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Clinical Alert
SEPTEMBER 2016
Hot Topic: Self-Injectable Epinephrine
Epinephrine auto-injector is indicated for the emergency treatment of type 1 allergic
reactions, including anaphylaxis. The pre-filled auto-injector device allows a person
experiencing a life-threatening allergic reaction, or their caregiver, to administer a fixeddose of epinephrine intramuscularly or subcutaneously (SC) into the thigh. People with
a history of anaphylactic reactions to allergens, such as food or bee stings, often carry
epinephrine in case of an accidental exposure. Two doses may be needed for a severe
persistent anaphylactic reaction. Epinephrine auto-injector is kept on hand at schools
and also used by first responders. Epinephrine auto-injectors are intended as emergency
supportive therapy and are not a substitute for immediate medical care.
The most commonly prescribed brand of epinephrine auto-injector is Mylan’s EpiPen®
for adults and EpiPen Jr® for children, for which 3.6 million prescriptions were written
in 2015. Mylan acquired the product in 2007; since that time, the price has increased
more than 400% to its current price of about $600 for a pack of 2 single-dose syringes.
Recently, United States senators have questioned the reasons behind the price increase.
The increasing cost can impact patient access to this medication. Mylan offers the My
EpiPen Savings Card® to help patients with commercial insurance cover copays for
EpiPen; and on August 25, 2016, introduced a savings card that will cover approximately
50% of the cost of EpiPen for eligible patients paying the full amount of the drug. In
the next several weeks, Mylan will also launch authorized generic (AG) versions of both
strengths of EpiPen 2-pack cartons; the AG price is expected to be about half the price
of the brand. Teva is also working toward introducing a generic version of EpiPen in late
2017 or early 2018, pending FDA approval.
In October 2015, Sanofi voluntarily recalled all supply of Auvi-Q®, an epinephrine
auto-injector with audio and visual cues, due to potential device malfunction; no
date has been published on its market return. In 2016, Impax stopped manufacturing,
Adrenaclick® epinephrine auto-injector; Impax does, however, make an AG version of
Adrenaclick that is currently available in the same adult and pediatric fixed-dosages as
EpiPen. Impax's generic is not interchangeable for EpiPen. Each product has its unique
administration instructions; patients and/or caregivers switching to a different product
should receive proper training.
New Guidelines for Chronic Pain in Cancer Survivors
The American Society of Clinical Oncology (ASCO) released the first guidelines for
managing chronic pain in cancer survivors. Cancer survivors may have complex pain
syndromes after cancer treatment, some of which may involve chemotherapy-induced
neuropathy or neuralgias. Key recommendations involve screening and comprehensive
assessment; treatment and care options; and risk assessment, mitigation, and universal
precautions with opioid use. ASCO advises pain screening at each patient encounter;
if new-onset of pain is reported, the patient should be assessed for recurrent disease,
secondary malignancy, or late-onset treatment effects.
Regarding treatment of pain, the guidelines recommend both non-pharmacologic
and pharmacologic interventions. Nonsteroidal anti-inflammatory drugs (NSAIDs),
acetaminophen, and adjuvant analgesics (e.g., antidepressants and/or anticonvulsants
for neuropathic pain or chronic widespread pain) are recommended to relieve pain
Drug Information Highlights
• The first AB-rated generics for Roche’s
Tamiflu® (oseltamivir) 30, 45, and 75 mg
capsules were approved. FDA approved
Natco/Alvogen oseltamivir with 180-day
generic exclusivity eligibility. Based on a
settlement agreement, Natco/Alvogen is
able to market this generic product prior
to the end of Tamiflu’s pediatric exclusivity
period (prior to 02/23/2017).
• Safety labeling changes were announced for
methadone and buprenorphine products
when used by pregnant women in the
treatment of opioid use disorder. During
use, the fetus is also exposed to these
products, potentially leading to neonatal
opioid withdrawal syndrome (NOWS). While
this is a manageable condition, it must be
recognized and treated to limit the risk of
life-threatening withdrawal symptoms. The
labeling changes are intended to inform
healthcare professionals (HCPs) of these
risks while recognizing the role of these
medications in the treatment of opioid
addiction.
• Arbor Pharmaceuticals announced a
voluntary recall of 3 lots of acetylcysteine
(Cetylev™) 500 mg effervescent tablets for
oral solution (NDC: 24338-0700-10; Lots:
005C16, 006C16, 007C16; Exp: 02/2018) due
to an inadequate seal of the blister pack.
Damaged seals could result in increased
oxygen and moisture exposure, potentially
leading to inadequate effect or microbial
contamination. No adverse events related
to this recall have been reported to date.
Cetylev is used to treat acetaminophen
overdose.
• The FDA announced continued warning
for use of oral ketoconazole to treat skin
and nail fungal infections due to the risk of
potential adverse effects on the liver and
adrenal glands and the risk of serious drug
interactions. Ultimately, the risks of using
ketoconazole for these infections outweighs
its benefit. While the FDA has already
approved labeling changes to reflect this
warning, a more recent safety review found
that ketoconazole is still prescribed for these
uses and 1 death has been reported due to
liver failure associated with ketoconazole
use for a nail fungal infection. The FDA
reiterated their recommendation that
ketoconazole tablets only be used for serious
fungal infections when no other antifungal
treatments are available.
Editorial Staff
Maryam Tabatabai, PharmD Carole Kerzic, RPh
Editor in Chief
Executive Editor
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September 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
and improve function in eligible patients. Topical analgesics are also recommended,
but corticosteroids are not recommended solely for use of pain management. In states
allowing access to medical cannabis or cannabinoids, these products also may be
considered following a review of the benefits and risks of available formulations.
ASCO recommends a trial of opioids in carefully selected cancer survivors who have
chronic pain that causes continued distress or impairment and has not responded to
more conservative approaches. They further state that nonopioid analgesics and/or
adjuvants may be added as clinically appropriate. However, an assessment of the risks and
benefits of opioids for pain management should be completed prior to use and should be
considered throughout treatment. Universal precautions discussed in the guidelines aim
to minimize abuse, addition, and opioid-related deaths. For instance, ASCO recommends
caution when prescribing other centrally-acting drugs (e.g., benzodiazepines) to patients
using opioids, and providers should discuss safe storage, use, and disposal of opioids
with patients. The full guidelines can be found at https://www.asco.org.
Updated Guidelines on Aspergillosis and Coccidiodomycosis
Recently, the Infectious Diseases Society of America (IDSA) updated guidelines on the
treatment of aspergillosis and coccidioidomycosis. The aspergillosis guidelines, last
published in 2008, were updated with new data on new and existing therapies since the
prior guideline publication, and the coccidioidomycosis guidelines include expanded
recommendations for diagnosing and managing early infections.
Infection due to Aspergillus species may be life-threatening, particularly in
immunocompromised patients. IDSA recommends triazole antifungals (e.g.,
isavuconazonium, itraconazole, posaconazole, voriconazole) as the preferred agents
for the treatment and prevention of invasive aspergillosis for most adult patients
(strong recommendation, high-quality evidence). Therapeutic drug monitoring may be
valuable in enhancing efficacy with some of these agents. Alternative therapies include
amphotericin B preparations and echinocandins (anidulafungin, caspofungin, micafungin)
in select patients. Colony stimulating factors may be considered in neutropenic patients
with suspected or confirmed invasive aspergillosis (weak recommendation, low-quality
evidence). Recommendations for pediatric patients essentially mirror those for adults,
with the caveat that dosing of certain antifungals in this population is unknown. The
guidelines also detail the recommendations for extrapulmonary aspergillosis (in many
cases voriconazole is preferred), as well as the preferred methods for prophylaxis in
various immunocompromised populations.
Coccidioidomycosis species are endemic to certain lower deserts of the western U.S., as
well as parts of Central and South America, and transmission typically occurs by inhalation;
thus, the lung is the most common site of primary infection. Most acute infections are
asymptomatic or cause self-limited symptoms. However, coccidioidomycosis can be
concerning in those with severe or disseminated disease and in immunocompromised
patients. IDSA recommends antifungal therapy in select high-risk patients with newly
diagnosed uncomplicated coccidioidal pneumonia, specifically with fluconazole (≥
400 mg/day) in non-pregnant adults. Low-risk patients may be managed with close
observation and supportive measures. Oral fluconazole or itraconazole are also
recommended for patients with symptomatic cavitary pneumonia or ruptured cavities.
In general, infections at non-lung sites should be treated with fluconazole or itraconazole
when treatment with oral antifungals is recommended. Intravenous (IV) amphotericin B
may be considered as an alternative in these patients. Notably, the guidelines recommend
life-long treatment with fluconazole with doses of 400 to 1,200 mg/day in adults with
coccidioidal meningitis and, while fluconazole requires a dose adjustment for significant
renal impairment (generally a 50% dose reduction), the guidelines state that there is
no role for doses less than 400 mg in this population despite renal impairment. The
guidelines also provide details on management and prevention of coccidioidomycosis
infections in special at-risk populations, such as solid organ transplant recipients, stem
cell transplant recipients, pregnant patients, and those with human immunodeficiency
virus (HIV)-coinfection.
• The FDA has approved etanercept-szzs
(Erelzi™) Sandoz’s biosimilar to Amgen’s
tumor necrosis factor alfa (TNFα) inhibitor
Enbrel®, granting Erelzi all of Enbrel’s
indications, which include rheumatoid
arthritis (RA), ankylosing spondylitis (AS),
juvenile idiopathic arthritis (JIA), plaque
psoriasis (PsO), and psoriatic arthritis (PsA).
The launch of Erelzi is contingent upon
patent litigation and at the earliest is not
expected until fourth quarter of 2018. This is
the third biosimilar approved in the U.S.
• The U.S. Preventive Services Task Force
(USPSTF) released a final recommendation
statement regarding screening for lipid
disorders in children and adolescents.
After a review of the literature, the USPSTF
determined that the current evidence is
insufficient to determine the benefits and
risks associated with screening children and
adolescents 20 years of age or younger for
lipid disorders.
Pipeline News: Upcoming Prescription
Drug User Fee Acts (PDUFA) Dates
•September 1 2016: Blincyto®; blinatumomab;
IV CD19-directed CD3 T-cell engager; pediatric
Philadelphia-negative relapsed/refractory
B-precursor acute lymphoblastic leukemia;
Amgen/Onyx.
•September 14, 2016: Xeglyze; abametapir;
topical antiparasitic; head lice; Hatchtech/
Dr. Reddy’s.
•September 14, 2016: Yosprala; aspirin/
omeprazole; oral fixed-dose NSAID/proton
pump inhibitor; cardiovascular (CV) disease
prevention; Aralez.
•September 20, 2016: Invokamet XR;
canagliflozin/metformin XR; oral fixed-dose
sodium-glucose cotransporter 2 (SGLT2)
inhibitor/biguanide; type 2 diabetes (T2DM);
Janssen.
•September 23, 2016: Rexulti®, brexpiprazole;
oral antipsychotic; schizophrenia maintenance
(adults); Lundbeck/Otsuka.
•September 25, 2016: ABP-501; adalimumab,
biosimilar to Abbvie’s Humira®; SC TNFα
inhibitor; AS, RA, JIA, PsO, PsA, ulcerative
colitis, and Crohn’s disease; Amgen.
•September 25, 2016: Remoxy; oxycodone;
oral abuse-deterrent opioid agonist; chronic
pain; Durect Pain Therapeutics.
•September 30, 2016: Orkambi®; lumacaftor/
ivacaftor; oral cystic fibrosis transmembrane
conductance regulator (CFTR) corrector/
potentiator; cystic fibrosis in ages 6 to 11
years with homozygous F508del mutation;
Vertex.
•Quarter 3, 2016: 20% IGSC; immunoglobulin;
SC IgG immunoglobulin; primary
immunodeficiency; Baxalta/Shire.
•Quarter 3, 2016: Xultophy; insulin degludec/
liraglutide; SC fixed-dose long-acting insulin
and glucagon-like peptide-1 (GLP-1) agonist;
T2DM; Novo Nordisk.
It is important to note that not all medications recommended in the guidelines carry FDA-approved indications for aspergillosis or
coccidiomycosis infections. The full guidelines can be found at http://www.idsociety.org.
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Recent FDA Approvals
Generic
Name
Trade
Name
lorcaserin,
extendedrelease (ER)
FDA
Status
Description
Applicant
Belviq XR®
The FDA approved lorcaserin ER (Belviq XR), a serotonin 2C receptor agonist, as
an adjunct to diet and exercise for chronic weight management in adults with
an initial body mass index (BMI) ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 with at least
1 weight-related comorbid condition. The safety and efficacy of concurrent use
with other weight loss agents and its effect on CV morbidity and mortality have
not been established. Lorcaserin ER should be discontinued if 5% weight loss is
not achieved after 12 weeks of therapy. Similarly, lorcaserin immediate-release
(Belviq®) is already available as a 10 mg tablet that is dosed twice daily.
Eisai
FDA NDA
approval
07/15/2016
lixisenatide
Adlyxin™
Lixisenatide (Adlyxin), a once-daily GLP-1 receptor agonist, was FDA approved
as an adjunct to diet and exercise to improve glycemic control in adults with
T2DM. The initial dose is 10 mcg once SC daily for 14 days; on day 15, the dose
is increased to 20 mcg once daily. The dose should be administered within
1 hour before the first meal of the day. Lixisenatide was approved as disposable
prefilled syringes containing 14 pre-set doses of 10 mcg and 20 mcg per dose.
SanofiAventis
FDA NDA
approval
07/27/2016
lisinopril
Qbrelis™
The FDA approved lisinopril oral solution (Qbrelis), an angiotensin converting
enzyme (ACE) inhibitor, for treatment of hypertension in patients 6 years of age
and older, adjunct therapy for heart failure, and treatment of acute myocardial
infarction. Dosage ranges from 5 mg to 40 mg once daily for adults and
0.07 mg/kg (up to 5 mg total) once daily in pediatric patients. Qbrelis is
approved as a 1 mg/mL oral solution.
Silvergate
FDA NDA
approval
07/29/2016
fluticasone
furoate
Flonase®
Sensimist™
An over-the-counter (OTC) fluticasone furoate nasal spray (Flonase Sensimist)
gained FDA approval to treat symptoms of hay fever or upper respiratory
allergies in patients ≥ 2 years of age and for itchy, watery eyes in patients ≥ 12
years. Flonase Sensimist is approved as a 27.5 mcg spray. Dosage is 2 sprays/
nostril once daily in patients ≥ 12 years and 1 spray/nostril once daily in ages 2
to 11 years. The recommended dosage of the OTC corticosteroid nasal spray is
similar to its prescription version, Veramyst®.
Glaxo
SmithKline
FDA sNDA
approval
08/02/2016
pembrolizumab
Keytruda®
Under an accelerated approval, the FDA has expanded the indication for
pembrolizumab (Keytruda), an injectable programmed death receptor-1
inhibitor, to include treatment of recurrent or metastatic squamous cell
carcinoma of the head and neck (HNSCC) that has progressed on or after
platinum-containing chemotherapy. It is also used for the treatment
unresectable or metastatic melanoma and metastatic non-small cell lung
cancer. The dosage for HNSCC is 200 mg by IV infusion every 3 weeks.
Merck
FDA sNDA
priority
approval
08/05/2016
granisetron
Sustol®
The FDA approved granisetron (Sustol), a 5-HT3 receptor antagonist, indicated
in combination with other antiemetics in adults for the prevention of acute
and delayed nausea and vomiting associated with initial and repeat courses
of moderately emetogenic chemotherapy (MEC) or anthracycline and
cyclophosphamide combination chemotherapy regimens. The recommended
dose is 10 mg given by slow SC injection by an HCP, at least 30 minutes prior
to start of chemotherapy on day 1. The dose should not be given more often
than once every 7 days or once every 14 days in patients with moderate renal
impairment. Sustol is approved as a 10 mg/0.4 mL single-dose, prefilled syringe.
Heron
FDA NDA
approval
08/09/2016
oxycodone/
naltrexone,
extendedrelease
Troxyca® ER
The scheduled II controlled-substance oxycodone/naltrexone (Troxyca ER)
is a fixed-dose combination opioid agonist/opioid antagonist product with
abuse-deterrent features. It is approved for the management of pain severe
enough to require daily, around-the-clock, long-term opioid treatment and
for which alternative treatment options are inadequate. Troxyca ER carries
boxed warnings regarding the risks of addiction, abuse, and misuse; lifethreatening respiratory depression; accidental ingestion; neonatal opioid
withdrawal syndrome; and cytochrome P450 3A4 interactions which can result
in oxycodone overdose. Troxyca ER is approved as 60/7.2 mg and 80/9.6 mg
capsules. Single doses greater than 40/4.8 mg, or a total daily dose greater than
80/9.6 mg, are reserved for patients who have demonstrated tolerance to an
opioid of comparable potency. Troxyca ER is approved as 10/1.2 mg, 20/2.4 mg,
30/3.6 mg, 40/4.8 mg, 60/7.2 mg, and 80/9.6 mg extended-release capsules.
Pfizer
FDA NDA
approval
08/19/2016
ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; sNDA = Supplemental New Drug Application
Contact: Dona Jones, Executive Assistant, djones@magellanhealth.com
https://www1.magellanrx.com/magellan-rx/publications/pharmacy-clinical-alerts.aspx
© 2016, Magellan Health, All Rights Reserved.
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September 2016
References
www.fda.gov
www.imshealth.com
www.mylan.com
http://natcopharma.co.in
www.uspreventiveservicestaskforce.org
www.whitehouse.gov