Shown 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 trials

34.8% versus 8.3 %42.9% versus 9.3%

Does not affect exacerbations or alter the course of the disease

Dalfampridine (Ampyra ®)

SafetyContraindications:

History of seizures- OR CVAModerate 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%

Dalfampridine (Ampyra ®)

Dosage and Cost10 mg PO every 12 hoursDo not crush, chew, dissolve or split tablets

Cost: $35.20 per day (AWP)

Dalfampridine (Ampyra ®)Criteria



Fingolimod (Gilenya®)

PharmacologyInteracts with sphingosine 1- phosphate

receptorsBlocks lymphocytic egress from lymph nodes

Reduces 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)


PharmacokineticsTmax is reached in 12 – 16 hoursBioavailability = 93%Steady state concentrations: 1 to 2 monthsMetabolized by CYP4F2

Minor: 2D6, 2E1, 3A4, 4F12Only related drug interaction: ketoconazole

Half-life = 6 to 9 days

Fingolimod (Gilenya®)Efficacy

Double-blind randomized trial (n = 1272)Annualized relapse rate

Fingolimod 0.5 mg 0.18Placebo 0.40

Cumulative probability of disability progressionFingolimod 0.5 mg 17.7%Placebo 24.1%

Double-blind randomized trial (n = 1292)Annualized relapse rate

Fingolimod 0.5 mg 0.16 Interferon beta-1a 0.33

Kappos L et al. N Engl J Med 2010;362:387Cohen JA et al. N Engl J Med 2010;362:402


SafetyMost common:

Headache CoughDiarrhea Back Pain

Increased risk of viral infectionsTransient bradycardia

Including first or second degree AV blockMacular edema (first 3 – 4 months)Dose dependent reduction in FEV1 (3.1%)


Dosage and Cost0.5 mg oral once daily

Cost (1 year of treatment):Interferon beta-1A $38,000Fingolimod $57,000 (estimated)

Fingolimod (Gilenya®)Criteria

New Pharmacological ClassMore Efficacious Safer Pharmacokinetic Advantage

(clinically relevant) More Cost Effective

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

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-

Prolia- 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?

Risedronate (Atelvia)Delayed-release similar to Actonel, except

its meant to be taken AFTER meals rather than 30-60 minutes before like other bisphosphonates-may reduce malabsorption of calcium and iron. Still need to take with plenty of water and sit upright for 30-60 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)

Sipuleucel-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


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

Sipuleucel-T (Provenge®)Efficacy

2 similar clinical trials: randomized, double-blind, placebo controlled N = 639

Results were similarOverall survival in months

25.8 versus 21.725.9 versus 21.4Both statistically significant

(p = 0.032 and p = 0.01)


SafetySolely for autologous useMost 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


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

Sipuleucel-T (Provenge®)Criteria


relevant) More Cost Effective- BUT NOT IN MOST

OLDER MEN IN LTC- CHECK GLEASON SCORE!

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

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 14.8 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.

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 -- 10.1 months -- in the 3-group clinical triaI(P < .003). It only worked in a small percentage of patients.

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.

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.

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??

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 18991, 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.


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.


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.

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

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.

Benlysta- 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

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

Actemra- cont’dMonitor Lipids q 4-8 wksInteractions 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?

Asenapine (Saphris ®)

PharmacologyAtypical antipsychoticProbable mechanism of action

Dopamine (D2) antagonismSerotonin (5-HT2A) antagonism

IndicationsAcute 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!!


PharmacokineticsRapidly 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!

Asenapine (Saphris ®)Efficacy

Three 6 week studies for schizophreniaRandomized, 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 disorder

Both studies: asenapine and olanzapine > placebo

Polkin et al. J Clin Psychiatry 2007;68:1492Kane et al. J Clin Psychopharmacol 2010;30-106McIntyre et al. Bipolar Disord 2009;11:673


SafetyWarnings similar to other atypicalsAssociated with increased QT intervalMost 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!!


Dosage and CostSchizophrenia: 5 mg SL twice daily

No added benefit with 10 mg doseBipolar disorder: 10 mg SL twice dailyRemember DO NOT SWALLOW

If swallowed bioavailability is < 2%No food or water for 10 minutesCost: Asenapine $575

Risperidone $474 NOW GENERIC and much less- 60 X1mg for $198

Olanzapine $299

Asenapine (Saphris ®)Criteria- NONE



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. 2011 Feb 15;68(4):301-8

Lurasidone (Latuda)The 10th oral atypical antipsychotic-no

advantageBest current review- See Pharmacists Letter

Feb 2011Many going generic and much lower cost

with similar efficacy and safety, eg Zyprexa, Seroquel, Invega and Geodon

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. 2011 Mar;49(3):19-

22. Epub 2011 Feb 16.

Telavancin (Vibativ®)

PharmacologySemi-synthetic lipoglycopeptide

A derivative of vancomycinMechanisms of action

Inhibits 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)


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%)

Telavancin (Vibativ®)Efficacy

Double-blind, randomized trial versus vancomycin (N= 1867)

Skin and skin structure infectionsSuspected or confirmed Gram positive infectionNon-inferiority proven

Stryjewski et al. Clin Infect Dis 2008;46:1683


SafetyDifferences 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%


Dosage and Cost10 mg/kg IV daily over one hourFor CrCl 30 - 50 ml/min: 7.5 mg/kg dailyFor CrCl 10 - 29 ml/min: 10 mg/kg q48hrInsufficient data for < 10 ml/min

Cost: Vancomycin $4.49 / 1 gmTelavancin $44.96 / 250

mg

Telavancin (Vibativ®)Criteria- NONE


relevant) ?More Cost Effective

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.

Boceprevir-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.

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.

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.

Antiinfectives …

Ceftaroline fosamil (Teflaro) ForestInjectable cephalosporin with some MSRA

activityTx 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 www.teflaro.com for full info.

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 35-40 ml/min (Cooper JW JGDT 1991)

AntifungalsIsavuconazole (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 http://www.cop.ufl.edu/education/continuing-education/consultant-course-descriptions/

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.

Fidaxomicin 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.

Specific antimicrobial therapy

Clostridium difficle monoclonal antibody (Medarex) for CDAD N Engl J Med. 2010 Jan 21;362(3):197-205.

Treatment with monoclonal antibodies (mca) against Clostridium difficile toxins and recurrence rate was lower with mca when added to metronidazole or vancomycin antiinfectives

Dabigatran (Pradaxa ®)

PharmacologyOral direct thrombin inhibitor

Inhibits both clot-bound and circulating thrombinDecreases thrombin-stimulated platelet aggregation

Less variable effect than warfarinMonitoring not requiredIndication:

For prevention of thromboembolic stroke in patients with non-valvular atrial fibrillation


PharmacokineticsRapidly absorbed from GI

Converted to active formTime to peak

1 hour if fasting, 3 hours after high fat mealNot metabolized by hepatic enzymesEliminated renallyHalf-life = 12 to 17 hours

Dabigatran (Pradaxa ®)Efficacy

RE-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 1.71 %

Patients with severe heart valve disorder excluded SJ Connelly et al. N Engl J Med 2009;361:1139SJ Connelly et al. N Engl J Med 2010;363:1875


Safety (from studies on previous slide…)Major bleeding

Warfarin 3.57%Dabigatran 110 mg 2.87%Dabigatran 150 mg 3.32%

Hemorrhagic stokeWarfarin 0.38%Dabigatran 0.12%

Major GI bleedingWarfarin 1.02%Dabigatran 150 mg 1.51%

The MI question….higher but N.S.


Dosage and Cost150 mg twice daily

DO NOT break, chew or empty capsulesFor CrCl 15 to 30 ml/hr: 75 mg twice dailyFor CrCl <15 ml/hr not recommended

For conversion from warfarin or other anticoagulants…see prescribing information

Cost: Pradaxa $230 / monthWarfarin $14 / month+

COST OF INR Monitoring?

Dabigatran (Pradaxa ®)Criteria

New Pharmacological Class-also see apixaban (NEJM Feb 11)

More Efficacious-RELY-ABLE trial is LT follow-up-see www.clinicaltrials.gov

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

Dabigatran 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.

Apixaban and RivaroxabanApixaban 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

Other Anticoagulants

Ticagrelor – NDA filedCompetitor for clopidogrelLarge international outcomes trial initiated in late

2010

Pegloticase (Krystexx) & Febuxostat (Uloric)

Pegloticase (Krystexx®)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. 2011 Jan

8;377(9760):165-77. Epub 2010 Aug 16 for gout therapeutics review

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 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.

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;363:2406-2415

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-!!

COPD 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?

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 !

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!

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

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

omeprazole or lansoprazole?

SummaryNew 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!

Questions?

Want a copy of these slides? Dr. May [email protected] for original 69 or go to

www.cooperconsultantpress.com or www.ghca.org for LTC modified set of 110

james w. cooper, rph,phd, bcps, cgp, fascp, fashp, fcp, emeritus professor of pharmacy, uga and...

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