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Clinical Alert
JULY 2016
Hot Topic:
FDA Approves Epclusa®: First Pangenotypic Agent to Treat Chronic
Hepatitis C Virus (HCV)
On June 28, 2016, under a priority review, the Food and Drug Administration (FDA)
approved the first pangenotypic oral direct-acting antiviral agent to treat chronic HCV
infection, targeting genotypes 1-6. Approximately 70-75% of people infected with HCV in
the United States (U.S.) have genotype 1; about 15-20% have genotype 2; and 10-12% are
infected with genotype 3. Only a small proportion of patients in the U.S. have genotypes
4, 5, or 6. Genotype 3 is considered to be the most difficult genotype to treat.
Gilead’s new breakthrough therapy, Epclusa, is a once daily fixed-dose combination of
400 mg sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor, and 100 mg
velpatasvir, an HCV NS5A inhibitor. Epclusa is indicated alone for use in adults with
HCV, without cirrhosis or with compensated cirrhosis; it is also indicated in combination
with weight-based ribavirin in those with decompensated cirrhosis (Child-Pugh B or C).
The recommended dose of Epclusa is one 400/100 mg tablet once daily, taken without
regard to food, for 12 weeks.
The approval of Epclusa was supported by the ASTRAL phase 3 clinical trials that reported
high sustained viral response (SVR) rates with Epclusa. Pooled data from ASTRAL-1, -2,
and -3, with a total of 1,558 patients with HCV genotypes 1-6, without cirrhosis or with
compensated cirrhosis, revealed SVR rates of 95% or above with Epclusa (12-week
duration) for all genotypes regardless of the presence of cirrhosis, high baseline HCV
RNA level, prior treatment experience, or presence of NS5A RAV mutations. Relapse
rates of 1% or less were reported. ASTRAL-4 studied Epclusa with and without ribavirin
in 267 patients with HCV genotypes 1-6 and decompensated cirrhosis. The overall SVR
rate was 94% in patients treated for 12 weeks with Epclusa + ribavirin compared to 83%
with Epclusa alone. However, in patients with genotype 3 and decompensated cirrhosis,
SVR rates as low as 50% and 85%, were reported with Epclusa alone and with Epclusa +
ribavirin, respectively. The most common adverse effects with Epclusa were headache
and fatigue; anemia, nausea, insomnia, and diarrhea were also reported when ribavirin
was included. Ribavirin contraindications apply when taken in combination with Epclusa.
Epclusa has also been studied in HIV-coinfected patients with HCV genotypes 1 through
4 in the ASTRAL-5 trial; results have not been published.
Currently, there are several all-oral antiviral regimens, with and without ribavirin, that
provide SVR rates over 90% when treating HCV genotype 1 infection, the most common
genotype in the U.S. Sofosbuvir/velpatasvir (Epclusa) provides a single tablet oral option
without ribavirin for all genotypes, including genotypes 2 and 3. In the U.S., fewer patients
are infected with genotypes 4, 5, and 6, so the greater impact on these genotypes will be
realized globally in countries where these specific genotypes are far more prevalent.
LEADER Trial Reports Cardiovascular Outcomes of Liraglutide
Type 2 diabetes is associated with a high risk of cardiovascular (CV) complications.
Studies have confirmed that glycemic control leads to decreased risk of microvascular
complications; however, the same has not been proven regarding macrovascular risks,
such as CV disease. Recently, the New England Journal of Medicine published results
Drug Information Highlights
• In 2013, the FDA removed indications
for the treatment of fungal infections of
the skin and nails from ketoconazole oral
tablet labeling due to reports of serious
liver damage, adrenal insufficiency, and
serious drug interactions. Since that time,
1 death due to oral ketoconazole use to
treat a fungal infection of the nails has
been reported. The agency is again warning
healthcare professionals (HCPs) to avoid
prescribing ketoconazole oral tablets for this
off-label use. Oral ketoconazole should only
be used when other antifungal therapies
are either not available or not tolerated.
Topical ketoconazole formulations have not
been linked to these serious adverse effects.
Other treatment options, available overthe-counter (OTC) or with a prescription,
have their unique risks. This, coupled with
the fact that, in otherwise healthy patients,
fungal infections of the skin and nails are not
a life-threatening condition, should prompt
prescribers to consider the risks and benefits
of any antifungal agent when treating fungal
infections of the skin and nails.
• Since 2009, current labeling of OTC aspirincontaining antacids includes warnings of
bleeding risks. However, since then, the FDA
has received 8 reports of serious bleeding,
all requiring hospitalization. The FDA
continues to monitor this safety concern
and advises consumers to always read the
label before taking any OTC product and to
consider antacid products that do not contain
aspirin to relieve symptoms of heartburn,
indigestion, or upset stomach. Factors that
increase the risk for bleeding include: age
over 60 years, history of stomach ulcers
or bleeding problems, use of other blood
thinning agents, consuming 3 or more
alcoholic drinks every day, and taking an
aspirin-containing antacid at higher dosages
or durations than recommended in the label.
• The Centers for Disease Control and
Prevention (CDC) advises against the use
of FluMist® Quadrivalent (live attenuated
influenza vaccine [LAIV]) intranasal spray
during the 2016-2017 influenza season. This
stance is based on data showing that, during
the 2015-2016 flu season, the LAIV was only
3% effective against any flu virus in children
2 to 17 years of age. Data from the prior 2
seasons also showed lower than expected
results. The CDC continues to recommend
Editorial Staff
Maryam Tabatabai, PharmD Carole Kerzic, RPh
Editor in Chief
Executive Editor
1
July 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
of the highly anticipated LEADER trial, a large study evaluating the CV outcomes of the
glucagon-like peptide-1 (GLP-1) agonist, liraglutide (Victoza®; Novo Nordisk). The study
followed 9,340 patients with type 2 diabetes over a median of 3.8 years and found that
liraglutide was associated with a significant 13% relative reduction in the first occurrence
of a major coronary event (death from CV cause, nonfatal myocardial infarction [MI], or
nonfatal stroke) as compared to placebo. While the rate of death from CV or other causes
was lower with liraglutide, the rates of nonfatal MI, nonfatal stroke, and hospitalization
for heart failure (HF) were not significantly lower than reported with placebo.
The LEADER trial is the second study to assess the CV benefit and safety of an antidiabetic
agent. In November 2015, results of the EMPA-REG OUTCOME trial, which evaluated
the CV benefit and safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor,
empagliflozin (Jardiance®; Boehringer Ingelheim), as add-on to standard-of-care were
published. Empagliflozin led to a 14% reduction in the first occurrence of a major CV
event (composite of CV death, nonfatal MI, nonfatal stroke) and was deemed superior to
placebo. This reduction was almost entirely due to an impact on CV death, as it did not
reduce nonfatal MI or nonfatal stroke.
Focused Guidelines for the Treatment of Heart Failure
The American College of Cardiology (ACC) along with the American Heart Association
(AHA) and the Heart Failure Society of America (HFSA) published a focused guideline
on new pharmacologic therapy for HF, which is an update to the 2013 American College
of Cardiology Foundation (ACCF)/AHA guideline on the management of HF. The new
guidance highlights 2 new agents, valsartan/sacubitril (Entresto®) and ivabradine
(Corlanor®). Entresto is a new combination known as an angiotensin-neprilysin inhibitor
(ARNI). Specifically, an ARNI is an angiotensin receptor blocker (ARB) plus a new class of
drug, a neprilysin inhibitor; neprilysin is an enzyme that degrades vasoactive peptides
in the body.
The guidelines recommend, in select patients with chronic HF with reduced ejection
fraction (HFrEF), treatment with an angiotensin-converting enzyme inhibitor (ACEI),
ARB, or ARNI in conjunction with an evidence-based beta-blocker and an aldosterone
antagonist (Class I, Level A [ACEI, ARB] and Level B-R [ARNI] evidence). Patients with
chronic symptomatic HFrEF (NYHA class II or III) who tolerate an ACEI or an ARB should
be switched to an ARNI to further reduce morbidity and mortality (Class I, Level B-R
evidence). ARNI should not be administered concomitantly or within 36 hours of an ACEI
or in patients with a history of angioedema. Entresto is currently the only ARNI agent
on the market.
The consensus group also determined that ivabradine, a sinoatrial node modulator, may
be beneficial to reduce HF hospitalization for patients with symptomatic stable chronic
HFrEF (left ventricular ejection fraction [LVEF] ≤ 35%) who are receiving guidelinedirected care, including a beta-blocker at the maximum tolerated dose, and who are in
sinus rhythm (heart rate ≥ 70 bpm at rest) (Class IIa, Level B-R evidence).
yearly flu vaccination for everyone 6 months
and older, with either the inactivated or
recombinant vaccine injections, which
conferred an estimated 63% efficacy against
any flu virus during 2015-2016 among children
2 to 17 years of age. In recent years, FluMist,
the only non-injectable flu vaccine, accounted
for about one-third of child flu vaccinations.
The CDC is working with manufacturers to
ensure an adequate vaccine supply in the
upcoming season.
Pipeline News: Upcoming Prescription
Drug User Fee Acts (PDUFA) Dates
•July, 2016: Lyxumia®; lixisenatide; subcutaneous
(SC) GLP-1 agonist; type 2 diabetes; Sanofi/
Zealand.
•July, 2016: pegfilgrastim; biosimilar to
Neulasta®; SC colony stimulating factor;
neutropenia in cancer patients receiving
myelosuppressive chemotherapy; Sandoz.
•July, 2016: Viekira Pak™ (once daily); ombitasvir/
paritaprevir/ritonavir + dasabuvir; oral hepatitis
C antiviral; chronic hepatitis C genotype 1;
Abbvie.
•July, 2016: iDegLira; insulin degludec/liraglutide;
SC long-acting insulin and GLP-1 agonist; type 2
diabetes; Novo Nordisk.
•July 1, 2016: Syndros®; dronabinol; cannabinoid
oral spray; chemotherapy-induced nausea and
vomiting, cachexia or unexplained weight loss
due to HIV/AIDS; Insys.
•July 19, 2016: Relistor®; methylnaltrexone; oral
peripheral opioid antagonist; opioid-induced
constipation; Salix.
•July 21, 2016: Vesneo™; latanoprostene bunod;
ophthalmic prostaglandin analog; glaucoma,
ocular hypertension; Bausch + Lomb/NicOx.
•July 22, 2016: lifitegrast; ophthalmic DC11a/
DC18 antagonist; dry eye; Shire.
•August, 2016: iGlarLixi; insulin glargine/
lixisenatide; SC insulin analog/GLP-1
agonist; type 2 diabetes; Sanofi/Zealand.
•Quarter 3, 2016: immune globulin
subcutaneous (human), 20%; immunoglobulin;
primary immunodeficiency; Baxalta/Shire.
FDA Strengthens Warnings for Canagliflozin and Dapagliflozin
The FDA strengthened existing warnings for antidiabetic agents containing the SGLT2 inhibitors canagliflozin (Invokana®, Invokamet®)
or dapagliflozin (Farxiga®, Xigduo XR®) regarding the risk of acute kidney injury.
The agency received reports of 101 confirmed cases of acute kidney injury in patients treated with either canagliflozin or dapagliflozin;
some patients required hospitalization and dialysis. In approximately half of the cases, acute kidney injury occurred within 1 month
of starting therapy. Most patients improved after stopping the drug. Possible contributing factors reported in some patients were
dehydration, hypotension, or concurrent use of other medications that can affect the kidneys.
Manufacturers of canagliflozin and dapagliflozin are required to update their labels. Providers should consider factors predisposing
patients to kidney injury, such as decreased blood volume, chronic renal impairment, congestive heart failure, and concurrent
medications (diuretics, ACE inhibitors, ARBs, and NSAIDs), prior to prescribing these agents; use should be discontinued if kidney
injury occurs. Patients should seek immediate medical attention if they experience decreased urine output or swelling of the lower
extremities.
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July 2016
Whole Health Rx Corner
Provided on a quarterly basis, compliments of Magellan’s Whole Health Rx, a behavioral health center of excellence, ensuring appropriate prescribing pracces
Smartphones for Bipolar Disorder Monitoring
Bipolar disorder has a recurrent and chronic nature that results in impaired functioning
of daily life. Patients often have poor insight into their disease state which further
complicates the ability to recognize changing moods and other symptoms, increasing
the risk and rate of relapses.
A German pilot study hypothesized that improved availability of daily patient data to
patients and their prescribers via a smartphone would provide for earlier intervention
during bipolar relapse. Smartphones have been suggested as a low cost device that may
be able to measure patient information on a daily basis; most patients already use these
devices on a daily basis, they are easy to use, and most have built-in sensor capabilities
(e.g., global positioning system [GPS]).
Safety of Varenicline and Bupropion
The smoking cessation agents, varenicline
(Chantix®) and bupropion sustained-release
(Zyban®), carry boxed warnings of increased risk
for neuropsychiatric adverse effects (agitation,
hostility, depressed mood, changes in behavior).
Bupropion also carries a boxed warning of
suicidal thinking and behavior in children,
adolescents, and young adults. However, a
study published in The Lancet that included
8,144 smokers, half of which had a psychiatric
disorder that was either stable or in remission,
suggests otherwise. The study randomized
subjects to varenicline, bupropion, nicotine
patch, or placebo and found that the incidence
of moderate to severe neuropsychiatric
events was similar for all groups, except
varenicline, which was associated with a
lower risk compared to placebo (1.3% versus
2.4%) in the non-psychiatric cohort only. In
addition, varenicline was favored in achieving
abstinence from smoking compared to other
agents. This study was funded by Pfizer and
GlaxoSmithKline, manufacturers of Chantix and
Zyban, respectively.
The investigators aimed to determine if smartphone data can predict impending clinical
symptoms in bipolar disorder. Adults with bipolar I or bipolar II disorder, according to
DSM-IV criteria, and with basic skills using a smartphone, were recruited from an
outpatient psychiatric department. Thirteen participants were given a smartphone with
a pre-installed application, or app, for the 12-month study period. The phone had an
unlimited call, text, and data plan and patients were encouraged to use it as their primary
mobile device. The app, Social Information Monitoring for Patients with Bipolar Affective
Disorder (SIMBA), is able to record data through questionnaires and GPS sensors. Patients
self-reported mood (affect and energy level) once a day through a random time 2-item
questionnaire that notified them via a beep. Patients met every 8 weeks with the treating
clinician who completed assessments of manic and depressive symptoms using clinical rating scales (e.g., Young Mania Rating Scale [YMRS]
and Hamilton Depression Scale [HAM-D]); the treating clinicians were blinded to the smartphone data.
The results suggested that overall symptom changes were related to smartphone measures. Lower self-reported mood measured by
the smartphone app, a decrease in social communication (e.g., outgoing calls or texts), and a decline in physical activity (measured by
cell tower movement or distance traveled) predicted higher overall levels of clinical depressive symptoms. Likewise, decreased physical
activity and increased social communication predicted higher overall levels of clinical manic symptoms. However, self-reported mood
did not predict manic symptoms. While the authors hypothesized that physical activity would increase prior to or during clinical mania,
the results suggest that activity decreased with both clinical depression and mania.
This study had several limitations: small sample size, self-reported data, and low compliance rates (55.7%). Smartphones may have the
potential to monitor symptoms for bipolar patients, but larger studies are needed to confirm their benefit.
New Guidance on the Management of Chronic Insomnia
Approximately 6-10% of adults suffer from insomnia, particularly women and older adults. Treatments include psychological and
pharmacological therapies, or a combination of both. Medications approved by the FDA for the treatment of insomnia include:
benzodiazepine hypnotics; nonbenzodiazepine hypnotics (zaleplon, zolpidem, and eszopiclone); the orexin receptor antagonist,
suvorexant (Belsomra®); the melatonin receptor agonist, ramelteon (Rozerem®); and the antidepressant doxepin. Select antidepressants,
antihistamines, antipsychotics, and melatonin have also been used for the treatment of insomnia.
The American College of Physicians (ACP) recently developed a guideline for the treatment of adults with chronic insomnia. ACP
recommends nonpharmacologic therapy, specifically cognitive behavioral therapy (CBT), as initial therapy for all patients. CBT for
insomnia consists of a combination of education and treatments targeting behaviors, such as sleep restriction to improve sleep
efficiency, stimulus control to establish consistency, and sleep hygiene. For those in whom CBT alone did not provide adequate relief,
clinicians and patients should decide if pharmacologic therapy is appropriate only after a full discussion of the risks, benefits, and
costs of short-term drug therapy. Potential benefits of pharmacologic treatment include improved sleep outcomes (e.g., sleep onset
latency, total sleep). ACP’s review found that evidence is insufficient to evaluate the balance of the benefits and harms of long-term
use of pharmacologic treatments in adults with chronic insomnia disorder. However, most studies evaluated by ACP focused on newer
medications; there is a paucity of data with older and off-label medications.
Another notable finding from ACP’s literature evaluation is that serious adverse effects, such as dementia and fractures, may be
associated with hypnotic drugs. Product labels of hypnotics warn about cognitive and behavioral changes, such as possible driving
impairment and motor vehicle accidents. The FDA also recommends short-term use and lower doses of hypnotics in older or debilitated
adults who may be more susceptible to adverse effects. Ultimately, while short-term pharmacologic therapy may be appropriate for
some individuals, the skills learned through CBT can manage insomnia over the longer term.
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July 2016
Recent FDA Approvals
Generic
Name
Trade
Name
buprenorphine
FDA
Status
Description
Applicant
Probuphine®
A buprenorphine implant (Probuphine), was FDA-approved for the
maintenance treatment of opioid dependence in patients who have
achieved and sustained prolonged clinical stability on low-to-moderate
doses (≤ 8mg/day) of a transmucosal buprenorphine-containing product.
It is not recommended for use in new patients who have not established
prolonged clinical stability. It is only available through a Risk Evaluation
and Mitagation Strategies (REMS) program due to risks associated with
removal and insertion of the implant. Four rod-shaped implants are inserted
subdermally by a HCP in the upper arm to remain in place for 6 months.
There are no data on the use of this implant beyond 1 dose in each arm.
Each implant contains 74.2 mg of buprenorphine (80mg buprenorphine HCl)
for a total of 296.8 mg per dose. It is a scheduled III controlled drug.
Titan
FDA NDA
priority
approval
05/26/2016
daclizumab
Zinbryta™
An interleukin-2 receptor blocking antibody, daclizumab (Zinbryta), has
received approval for the treatment of relapsing forms of multiple sclerosis
(MS). It carries a boxed warning for the potential risk of severe hepatic
injury including autoimmune hepatitis and other immune mediated
disorders. The use of daclizumab should be reserved for patients with
inadequate response to 2 or more MS medications. It will be available
though the restricted distribution Zinbryta REMS program. Daclizumab is
a long-acting subcutaneous injection self-administered at a recommended
dose of 150 mg once monthly. The injection is approved as a 150 mg/mL
solution in a single-dose prefilled syringe.
Biogen
FDA BLA
approval
05/27/2016
linagliptin/
metformin
Jentadueto
XR®
Jentadueto XR, a fixed-dose combination of the dipeptidyl peptidase 4
inhibitor, linagliptin, with metformin extended-release (ER), has been approved
in a once daily formulation. It is indicated as adjunct to diet and exercise
to improve glycemic control in patients with type 2 diabetes. It carries a
boxed warning for the potential risk for lactic acidosis, due to the metformin
component. Jentadueto XR is dosed once a day based on the patient’s current
regimen, but not to exceed a total daily dose of linagliptin 5 mg and metformin
2,000 mg. It is approved as tablets containing 2.5 mg linagliptin/1,000 mg
metformin ER and 5 mg linagliptin/1,000 mg metformin ER.
Boehringer
Ingelheim
FDA NDA
approval
05/27/2016
obeticholic acid
Ocaliva™
The FDA granted accelerated approval and breakthrough therapy
designation for the first in class farnesoid X receptor agonist, obeticholic
acid (Ocaliva). It is indicated for the treatment of primary biliary cholangitis
(PBC) in adults with inadequate response to ursodeoxycholic acid (UDCA), to
be used in combination with UDCA, or as monotherapy in those intolerant
to UDCA. PBC is a rare autoimmune cholestatic liver disease. Obeticholic
acid received accelerated approval based on the reduction in alkaline
phosphate (ALP). It will be available through a specialty pharmacy network.
Approved as 5 mg and 10 mg oral tablets, the starting dose is
5 mg daily and may be increased to a maximum of 10 mg daily if there is
inadequate reduction in ALP and/or total bilirubin after 3 months of therapy.
It is contraindicated in patients with complete biliary obstruction.
Intercept
FDA NDA
priority
approval
05/27/2016
nebivolol/
valsartan
Byvalson™
A fixed-dose combination of nebivolol, a beta adrenergic blocker, and
valsartan, an angiotensin II receptor blocker (ARB), has been approved for
the treatment of hypertension. It carries a boxed warning regarding use in
pregnant patients which may cause fetal harm. The recommended dose is
5 mg nebivolol and 80 mg valsartan once daily. It is contraindicated in patients
with severe bradycardia, heart block greater than first degree, cardiogenic
shock, decompensated cardiac failure, sick sinus syndrome (unless a
permanent pacemaker is in place), or severe hepatic impairment, and patients
who are hypersensitive to any component of the product. In patients with
diabetes, it should not be co-administered with aliskiren. Byvalson is approved
as an oral tablet containing 5mg nebivolol and 80 mg valsartan.
Actavis/
Forest
FDA NDA
approval
06/03/2016
ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; sNDA = Supplemental New Drug Application
References
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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July 2016
www.fda.gov www.hfsa.org www.thelancet.com www.nejm.org
www.ncbi.nlm.nih.gov
www.regulations.gov