Transcript AJWC New Drug Update 2011

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
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, BoehringerIngleheim*, 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 Meds
 Please go to www.cooperconsultantpress.com 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 www.ghca.org
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”.
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
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
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
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
Pitavastatin (Livalo ®)
Efficacy
 Comparative efficacy (not outcome) studies published!
 4 mg = atorvastatin 20 mg
 N = 307, at 8 -12 months, open-label study
 Total 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 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
SaitoY et al. Atherosclerosis 2002;162:373
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
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
 Atorvastatin
 Fluvastatin
 Rosuvastatin
 Simvastatin
 Lovastatin
 Pravastatin
$121
$100
$103
$140
$28
$22
$26
Pitavastatin (Livalo ®)
Criteria Met?
 New Pharmacological Class
 More Efficacious
 Safer
 Pharmacokinetic Advantage
 More Cost Effective
(clinically relevant)
Other Newer CHD/ Apolipoprotein affecting/
Hypolipidemics
Cholesterol and lipoprotein management
 Darapladib (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 –epubRAISE HDL
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
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
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)
 Three drugs better than two in HbA1c reduction
 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;32:1224. Diabetologia 2009;52:2046.
Lancet 2009;374:39*
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
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
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 ?
Other Diabetes drugs in works
Diabetes
 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
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, BUT
 Many side effects- nausea, drowsiness, dizziness, fainting and
nightmares
 Never use in lactating woman as lowers breast milk
production.
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
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)
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
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%
 Dizziness 7%
 Headache 7%
Asthenia 7%
Back pain 5%
Balance disorder 5%
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)
Dalfampridine (Ampyra ®)
Criteria
 New Pharmacological Class
 More Efficacious
 Safer
 Pharmacokinetic Advantage
 More Cost Effective
(clinically relevant)
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)
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
Fingolimod (Gilenya®)
Efficacy
 Double-blind randomized trial (n = 1272)
 Annualized relapse rate
 Fingolimod 0.5 mg
0.18
 Placebo
0.40
 Cumulative probability of disability progression
 Fingolimod 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;362:387
Cohen JA et al. N Engl J Med 2010;362:402
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%)
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)
Fingolimod (Gilenya®)
Criteria
 New Pharmacological Class
 More Efficacious
 Safer
 Pharmacokinetic Advantage
 More Cost Effective
(clinically relevant)
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’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?
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®)
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
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
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 = 0.032 and p = 0.01)
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
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
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!
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 fourdose 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.
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.
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.
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 Blymphocyte stimulatorSteroid 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’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 pretreatment 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’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?
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!!
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!
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
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!!
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
Asenapine (Saphris ®)
Criteria- NONE
 New Pharmacological Class
 More Efficacious
 Safer
 Pharmacokinetic Advantage
 More Cost Effective
(clinically relevant)
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 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
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®)
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)
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%)
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
Telavancin (Vibativ®)
Safety
 Differences in adverse effects
Nausea
Vomiting
Taste disturbance
Foamy urine
Pruritis
Telavancin
(N = 929)
27%
14%
33%
13%
6%
Vancomycin
(N = 938)
15%
7%
7%
3%
13%
Telavancin (Vibativ®)
Dosage and Cost




10 mg/kg IV daily over one hour
For CrCl 30 - 50 ml/min: 7.5 mg/kg daily
For CrCl 10 - 29 ml/min: 10 mg/kg q48hr
Insufficient data for < 10 ml/min
 Cost:
Vancomycin
Telavancin
$4.49 / 1 gm
$44.96 / 250 mg
Telavancin (Vibativ®)
Criteria- NONE
 New Pharmacological Class
 More Efficacious
 Safer
 Pharmacokinetic Advantage
 More Cost Effective
(clinically relevant) ?
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 lifethreatening skin reactions, including three cases of StevensJohnson 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 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.
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) 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 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)
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
http://www.cop.ufl.edu/education/continuingeducation/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’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.
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 ®)
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
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
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
1.71 %
 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
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
0.12%
 Major GI bleeding
 Warfarin
 Dabigatran 150 mg
1.51%
 The MI question….higher but N.S.



3.57%
0.38%
1.02%
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?
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/VTE
 Three large phase III studies have looked at dabigitran vs.
enoxaparin in VTE prevention after orthopedic surgery- RENOVATE, 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 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
Other Anticoagulants
 Ticagrelor – NDA filed
 Competitor for clopidogrel
 Large international outcomes trial initiated in late 2010
Pegloticase (Krystexx) & Febuxostat (Uloric)
Pegloticase (Krystexx®)
 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. 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 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.
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 metaanalysis- BEST Review of COPD Tx to date- and FREE!
AVOID THEOPHYLLINE IN COPD-!!
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?
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 opioidnaïve 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?
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!
Questions?
Want a copy of these slides? Dr. May at
[email protected] for original 69 or go to
www.cooperconsultantpress.com or www.ghca.org
for LTC modified set of 110