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Clinical Alert
MARCH 2016
Updated Guidance for Hepatitis C Virus (HCV) and Expanded Indications
The American Association for the Study of Liver Diseases (AASLD) and the Infectious
Diseases Society of America (IDSA) updated their guidance on the management of HCV
infection. Among several important updates, considerations for patients with HIV/HCV
co-infection, decompensated cirrhosis (Child-Pugh B or C), HCV infection post-liver
transplant, and severe renal impairment are specifically addressed.
AASLD/IDSA recommend a number of direct-acting antiviral all-oral regimens to treat
HCV genotype (GT) 1 infection that provide sustained virologic response (SVR) rates
exceeding 90%, including elbasvir/grazoprevir (Zepatier®; Merck), a new fixed-dose
combination of an NS5A inhibitor and HCV NS3/4A protease inhibitor. Regimens vary
based on the HCV subtype and prescence of cirrhosis. In addition, detection of NS5A
resistance-associated variants (RAVs) is one of the strongest pre-treatment predictors
of treatment outcome with NS5A-containing regimens, such as elbasvir/grazoprevir, in
patients with GT 1a infection. NS5A RAVs that cause a 5-fold decrease in NS5A inhibitor
activity can significantly reduce SVRs of NS5A-containing regimens in patients with
genotype 1a. AASLD/IDSA recommend RAV testing, particularly at the M28, Q30, L31,
and Y93 positions, prior to selecting an HCV antiviral regimen in patients with GT 1a.
At the population level, approximately 10% to 15% of patients with GT 1 and no prior
exposure to NS5A inhibitors will test positive for HCV NS5A RAVs at baseline.
Recommendations for elbasvir/grazoprevir follow the Food and Drug Administration
(FDA) approved indications, including as a first-line option for most patients with GTs 1
and 4; AASLD/IDSA also suggest this agent as an alternative for treatment-naïve GT 1a
patients with high fold-change NS5A RAVs, either without cirrhosis or with compensated
cirrhosis (Child-Pugh A).
In February, the FDA expanded the patient populations for Gilead’s oral fixed-dose
combination, ledipasvir/sofosbuvir (Harvoni®), and Bristol-Myers Squibb’s, daclatasvir
(Daklinza™). The expanded populations are included in the guidelines, however some
recommended regimens may differ between FDA and AASLD/IDSA. Ledipasvir/sofosbuvir
is now indicated for GT 1- or 4-infected liver transplant recipients without cirrhosis
or with compensated cirrhosis and for GT 1-infected patients with decompensated
cirrhosis. Ledipasvir/sofosbuvir is approved in combination with ribavirin (RBV) for 12
weeks for these expanded indications.
The FDA expanded the patient populations for daclatasvir (Daklinza) to include patients with
GT 1 and compensated cirrhosis and patient with GTs 1 or 3 with decompensated cirrhosis,
recurrent HCV post-liver transplant or HIV-coinfection. It is approved in combination
with sofosbuvir for 12 weeks for all indications; the addition of RBV is recommended if
decompensated cirrhosis or recurrence post-liver transplant occurs in patients with GT 1
or 3 and if compensated cirrhosis is present in patients with GT 3.
Increased Risk of Dementia Associated with Proton Pump Inhibitors
A large observational study identified a link between the use of proton pump inhibitors
(PPIs) and an increased risk of dementia in the elderly. PPIs, such as esomeprazole,
lansoprazole, omeprazole, pantoprazole, and rabeprazole, are widely used to treat
upper gastrointestinal tract acid-related disorders such as gastroesophageal reflux
Drug Information Highlights
•AstraZeneca announced a voluntary recall
of 3 lots of Tudorza® Pressair® (aclidinium
bromide) used for maintenance treatment
of chronic obstructive pulmonary disease
(COPD). The recall involves the 60 dose-count
devices only. The counter ring for some
devices was not initially set to “60” in the
viewing window, which can potentially result
in the device locking by reaching “0” prior
to 60 doses being dispensed. The affected
products include Lot# 1144394,
Lot# 1145539, and Lot# 1145868, all of which
were distributed between July 2015 and
September 2015. AstraZeneca has instructed
to stop distribution of the 3 lots immediately
and arrange for return to Stericycle by calling
(866) 367-5604. No other lots are being
recalled at this time. For more information call
(800) 237-8898.
•Following recommendations from its advisory
panel, the FDA declined to approve Merck’s
lipid-lowering agents, ezetimibe (Zetia®) and
ezetimibe/simvastatin (Vytorin®), for risk
reduction of cardiovascular (CV) events (CV
death, nonfatal myocardial infarction, nonfatal
stroke, hospitalization for unstable angina, or
need for revascularization) in patients with
coronary artery disease. The supplemental
applications for CV risk reduction were based
on results from the IMPROVE-IT study. In their
Complete Response Letter (CRL), the agency
stated that ezetimibe failed to demonstrate
an effect on CV morbidity and mortality given
either alone or in combination with simvastatin.
Merck is reviewing the CRL to determine their
next steps.
•The American College of Physicians (ACP)
published updated depression treatment
guidelines for adults. Second-generation
antidepressants (SGAs) are often initially
prescribed for patients with depression;
however ACP found no significant difference
between SGAs and cognitive behavioral
therapy (CBT) in treatment response. ACP
states that CBT is a reasonable approach for
initial treatment and advises that clinicians
should select either SGA or CBT to treat
patients with major depressive disorder
(MDD) and further suggest that selection
should consider treatment effects, adverse
effects, cost, accessibility, and patient
preferences. The complete guidelines can be
accessed at http://annals.org.
Editorial Staff
Maryam Tabatabai, PharmD Carole Kerzic, RPh
Editor in Chief
Executive Editor
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March 2016
Lara Frick, PharmD, BCPS, BCPP, CGP
Deputy Editor
Raquel Holmes, RPh, MHM, AAHIV Deputy Editor
Leslie Pittman, PharmD Eileen Zimmer, PharmD, MBA
Deputy Editor
Deputy Editor
disease (GERD) and gastric ulcers. The study was conducted between 2004 and 2011
and included data from the largest German public health insurer. A total of 73,679 patients
aged 75 years and older who did not have dementia at baseline were identified. Of these
patients, 4% used PPIs regularly (e.g. at least one prescription per quarter) during at least
one 12- to 18-month interval during the study period. After adjusting for confounders,
including age, depression, stroke, and polypharmacy (≥ 5 drugs), the study reported a 44%
higher risk of developing dementia (95% confidence interval, 1.36 to 1.52; p<0.001) in
patients who regularly used a PPI. The effect of occasional PPI use was also examined and
was associated with a 16% increased risk of dementia (95% CI, 1.13 to 1.19).
Although reasons for the increase in dementia with PPI use are unclear, researchers
suggest that some PPIs may cross the blood-brain barrier and may increase amyloid
levels in the brain. The effect of PPIs on vitamin B12 deficiency, a known influence on
cognitive decline, was not included in this study. In addition, the socio-economic status
of patients was not taken into account. Finally, to establish a causal relationship of PPI
use on the incidence of dementia, randomized, prospective clinical trials are needed.
Appropriate Antibiotic Use for Respiratory Tract Infections
Pipeline News: Upcoming Prescription
Drug User Fee Acts (PDUFA) Dates
•March 2016: ixekizumab; subcutaneous (SC)
interleukin 17A; moderate to severe plaque
psoriasis; Lilly.
•March 2016: emtricitabine/rilpivirine/tenofovir
alafenamide fumarate; oral antiretroviral; HIV
infection; Gilead/Janssen.
•March 29, 2016: Xadago®; safinamide; oral
once-daily alpha-aminoamide; adjunct for early-,
mid- and late-stage Parkinson’s disease; Meiji
Eika/Newron.
•March 30, 2016: reslizumab; IV anti-IL-5
monoclonal antibody; moderate to severe
asthma with eosinophilia not controlled with
inhaled corticosteroids; Teva.
•April 1, 2016: dronabinol oral solution;
cannabinoid; chemotherapy-induced nausea
and vomiting, cachexia or an unexplained
significant weight loss in AIDS; Insys.
•First Half, 2016: Remsima™; infliximab,
biosimilar to Remicade®; IV TNF-alpha inhibitor;
rheumatoid arthritis and all other Remicade
approved indications; Celltrion/Pfizer/Hospira.
Acute respiratory tract infection (ARTI) results in more outpatient physician visits and
antibiotic prescriptions than any other condition. Antibiotics are often prescribed
inappropriately for ARTI contributing to antibiotic resistance, medication-related
adverse events, and excess costs. The American College of Physicians (ACP) and Centers
for Disease Control and Prevention (CDC) have collaborated to offer recommendations on the appropriate use of antibiotics for
ARTIs, which may include acute uncomplicated bronchitis, pharyngitis, acute rhinosinusitis, and the common cold. Recommendations
provided are limited to healthy and immunocompetent adults without chronic lung disease (e.g., cystic fibrosis, bronchiectasis, chronic
obstructive pulmonary disease).
In general, antibiotic use provides no benefit in cases of acute bronchitis or the common cold; patients may find relief from symptoms
with the use of cough suppressants, expectorants, antihistamines, and decongestants.
Antibiotics may have limited benefit in cases of acute rhinosinusitis for symptoms lasting longer than 10 days, severe symptoms (e.g.,
fever > 39⁰C, purulent nasal discharge, or facial pain) lasting longer than 3 consecutive days, or if symptoms worsen after initially
improving. Recommended oral regimens are amoxicillin-clavulanate (500/125 mg three times daily or 875/125 mg twice daily) or
amoxicillin 500 mg twice daily for 5 to 7 days.
For patients diagnosed with pharyngitis and positive streptococcal infection, antibiotics may decrease the length of illness and prevent
further complications, such as acute rheumatic fever. If acute group A streptococcal pharyngitis has been confirmed, patients should be
treated with a narrow-spectrum antibiotic for 10 days. Recommended oral treatment regimens for patients without penicillin allergy
include: penicillin V (250 mg four times daily or 500 mg twice daily) or amoxicillin (50 mg/kg once daily or 25 mg/kg twice daily) for 10 days.
The complete guidance, including in-depth prescribing strategies and alternative treatment options for persons with penicillin allergies,
can be accessed at http://annals.org.
Benefits and Risks of Long-Term Bisphosphonate Therapy
An American Society for Bone and Mineral Research (ASBMR) task force has provided guidance regarding bisphosphonate (BP) therapy
duration for patients with osteoporosis. The recommendations are based primarily on 2 trials, FLEX (Fracture Intervention Trial Longterm Extension) and HORIZON extension which provided evidence for long-term BP use. The task force advises healthcare professionals
(HCPs) to reassess the benefits and risks of BP therapy after 5 years of oral or 3 years of intravenous (IV) therapy. Benefit includes
continued reduction in the risk of vertebral fracture. Risks, although infrequent, include jaw osteonecrosis (ONJ) and atypical femoral
fracture. Unlike ONJ, the risk of atypical femoral fracture increases with BP therapy duration. Oral or intravenous BP therapy for up
to 10 years and 6 years, respectively, should be considered for older women (70 to 75 years of age) at high risk of fracture, with a
history of major osteoporotic fracture (e.g., hip, spine or multiple other fractures) before or during BP therapy. Periodic evaluations to
reassess the benefits and risks of therapy are still recommended throughout treatment. After 3 to 5 years of BP therapy, a 2 to 3 year
drug holiday may be considered in women without history of major osteoporotic fracture or high fracture risks. The task force discloses
that that their approach for long-term BP therapy is based on limited evidence and applies only for reduction of vertebral fracture in a
predominantly Caucasian postmenopausal female population. Clinical judgement is still essential.
This approach, with certain modifications, may also apply to men with osteoporosis and patients with glucocorticoid-induced
osteoporosis (GIO), although less evidence is available. If glucocorticoid therapy is discontinued in patients with GIO, bisphosphonate
therapy may be discontinued depending on the presence of certain risk factors. If the risk of fracture remains elevated, BP therapy
should be continued; however, current GIO guidelines do not provide recommendations on duration. Both men with osteoporosis and
women with GIO who have received BP therapy for over 5 years and still require bone-protective therapy may consider switching to
teriparatide (Forteo®). Men with GIO who continue to receive glucocorticoids may benefit from continuation of BP therapy.
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March 2016
Recent FDA Approvals
Generic
Name
Trade
Name
dexlansoprazole
FDA
Status
Description
Applicant
Dexilant™
SoluTab
Dexlansoprazole delayed-release (DR) orally disintegrating tablet (Dexilant
SoluTab) has received approval for the treatment of heartburn associated with
gastroesophageal reflux disease (GERD) and for maintaining healing of erosive
esophagitis (EE) in adults. The recommended dosing for healed EE maintenance is
30 mg once daily for up to 6 months and for symptomatic non-erosive GERD, the
dose is 30 mg once daily for 4 weeks. Dexilant SoluTab should be taken at least 30
minutes prior to a meal. Dexilant is also available as 30 and 60 mg DR capsules that
carry the additional indication of healing of all grades of EE. Two 30 mg Dexilant
SoluTabs are not interchangeable with one 60 mg Dexilant DR capsule.
Takeda
FDA NDA
approval
01/26/2016
sumatriptan
succinate
Onzetra™
Xsail™
The FDA has approved sumatriptan nasal powder (Onzetra Xsail), a triptan for acute
treatment of migraine, with or without aura, in adults. It is not indicated for migraine
attack prophylaxis or for the treatment of cluster headache. Available as a capsule in a
disposable nosepiece, it is for use only with the Xsail breath-powered delivery device.
The recommended dose is 22 mg, administered by use of 1 nosepiece (11 mg) in each
nostril. A second dose may be taken after at least 2 hours have passed if migraine has
not resolved. A maximum of 2 doses may be given in a 24-hour period.
Avanir
FDA NDA
approval
01/27/2016
amphetamine
Adzenys
XR-ODT™
The central nervous system stimulant amphetamine extended-release (Adzenys
XR-ODT) was approved in an orally disintegrating tablet formulation for the
treatment of attention deficit hyperactivity disorder (ADHD) in patients 6 years
and older. The recommended starting dose is 6.3 mg once daily for patients 6 to
17 years of age and 12.5 mg once daily for adults, both dosed in the morning.
Amphetamine products should not be substituted on a milligram-per-milligram
basis due to differences in pharmacokinetics and amphetamine base compositions.
Adzenys XR-ODT is a schedule II controlled substance and is approved in a variety of
strengths ranging from 3.1 mg to 18.8 mg.
Neos
FDA NDA
approval
01/28/2016
sumatriptan
succinate
Zembrace™
SymTouch™
Injection
The self-administered sumatriptan succinate injection (Zembrace SymTouch)
was FDA approved for the acute treatment of migraine, with or without aura, in
adults. It is not indicated for migraine prophylaxis. Available as a 3 mg prefilled,
single-dose disposable autoinjector, the recommended dose is 3 mg injected SC.
The maximum cumulative daily dose is 12 mg and each 3 mg injection should be
separated by at least 1 hour.
Dr. Reddys
FDA NDA
approval
01/28/2016
fosaprepitant
dimeglumine
Emend® for
injection
The agency has approved the use of fosaprepitant dimeglumine as a single
150 mg IV dose, in combination with other antiemetic agents, for the prevention
of delayed nausea and vomiting in adults receiving initial and repeat courses of
moderately emetogenic cancer chemotherapy (MEC). Fosaprepitant dimeglumine
for injection is a substance P/neurokinin-1 (NK1) receptor antagonist. It is available
as 150 mg lyophilized powder for reconstitution and is dosed as a single 150 mg
IV infusion administered over 20 to 30 minutes approximately 30 minutes prior
to giving chemotherapy. Fosaprepitant dimeglumine for injection, in combination
with other antiemetic agents, is also indicated for acute and delayed nausea and
vomiting associated with initial and repeat courses of highly emetogenic cancer
chemotherapy (HEC), including high-dose cisplatin.
Merck
FDA sNDA
approval
02/01/2016
betamethasone
dipropionate
Sernivo™
Betamethasone dipropionate spray for topical use (Sernivo) was approved for
the treatment of mild to moderate plaque psoriasis in adults. The high potency
corticosteroid was approved as a 0.05% spray and should be applied to the affected
skin areas twice daily as directed. The face, scalp, axilla, groin and other intertriginous
areas should be avoided. Treatment should be discontinued when control is achieved
with duration not exceeding 4 weeks.
Promius
FDA NDA
approval
02/05/2016
brivaracetam
Briviact®
The FDA has approved the anticonvulsant brivaracetam (Briviact) as adjunctive
therapy in the treatment of partial-onset seizures in patients 16 years of age and
older with epilepsy. Brivaracetam was approved in 5 tablet strengths ranging from
10 to 100 mg, a 10 mg/mL oral solution and as a 50 mg/5 mL single-dose vial for
IV injection. The recommended starting dosage is 50 mg twice daily to be adjusted
as needed based on patient tolerability. The injection formulation may be used
when oral administration is not an option. Brivaracetam is scheduled to receive
classification by the Drug Enforcement Administration (DEA) within the next 90 days,
after which time it will become available for distribution.
UCB
FDA NDA
approval
02/19/2016
Contact: Dona Jones, Executive Assistant, [email protected]
https://www1.magellanrx.com/magellan-rx/publications/pharmacy-clinical-alerts.aspx © 2016, Magellan Health, All Rights Reserved.
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March 2016
References
http://annals.org http://archneur.jamanetwork.com
www.empr.com
www.fda.gov
http://jnnp.bmj.com
www.medscape.com
http://nn.neurology.org