1486 on Drugs and Therapeutics Durlaza – A 24-Hour Extended-Release Aspirin ...p 7 Fluad – An Adjuvanted Seasonal Influenza Vaccine for Older Adults ...p 8 Talimogene Laherparepvec Iml
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IN THIS ISSUE
ISSUE
1433
Volume 56
Published by The Medical Letter, Inc • A Nonprofi t Organization
ISSUE No
1486
on Drugs and Therapeutics
Durlaza – A 24-Hour Extended-Release Aspirin p 7
Fluad – An Adjuvanted Seasonal Influenza Vaccine for Older Adults p 8
Talimogene Laherparepvec (Imlygic) for Unresectable Melanoma p 8
Elvitegravir (Vitekta) for HIV p 10
Mepolizumab (Nucala) for Severe Eosinophilic Asthma p 11
Correction p 12
Trang 2
7
on Drugs and Therapeutics
ISSUE
1433
Volume 56
ISSUE No
1486 Fluad – An Adjuvanted Seasonal Influenza Vaccine for Older Adults Talimogene Laherparepvec (Imlygic) for Unresectable Melanoma p 8 p 8
Elvitegravir (Vitekta) for HIV p 10
Mepolizumab (Nucala) for Severe Eosinophilic Asthma p 11
ALSO IN THIS ISSUE
The FDA has approved Durlaza (New Haven
Pharmaceuticals), a 24-hour extended-release (ER)
aspirin formulation available only by prescription, for
secondary prevention of myocardial infarction (MI)
and stroke
Durlaza — A 24-Hour
Extended-Release Aspirin
▶
Pronunciation Key
Durlaza: dur lah’ za
RATIONALE — Aspirin’s antiplatelet effects are
irreversible and persist for the life of the platelet
Immediate-release (IR) aspirin is cleared from serum
within 6 hours after a dose New platelets released into
the systemic circulation after IR aspirin is cleared will
be active until the next dose is taken Patients with
diabetes and coronary artery disease (CAD) may have
high platelet turnover; a study in patients with CAD
and type 2 diabetes treated with once-daily low-dose
IR aspirin found increased platelet aggregation at the
end of the 24-hour dosing interval.1 An ER formulation
that releases acetylsalicylic acid (ASA) over a 24-hour
period could inhibit platelet aggregation throughout
the dosing interval
CLINICAL STUDIES — Approval of Durlaza was
based on earlier clinical trials that established the
effi cacy of low-dose aspirin in preventing secondary
cardiovascular events and on a bioequivalence study
in which it was compared to IR aspirin Fifty healthy
adults were each randomized to receive 2 of 5 possible
single doses of ER aspirin (20, 40, 81, 162.5, or 325
mg) and IR aspirin (5, 10, 20, 40, or 81 mg) in a total of
4 periods, each separated by a washout period of ≥14
days Both ER and IR aspirin produced dose-dependent
inhibition of all pharmacodynamic parameters (serum
thromboxane B2 [TXB2], urine 11-dehydro-TXB2, and
arachidonic acid-induced platelet aggregation) A
2-fold higher dose of ER aspirin was required to
1 KH Christensen et al Reduced antiplatelet effect of aspirin dur-ing 24 hours in patients with coronary artery disease and type 2 diabetes Platelets 2015; 26:230.
2 J Patrick et al A randomized trial to assess the pharmacody-namics and pharmacokinetics of a single dose of an extended-release aspirin formulation Postgrad Med 2015; 127:573.
3 PA Gurbel et al Durability of antiplatelet effect of a novel ex-tended-release formulation of acetylsalicylic acid, Durlaza in patients with diabetes Circulation 2015; 132 (suppl 3): Abstract 19503.
4 Approximate WAC WAC = wholesaler acquisition cost or manufac-turer's published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transac-tional price Source: AnalySource® Monthly January 5, 2016 Re-printed with permission by First Databank, Inc All rights reserved
©2016 www.fdbhealth.com/policies/drug-pricing-policy.
produce the same level of TXB2 inhibition as IR aspirin Dose-normalized peak serum concentrations of ASA were 6-fold higher with IR aspirin than with ER aspirin ASA concentrations were measurable for up to 6 hours after a dose of IR aspirin, and for 8 hours, which was the last study assessment, with the ER formulation.2
In an unpublished 14-day study (available only as an
abstract), the antiplatelet effects of Durlaza persisted
for 24 hours in 40 patients with type 2 diabetes and cardiovascular risk factors.3
DOSAGE, ADMINISTRATION, AND COST — Durlaza is
available as 162.5-mg capsules The recommended dosage is one capsule taken once daily with a full glass of water The capsule must be swallowed whole
and should not be crushed or chewed Taking Durlaza
with alcohol could result in immediate release of aspirin; it should not be taken within 2 hours before or
one hour after drinking alcohol One Durlaza capsule
costs $6.4
CONCLUSION — There is no evidence that the new
extended-release aspirin formulation (Durlaza),
which is available only by prescription, is as safe or
as effective as low-dose immediate-release aspirin in preventing cardiovascular events ■
For further information call: 800-211-2769
Trang 3The Medical Letter ® Vol 58 (1486) January 18, 2016
Fluad – An Adjuvanted Seasonal
Influenza Vaccine for Older Adults
▶
The FDA has approved Fluad (Seqirus), an adjuvanted
trivalent seasonal influenza vaccine, for immunization
of adults >65 years old It will become available later
this year for use during the 2016-2017 influenza
season Fluad is the second influenza vaccine to be
approved in the US specifi cally for older adults; Fluzone
High-Dose was the fi rst.1 Fluad has been available in
other countries for many years
THE NEW VACCINE — Older adults may have a lower
antibody response to influenza vaccination than
younger adults and their antibody levels may decline
more rapidly Fluad contains MF59, an oil-in-water
emulsion of squalene oil that increases the immune
response by recruiting antigen-presenting cells to the
injection site and promoting uptake of influenza virus
antigens Like all trivalent seasonal influenza vaccines
available in the US, Fluad contains antigens from two
influenza A viruses and one influenza B virus It may
also contain trace amounts of egg protein, neomycin,
kanamycin, and/or barium
1 Influenza vaccine for 2015-2016 Med Lett Drugs Ther 2015; 57:125.
2 SE Frey et al Comparison of the safety and immunogenicity of
an MF59-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects Vaccine 2014; 32:5027.
3 PG Van Buynder et al The comparative effectiveness of adju-vanted and unadjuadju-vanted trivalent inactivated influenza vac-cine (TIV) in the elderly Vacvac-cine 2013; 31:6122.
4 S Mannino et al Effectiveness of adjuvanted influenza vaccina-tion in elderly subjects in northern Italy Am J Epidemiol 2012; 176:527.
5 CA DiazGranados et al Effi cacy of high-dose versus standard-dose influenza vaccine in older adults N Engl J Med 2014; 371:635
6 CA DiazGranados et al Prevention of serious events in adults 65 years of age or older: a comparison between high-dose and stan-dard-dose inactivated influenza vaccines Vaccine 2015; 33:4988
Table 1 Seasonal Influenza Vaccines for Older Adults
Vaccine Formulation Composition
Fluad (Seqirus) 0.5 mL syringe Trivalent; 15 mcg HA
from each strain
Fluzone High-Dose 0.5 mL syringe Trivalent; 60 mcg HA
HA = hemagglutinin antigen
vaccines in preventing laboratory-confi rmed influenza
in older adults.5,6 Injection-site reactions occur more
frequently with Fluzone High-Dose than with
standard-dose vaccines
CONCLUSION — Fluad appears to be more
immuno-genic in adults ≥65 years old than an unadjuvanted
trivalent seasonal influenza vaccine How Fluad compares to Fluzone High-Dose in effi cacy and safety
remains to be determined ■
CLINICAL STUDIES — FDA approval of Fluad was based
on the results of a randomized controlled trial in 7082
adults >65 years old that found the immunogenicity
of the new vaccine to be noninferior to that of an
unadjuvanted trivalent seasonal influenza vaccine
(Agriflu) Compared to Agriflu, Fluad elicited signifi cantly
greater antibody responses against all three strains
3 weeks after vaccination, but the differences did not
meet the prespecifi ed criteria for superiority Pain and
tenderness at the injection site occurred more frequently
with Fluad than with the unadjuvanted vaccine.2
In observational studies, older adults who received the
adjuvanted influenza vaccine were less likely than those
who received an unadjuvanted standard-dose trivalent
vaccine to have symptomatic influenza illness or be
hospitalized for influenza.3,4
Versus Fluzone High-Dose – No studies are available
comparing Fluad with Fluzone High-Dose Fluzone
High-Dose has induced signifi cantly greater antibody
responses and was more effective than standard-dose
The FDA has approved talimogene laherparepvec
(Imlygic – Amgen), a genetically modifi ed herpes
simplex virus, for intralesional treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that has recurred following surgery It is the fi rst oncolytic virotherapy to become available in the US
Talimogene Laherparepvec (Imlygic)
for Unresectable Melanoma
▶
Pronunciation Key Talimogene laherparepvec: tal im’ oh jeen la her” pa rep’ vek
Imlygic: im lye’ jik
MECHANISM OF ACTION — Melanoma tumors
are immunogenic and often accessible, which makes them good targets for intralesional viral immunotherapy.1,2 Talimogene laherparepvec (T-VEC)
is a herpes simplex type 1 virus (HSV-1) that has been modifi ed to reduce its pathogenicity in healthy cells and promote its replication in tumor cells The virus is also encoded with the gene for granulocyte macrophage-colony stimulating factor (GM-CSF), which induces T-cell proliferation and activation.3
Virus-induced tumor lysis causes the release of tumor antigens, which together with GM-CSF is thought to produce an antitumor immune response
Trang 4Exogenous GM-CSF has been studied for treatment
of melanoma In an open-label trial in 245 patients
with unresectable stage III or IV melanoma, treatment
with the anti-CTLA4 monoclonal antibody ipilimumab
(Yervoy) plus subcutaneous sargramostim (a human
recombinant GM-CSF product available as Leukine)
signifi cantly increased median overall survival
compared to ipilimumab alone (17.5 vs 12.7 months)
The rate of survival at 1 year was also higher with
the combination (68.9% vs 52.9%), and it caused less
grade 3+ toxicity.4
CLINICAL STUDIES — In an open-label trial, 436
patients with unresectable stage IIIB-IV melanoma
accessible to direct or ultrasound-guided injection
were randomized to receive intralesional T-VEC or
subcutaneous GM-CSF for at least 24 weeks Patients
with bone metastases, growing hepatic metastases,
or >3 visceral nonpulmonary metastases were
excluded from the trial The durable response rate
(defi ned as an objective response lasting ≥6 months)
was signifi cantly greater with T-VEC than with
GM-CSF (16.3% vs 2.1%) T-VEC was more likely to induce
a durable response in patients with stage III melanoma
than in those with stage IV disease (33% vs 8%).5
Median overall survival was 22.9 months with T-VEC
and 19.0 months with GM-CSF; this difference was not
statistically signifi cant.6
ADVERSE EFFECTS — In the clinical trial, the most
common adverse effects of T-VEC (occurring in ≥10% of
patients and more commonly than with GM-CSF) were
fatigue, chills, pyrexia, influenza-like illness,
injection-site pain, nausea, vomiting, diarrhea, constipation,
headache, myalgia, arthralgia, and pain in extremities;
severe adverse reactions were uncommon
Clinical herpetic infections, including cold sores
and keratitis, have been reported in patients
receiving T-VEC; the drug should not be used in
immunocompromised patients Accidental exposure
to T-VEC can lead to herpetic transmission among
caregivers and close contacts of patients Cellulitis,
systemic bacterial infection, impaired injection-site
healing, and immune-mediated events have also
been reported
PREGNANCY — No data on the use of T-VEC during
pregnancy are available, but wild-type HSV-1 has the
potential to cross the placenta and the virus can be
transmitted during parturition Fetuses and neonates
infected with wild-type HSV-1 are at risk for serious
adverse effects, including multi-organ failure and
death T-VEC should not be used in pregnant women,
and healthcare providers who are pregnant should not prepare or administer the drug
DRUG INTERACTIONS — Concurrent administration of
acyclovir (Zovirax, and generics) or another antiviral
drug could interfere with the effectiveness of T-VEC
DOSAGE, ADMINISTRATION, AND COST — Imlygic is
available in 1-mL single-use vials containing 106 or
108 plaque-forming units (PFU) of T-VEC in a frozen suspension Patients should receive the 106 PFU/
mL concentration at week 0 and the 108 PFU/mL concentration at week 3 and every 2 weeks thereafter Injection volume per lesion ranges from 0.1-4 mL, depending on lesion size; no more than 4 mL should
be injected per treatment session
Lesions that have developed since the previous treatment should be treated fi rst, with remaining lesions prioritized based on size Treatment should be continued for at least 6 months or until all injectable lesions have been treated, unless another drug therapy
is required T-VEC treatment can be restarted if new lesions appear
A 1-mL vial of Imlygic containing 108 PFU of talimogene laherparepvec costs $4400.7
CONCLUSION — Injection of the genetically modifi ed
herpes simplex virus talimogene laherparepvec
(Imlygic) into unresectable cutaneous, subcutaneous,
and nodal melanoma lesions appears to be only modestly effective How it compares in effi cacy and safety with the numerous other agents now available for treatment of melanoma remains to be determined
All of them, including Imlygic, are very expensive ■
1 SS Agarwala Intralesional therapy for advanced melanoma: promise and limitation Curr Opin Oncol 2015; 27:151
2 N Dharmadhikari et al Oncolytic virus immunotherapy for mel-anoma Curr Treat Options Oncol 2015; 16:326.
3 HL Kaufman et al Current status of granulocyte-macrophage colony-stimulating factor in the immunotherapy of melanoma
J Immunother Cancer 2014; 2:11.
4 FS Hodi et al Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial JAMA 2014; 312:1744
5 RH Andtbacka et al Talimogene laherparepvec improves du-rable response rate in patients with advanced melanoma J Clin Oncol 2015; 33:2780.
6 YA Luo Statistical review – Imlygic Available at: www.fda gov/downloads/BiologicsBloodVaccines/CellularGeneThera-pyProducts/ApprovedProducts/UCM474614.pdf Accessed January 7, 2016.
7 Approximate WAC WAC = wholesaler acquisition cost or manufac-turer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transac-tional price Source: AnalySource® Monthly January 5, 2016 Re-printed with permission by First Databank, Inc All rights reserved
©2016 www.fdbhealth.com/policies/drug-pricing-policy.
Trang 5The Medical Letter ® Vol 58 (1486) January 18, 2016
Table 1 Integrase Strand Transfer Inhibitors (INSTIs) and Combinations
Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide – 150/150/200/10 mg tabs 1 tab once/d 5,6
Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate – 150/150/200/300 mg tabs 1 tab once/d 5,7
1 Approximate WAC for 30 days’ treatment WAC = wholesaler acquisition cost, or manufacturer's published price to wholesalers; WAC represents published catalogue or list prices and may not represent actual transactional prices Source: AnalySource® Monthly January 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy
2 Not recommended for use in patients with CrCl <50 mL/min
3 An additional 50-mg tablet of dolutegravir should be taken 12 hours after Triumeq if used in combination with efavirenz, fosamprenavir/ritonavir, tipranavir/
ritonavir, carbamazepine, or rifampin.
4 Dose for INSTI-naive patients INSTI-experienced patients with certain INSTI-associated resistance mutations or clinically suspected INSTI resistance should take 50 mg bid.
5 Taken with food
6 Not recommended for use in patients with CrCl <30 mL/min
7 Should not be started in patients with CrCl <70 mL/min and patients should be switched to an alternative regimen if CrCl falls below 50 mL/min during treatment.
8 Only FDA-approved for use in antiretroviral treatment-experienced adults Must be taken in combination with a protease inhibitor (PI) coadministered with rito-navir and another antiretroviral drug The dose of elvitegravir is 85 mg when the coadministered PI is atazarito-navir or lopirito-navir and 150 mg when it is darurito-navir, fosamprenavir, or tipranavir (see table 2).
9 30 tabs of either strength cost the same amount.
10 Also available as 25- and 100-mg chewable tabs, and as 100-mg packets Formulations are not bioequivalent and one cannot be substituted for another.
Elvitegravir (Vitekta) for HIV
▶
The FDA has approved elvitegravir (Vitekta – Gilead),
an integrase strand transfer inhibitor (INSTI), for use
with a protease inhibitor (PI) plus ritonavir and other
antiretroviral drugs for treatment of HIV-1 infection
in treatment-experienced adults Elvitegravir is also
available in a fi xed-dose combination (Stribild) with
the pharmacokinetic enhancer cobicistat and the
nucleoside/nucleotide reverse transcriptase
inhibi-tors (NRTIs) emtricitabine and tenofovir disoproxil
fumarate (DF).1 A similar combination (Genvoya) that
includes tenofovir alafenamide instead of tenofovir DF
was recently approved by the FDA and will be reviewed
in a future issue
Pronunciation Key Elvitegravir: el” vi teg’ ra veer Vitekta: vye tek’ tuh
versa, but often remain susceptible to dolutegravir.6
Dolutegravir resistance mutations have not been reported with use of the drug in fi rst-line therapy.2
CLINICAL STUDIES — In a double-blind trial, 702
treatment-experienced patients with HIV-1 infection were randomized to receive elvitegravir 150 mg once daily (85 mg once daily with a background regimen containing atazanavir or lopinavir) or raltegravir 400 mg twice daily All patients were also taking a background regimen consisting of a PI boosted with ritonavir and a second antiretroviral drug Elvitegravir was found to be noninferior to raltegravir; the percentages of patients who achieved and maintained a virologic response (HIV RNA <50 copies/mL), the primary endpoint, were 59% and 48% with elvitegravir and 58% and 45% with raltegravir at 48 and 96 weeks, respectively.7,8
ADVERSE EFFECTS — The most common adverse
effects reported with elvitegravir in the clinical trial were diarrhea (7%), nausea (4%), and headache (3%) Abdominal pain, dyspepsia, vomiting, fatigue, depres-sion, insomnia, suicidal ideation, suicide attempt, and rash have occurred less frequently
PREGNANCY — Elvitegravir is classifi ed as category B
(no evidence of risk in animals; no adequate studies in women) for use during pregnancy
DRUG INTERACTIONS — Elvitegravir is metabolized
by CYP3A Coadministration with drugs that induce CYP3A may decrease elvitegravir serum concentrations, leading to loss of effect and development of resistance, and is not recommended.9 Antacids and supplements containing polyvalent cations may also decrease plasma
TREATMENT OF HIV — First-line therapy for HIV usually
consists of two NRTIs in combination with either
darunavir boosted with ritonavir or an INSTI.The choice
of drugs for treatment-experienced patients depends
on their previous treatment and resistance mutations.2
INSTIs — INSTIs block the activity of HIV-1 integrase,
preventing viral DNA from integrating with cellular
DNA Dolutegravir is taken once daily and is available
alone (Tivicay)3 and in combination with the NRTIs
abacavir and lamivudine (Triumeq).4 Raltegravir
(Isentress) is generally well tolerated and is not
metabolized by CYP3A, but must be taken twice daily
and is not available in fi xed-dose combinations with
NRTIs.5 HIV strains that become resistant to raltegravir
are usually cross-resistant to elvitegravir, and vice
Trang 6concentrations of elvitegravir; administration should be
separated by at least 2 hours
Atazanavir/ritonavir and lopinavir/ritonavir substantially
increase serum concentrations of elvitegravir and a
lower dose of elvitegravir should be used when taken
concomitantly (see Table 2)
Elvitegravir must be used in combination with a
pharmacokinetic enhancer such as ritonavir to
achieve therapeutic serum concentrations with
once-daily dosing It must also be coadministered with a
virologically active PI and another virologically active
antiretroviral drug in treatment-experienced patients
These coadministered drugs may affect the metabolism
of other drugs; numerous drug interactions are described
in the labeling
DOSAGE AND ADMINISTRATION — Elvitegravir should
be taken once daily with food in combination with a PI
coadministered with ritonavir (see Table 2 for
recom-mended dosages) and another antiretroviral drug
CONCLUSION — The once-daily integrase strand
transfer inhibitor elvitegravir (Vitekta) was noninferior
to twice-daily raltegravir for treatment of HIV-1
infec-tion in antiretroviral treatment-experienced adults It
must be taken with ritonavir, another protease inhibitor,
and other antiretroviral drugs ■
Table 2 Recommended Elvitegravir Dosage 1
Fosamprenavir 700 mg/RTV 100 mg bid Tipranavir 500 mg/RTV 200 mg bid
RTV = ritonavir
1 Elvitegravir plus a protease inhibitor (PI) and ritonavir must be coadministered
with another antiretroviral drug.
2 No dosing recommendations are available for elvitegravir with other
ritonavir-boosted PIs or with cobicistat-ritonavir-boosted PIs
1 A 4-drug combination (Stribild) for HIV Med Lett Drugs Ther
2012; 54:95.
2 Panel on Antiretroviral Guidelines for Adults and Adolescents
Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents Department of Health and Human
Services Available at: www.aidsinfo.nih.gov/ContentFiles/
AdultandAdolescentGL.pdf Accessed January 7, 2016.
3 Dolutegravir (Tivicay) for HIV Med Lett Drugs Ther 2013; 55:77.
4 Triumeq: a 3-drug combination for HIV Med Lett Drugs Ther
2015; 57:7.
5 Two new drugs for HIV infection Med Lett Drugs Ther 2008; 50:2.
6 S Fourati et al Cross-resistance to elvitegravir and dolutegravir
in 502 patients failing on raltegravir: a French national study of
raltegravir-experienced HIV-1-infected patients J Antimicrob
Chemother 2015; 70:1507.
7 JM Molina et al Effi cacy and safety of once-daily elvitegravir
versus twice-daily raltegravir in treatment-experienced
pa-tients with HIV-1 receiving a ritonivir-boosted protease
inhibi-Pronunciation Key Mepolizumab: me" poe liz' ue mab Nucala: new ka' la
Mepolizumab (Nucala) for Severe
Eosinophilic Asthma
▶
The FDA has approved mepolizumab (Nucala - GSK), a
subcutaneously injected humanized interleukin-5 (IL-5) antagonist monoclonal antibody, for maintenance treatment of severe asthma in patients ≥12 years old who have an eosinophilic phenotype
EOSINOPHILIC PHENOTYPE — Severe asthma has
been defi ned as asthma that can only be controlled with high-dose inhaled glucocorticoids plus a second controller medication and/or systemic glucocorticoids,
or that remains uncontrolled despite this therapy What constitutes an eosinophilic phenotype is not well defi ned, but patients in this category generally have severe disease with high eosinophil levels in blood and sputum despite treatment with a glucocorticoid.1
MECHANISM OF ACTION — IL-5 is the major cytokine
responsible for the growth, differentiation, recruitment, and activation of eosinophils Mepolizumab binds to IL-5 receptors, reducing the production and survival of eosinophils and decreasing airway inflammation
Table 1 Pharmacology
Formulation 100 mg single-dose vials
Metabolism Degradation by proteolytic enzymes Half-life (terminal) 16-22 days
tor: randomized, double-blind, phase 3, non-inferiority study Lancet Infect Dis 2012; 12:27.
8 R Elion et al A randomized phase 3 study comparing once-daily elvitegravir with twice-daily raltegravir in treatment-experi-enced subjects with HIV-1 infection: 96-week results J Acquir Immune Defi c Syndr 2013; 63:494.
9 Inhibitors and inducers of CYP enzymes and p-glycoprotein Med Lett Drugs Ther 2013; 55:e44.
CLINICAL STUDIES — FDA approval of mepolizumab
was based on the results of three randomized, double-blind, placebo-controlled trials
In one trial, 621 patients who had ≥2 asthma exacer-bations requiring systemic glucocorticoid therapy in the preceding year and evidence of eosinophilic airway inflammation at study entry or within the previous year were randomized to receive IV mepolizumab 75,
250, or 750 mg or placebo every 4 weeks for 13 doses Evidence of eosinophilic inflammation was defi ned as
a sputum eosinophil count ≥3%, an exhaled nitric oxide concentration ≥50 ppb, a peripheral blood eosinophil
Trang 7The Medical Letter ® Vol 58 (1486) January 18, 2016
Correction: Cobicistat (Tybost) and Combinations for HIV
(Med Lett Drugs Ther 2015; 57:159)
The third sentence in the adverse effects section on page 160
was incorrect Cobicistat inhibits tubular secretion of creatinine, not reabsorption
1 KF Chung et al International ERS/ATS guidelines on defi nition, eval-uation and treatment of severe asthma Eur Respir J 2014; 43:343.
2 ID Pavord et al Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial Lancet 2012; 380:651.
3 HG Ortega et al Mepolizumab treatment in patients with severe eosinophilic asthma N Engl J Med 2014; 371:1198.
4 EH Bel et al Oral glucocorticoid-sparing effect of mepolizumab
in eosinophilic asthma N Engl J Med 2014; 371:1189.
5 W Busse et al High eosinophil count: a potential biomarker for as-sessing successful omalizumab treatment effects J Allergy Clin Immunol 2013; 132:485.
6 P Haldar et al Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis J Allergy Clin Immunol 2014; 133:921.
7 Approximate WAC WAC = wholesaler acquisition cost or man-ufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an ac-tual transactional price Source: AnalySource® Monthly Janu-ary 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.
count ≥300 cells/mcL, or a prompt deterioration of
asthma control after a ≤25% reduction in maintenance
oral or inhaled glucocorticoid dosage The rate of
clinically signifi cant asthma exacerbations, the primary
endpoint, was signifi cantly lower in patients treated with
the three doses of mepolizumab than with placebo (1.24,
1.46, and 1.15 per patient-year, respectively, vs 2.40).2
In a second trial, 576 patients with severe asthma who
had ≥2 exacerbations requiring systemic glucocorticoid
therapy within the previous year and evidence of
eosinophilic inflammation (peripheral blood eosinophil
count ≥150 cells/mcL at screening or ≥300 cells/
mcL any time in the previous year) were randomized
to receive mepolizumab 75 mg IV or 100 mg SC or
placebo every 4 weeks for 32 weeks Compared to those
receiving placebo, the annualized frequency of clinically
signifi cant exacerbations, the primary endpoint, was
reduced by 47% with IV mepolizumab and by 53% with SC
mepolizumab, both statistically signifi cant differences
In a prespecifi ed subgroup analysis, patients with a
blood eosinophil count ≥500 cells/mcL at baseline had
greater reductions in clinically signifi cant exacerbations
compared to placebo with both formulations of
mepolizumab (74% with IV and 80% with SC).3
In a third trial in 135 patients with a ≥6-month history of
maintenance treatment with a systemic glucocorticoid
and evidence of eosinophilic inflammation (peripheral
blood eosinophil count ≥300 cells/mcL during the
12 months prior to screening or ≥150 cells/mcL
during the optimization phase), patients treated with
mepolizumab 100 mg SC every 4 weeks for 20 weeks
were 2.39 times more likely than those receiving
placebo to have their glucocorticoid dose reduced The
median reduction in glucocorticoid dose from baseline
was 50% with mepolizumab and 0% with placebo.4
VERSUS OMALIZUMAB — Use of mepolizumab
may overlap with omalizumab (Xolair), an anti-IgE
monoclonal antibody approved for use in patients
with moderate to severe persistent asthma not well
controlled with an inhaled glucocorticoid who have
well-documented specifi c sensitization to a perennial
airborne allergen In one study, the results of a
pre-planned subgroup analysis suggested that omalizumab
may be particularly effective in atopic patients with
high blood eosinophil levels.5 No studies are available
comparing mepolizumab with omalizumab
ADVERSE EFFECTS — In clinical trials, common
adverse effects of mepolizumab (reported in ≥5%
of patients and more frequently than with placebo)
included injection-site reactions, headache, back pain,
and fatigue Hypersensitivity reactions have occurred, generally within hours, but sometimes within days Herpes zoster infections have occurred rarely
PREGNANCY — There are no adequate studies of
mepolizumab in pregnant women There was no evidence of fetal harm in monkeys treated with IV mepolizumab at doses that produced exposures up
to 30 times those achieved with the recommended human dose
DOSAGE, ADMINISTRATION, AND COST — The
recommended dosage of mepolizumab is 100
mg injected subcutaneously into the upper arm, thigh, or abdomen every 4 weeks The optimal duration of treatment has not been established; in one study, following a 1-year course of treatment with mepolizumab, blood and sputum eosinophil counts increased signifi cantly within 3 months after discontinuation of the drug, and exacerbation rates returned to near pretreatment levels 3 to 6 months after cessation.6 A single dose of Nucala costs $2500.7
CONCLUSION — Mepolizumab (Nucala) injected
subcutaneously every 4 weeks has reduced exacer-bations and maintenance oral glucocorticoid doses in patients with severe asthma and high eosinophil counts The long-term effi cacy and safety of mepolizumab have not been established, and it is very expensive ■
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1 Review the effi cacy of 24-hour extended-release aspirin (Durlaza) for secondary prevention of myocardial infarction and stroke.
2 Review the effi cacy and safety of the adjuvanted seasonal influenza vaccine (Fluad) in adults ≥65 years old.
3 Review the effi cacy and safety of the oncolytic virotherapy talimogene laherparepvec (Imlygic) for local treatment of unresectable cutaneous, subcutaneous, and nodal
lesions in patients with recurrent melanoma.
4 Review the effi cacy and safety of the integrase strand transfer inhibitor elvitegravir (Vitekta) in combination with other antiretroviral drugs for treatment of HIV-1 infection
in treatment-experienced adults.
5 Review the effi cacy and safety of the interleukin-5 antagonist monoclonal antibody mepolizumab (Nucala) for maintenance treatment of severe asthma in patients ≥12
years old with an eosinophilic phenotype.
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Issue 1486 Questions
(Correspond to questions #11-20 in Comprehensive Exam #74, available July 2016)
6 Which lesions should be treated before any others during a talimogene laherparepvec treatment session?
a the largest lesions
b lesions that have developed since the previous treatment session
c lesions in closest proximity to visceral organs
d lesions accessible only via ultrasound-guided injection
Elvitegravir (Vitekta) for HIV
7 HIV strains that become resistant to raltegravir are usually susceptible to:
a elvitegravir
b dolutegravir
d neither
8 In treatment-experienced patients, elvitegravir has been shown
to be noninferior to:
a raltegravir
b dolutegravir
d neither
Mepolizumab (Nucala) for Severe Eosinophilic Asthma
9 Mepolizumab:
a inhibits IL-5 activity, reducing eosinophil production and inflammation
b is administered intramuscularly
c has been shown to be superior to omalizumab
d all of the above
10 A 25-year-old man with severe asthma has had frequent exacerbations requiring hospitalization despite using a high-dose inhaled glucocorticoid and a long-acting beta2-agonist He has been taking prednisone 30 mg/day since his most recent exacerbation You are considering using mepolizumab in this patient Which of the following statements about its use is true?
a It can reduce exacerbations in patients with high peripheral blood eosinophil counts.
b It can reduce oral glucocorticoid doses in patients with high peripheral blood eosinophil counts.
c Hypersensitivity reactions have been reported with its use.
d all of the above
Durlaza – A 24-Hour Extended-Release Aspirin
1 Durlaza:
a is available only by prescription
b is taken once a day
c should not be taken within 2 hours before or one hour after
drinking alcohol
d all of the above
2 Compared to immediate-release aspirin, Durlaza:
a is similarly effective in preventing secondary
cardiovascular events
b causes fewer gastrointestinal bleeding events
c is longer acting
d all of the above
Fluad – An Adjuvanted Seasonal Influenza Vaccine for Older Adults
3 Which of the following statements about influenza vaccination
in older adults is true?
a Older adults may have a lower antibody response to
influenza vaccine than younger adults.
b Fluzone High-Dose and Fluad appear to induce a greater
immune response than standard-dose unadjuvanted
vaccines.
c Fluzone High-Dose and Fluad appear to cause more
injection-site reactions than standard-dose unadjuvanted
vaccines.
d all of the above
4 Fluad contains:
a an oil-in-water emulsion of squalene oil
b a higher amount of antigen than Fluzone High-Dose
c antigens from two influenza B viruses
d all of the above
Talimogene Laherparepvec (Imlygic) for Unresectable Melanoma
5 Compared to subcutaneous GM-CSF, what has intralesional
talimogene laherparepvec been shown to signifi cantly improve
in patients with unresectable stage IIIB-IV melanoma?
a overall survival
b quality-adjusted survival
c durable response rate
d rate of discontinuation due to toxicity
ACPE UPN: Per Issue Exam: 0379-0000-16-486-H01-P; Release: January 18, 2016, Expire: January 18, 2017 Comprehensive Exam 74: 0379-0000-16-074-H01-P; Release: July 2016, Expire: July 2017
PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT/EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR-IN-CHIEF: Jean-Marie Pflomm,
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