A Stool DNA Test Cologuard for Colorectal Cancer Screening ...p 99p 100 Rescheduling of Hydrocodone Combination Products ...p 101 In Brief: PCV13 for Adults ≥65 Years Old ...p 102 Influ
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on Drugs and Therapeutics
Objective Drug Reviews Since 1959
IN THIS ISSUE
ISSUE
1433
Volume 56
Published by The Medical Letter, Inc • A Nonprofi t Organization
ISSUE No
1453 Influenza Vaccine for 2014-2015 .Empagliflozin (Jardiance) for Diabetes .p 97p 99
A Stool DNA Test (Cologuard) for Colorectal Cancer Screening .p 100
Rescheduling of Hydrocodone Combination Products .p 101
In Brief: PCV13 for Adults >65 Years Old .p 102
Trang 297
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Objective Drug Reviews Since 1959
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ALSO IN THIS ISSUE
ISSUE
1433
Volume 56
ISSUE No
1453 Empagliflozin (Jardiance) for Diabetes A Stool DNA Test (Cologuard) for Colorectal Cancer Screening p 99p 100
Rescheduling of Hydrocodone Combination Products p 101
In Brief: PCV13 for Adults ≥65 Years Old p 102
Influenza Vaccine for 2014-2015
▶
Annual vaccination against influenza A and B viruses
has been shown to decrease influenza illness and its
complications.1
EFFECTIVENESS — The effectiveness of the seasonal
vaccine in preventing influenza in healthy adults
depends on the match between the vaccine and
circulating strains Vaccine effectiveness is highest
(50-80% in young adults; lower in the elderly) when
the match is close, but even when the match is poor,
vaccination has been shown to reduce the risk of death
from influenza.2 In addition, vaccination of children
and adolescents can protect unvaccinated residents
of the same community.3
Live vs Inactivated – The intranasal live-attenuated
influenza vaccine, FluMist Quadrivalent, is only
recommended for healthy, non-pregnant persons 2-49
years old It appears to be more effective than the
inactivated vaccine in children ≤6 years old.4 In adults,
the inactivated influenza vaccine has been more
effective than the intranasal live vaccine.5
High-Dose Inactivated Vaccine – Older adults may have
a lower antibody response to influenza vaccination than
younger adults.6 Fluzone High-Dose, which contains
60 mcg of hemagglutinin antigen from each strain
compared to 15 mcg in the conventional vaccine,
induced signifi cantly higher antibody responses than the
standard-dose inactivated influenza vaccine in a study in
31,989 adults ≥65 years old, with no increase in serious
adverse effects It was more effective than the
standard-dose vaccine in preventing influenza;
laboratory-confi rmed influenza illness occurred in 1.4% of adults
who received the high-dose vaccine compared to 1.9%
of those who received the standard-dose vaccine.7
Table 1 2014-2015 Seasonal Influenza Vaccine 1 Composition
Trivalent Vaccine (Inactivated)
A/California/7/2009 H1N1-like A/Texas/50/2012 H3N2-like B/Massachusetts/2/2012-like (Yamagata lineage)
Quadrivalent Vaccine (Live-Attenuated and Inactivated)
A/California/7/2009 H1N1-like A/Texas/50/2012 H3N2-like B/Massachusetts/2/2012-like (Yamagata lineage) B/Brisbane/60/2008-like (Victoria lineage)
Who Should Be Vaccinated
Everyone ≥6 months old without a specifi c contraindication, including pregnant women
Timing
Now through the end of the influenza season (about May 2015)
Choice of Vaccine 2
Pregnant women
Inactivated standard-dose vaccine
Healthy children 2-8 years old
Preferred: intranasal live-attenuated vaccine (FluMist Quadrivalent)
Alternative: inactivated vaccine 3 if FluMist is contraindicated or
unavailable
Healthy adults <65 years old Preferred: inactivated standard-dose vaccine Adults ≥65 years old
Standard-dose inactivated vaccine or Fluzone High-Dose
Patients with egg allergy
Preferred: FluBlok (≥18 years)4
Patients with gelatin allergy
Should not receive FluMist Quadrivalent or Fluzone trivalent
inactivated vaccine
1 LA Grohskopf et al Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immuniza-tion Practices (ACIP) – United States, 2014-15 influenza season MMWR Morb Mortal Wkly Rep 2014; 63:691.
2 See Table 2 for available vaccines and specifi c age recommendations.
3 For 2014-2015, the ACIP recommends that Afluria not be administered
to children <9 years of age due to a possible increased risk of fever and febrile seizures.
4 Other inactivated vaccines may be used with caution For patients with a history of hives, other inactivated vaccines should be administered by a healthcare provider familiar with potential manifestations of egg allergy; vaccine recipients should be observed for ≥30 minutes after vaccination For severe allergy, other inactivated vaccines should be administered
by a physician with experience in the recognition and management of severe allergic conditions.
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Trang 3The Medical Letter ® Vol 56 (1453) October 13, 2014
Influenza vaccination has been associated with Guillain -Barré syndrome, but the absolute risk is very low, and influenza infection itself has also been asso-ciated with Guillain-Barré syndrome.13,14
Live – The intranasal live-attenuated vaccine is generally
well tolerated, but it can cause runny nose, nasal con-gestion, and sore throat It is not recommended for use
in children 2-4 years old who have asthma or have had
a wheezing episode in the previous 12 months Rapid influenza diagnostic tests may be falsely positive if used
within a week after vaccination with FluMist Quadrivalent.
Vaccinees may shed the vaccine-strain virus for a few days after vaccination, but person-to- person transmission has been rare, and serious illness resulting from transmission has not been reported Nevertheless, persons who care for severely immunocompromised patients in protected environments should not receive the live vaccine or should avoid contact with the patient(s) for 7 days after receiving it
DOSAGE — A 0.5-mL IM dose of inactivated influenza
vaccine is recommended for adults and children ≥3
CARDIOVASCULAR BENEFITS — A meta-analysis of
6 randomized trials found that influenza vaccination
was associated with a reduced risk of major adverse
cardiovascular events in patients at high risk for
car-diovascular disease; the reduction in risk was greatest
for those with a recent acute coronary syndrome.8
PREGNANCY — Vaccination of pregnant women not
only protects them against influenza-associated
ill-ness, which can be especially severe during pregnancy,
but also protects their newborn infants for up to the
fi rst 6 months of life.9,10
TIMING — Serum antibodies reach maximum levels in
most adults about 2 weeks after influenza vaccination
and generally persist for at least 6-8 months Antibody
levels may decline more rapidly in older adults.11,12
ADVERSE EFFECTS — Inactivated – Except for soreness
at the injection site, adverse reactions to inactivated
influenza vaccines are uncommon In clinical t rials,
Fluzone High-Dose and Fluzone Intradermal have
caused more injection-site reactions than
conven-tional inactivated influenza vaccines
Table 2 Seasonal Influenza Vaccines for 2014-2015
Vaccine Formulations Mercury Content Recommended Age Cost 1
Inactivated Influenza Vaccines (IIV)
Trivalent (IIV3)
5 mL multidose vial 24.5 mcg/0.5 mL dose >9 years 3 10.55
Fluarix (GSK) 0.5 mL syringe 2 none >3 years 15.90
FluBlok (Protein Sciences)4 0.5 mL vial 2 none >18 years 32.75 5
Flucelvax (Novartis)6 0.5 mL syringe 2 none >18 years 19.13
FluLaval (GSK) 5 mL multidose vial <25 mcg/0.5 mL dose >3 years 7.65
Fluvirin (Novartis) 0.5 mL syringe 2 <1 mcg/0.5 mL dose >4 years 14.81
5 mL multidose vial 25 mcg/0.5 mL dose >4 years 13.63
Fluzone (Sanofi Pasteur) 0.5 mL syringe 2 none >3 years 12.49
5 mL multidose vial 25 mcg/0.5 mL dose >6 months 7 10.69
Fluzone High-Dose 8 0.5 mL syringe 2 none >65 years 29.40 5
Fluzone Intradermal 9 0.1 mL syringe 2 none 18-64 years 15.62 5
Quadrivalent (IIV4)
Fluarix Quadrivalent (GSK) 0.5 mL syringe 2 none >3 years 15.90
FluLaval Quadrivalent (GSK) 5 mL multidose vial <25 mcg/0.5 mL dose >3 years 14.90
0.5 mL syringe 2 none >3 years 15.90 5
(Sanofi Pasteur) 0.5 mL vial 2 none >3 years 17.97
5 mL multidose vial 25 mcg/0.5 mL dose >6 months 7 16.15
Live-Attenuated Influenza Vaccine (LAIV)
FluMist Quadrivalent (Medimmune) 0.2 mL sprayer 10 none 2-49 years 11 22.70
1 Private sector cost (including excise tax) per dose as of August 1, 2014 according to the CDC Vaccine Price List Available at www.cdc.gov/vaccines/
programs/vfc/awardees/vaccine-management/price-list/index.html Accessed October 2, 2014.
2 Sold in boxes of 10.
3 FDA-approved for use in persons ≥5 years of age For 2014-2015, the ACIP recommends that Afluria not be administered to children <9 years of age due to a
possible increased risk of fever and febrile seizures.
4 Recombinant hemagglutinin vaccine.
5 List price, including excise tax, per dose according to the manufacturer
6 Cell culture-based vaccine.
7 Children 6-35 months old should receive a 0.25-mL dose.
8 Fluzone High-Dose is an alternative to standard-dose inactivated influenza vaccines for persons ≥65 years old; it contains 60 mcg of hemagglutinin antigen
from each strain compared to 15 mcg in the conventional vaccine.
9 Contains 9 mcg of hemagglutinin antigen from each strain.
10 Each syringe-like sprayer contains a single 0.2-mL dose given intranasally (0.1 mL in each nostril); sold in boxes of 10.
11 Only for healthy non-pregnant persons It is the preferred vaccine for children 2-8 years old without a specifi c contraindication.
Trang 4years old; 0.25 mL IM is recommended for children
6-35 months old Fluzone Intradermal is given as
a 0.1-mL dose, using the supplied microinjection
system The dosage of FluMist Quadrivalent is 0.1 mL
in each nostril
Children 6 months to 8 years old who are being
vaccinated for the fi rst time or who have not received 2
or more doses of the seasonal influenza vaccine since
July 1, 2010 should receive 2 doses at least 4 weeks
apart Only one dose is required for children 6 months
to 8 years old who previously received 1 dose of the
2013-2014 seasonal influenza vaccine
CONCLUSION — Seasonal influenza vaccine is
effective in preventing influenza and is
recommend-ed for everyone ≥6 months old without a specific
contraindication ■
1 LA Grohskopf et al Prevention and control of seasonal
influenza with vaccines: recommendations of the Advisory
Committee on Immunization Practices (ACIP) – United States,
2014-15 influenza season MMWR Morb Mortal Wkly Rep
2014; 63:691.
2 KL Nichol et al Effectiveness of influenza vaccine in the
community-dwelling elderly N Engl J Med 2007; 357:1373.
3 M Loeb et al Effect of influenza vaccination of children on
infection rates in Hutterite communities: a randomized trial
JAMA 2010; 303:943.
4 RB Belshe et al Live attenuated virus versus inactivated
influenza vaccine in infants and young children N Engl J Med
2007; 356:685.
5 AS Monto et al Comparative effi cacy of inactivated and live
attenuated influenza vaccines N Engl J Med 2009; 361:1260.
6 K Goodwin et al Antibody response to influenza vaccination in
the elderly : a quantitative review Vaccine 2006; 24:1159.
7 CA DiazGranados et al Effi cacy of high-dose versus
standard-dose influenza vaccine in older adults N Engl J Med 2014;
371:635
8 JA Udell et al Association between influenza vaccination
and cardiovascular outcomes in high-risk patients: a
meta-analysis JAMA 2013; 310:1711.
9 MG Thompson et al Effectiveness of seasonal trivalent
influenza vaccine for preventing influenza virus illness among
pregnant women: a population-based case-control study
during the 2010-2011 and 2011-2012 influenza seasons Clin
Infect Dis 2014; 58:449.
10 SA Madhi et al Influenza vaccination of pregnant women and
protection of their infants N Engl J Med 2014; 371:918.
11 JJ Song et al Long-term immunogenicity of influenza vaccine
among the elderly : risk factors for poor immune response and
persistence Vaccine 2010; 28:3929.
12 J Castilla et al Decline in influenza vaccine effectiveness with
time after vaccination, Navarre, Spain, season 2011/12 Euro
Surveill 2013; 18:pii:20388.
13 JC Kwong et al Risk of Guillain-Barré syndrome after seasonal
influenza vaccine and influenza health-care encounters: a
self-controlled study Lancet Infect Dis 2013; 13:769.
14 LL Polakowski et al Chart-confi rmed Guillain-Barré syndrome
after 2009 H1N1 influenza vaccination among the Medicare
population, 2009-2010 Am J Epidemiol 2013; 178:962.
Empagliflozin (Jardiance) for
Diabetes
▶
Empagliflozin (Jardiance – Boehringer Ingelheim/Lilly),
an SGLT2 inhibitor, has been approved by the FDA for oral treatment of type 2 diabetes It is the third SGLT2 inhibitor to be approved for this indication.1,2
MECHANISM OF ACTION — SGLT2 (sodium-glucose
co-transporter 2), a membrane protein expressed mainly in the kidney, transports fi ltered glucose from the proximal renal tubule into tubular epithelial cells
SGLT2 inhibitors decrease renal glucose reabsorption and increase urinary glucose excretion, resulting in a reduction in blood glucose levels
CLINICAL STUDIES — In randomized, double-blind
trials in patients with type 2 diabetes, use of empa-gliflozin, alone and in combination with metformin, a sulfonylurea, pioglitazone, or insulin, reduced HbA1c
Table 2 Some Empagliflozin Clinical Trials
Study Design Drug Regimen Change (%)*
Monotherapy in Treatment-Naive Patients
M Roden et al 3 Empagliflozin 10 mg -0.66
24 weeks 25 mg -0.78 (n=899) Sitagliptin 100 mg -0.66
Add-on Therapy
HU Häring et al 4 Metformin
24 weeks + Empagliflozin 10 mg -0.70 (n=637) 25 mg -0.77
HU Häring et al 5 Metformin + sulfonylurea
24 weeks + Empagliflozin 10 mg -0.82 (n=666) 25 mg -0.77
+ Placebo -0.17
J Rosenstock et al 6 Insulin ± metformin
52 weeks + Empagliflozin 10 mg -1.18 (n=563) 25 mg -1.27
CS Kovacs et al 7 Pioglitazone ± metformin
24 weeks + Empagliflozin 10 mg -0.60 (n=498) 25 mg -0.70
+ Placebo -0.10
M Ridderstråle et al 8 Metformin
52 weeks/104 weeks + Empagliflozin 25 mg -0.73/-0.66 (n=1549) + Glimepiride 1-4 mg -0.66/-0.55
*Mean change from baseline.
Table 1 Pharmacology
Class Sodium-glucose co-transporter 2 (SGLT2)
inhibitor Formulation 10, 25 mg tablets Route Oral
Tmax 1.5 hours Metabolism Glucuronidation (UGT2B7, 1A3, 1A8, and 1A9) Elimination Urine (54.4%); feces (41.2%)
Half-life (terminal) 12.4 hours
Trang 5The Medical Letter ® Vol 56 (1453) October 13, 2014
The FDA has approved Cologuard (Exact Sciences),
a stool DNA test, to screen average-risk adults ≥50 years old for colorectal cancer
COLORECTAL CANCER SCREENING — Conventional
screening for colorectal cancer includes noninvasive and invasive tests Fecal immunochemical tests (FITs) for occult blood have largely replaced guaiac-based tests for noninvasive screening Invasive options include double-contrast barium enema, flexible sigmoidoscopy, colonoscopy, and computed tomography colonography ("virtual colonoscopy") Multiple guidelines recommend screening average-risk patients with colonoscopy beginning at age 50 and repeating every 10 years The American College of Gastroenterology recommends that screening begin
at age 45 for African Americans.1 When colonoscopy
A Stool DNA Test (Cologuard) for
Colorectal Cancer Screening
▶
ADVERSE EFFECTS — SGLT2 inhibitors do not cause
hypoglycemia when used alone Empagliflozin,
like other SGLT2 inhibitors, has been associated
with genitourinary symptoms and genital mycotic
infections According to the package insert, genital
mycotic infections occurred in 5.4% of women
and 3.1% of men taking empagliflozin 10 mg daily,
compared to 1.5% of women and 0.4% of men taking
placebo Urinary tract infections occurred in 9.3% and
7.6% of patients taking empagliflozin 10 mg and 25
mg, respectively, and in 7.6% of those taking placebo
SGLT2 inhibitors have a modest diuretic effect
that could lead to dehydration, hypovolemia, and
hypotension, particularly in elderly patients with renal
dysfunction or who are also taking a diuretic Use of
empagliflozin has been associated with increases in
serum creatinine and decreases in eGFR, especially in
patients with moderate renal impairment The effi cacy
of the drug decreases with worsening renal function
Increases in LDL cholesterol and hematocrit have been
reported in patients taking empagliflozin
PREGNANCY — Empagliflozin is classifi ed as cate
-gory C (developmental toxicity in animals; no adequate
studies in women) for use during pregnancy
DRUG INTERACTIONS — Use of an SGLT2 inhibitor
in combination with insulin or a sulfonylurea can
increase the risk of hypoglycemia Concurrent use of
an SGLT2 inhibitor and a diuretic may increase the risk
of volume depletion
DOSAGE AND ADMINISTRATION — The recommended
starting dosage of empagliflozin is 10 mg once daily,
taken in the morning with or without food The dose
can be increased to 25 mg Empagliflozin should not be
started in patients with an eGFR <45 mL/min/1.73 m2
and should be discontinued in those whose eGFR falls and remains persistently below this level
CONCLUSION — Empagliflozin (Jardiance), the third
SGLT2 inhibitor to become available in the US, is moderately effective in reducing HbA1c It appears to
be similar in effi cacy and safety to the other available SGLT2 inhibitors, but direct comparisons are lacking The long-term safety of these drugs is unknown ■
1 Canagliflozin (Invokana) for type 2 diabetes Med Lett Drugs Ther 2013; 55:37.
2 Dapagliflozin (Farxiga) for type 2 diabetes Med Lett Drugs Ther 2014; 56:13.
3 M Roden et al Empagliflozin monotherapy with sitagliptin
as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial Lancet Diabetes Endocrinol 2013; 1:208.
4 HU Häring et al Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial Diabetes Care 2014; 37:1650.
5 HU Häring et al Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial Diabetes Care 2013; 36:3396.
6 J Rosenstock et al Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections
of insulin in obese inadequately controlled type 2 diabetes Diabetes Care 2014; 37:1815.
7 CS Kovacs et al Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial Diabetes Obes Metab 2014; 16:147.
8 M Ridderstråle et al Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial Lancet Diabetes Endocrinol 2014; 2:691.
Table 3 SGLT2 Inhibitors
Canagliflozin – Invokana 100-300 mg once/d $312.00
(Janssen)
Dapagliflozin – Farxiga 5-10 mg once/d 312.00
(BMS/AstraZeneca)
Empagliflozin – Jardiance 10-25 mg once/d 300.90
(Boehringer Ingelheim/Lilly)
1 Approximate wholesale acquisition cost (WAC) for 30 days’ treatment
Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™)
September 5, 2014 Reprinted with permission by FDB, Inc All rights
reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy
Actual retail prices may be higher.
signifi cantly more than placebo Treatment with
em-pagliflozin also resulted in reductions in systolic blood
pressure and weight.3-8
View our detailed online table: SGLT-2 Inhibitors
Trang 6tions The Cologuard collection kit is shipped directly
to the patient’s home It contains written instructions,
a bracket and a sample container that are placed on the toilet to collect the stool sample, a separate tube for collection of part of the sample for hemoglobin testing, a bottle of liquid preservative that is poured into the sample container, and a shipping box and la-bels Patients send the sample back to the laboratory, which must receive it within 72 hours of collection
A positive result should be followed by a diagnostic colonoscopy
How often patients should be screened with the
Cologuard test has not been established The
manu-facturer has suggested once every three years and the Centers for Medicare and Medicaid Services (CMS)
is proposing coverage for that interval According to
the manufacturer, the Cologuard test costs $599 The
Medicare reimbursement rate for FITs is about $23
CONCLUSION — One-time screening with a new
stool DNA test (Cologuard) detected 92% of cases
of colorectal cancer in asymptomatic average-risk persons, but it detected less than half of advanced precancerous lesions and produced a substantial number of false-positive results ■
The Drug Enforcement Administration (DEA) has reclassifi ed all hydrocodone combination products
as schedule II controlled substances; they were previously classifi ed as schedule III.1 Hydrocodone
alone (Zohydro ER) is already a schedule II controlled
substance.2
Rescheduling of Hydrocodone Combination Products
▶
1 DK Rex et al American College of Gastroenterology guide-lines for colorectal cancer screening 2009 Am J Gastroenterol 2009; 104:739.
2 Cancer screening Treat Guidel Med Lett 2012; 10:87.
3 TF Imperiale et al Multitarget stool DNA testing for colorectal-cancer screening N Engl J Med 2014; 370:1287.
4 JK Lee et al Accuracy of fecal immunochemical tests for colorectal cancer Ann Intern Med 2014; 160:171.
is not available or the patient declines the procedure,
guidelines recommend screening with flexible
sig-moidoscopy every 5 years and/or fecal occult blood
tests annually Some guidelines now recommend
computed tomography colonography every 5 years as
another alternative for average-risk patients.2
THE NEW TEST — The stool DNA test includes
molecular assays for DNA mutation and methylation
biomarkers associated with colorectal neoplasia
(KRAS mutations and NDRG4 and BMP3 methylation)
and a non-DNA immunochemical assay for human
hemoglobin that is almost identical to the assay used
in FITs A reference gene (Beta-actin) for the estimation
of the total amount of human DNA present in each
sample is also included The results of the mutation,
methylation, and hemoglobin assays are combined to
produce a composite score that is then compared to a
cutoff value to determine a positive or negative result
CLINICAL STUDY — A clinical study in asymptomatic
persons ≥50 years old at average risk for colorectal
cancer compared the stool DNA test with a FIT (OC
FIT-CHEK), each performed on the same stool sample All
participants also underwent screening colonoscopy as
the reference standard Out of 9989 patients, 65 had
colorectal cancer and 757 had advanced precancerous
lesions detected on colonoscopy
The sensitivity for detecting colorectal cancer was
92.3% with the DNA test (60 of 65) and 73.8% (48
of 65) with FIT (A recent meta-analysis indicates
that the sensitivity of FITs varies with the assay
cutoff value for a positive test result; at the lowest
cutoff value, the sensitivity of FITs was 89%.4) The
sensitivity for detecting advanced precancerous
lesions was 42.4% (321 of 757) with the DNA test
and 23.8% (180 of 757) with FIT Both differences
were statistically signifi cant The DNA test identifi ed
42.4% of serrated sessile polyps ˃1 cm; FIT detected
only 5.1% of these lesions
Among 9167 subjects with either non-advanced
ade-nomas or negative results on colonoscopy, 1231 had
positive fi ndings with the DNA test compared to 472
with FIT, resulting in specifi cities of 86.6% and 94.9%,
respectively Among 4457 participants with only
neg-ative fi ndings on colonoscopy, the specifi city of the
DNA test was also lower than that of FIT (89.8% [455
positive] vs 96.4% [162 positive]).3
ADMINISTRATION AND COST — As with FIT, use of
Cologuard requires the patient to collect a single stool
sample, and there are no dietary or medication
restric-Table 1 Some Hydrocodone Combination Products
Hydrocodone/acetaminophen 1 (Lortab, Norco, Vicodin, Vicodin ES,
Vicodin HP)
Hydrocodone/ibuprofen 1 (Vicoprofen, Reprexain) Hydrocodone/chlorpheniramine (Vituz)
Hydrocodone polistirex/chlorpheniramine polistirex 1 (Tussicaps,
Tussionex Pennkinetic)
Hydrocodone/homatropine 1 (Tussigon)
Hydrocodone/pseudoephedrine 1 (Rezira)
Hydrocodone/chlorpheniramine/pseudoephedrine 1 (Zutripro)
1 Also available generically.
Trang 7The Medical Letter ® Vol 56 (1453) October 13, 2014
HYDROCODONE — Hydrocodone is a semisynthetic
opioid agonist It is widely prescribed in combination
with acetaminophen or ibuprofen for treatment of pain3
and is also available in combination with homatropine,
chlorpheniramine, and/or pseudoephedrine for relief
of cough and nasal congestion
THE NEW SCHEDULE — Schedule II controlled
sub-stances are those that have an accepted medical use
in the US and a high potential for abuse that can result
in severe psychological and physical dependence
Drugs classifi ed as schedule III have less potential for
abuse and a lower risk of physical and psychological
dependence
The change in scheduling for hydrocodone
combi-nation products has resulted in more restrictive
prescribing regulations Refi lls are no longer allowed
Prescriptions that were written before October 6, 2014
may be allowed to be refi lled until April 7, 2015 Under
the new schedule, prescriptions for hydrocodone
combination products must be written; these products
cannot be prescribed over the phone or by fax Many
states have additional laws that limit the quantity of
a schedule II drug that can be prescribed on a single
prescription, and some states do not allow physician
assistants, nurse practitioners, or optometrists to
prescribe schedule II controlled substances
ALTERNATIVES FOR PAIN — Most opioid analgesics
are classifi ed as schedule II controlled substances
Fixed-dose combinations of codeine and
aceta-minophen are schedule III or schedule V controlled
substances
Codeine is converted to morphine, its active
me-tabolite, by CYP2D6 Signifi cant toxicity can occur
in CYP2D6 ultra-metabolizers, and CYP2D6 poor
metabolizers may not experience any analgesic
effect Codeine is contraindicated for use in children
undergoing tonsillectomy and/or adenoidectomy.4
Tramadol (Ultram, and others) is a
centrally-acting opioid agonist that also blocks reuptake
of norepinephrine and serotonin Its effectiveness
in combination with acetaminophen for treatment
of chronic pain is comparable to that of codeine or
oxycodone combined with acetaminophen Use of
tramadol for treatment of acute pain is limited by the
need for slow dose titration to improve tolerability
when starting the drug Tramadol is a schedule IV
controlled substance
In single full doses, some nonselective nonsteroidal
anti-inflammatory drugs (NSAIDs) have shown an
1 Drug Enforcement Administration Final Rule Schedules
of controlled substances: rescheduling of hydrocodone combination products from schedule III to schedule II Federal Register, August 22, 2014; 79(163): 49661 Available at https:// federalregister.gov/a/2014-19922 Accessed October 2, 2014.
2 Extended-release hydrocodone (Zohydro ER) for pain Med Lett Drugs Ther 2014; 56:45.
3 Drugs for pain Treat Guidel Med Lett 2013; 11:31.
4 FDA FDA Drug Safety Communication: safety review update of codeine use in children; new boxed warning and contraindication
on use after tonsillectomy and/or adenoidectomy February
20, 2013 Available at www.fda.gov/Drugs/DrugSafety/ucm 339112.htm Accessed October 2, 2014
IN BRIEF
PCV13 for Adults ≥65 Years Old
The US Advisory Committee on Immunization Prac-tices (ACIP) now recommends routine immunization with 13-valent pneumococcal conjugate vaccine
(PCV13; Prevnar 13), in addition to the 23-valent
pneumococcal polysaccharide vaccine (PPSV23;
Pneumovax 23), for all adults ≥65 years old.1
An unpublished, randomized, double-blind trial (CAPiTA) in about 85,000 adults ≥65 years old found that vaccination with PCV13 reduced fi rst episodes
of vaccine-type community-acquired pneumonia and invasive pneumococcal disease by 46% and 75%, respectively, compared to placebo.2
Adults ≥65 years old who previously received
≥1 dose of PPSV23 should also receive PCV13, but
at least one year after the last dose of PPSV23 For those receiving the pneumococcal vaccine for the
fi rst time, PCV13 should be given fi rst, followed 6-12 months later by PPSV23 PCV13 can be given at the same time as an inactivated influenza vaccine Currently, Medicare only pays for one lifetime dose
of a pneumococcal vaccine for healthy patients ■
1 S Tomczyk et al Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Ad-visory Committee on Immunization Practices (ACIP) MMWR Morb Mortal Wkly Rep 2014; 63:822
2 M Bonten et al Community acquired pneumonia immunisa-tion trial in adults (CAPITA) Abstract #O-015 Internaimmunisa-tional Symposium on Pneumococci and Pneumococcal Diseases
2014 Available at: http://isppd.meetingxpert.net/ISPPD_433/ poster_90453/program.aspx/anchor90453 Accessed Octo-ber 2, 2014.
equal or greater analgesic effect than usual doses of
an oral opioid combined with acetaminophen
CONCLUSION — All hydrocodone combination
products are now classifi ed as schedule II controlled substances Less restricted alternatives for pain include acetaminophen with codeine, tramadol, and nonsteroidal anti-inflammatory drugs (NSAIDs) ■
Note: An addendum to this article has been published
Trang 8
144
on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Addendum: PCV13 for Adults 65 Years and Older
(Med Lett Drugs Ther 2014; 56:102)
In 2014, the US Advisory Committee on Immunization
Practices (ACIP) recommended that all adults 65 years
old and older being vaccinated against pneumococcus for
the fi rst time receive the pneumococcal conjugate vaccine
(PCV13) followed 6 to 12 months later by the pneumococcal
polysaccharide vaccine (PPSV23) In June 2015, the ACIP
changed the recommended interval between the two
vaccines to >1 year for immunocompetent adults ≥65
years old (MMWR Morbid Mortal Wkly Rep 2015; 674:944)
Separating the vaccines by a year or more may improve
the immune response to the serotypes in both vaccines If
a dose of PPSV23 is given earlier than the recommended
interval, it does not need to be repeated.
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EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D.,
F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School;
Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N Juurlink, BPhm, M.D., Ph.D.,
Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Franco M Muggia, M.D., New York University Medical Center; Sandip K Mukherjee,
M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle
R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell
University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofi t organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors do not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission.
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Upon completion of this program, the participant will be able to:
1 Review the seasonal influenza vaccines available this year and discuss which vaccines are appropriate given certain patient-specifi c characteristics.
2 Review the effi cacy and safety of empagliflozin (Jardiance) for treatment of type 2 diabetes.
3 Review the effi cacy of the new stool DNA test for colorectal cancer screening.
4 Discuss the reclassifi cation of hydrocodone combination products as schedule II controlled substances.
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Issue 1453 Questions
(Correspond to questions #71-80 in Comprehensive Exam #71, available January 2015)
6 Empagliflozin reduces blood glucose levels by:
a increasing renal glucose reabsorption
b decreasing renal glucose reabsorption
c decreasing urinary glucose excretion
d all of the above
7 In clinical trials in patients with diabetes, use of empagliflozin resulted in reductions in:
a HbA1c
b systolic blood pressure
c weight
d all of the above
A Stool DNA Test (Cologuard) for Colorectal Cancer Screening
8 A 50-year-old woman recently saw an advertisement for
Cologuard and asks whether she should be screened for
colorectal cancer with this test You could tell her that:
a colorectal cancer screening for average-risk patients is recommended beginning at age 50
b colonoscopy is the preferred method of screening
c a positive result with Cologuard should be followed by a
diagnostic colonoscopy
d all of the above
9 The Cologuard stool DNA test includes molecular assays for:
a KRAS gene point mutations
b methylated target DNA (NDRG4 and BMP3)
c hemoglobin
d all of the above
Rescheduling of Hydrocodone Combination Products
10 All combination products containing hydrocodone have been reclassifi ed by the Drug Enforcement Administration to:
a schedule I
b schedule II
c schedule IV
d schedule V
Influenza Vaccine for 2014-2015
1 Compared to trivalent influenza vaccines, quadrivalent influenza
vaccines offer additional protection against:
a influenza A viruses
b influenza B viruses
c influenza C viruses
d all of the above
2 A mother brings her otherwise healthy 3-year-old son in for a
routine check-up and asks which seasonal influenza vaccine her
son should receive You could tell her that:
a the intranasal live-attenuated vaccine appears to be more
effective in younger children than the inactivated vaccine
b the intranasal live-attenuated vaccine is preferred for
healthy children 2-8 years old
c children 6 months to 8 years old who are being vaccinated
for the fi rst time should receive 2 doses this year given at
least 4 weeks apart
d all of the above
3 Compared to conventional standard-dose vaccines which
contain 15 mcg of hemagglutinin antigen (HA) from each strain,
Fluzone High-Dose contains how much HA from each strain?
a 25 mcg
b 30 mcg
c 50 mcg
d 60 mcg
4 A 40-year-old man with asthma and a history of hives related to
egg exposure asks for a flu shot Which of the following would
be the safest choice for this patient?
a Fluzone High-Dose
b FluMist Quadrivalent
c FluBlok
d Fluzone Intradermal
Empagliflozin (Jardiance) for Diabetes
5 Adverse effects of empagliflozin include:
a genital mycotic infections
b urinary tract infections
c hypotension
d all of the above
ACPE UPN: Per Issue Exam: 0379-0000-14-453-H01-P; Release: October 13, 2014, Expire: October 13, 2015 Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016
EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D.,
F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller University; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital, Copenhagen; Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R.,
Weill Medical College of Cornell University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofi t organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without resulting from any error, inaccuracy, or omission.
Subscription Services
The Medical Letter, Inc Call: 800-211-2769 or 914-235-0500 To reproduce any portion of this issue, 1 year - $98; 2 years - $189; E-mail: info@medicalletter.org
145 Huguenot St Ste 312 Fax: 914-632-1733 please e-mail your request to: 3 years - $279 $49 per year Call: 800-211-2769
New Rochelle, NY 10801-7537 E-mail: custserv@medicalletter.org permissions@medicalletter.org for students, interns, residents, and Special rates available for bulk
Reprints - $12 each