1. health and fitness
2. therapy

CPE
New therapeutic agents
marketed in 2014: Part 3
Daniel A. Hussar
Daniel A. Hussar, PhD, Remington Professor
of Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia
Abstract
Objective: To provide information about the most important properties of new
therapeutic agents marketed in 2014.
Data sources: Product labeling supplemented selectively with published studies and drug information reference sources.
Data synthesis: This third part of a four-part series considers 11 new therapeutic agents marketed in the United States in 2014: dulaglutide, olodaterol hydrochloride, peginterferon beta-1a, netupitant/palonosetron hydrochloride, ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir and dasabuvir sodium
monohydrate, peramivir, ceftolozane sulfate/tazobactam sodium, luliconazole,
efinaconazole, and tavaborole. Indications and information on dosage and administration for these agents are reviewed, as are the most important pharmacokinetic
properties, drug interactions and other precautions, and practical considerations.
When possible, the properties of the new drugs are compared with those of older
agents marketed for the same indications.
Conclusion: Dulaglutide is the fourth glucagon-like peptide-1 receptor agonist
for type 2 diabetes. Olodaterol is a long-acting beta-2-adrenergic agonist. Peginterferon beta-1a treats relapsing forms of multiple sclerosis and is administered less
frequently than formulations of interferon beta-1a. Netupitant/palonosetron treats
nausea and vomiting with initial and repeat courses of cancer chemotherapy. Ledipasvir/sofosbuvir is the first regimen for chronic hepatitis C virus (HCV) genotype 1 infection that does not require use with either interferon or ribavirin and
that can be used for only 8 weeks in some patients. Ombitasvir/paritaprevir/ritonavir with dasabuvir, an all-oral regimen, treats chronic HCV infection. Peramivir,
the third neuraminidase inhibitor for influenza, is administered as a single dose
by I.V. Ceftolozane/tazobactam treats complicated intra-abdominal and urinary
tract infections by I.V. Ceftolozane is a cephalosporin antibiotic, and tazobactam is
a beta-lactamase inhibitor. Luliconazole, a topically applied imidazole antifungal
agent, targets tinea pedis, tinea cruris, and tinea corporis. Efinaconazole and tavaborole are topically applied antifungal agents for onychomycosis of the toenails.
Pharm Today. 2015;21(4);76–87
Accreditation information
Provider: American Pharmacists Association
Target audience: Pharmacists
Release date: April 1, 2015
Expiration date: April 1, 2018
Learning level: 1
ACPE number: 0202-0000-15-141-H01-P
CPE credit: 2 hours (0.2 CEUs)
Fee: There is no fee associated with this activity
for members of the American Pharmacists Association. There is a $25 fee for nonmembers.
The American Pharmacists Association is accredited by the Accreditation Council
for Pharmacy Education as a provider of continuing pharmacy education (CPE). The
ACPE Universal Activity Number assigned to this activity by the accredited provider
is 0202-0000-15-141-H01-P.
Disclosures: Daniel A. Hussar, PhD, and APhA’s editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants,
employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see
the APhA Accreditation Information section at www.pharmacist.com/education.
Development: This home-study CPE activity was developed by the American Pharmacists
Association.
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Correspondence: Daniel A. Hussar, Remington Professor of Pharmacy, Philadelphia
College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, PA 19104;
[email protected]
Disclosure: The author declares no conflicts
of interest or financial interests in any product
or service mentioned in this article.
Learning objectives
At the conclusion of this knowledgebased activity, the pharmacist will be
able to
■■ Identify the new therapeutic agents and
explain their appropriate use.
■■ Identify the indications, most important
adverse events, and other risks of each
of the new therapeutic agents.
■■ S tate the route of administration for
each new drug and the important
considerations regarding dosage and
administration.
■■ Demonstrate appropriate counseling
about use of the new medications and
precautions to observe.
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NEW THERAPEUTIC AGENTS MARKETED IN 2014: PART 3
Preassessment questions
Before participating in this activity, test your knowledge by answering
the following questions. These questions will also be part of the CPE
assessment.
1. Which of the following agents is administered subcutaneously?
a.Dulaglutide
b.Peramivir
c.Ceftolozane
d.Netupitant
2. With the use of which of the following agents do approximately one-half of patients experience influenza-like symptoms as
adverse events?
a.Ombitasvir
b.Netupitant
c. Peginterferon beta-1a
d.Dulaglutide
3. Which of the following statements is correct regarding ledipasvir/sofosbuvir?
a. It is the first regimen demonstrated to be effective for the
treatment of all genotypes of chronic HCV infection.
b. It is the first regimen demonstrated to be effective in a
4-week course of treatment for some patients with chronic
HCV infection.
c. It is the first regimen demonstrated to be effective for the
treatment of HCV infection that does not require administration with either interferon or ribavirin.
d. In patients with chronic HCV genotype 1 infection, treatment should be continued for at least 24 weeks.
Objectives
This third part of a four-part series considers 11 new therapeutic agents marketed in the United States in 2014: dulaglutide, olodaterol hydrochloride, peginterferon beta-1a, netupitant/palonosetron hydrochloride, ledipasvir/sofosbuvir,
ombitasvir/paritaprevir/ritonavir and dasabuvir sodium
monohydrate, peramivir, ceftolozane sulfate/tazobactam
sodium, luliconazole, efinaconazole, and tavaborole (Table
1). Indications and information on dosage and administration for these agents are reviewed, as are the most important
pharmacokinetic properties, drug interactions, and other
precautions. Practical considerations for use of these new
agents are also discussed. When possible, the properties of
the new drugs are compared with those of older agents marketed for the same indications.
Antidiabetic agent
Dulaglutide (Trulicity—Eli Lilly) is the fourth glucagon-like
peptide-1 (GLP-1) receptor agonist approved in the United
States, joining exenatide (Byetta), extended-release exenatide
(Bydureon), liraglutide (Victoza), and albiglutide (Tanzeum).
These agents augment glucose-dependent insulin secretion,
decrease glucagon secretion, and slow gastric emptying, resulting in lower fasting glucose and reduced postprandial
glucose excursions in patients with type 2 diabetes.
Dulaglutide is a fusion protein that consists of two identical, disulfide-linked chains, each containing an N-terminal
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GLP-1 analog sequence covalently linked to the Fc portion
of a modified human immunoglobulin G4 heavy chain. The
GLP-1 analog portion of dulaglutide is 90% homologous to
endogenous human GLP-1. Structural modifications have
been made to the GLP-1 part of the molecule to confer resistance to dipeptidyl peptidase 4 (DPP-4)–mediated proteolysis.
GLP-1 agonists are administered subcutaneously. Like
extended-release exenatide and albiglutide, dulaglutide is
administered once a week. Liraglutide is administered once
a day, and the Byetta formulation of exenatide is administered twice a day. The specific indication for dulaglutide is
the same as for the other agents in this class: it is used as an
adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes.
Effectiveness of dulaglutide was demonstrated in six
clinical trials that included more than 3,300 patients with
type 2 diabetes. It has been studied as a stand-alone therapy
as well as in combination with other antidiabetic agents,
including metformin, a sulfonylurea (e.g., glimepiride), a
thiazolidinedione (e.g., pioglitazone), and prandial (mealtime) insulin (e.g., insulin lispro), but not in combination
with basal insulin. Use of dulaglutide resulted in a lowering of glycosylated hemoglobin (A1C) concentrations and
improvement in blood glucose control. In studies in which
dulaglutide was compared with sitagliptin (Januvia) and
twice-a-day exenatide, the new drug provided greater reductions in A1C and fasting plasma glucose concentrations
than the latter agents.
As with the other GLP-1 agonists, dulaglutide is not recommended as first-line therapy for patients whose diabetes
is inadequately controlled with diet and exercise. Metformin
is the usual initial treatment of choice in patients with type
2 diabetes who do not have risk factors that would preclude
use of this agent. Many patients with diabetes, however, do
not experience adequate glycemic control with use of metformin alone, and a GLP-1 agonist is among the options available for addition to the regimen.
The limitations of use, warnings, and other risks associated with dulaglutide are generally similar to those for the
other GLP-1 agonists. It is not indicated for the treatment of
patients with type 1 diabetes or patients with diabetic ketoacidosis. Dulaglutide has not been studied in patients with
severe gastrointestinal disease, including severe gastroparesis, and its use is not recommended in patients with preexisting severe problems of this type. Acute pancreatitis has been
infrequently experienced with use of the GLP-1 agonists, including dulaglutide, and treatment should be promptly discontinued if pancreatitis is suspected. Dulaglutide was not
studied in patients with a history of pancreatitis, and other
antidiabetic agents should be considered for use in patients
with such a history.
Two risks associated with dulaglutide therapy are included in a boxed warning. There have been reports of thyroid C-cell tumors, including medullary thyroid carcinoma
(MTC), in studies of GLP-1 agonists in rodents. Although it is
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NEW THERAPEUTIC AGENTS MARKETED IN 2014: PART 3
Table 1. New therapeutic agents marketed in the United States in 2014: Part 3a
Generic name
Ceftolozane sulfate/tazobactam
sodium
Dulaglutide
Efinaconazole
Ledipasvir/sofosbuvir
Luliconazole
Netupitant/palonosetron
hydrochloride
Trade name
Manufacturer
Therapeutic
classification
Route of
administration
FDA
classificationb
Zerbaxa
Trulicity
Jublia
Harvoni
Luzu
Cubist
Eli Lilly
Valeant
Gilead Sciences
Valeant
Antibacterial
Antidiabetic
Antifungal
Antiviral
Antifungal
I.V.
Subcutaneous
Topical
Oral
Topical
1,4-P
1-S
1-S
1,4-P
1-S
Akynzeo
Antiemetic
Oral
1,4-S
Olodaterol hydrochloride
Ombitasvir/paritaprevir/
ritonavir; dasabuvir sodium
monohydrate
Striverdi Respimat
Eisai
Boehringer
Ingelheim
Bronchodilator
Oral inhalation
1-S
Viekira Pak
AbbVie
Oral
1,4-P
Peginterferon beta-1a
Peramivir
Tavaborole
Plegridy
Rapivab
Kerydin
Biogen Idec
BioCryst
PharmaDerm
Antiviral
Multiple
sclerosis agent
Antiviral
Antifungal
Subcutaneous
I.V.
Topical
1-S
1-S
1-S
a
Additional agents marketed during 2014 are considered in part 1 (see pages 68–79 in the October 2014 Pharmacy Today), part 2 (see pages 69–80 in the
November 2014 Pharmacy Today), and a subsequent part of this series.
b
FDA classification of new drugs: 1 = new molecular entity; 4 = combination product; P = priority review; S = standard review.
not known whether dulaglutide causes these tumors in humans, its use is contraindicated in patients with a personal or
family history of MTC or in patients with multiple endocrine
neoplasia syndrome type 2. Adverse events most often reported (and their incidence with doses of 0.75 mg and 1.5 mg
once a week, respectively) in clinical studies of dulaglutide
include nausea (12%; 21%), diarrhea (9%; 13%), vomiting (6%;
13%), abdominal pain (7%; 9%), and decreased appetite (5%;
9%). Severe hypersensitivity reactions have been infrequently experienced; treatment should be discontinued if such a
reaction occurs.
Many patients with diabetes are overweight. Some antidiabetic agents, such as insulin and the sulfonylureas,
have been associated with weight gain during treatment.
Conversely, many patients treated with a GLP-1 agonist experience weight loss. Although dulaglutide and albiglutide
have not been directly compared in clinical studies, the data
from studies in which the two drugs were evaluated on an
individual basis suggest that use of dulaglutide is associated
with a greater loss of weight.
Dulaglutide is classified in Pregnancy Category C and
should be used during pregnancy only if the anticipated
benefit justifies the risk to the fetus. Because it is not known
whether the drug is excreted in human milk, a decision
should be made whether to discontinue breastfeeding or not
use the drug. Effectiveness and safety of dulaglutide in patients younger than 18 years have not been established.
Dulaglutide and the other GLP-1 agonists are not likely to
cause hypoglycemia. However, there is an increased risk of
this response if it is used in combination with insulin or an
insulin secretagogue (e.g., a sulfonylurea), and a reduction in
the dosage of the latter agents may be necessary.
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Because dulaglutide slows gastric emptying, a potential
exists for alteration of the absorption and activity of concomitantly administered oral medications. Although clinically important changes of this type were not identified in
several studies, caution should be exercised when oral medications are used concurrently, particularly if their absorption is incomplete and/or not highly predictable when they
are used alone.
Following subcutaneous administration, the mean absolute bioavailability of dulaglutide is 65% and 47% with
single doses of 0.75 mg and 1.5 mg, respectively. The time to
maximum plasma concentration at steady state ranges from
24 to 72 hours. The drug is thought to be metabolized into
its component amino acids by general protein catabolic pathways. Dosage adjustment is not necessary in patients with
hepatic or renal impairment. However, the frequency of gastrointestinal adverse events (e.g., vomiting, diarrhea, dehydration) may be associated with a decline in renal function,
and caution should be exercised when initiating treatment or
increasing the dosage of dulaglutide in patients with renal
impairment.
Dulaglutide is administered by subcutaneous injection
in the abdomen, thigh, or upper arm. The recommended
initial dosage is 0.75 mg once a week; the dosage may be increased to 1.5 mg once a week for additional glycemic control. The maximum recommended dosage is 1.5 mg once a
week. If a dose is missed, the patient should administer it
as soon as possible if there are at least 3 days (72 h) until the
next scheduled dose. If fewer than 3 days remain before the
next scheduled dose, the missed dose should be skipped and
the next dose administered on the regularly scheduled day.
Dulaglutide injection is supplied in 0.75-mg and 1.5-mg
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NEW THERAPEUTIC AGENTS MARKETED IN 2014: PART 3
doses in single-dose pens and single-dose prefilled syringes.
The formulations should be stored in a refrigerator, although
a syringe or pen can be kept at room temperature for a period
that should not exceed 14 days. The formulations of dulaglutide and liraglutide, as well as the twice-daily formulations
of exenatide, are premixed and ready for administration,
whereas albiglutide and extended-release formulations of
exenatide require reconstitution before administration.
Bronchodilator
Olodaterol hydrochloride (Striverdi Respimat—Boehringer
Ingelheim) is a long-acting beta-2-adrenergic agonist (LABA)
that is administered by oral inhalation to provide a bronchodilating action. Its properties are most similar to those of the
other LABAs, salmeterol (Serevent), formoterol (Foradil; Perforomist), arformoterol (Brovana), indacaterol (Arcapta), and
vilanterol (available in the combination formulations Breo
Ellipta and Anoro Ellipta with fluticasone and umeclidinium, respectively).
Olodaterol is indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD),
including chronic bronchitis and/or emphysema. Its effectiveness was demonstrated in studies of more than 3,000
patients with a diagnosis of COPD. Patients treated with olodaterol showed improved lung function (e.g., improvements
in forced expiratory volume in 1 s [FEV1­]), compared with
those receiving placebo. In addition, patients treated with
olodaterol used less rescue albuterol compared with patients
receiving placebo.
Although the LABAs provide a long duration of clinical
benefit that permits once-daily administration of olodaterol,
indacaterol, and vilanterol, they have a slow onset of action
compared with the inhaled short-acting beta-2-adrenergic
agonists such as albuterol. Treatment with olodaterol should
not be initiated in patients with acutely deteriorating COPD,
and it should not be used for the relief of acute symptoms
(i.e., as rescue therapy for the treatment of acute episodes
of bronchospasm), for which an inhaled short-acting beta-2
agonist should be used.
LABAs have been reported to increase the risk of asthmarelated death, and as with other LABAs, the olodaterol labeling includes a boxed warning. The new drug is not indicated
for the treatment of asthma. Although salmeterol and formoterol both have a labeled indication for treatment of asthma and prevention of bronchospasm, they should be used
as additional therapy only for patients with asthma that is
not adequately treated with other asthma-controller medications (e.g., an inhaled corticosteroid) or whose disease severity warrants treatment with two maintenance therapies. All
LABAs are contraindicated in patients with asthma without
the use of a long-term asthma control medication. Salmeterol
and formoterol are also indicated for the prevention of exercise-induced bronchospasm. However, this is not a labeled
indication for olodaterol, indacaterol, or vilanterol.
Adverse events most commonly experienced in the
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clinical studies of olodaterol include nasopharyngitis (11%),
upper respiratory tract infection (8%), bronchitis (5%), and
cough (4%). Like other beta-2 agonists, olodaterol may cause
clinically relevant cardiovascular effects, including increases
in pulse rate and blood pressure and prolongation of the QT
interval. Therefore, it must be used with caution in patients
with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Because beta2 agonists may also increase the possibility of exacerbations
of conditions such as seizure disorders, diabetes, and thyrotoxicosis, olodaterol must be used with caution in patients
with these disorders. The beta-2 agonists may also cause
hypokalemia, although the reduction in serum potassium
concentrations is usually transient and supplementation is
not required.
Like the other beta-2 agonists, olodaterol may cause
paradoxical bronchospasm that may be life-threatening, and
some patients have experienced immediate hypersensitivity reactions, including angioedema. If a patient experiences
such a response, treatment should be immediately discontinued.
Olodaterol is classified in Pregnancy Category C and
should be used during pregnancy only if the anticipated
benefit justifies the risk to the fetus. Its effectiveness and
safety in pediatric patients have not been established.
Olodaterol should not be used concurrently with another
LABA, as an overdose may result, and it must be used with
caution in patients who are being treated with another adrenergic agent (by any route of administration) because the
sympathomimetic effects of the agents may be potentiated.
Conversely, the concomitant use of a beta-adrenergic blocking agent (e.g., metoprolol) may reduce the effects of both
drugs. Because beta blockers may cause bronchospasm, their
use should generally be avoided in patients with COPD.
Extreme caution must be observed if olodaterol is used
concurrently with a monoamine oxidase inhibitor, tricyclic
antidepressant, or another drug that prolongs the QT interval because of the risk of a potentiated action on the cardiovascular system. Xanthine derivatives, steroids, diuretics, or
nonpotassium–sparing diuretics may potentiate hypokalemia or electrocardiographic changes, and caution must be
exercised when they are used concomitantly with olodaterol.
Following oral inhalation, peak serum concentrations
of olodaterol are generally attained within 10 to 20 minutes,
and its absolute bioavailability is approximately 30%. Systemic availability of the drug is determined mainly by lung
absorption. Olodaterol is extensively metabolized by direct
glucuronidation and by O-demethylation at the methoxy
moiety followed by conjugation. However, none of the metabolites appears to contribute to the pharmacologic action of
the drug. Approximately 38% of the drug is recovered in the
urine and 53% in the feces. Dosage adjustment is not necessary in patients with renal or hepatic impairment, although
the action of the drug has not been evaluated in patients with
severe hepatic impairment. Concurrent use of ketoconazole
increases the concentration and exposure to olodaterol, but
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NEW THERAPEUTIC AGENTS MARKETED IN 2014: PART 3
an adjustment in dosage is not considered necessary.
Olodaterol hydrochloride is supplied as an aqueous solution in an aluminum cylinder (cartridge) for use with the
Striverdi Respimat inhaler as an oral inhalation spray. Each
actuation from the mouthpiece contains 2.7 mcg of olodaterol
hydrochloride, which is equivalent to 2.5 mcg of olodaterol.
The recommended dosage is 5 mcg (two actuations) once a
day at the same time of day.
When the unit for inhalation is used for the first time,
the cartridge containing the medication is inserted into the
inhaler and the unit is primed. Patients should actuate the
unit toward the ground until an aerosol cloud is visible and
repeat the process three times. The unit is then primed and
ready for use. If the unit is not used for more than 3 days,
patients should actuate the inhaler once to prepare it for use.
If it is not used for more than 21 days, patients should actuate
the inhaler until an aerosol cloud is visible and repeat the
process three times.
Salmeterol and formoterol are also available in combination with an inhaled corticosteroid in formulations (i.e.,
salmeterol/fluticasone propionate [Advair], formoterol/
budesonide [Symbicort]) for oral inhalation that are administered twice a day. Vilanterol is available in combination with
fluticasone propionate (Breo Ellipta) and the muscarinic antagonist umeclidinium (Anoro Ellipta) in formulations for
oral inhalation that are administered once a day. However,
olodaterol is not available in combination formulations at the
present time.
Multiple sclerosis agent
For many years, the options available for the treatment of patients with multiple sclerosis were limited to interferon beta1b (e.g., Betaseron), interferon beta-1a (Avonex; Rebif), and
glatiramer acetate (Copaxone). With the exception of Avonex,
which is administered intramuscularly, these products are
administered by subcutaneous injection. Within the last 5
years, the number of therapeutic agents approved for the
treatment of patients with multiple sclerosis has more than
doubled. Fingolimod (Gilenya), teriflunomide (Aubagio), and
dimethyl fumarate (Tecfidera) have an important advantage
over their predecessors because they are effective following
oral administration. Several other agents are administered
intravenously in the treatment of selected patients with multiple sclerosis, including natalizumab (Tysabri), mitoxantrone (Novantrone), and alemtuzumab (Lemtrada).
The amino acid sequence of the recombinant interferon
beta-1a is identical to that of the human interferon beta counterpart and the same as that of Avonex and Rebif. Peginterferon beta-1a (Plegridy—Biogen Idec) is formed by the attachment of a polyethylene glycol (PEG) chain that increases
the mass of the agent and reduces its clearance, thereby increasing its duration of action and permitting administration
just every 14 days.
Peginterferon beta-1a, administered subcutaneously, is
indicated for the treatment of patients with relapsing forms
of multiple sclerosis. Its labeled indication is more limited
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than the indications for comparable products that also include decreasing the frequency of clinical exacerbations and
delaying the accumulation of physical disability.
Effectiveness of peginterferon beta-1a was demonstrated
in a placebo-controlled study in which the primary outcome
was the annualized relapse rate over 1 year. The annualized
relapse rate in patients treated with the new drug was 0.26,
compared with 0.4 of those receiving placebo, representing a
relative reduction of 36%. Brain magnetic resonance imaging
evaluations also demonstrated a reduction in new or newly
enlarging lesions. The new drug has not been directly compared with other agents in clinical studies.
Most patients treated with an interferon product experience adverse events. The most commonly reported adverse
events in the clinical trials of peginterferon beta-1a include
injection site erythema (62%), injection site pain (15%), injection site pruritus (13%), influenza-like illness (47%), pyrexia
(45%), headache (44%), myalgia (19%), chills (17%), asthenia
(13%), and arthralgia (11%). Serious allergic reactions including anaphylaxis have occurred rarely as a complication of
treatment with an interferon, and peginterferon beta-1a is
contraindicated in patients with a history of hypersensitivity
to interferon beta, peginterferon, or any other component of
the formulation.
Other risks associated with use of peginterferon beta-1a
include hepatic adverse events (liver function tests should be
monitored), depression and suicide (any symptom of depression or suicidal ideation should be immediately reported),
seizures, congestive heart failure, and autoimmune disorders
(if a patient develops a new autoimmune disorder, discontinuation of treatment should be considered). Reductions of
peripheral blood counts have occurred, and complete blood
cell counts, differential white blood cell counts, and platelet
counts should be monitored during treatment.
Peginterferon beta-1a is classified in Pregnancy Category C and should be used during pregnancy only if the anticipated benefit justifies the risk to the fetus. It is not known
if the drug is excreted in human milk, so caution should be
exercised if it is administered to a woman who is breastfeeding. Effectiveness and safety of peginterferon beta-1a in pediatric patients have not been established.
The longer duration of action and less frequent administration (every 14 days) of peginterferon beta-1a provide advantages over other formulations containing interferon beta1a. The Avonex formulation is administered intramuscularly
once a week, and the Rebif formulation is administered subcutaneously three times a week.
Peginterferon beta-1a is administered subcutaneously
every 14 days in the abdomen, back of the upper arm, or
thigh, with the sites rotated. Prophylactic and concurrent use
of an analgesic and/or antipyretic may prevent or ameliorate
influenza-like symptoms. An initial dose of 63 mcg is administered on day 1, a dose of 94 mcg on day 15 (14 days later),
and the full dose of 125 mcg on day 29. A dose of 125 mcg is
administered every 14 days thereafter.
Peginterferon beta-1a is supplied in single-dose prefilled
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NEW THERAPEUTIC AGENTS MARKETED IN 2014: PART 3
pens and syringes containing 125 mcg of the drug in 0.5 mL.
Starter packs are also supplied with pens and syringes containing 63 mcg and 94 mcg. The products should be stored
in a refrigerator.
Antiemetic agent
Many of the antineoplastic agents included in cancer chemotherapy regimens are associated with the occurrence of nausea and vomiting, and antinauseant/antiemetic agents are
used to prevent and reduce the likelihood of these events.
The serotonin-3 (5-HT3) receptor antagonists ondansetron
(e.g., Zofran), granisetron (e.g., Kytril), dolasetron (Anzemet),
and palonosetron (Aloxi), as well as the substance P/neurokinin-1 (NK1) receptor antagonist aprepitant (Emend), have
often been included in antiemetic regimens. The serotonin-3
receptor antagonists prevent nausea and vomiting during the
acute phase after cancer chemotherapy, and the substance P/
NK1 receptor antagonist prevents nausea and vomiting during both the acute and delayed phases.
Netupitant/palonosetron hydrochloride (Akynzeo—Eisai) is a fixed combination of the new substance P/NK1 receptor antagonist netupitant with palonosetron, an agent
initially marketed in 2003. The new product is indicated for
the prevention of acute and delayed nausea and vomiting
associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy (including cisplatin-based chemotherapy).
Effectiveness of a netupitant/palonosetron plus dexamethasone regimen was evaluated in two clinical studies
comparing the agent with palonosetron plus dexamethasone. Results of the first study showed that 99%, 90%, and
90% of the patients treated with netupitant/palonosetron
plus dexamethasone regimen did not experience any vomiting or require rescue medication for nausea during the acute,
delayed, and overall phases, respectively. For patients receiving palonosetron plus dexamethasone, the corresponding
results were 90%, 80%, and 77%, respectively. Results of the
second clinical study were generally similar.
Adverse events experienced most often in the clinical
studies of netupitant/palonosetron included headache (8%),
asthenia (8%), dyspepsia (4%), fatigue (4%), constipation (3%),
and erythema (3%). Hypersensitivity reactions and serotonin
syndrome have occurred infrequently with use of palonosetron and other serotonin-3 receptor antagonists, with a higher risk of serotonin syndrome in patients also being treated
with serotonergic agents (e.g., selective serotonin reuptake
inhibitors).
Netupitant/palonosetron is classified in Pregnancy Category C and should be used during pregnancy only if the
anticipated benefit justifies the risk to the fetus. Because it is
not known whether the drugs are present in human milk, a
decision should be made whether to discontinue breastfeeding or not use the drug. Effectiveness and safety of netupitant/palonosetron in patients younger than 18 years of age
have not been established.
Netupitant is metabolized primarily via the CYP3A4
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pathway, and concurrent use with a strong cytochrome P450
(CYP) 3A4 inducer (e.g., rifampin) may reduce its concentration and action and should be avoided. Netupitant is a
moderate inhibitor of CYP3A4 and may increase the action
of a CYP3A4 substrate (e.g., dexamethasone, midazolam, alprazolam) that is administered concurrently. The CYP3A4
inhibitory effect can last for multiple days, and a twofold
increase in the systemic exposure of dexamethasone was observed 4 days after a single dose of netupitant. Accordingly,
a reduced dosage of dexamethasone is recommended in patients receiving netupitant/palonosetron.
Although netupitant/palonosetron may be used without dosage adjustment in patients with mild to moderate
hepatic impairment or mild to moderate renal impairment,
experience is very limited in patients with severe hepatic
impairment and in patients with severe renal impairment or
end-stage renal disease, and use in these patients should be
avoided.
Each capsule contains netupitant 300 mg and palonosetron 0.5 mg and may be administered with or without food.
In patients receiving highly emetogenic chemotherapy, including cisplatin-based chemotherapy, one capsule (300
mg/0.5 mg) should be administered approximately 1 hour
before the start of chemotherapy, with dexamethasone 12 mg
administered orally 30 minutes before chemotherapy on day
1 and 8 mg orally once daily on days 2 and 4. For patients
receiving anthracyclines and cyclophosphamide-based chemotherapy and chemotherapy that is not considered highly
emetogenic, the same regimen is recommended, but administration of dexamethasone on days 2 and 4 is not necessary.
Antiviral agents
An estimated 3.2 million Americans have chronic hepatitis C
virus (HCV) infection. Although many of these individuals
are asymptomatic and unlikely to experience serious consequences, many others experience complications such as
cirrhosis of the liver or even hepatic cancer and a need for
transplantation.
Until 2011, the standard treatment for patients with
chronic HCV infection was a regimen of peginterferon alfa
(administered by injection) and ribavirin for a period of 48
weeks. However, most patients experienced adverse events
with these medications, and the success rate in achieving a
cure (sustained virologic response [SVR], virus no longer detected in the blood at least 12 weeks after finishing treatment)
was less than 50%.
In 2011, boceprevir (Victrelis) and telaprevir (Incivek)
were marketed as the first direct-acting antiviral agents that
inhibit a protease enzyme essential for replication of HCV.
Each of these HCV protease inhibitors was used with peginterferon alfa and ribavirin in regimens that provided significantly higher cure rates in a shorter treatment period when
compared with previous regimens. However, many patients
experienced adverse events and/or drug interactions, and
the new agents had a short duration of action that required
administration several times a day.
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In late 2013, simeprevir (Olysio) and sofosbuvir (Sovaldi)
were marketed. They have important advantages over their
predecessors. The combination regimens in which they were
included are more effective and can be used for shorter treatment periods; in addition, both agents are well tolerated and
can be administered once a day. Simeprevir is an HCV protease inhibitor, whereas sofosbuvir has a unique mechanism
of action as a nucleotide analog inhibitor of HCV NS5B polymerase, which is essential for viral replication. Sofosbuvir
was the first agent that permitted, for some patients, the use
of regimens that did not include interferon. It was a gamechanger. The benefits of the regimens that include it have
been so impressive that use of boceprevir and telaprevir has
been rendered obsolete, and their marketing is being discontinued.
Important advances in the treatment of patients with
chronic HCV infection continued in 2014 with the approval
and marketing of two new combination regimens of antiviral agents. These products are considered individually in the
following sections.
Ledipasvir/sofosbuvir
Ledipasvir/sofosbuvir (Harvoni—Gilead Sciences) is a fixeddose formulation combining the new agent ledipasvir, an inhibitor of the HCV NS5A protein required for viral replication, with sofosbuvir. Indicated for the treatment of chronic
HCV genotype 1 infection in adults, the product is the first
regimen for this infection that does not require administration with either interferon or ribavirin.
Effectiveness of ledipasvir/sofosbuvir was demonstrated
in three studies involving more than 1,500 patients, with SVR
a primary endpoint. Participants were treated with ledipasvir/sofosbuvir with or without ribavirin. In treatment-naive
patients, 94% of those who received the combination for 8
weeks and 96% of those who received it for 12 weeks achieved
an SVR. In treatment-experienced patients with and without
cirrhosis, 94% of those treated for 12 weeks and 99% of those
treated for 24 weeks achieved an SVR. The inclusion of ribavirin in the regimen had little effect on SVR rates.
The ledipasvir/sofosbuvir regimen is the first demonstrated to be effective in a treatment period as short as 8
weeks. An 8-week course of treatment can be considered for
use in treatment-naive patients without cirrhosis who have
pretreatment HCV RNA of fewer than 6 million IU/mL.
Adverse events most commonly experienced in the clinical studies (and their incidence with a 12-week course of
treatment) include headache (14%), fatigue (13%), and nausea
(7%). Concurrent use of other products containing sofosbuvir
(i.e., Sovaldi) is not recommended because of the increased
possibility of adverse events. Use with simeprevir is also not
recommended because the concentrations and activity of
both simeprevir and ledipasvir may be increased.
The ledipasvir/sofosbuvir combination is classified in
Pregnancy Category B and should be used during pregnancy only if the anticipated benefit justifies the risk to the fetus.
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ated in pediatric patients.
Ledipasvir/sofosbuvir may be administered without regard to food. However, the solubility of ledipasvir decreases
as pH increases, and drugs that increase gastric pH are likely
to decrease the concentration of the new drug. Accordingly,
administration of antacids should be separated from administration of ledipasvir/sofosbuvir by a 4-hour period. An
H2-receptor antagonist (e.g., famotidine) may be administered simultaneously with or 12 hours apart from ledipasvir/
sofosbuvir at a dose that does not exceed doses comparable
to famotidine 40 mg twice a day. A proton pump inhibitor
in a dose comparable to omeprazole 20 mg or lower can be
administered simultaneously with ledipasvir/sofosbuvir
under fasted conditions.
Ledipasvir is metabolized to only a very limited extent,
and biliary excretion of unchanged drug is the major route
of elimination, with most of a dose recovered in the feces.
Dosage adjustment is not necessary in patients with mild,
moderate, or severe hepatic impairment or in patients with
mild or moderate renal impairment. The ledipasvir/sofosbuvir combination has not been studied in patients with severe
renal impairment or end-stage renal disease requiring hemodialysis. Exposure of the predominant metabolite of sofosbuvir is markedly increased in patients with severe renal
impairment, but a specific dosage reduction is not provided.
Both ledipasvir and sofosbuvir are substrates of the drug
transporter P-glycoprotein (P-gp). P-gp inducers such as rifampin and St. John’s wort may reduce the plasma concentrations and action of both drugs, and concurrent use is not
recommended. Concentrations of ledipasivr and sofosbuvir
are also reduced by antiepileptic drugs (e.g., carbamazepine,
oxcarbazepine, phenytoin), the antimycobacterial agents rifabutin and rifapentine, and the antiretroviral agents tipranivir and ritonavir. Concurrent use of these agents with ledipasvir/sofosbuvir is not recommended.
Use of ledipasvir/sofosbuvir in patients with HIV infection treated with antiretroviral regimens that include tenofovir disoproxil fumarate has been associated with increased
concentrations of tenofovir. Alternative treatment regimens
should be considered, or patients should be closely monitored for tenofovir-associated adverse events.
Ledipasvir, an inhibitor of P-gp, may increase the concentration of digoxin; concurrent use should be closely monitored. Use of ledipasvir/sofosbuvir in patients treated with
rosuvastatin (Crestor) may significantly increase the concentration of the latter agent, and concurrent use is not recommended.
Ledipasvir/sofosbuvir film-coated tablets contain 90 mg
and 400 mg of the drugs, respectively. The recommended
dosage is one tablet once a day for 12 weeks for treatmentnaive patients with or without cirrhosis. Treatment for a period of 8 weeks can be considered in treatment-naive patients
without cirrhosis who have pretreatment HCV RNA of fewer
than 6 million IU/mL. The ledipasvir/sofosbuvir regimen
has also been effective in treatment-experienced patients for
whom treatment has failed with either peginterferon alfa
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NEW THERAPEUTIC AGENTS MARKETED IN 2014: PART 3
plus ribavirin or an HCV protease inhibitor plus peginterferon alfa plus ribavirin. Ledipasvir/sofosbuvir is administered
in a dosage of one tablet once a day for 12 weeks in treatmentexperienced patients without cirrhosis, and for 24 weeks in
treatment-experienced patients with cirrhosis.
Ombitasvir/paritaprevir/ritonavir and dasabuvir
sodium monohydrate
Ombitasvir/paritaprevir/ritonavir and dasabuvir sodium
monohydrate (Viekira Pak—AbbVie) is the second all-oral
regimen with new antiviral agents approved for the treatment of patients with chronic HCV infection in 2014. The
regimen includes three new antiviral agents: ombitasvir, an
HCV NS5A inhibitor with activity most similar to that of ledipasvir; paritaprevir, an HCV NS3/4A protease inhibitor
with activity most similar to that of simeprevir; and dasabuvir, an HCV nonnucleoside NS5B palm polymerase inhibitor
with activity most similar to that of sofosbuvir. Dasabuvir
is supplied as an individual agent in tablets that are administered twice a day, whereas ombitasvir, paritaprevir, and
ritonavir are supplied in a combination formulation that is
administered once a day.
Ritonavir has been used for many years as a component
of regimens for the treatment of patients with HIV infection.
Although it inhibits HIV protease, it is included in certain
HIV antiretroviral regimens primarily because it is a potent
inhibitor of the CYP3A metabolic pathway and inhibits the
metabolism and prolongs the action of numerous other HIV
antiretroviral agents. Ritonavir is not active against HCV but
is included in Viekira Pak to inhibit the CYP3A-mediated
metabolism of paritaprevir.
Viekira Pak is indicated for the treatment of patients
with genotype 1 chronic HCV infection, including those
with compensated cirrhosis. Ribavirin should be used with
Viekira Pak in patients with HCV genotype 1a infection and
in patients with HCV genotype 1b infection with cirrhosis. It
is not recommended for use in patients with decompensated
liver disease.
Effectiveness of the Viekira Pak regimen was evaluated
in six studies that included more than 2,300 patients with
chronic HCV infection with and without cirrhosis. In the
studies, patients were randomly assigned to receive Viekira Pak or placebo, Viekira Pak with or without ribavirin, or
Viekira Pak with ribavirin for 12 or 24 weeks. The primary
endpoint of the studies was an SVR at least 12 weeks after
finishing treatment. An SVR was achieved by 91% to 100%
of the participants who received Viekira Pak at the recommended dosage. Although the two regimens have not been
directly compared, effectiveness of the Viekira Pak regimen
appears to be similar to that of combination ledipasvir and
sofosbuvir.
In the clinical studies, elevations of alanine aminotransferase (ALT) to greater than five times the upper limit of
normal (ULN) occurred in approximately 1% of the patients.
Use of Viekira Pak is contraindicated in patients with severe
hepatic impairment because of the risk of potential toxicity,
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and its use is not recommended in patients with moderate
hepatic impairment. Hepatic laboratory testing should be
performed during the first 4 weeks of starting treatment
and as clinically indicated thereafter. If ALT concentrations
remain persistently greater than 10 times the ULN, discontinuation of treatment should be considered. ALT elevations
were significantly more frequent in women who were using
ethinyl estradiol–containing medications such as contraceptive formulations. Use of these products must be discontinued before starting therapy with Viekira Pak, and alternative
methods of contraception (e.g., nonhormonal methods) are
recommended during treatment. Ethinyl estradiol–containing medications can be resumed approximately 2 weeks following completion of treatment with Viekira Pak.
In patients treated with Viekira Pak without ribavirin in
the clinical studies, the most frequently experienced adverse
events included nausea (8%), pruritus (7%), and insomnia
(5%). The incidence of these adverse events was approximately doubled in patients treated with Viekira Pak plus
ribavirin, and asthenia was reported by 9% of patients. In
these patients, it is important to observe the warnings and
precautions for ribavirin, particularly the pregnancy avoidance warning.
Viekira Pak is classified in Pregnancy Category B. However, if administered with ribavirin, the combination regimen is contraindicated in women who are pregnant and in
men whose female partners are pregnant. Effectiveness and
safety of Viekira Pak in patients younger than 18 years of age
have not been established.
Bioavailability of the Viekira Pak components is increased when they are administered with a meal of moderate to high fat content; therefore, the drugs should be administered with a meal without regard to fat or calorie content.
Paritaprevir and dasabuvir are metabolized predominantly
by CYP3A4 and CYP2C8, respectively, and ombitasvir is metabolized predominantly by amide hydrolysis followed by
oxidative metabolism.
A large percentage of the doses of all four agents (including ritonavir) is recovered in the feces. Clinically relevant
changes in exposure to the drugs are not likely to be experienced in patients with mild, moderate, or severe renal impairment. Dosage adjustment is not required in patients with
mild hepatic impairment. However, use of Viekira Pak is not
recommended in patients with moderate hepatic impairment and is contraindicated in patients with severe hepatic
impairment.
Although ritonavir is included in the Viekira Pak regimen for the specific purpose of inhibiting the CYP3A-mediated metabolism of paritaprevir and increasing its plasma
concentration, ritonavir increases the risk of potentially serious interactions with numerous medications. Use of Viekira
Pak is contraindicated in patients who are being treated with
drugs that are highly dependent on CYP3A for clearance (i.e.,
triazolam, orally administered midazolam, lovastatin, simvastatin, pimozide, alfuzosin, and ergot derivatives), with
which increased concentrations are associated with serious
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events. It is also contraindicated with use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) that markedly increase the
exposure of dasabuvir and may increase the risk of QT prolongation. In addition, concurrent use of Viekira Pak with
drugs that are strong inducers of CYP3A and/or CYP2C8
(i.e., rifampin, carbamazepine, phenytoin, phenobarbital, St.
John’s wort) is contraindicated because of the likelihood of
decreased efficacy of the Viekira Pak regimen.
Other drugs contraindicated with use of Viekira Pak include ethinyl estradiol−containing medications, efavirenz,
and sildenafil (Revatio) when used in the dosage recommended for treatment of patients with pulmonary arterial
hypertension.
Viekira Pak may also interact with numerous other medications; therefore, the product labeling should be consulted
for specific recommendations. Concurrent use of Viekira Pak
with darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, or
salmeterol is not recommended. The labeling for Viekira Pak
includes recommendations for specific dosage adjustments
and restrictions for the following agents when they are used
concurrently: ketoconazole, atazanavir, rosuvastatin, pravastatin, cyclosporine, tacrolimus, and omeprazole. Caution
must also be observed when Viekira Pak is used concurrently with an antiarrhythmic agent because of the risk of an
increased action of the latter agent.
Because ritonavir is an HIV-1 protease inhibitor, it can
select for HIV-1 protease inhibitor resistance–associated substitutions. Therefore, any HCV and HIV-1 coinfected patients
treated with Viekira Pak should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease
inhibitor drug resistance.
Viekira Pak comprises fixed-dose combination tablets
that each contain ombitasvir 12.5 mg, paritaprevir 75 mg,
and ritonavir 50 mg and tablets containing dasabuvir sodium monohydrate in a quantity equivalent to dasabuvir 250
mg. The drugs should be administered with a meal. The recommended dosage is two of the fixed-dose combination tablets once a day in the morning and one dasabuvir tablet twice
a day in the morning and evening. This regimen should be
administered for 12 weeks in patients with HCV genotype
1b infection, without cirrhosis. Ribavirin should be included
in this regimen and be administered for 12 weeks in patients
with HCV genotype 1a infection, without cirrhosis, and in
patients with HCV genotype 1b infection, with cirrhosis; and
for 24 weeks in patients with HCV genotype 1a infection,
with cirrhosis. The usual recommended dosage of ribavirin
is 1,000 mg per day for patients weighing 75 kg or less and
1,200 mg per day for patients weighing more than 75 kg, divided and administered twice a day with food.
In patients with an unknown genotype 1 subtype, mixed
genotype 1 infection, or HCV/HIV-1 coinfection, the dosage
recommendations for patients with HCV genotype 1a infection, including the use of ribavirin, should be followed. In
patients who have received a liver transplant and who have
normal hepatic function and mild fibrosis, Viekira Pak and
ribavirin should be used for a period of 24 weeks.
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Peramivir
At least 5% of Americans experience influenza infection during a typical influenza season, and more than 200,000 are
hospitalized from influenza-related complications each year.
Influenza A viruses are the cause of most influenza infections, although some patients experience infection caused
by influenza B viruses. Influenza virus neuraminidase is an
enzyme that releases viral particles from the plasma membrane of infected cells, and the inhibition of this enzyme is
the strategy used to develop antiviral agents that treat this
infection.
Peramivir (Rapivab—BioCryst) is the third neuraminidase inhibitor approved for the treatment of influenza, joining oseltamivir (Tamiflu) and zanamivir (Relenza). Administered by I.V. infusion, peramivir is indicated for the treatment
of acute uncomplicated influenza in patients 18 years and
older who have been symptomatic for no more than 2 days.
Oseltamivir is administered orally and zanamivir by oral inhalation for treatment and prophylaxis of influenza infection
in both adults and children.
Effectiveness of peramivir was demonstrated in a placebo-controlled study in which patients treated with a dose of
peramivir 600 mg experienced alleviation of their combined
influenza symptoms, on average, 21 hours sooner than those
receiving placebo. The median time to recovery to normal
temperature was approximately 12 hours sooner compared
with placebo. Almost all (99%) of the patients in the study
were infected with influenza A virus; an insufficient number
of patients were infected with influenza B virus to determine
the effectiveness of the drug in this influenza type. In a study
of patients with serious influenza requiring hospitalization,
peramivir plus standard of care did not improve the median
time to clinical resolution compared with standard of care
alone. Therefore, efficacy has not been established in the
most seriously ill patients for whom I.V. therapy might ordinarily be considered.
Diarrhea was the adverse event reported most often in the
clinical studies, having been experienced by 8% of patients.
There were rare reports of serious skin and hypersensitivity reactions, including erythema multiforme, and StevensJohnson syndrome has been reported in the postmarketing
experience. Some patients with influenza have experienced
neuropsychiatric events, including delirium, hallucinations,
and abnormal behavior, and patients should be monitored
for such responses.
Peramivir is classified in Pregnancy Category C and
should be used during pregnancy only if the anticipated
benefit justifies the risk to fetus. The drug’s effectiveness and
safety in patients younger than 18 years of age have not been
established.
Because peramivir is metabolized to only a very limited
extent and renal clearance of unchanged drug accounts for
approximately 90% of total clearance, dosage should be reduced in patients with impaired renal function.
Inactivated influenza vaccine can be administered at any
time relative to the use of peramivir. However, because antiwww.pharmacytoday.org
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viral drugs may inhibit viral replication, peramivir may reduce the efficacy of live attenuated influenza vaccine (LAIV)
intranasal. Because of the potential for interference, use of
LAIV intranasal should be avoided within 2 weeks before or
48 hours after administration of peramivir.
The recommended dosage of peramivir is a single 600mg dose administered by I.V. infusion over 15 to 30 minutes.
In patients with a creatinine clearance of 30–49 mL/minute,
the recommended dose is 200 mg; in patients with a creatinine clearance of 10–29 mL/minute, the recommended dose
is 100 mg. In patients with chronic renal impairment who are
maintained on hemodialysis, peramivir should be administered after dialysis at a dose adjusted on the basis of renal
function.
Peramivir is supplied in single-use vials containing 200
mg per 20 mL. The appropriate dose of the drug should be
diluted to a maximum of 100 mL in 0.9% or 0.45% sodium
chloride injection, 5% dextrose injection, or lactated ringer’s
injection. The diluted solution should be administered immediately or stored under refrigerated conditions for up to
24 hours. If the diluted solution is refrigerated, it should be
allowed to reach room temperature before administration.
Antibacterial agent
Ceftolozane sulfate/tazobactam sodium (Zerbaxa—Cubist)
is a combination of a new cephalosporin antibacterial agent
with a beta-lactamase inhibitor. Ceftolozane is primarily active against Gram-negative bacteria; like the other cephalosporins, ceftolozane inhibits bacterial cell wall synthesis and
exhibits a bactericidal action. Its properties and spectrum of
action are most similar to those of ceftazidime (e.g., Fortaz).
Tazobactam is an irreversible inhibitor of some beta-lactamase enzymes that is also included in some combination formulations with piperacillin (e.g., Zosyn). By inhibiting betalactamase enzymes, tazobactam protects ceftolozane against
inactivation that results from the action of these enzymes.
Ceftolozane/tazobactam is administered by I.V. infusion
and has been approved for the treatment of two types of
serious infections. It is indicated in a regimen that also includes metronidazole for the treatment of complicated intraabdominal infections (cIAI) caused by Enterobacter cloacae,
Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus
mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus
salivarius. It is also indicated for the treatment of complicated
urinary tract infections (cUTI), including pyelonephritis,
caused by E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa.
In microbiologically evaluable patients with cIAI, ceftolozane/tazobactam plus metronidazole was noninferior to
meropenem (e.g., Merrem) with regard to clinical cure rates
(94%). Ceftolozane/tazobactam was compared with levofloxacin (administered intravenously once a day) in patients with
cUTI; in patients infected with a levofloxacin-susceptible organism at baseline, the clinical cure rate was 83% and similar
to that with levofloxacin.
As with the other cephalosporins, as well as the other
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classes of beta-lactam antibacterial agents (i.e., penicillins,
carbapenems), ceftolozane is associated with a risk of hypersensitivity and anaphylactic reactions. The new drug is contraindicated in patients with known serious hypersensitivity
to ceftolozane/tazobactam, piperacillin/tazobactam, or another beta-lactam antibacterial agent. Because of the potential for cross-sensitivity with other beta-lactam antibacterial
agents, caution must be exercised if ceftolozane is considered
for use in any patient known to be allergic to any of the betalactam agents.
Almost all systemic antibacterial agents, including
ceftolozane, have been reported to cause Clostridium difficile–associated diarrhea (CDAD) that ranges in severity from
mild diarrhea to fatal colitis. CDAD should be considered
in all patients who experience diarrhea following use of an
antibacterial agent, including the period of time following
completion of treatment, because CDAD has been reported
to occur more than 2 months after the administration of antibacterial agents.
Other adverse events reported in the clinical studies of
ceftolozane/tazobactam (and the incidence in patients with
cIAI and cUTI, respectively) include nausea (8%; 3%), diarrhea (6%; 2%), headache (3%; 6%), and pyrexia (6%; 2%). Treatment was discontinued because of adverse events in 2% of
the patients treated with ceftolozane/tazobactam as well as
in 2% of the patients treated with comparator antibacterial
agents.
Ceftolozane/tazobactam is classified in Pregnancy Category B. Its effectiveness and safety in pediatric patients have
not been established.
Ceftolozane is metabolized to only a very limited extent
and is eliminated in the urine as unchanged drug. The metabolite of tazobactam is also eliminated via the kidneys.
Dosage adjustment is not necessary in patients with mild renal impairment but is recommended in patients with moderate or severe renal impairment. The activity of ceftolozane is
not likely to be significantly affected by hepatic impairment.
Ceftolozane sulfate/tazobactam sodium is supplied
in single-use vials in quantities equivalent to ceftolozane
1 g and tazobactam 500 mg. The vials should be stored in
a refrigerator. The recommended dosage is 1 g/500 mg every 8 hours by I.V. infusion over 1 hour. Duration of therapy
should be guided by the severity and site of the infection
and the patient’s clinical and bacteriological progress. In the
treatment of cIAI, ceftolozane/tazobactam was continued for
4 to 14 days (in conjunction with metronidazole 500 mg intravenously every 8 h); in the treatment of cUTI, it was used for
a period of 7 days.
The dosage should be reduced to 500 mg/250 mg of
ceftolozane/tazobactam every 8 hours in patients with moderate renal impairment (creatinine clearance between 30 and
50 mL/min), 250 mg/125 mg every 8 hours in patients with
severe renal impairment (creatinine clearance between 15
and 29 mL/min), and an initial loading dose of 500 mg/250
mg followed by maintenance doses of 100 mg/50 mg every 8
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sis. On hemodialysis days, the dose should be administered
at the earliest possible time following completion of dialysis.
When preparing ceftolozane/tazobactam for administration, the contents of a vial should be constituted with 10 mL
of sterile water for injection or 0.9% sodium chloride injection. The appropriate dose/volume should be withdrawn
from the vial and added to an infusion bag containing 100
mL of 0.9% sodium chloride injection or 5% dextrose injection. The diluted solution is stable for 24 hours when stored at
room temperature or 7 days when stored under refrigeration.
Antifungal agents
Three new topically applied antifungal agents marketed in
2014 for the treatment of dermatologic fungal infections are
considered individually in the following discussions. Tinea
pedis (athlete’s foot), tinea cruris (jock itch), and tinea corporis are the most common dermatologic fungal infections.
More than a dozen topically applied antifungal agents are
available for the treatment of these infections, including the
imidazole (azole) derivatives clotrimazole (e.g., Lotrimin AF),
econazole (e.g., Spectazole), ketoconazole, miconazole (e.g.,
Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and
sulconazole (Exelderm); the amines butenafine (e.g., Lotrimin Ultra), terbinafine (Lamisil AT), and naftifine (Naftin);
as well as ciclopirox (Loprox), tolnaftate (e.g., Tinactin), and
undecylenic acid and derivatives (e.g., Desenex).
Although many of these agents appear to be similar in
their effectiveness, the recommended duration of treatment
varies among the drugs, and some are available without a
prescription. Of the agents above, clotrimazole, miconazole,
butenafine, terbinafine, tolnaftate, and undecylenic acid are
available without a prescription.
Luliconazole
Luliconazole (Luzu—Valeant) is an imidazole antifungal
agent indicated for the topical treatment of interdigital tinea
pedis, tinea cruris, and tinea corporis caused by Trichophyton
rubrum and Epidermophyton floccosum in patients 18 years of
age and older. Its effectiveness was demonstrated in vehiclecontrolled studies. In a study in patients with interdigital
pedis, efficacy results at 4 weeks posttreatment were complete clearance in 26% and effective treatment in 48% of the
patients treated with the new drug, compared with 2% and
10%, respectively, in those in whom the vehicle was used.
In a study in patients with tinea cruris, efficacy results at 3
weeks posttreatment were complete clearance in 21% and effective treatment in 43% of the patients treated with luliconazole, compared with 4% and 19%, respectively, in those in
whom the vehicle was used.
The labeled indications for luliconazole do not include
tinea pedis on the bottom or sides of the foot. The new drug
has not been directly compared with other antifungal agents
in clinical studies.
As with the other topically applied antifungal agents,
luliconazole is well tolerated. The incidence of application
site reactions is less than 1%, an incidence similar to that of
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the vehicle. Luliconazole is classified in Pregnancy Category
C. Its effectiveness and safety in pediatric patients have not
been established.
Luliconazole cream contains the drug in a 1% concentration and is available only by prescription. It should be applied
to the affected area and approximately 1 inch of the immediate
surrounding area. In the treatment of interdigital tinea pedis,
it should be applied once a day for 2 weeks; in the treatment
of tinea cruris and tinea corporis, it should be applied once
a day for 1 week. The recommended duration of treatment
for luliconazole is shorter than that for the other topically applied imidazole derivatives, most of which are applied twice
a day for 4 weeks in the treatment of tinea pedis, and once or
twice a day for 2 weeks in the treatment of tinea cruris and
tinea corporis. However, both butenafine and terbinafine are
applied twice a day for just 1 week in the treatment of tinea
pedis. In addition, these two agents are available without a
prescription and at a considerably lower cost.
Onychomycosis—fungal infections of the nails—are
most often caused by dermatophytes such as T. rubrum. Oral
use of terbinafine (e.g., Lamisil) or itraconazole (e.g., Sporanox) for 12 weeks is the most effective treatment of onychomycosis of the toenails and fingernails. Griseofulvin has
also been used orally for these infections. However, relapse
rates are high, and patients are at risk of adverse events and
drug interactions. Ciclopirox (e.g., Penlac), the first antifungal
agent approved for topical treatment (in a nail lacquer formulation) of onychomycosis of the nails, is used for a period
of 48 weeks. It is less effective than the orally administered
antifungal agents but has little risk of adverse events.
Efinaconazole
Efinaconazole (Jublia—Valeant) is a topically applied imidazole antifungal agent that inhibits the biosynthesis of ergosterol, a constituent of fungal cell membranes. It is indicated
for the topical treatment of onychomycosis of the toenails
caused by T. rubrum and T. mentagrophytes. Its effectiveness was demonstrated in two vehicle-controlled studies in
which a significantly larger number of patients (18%; 15%)
treated with efinaconazole achieved a complete cure, compared with 3% and 6% of those treated with the vehicle. A
mycologic cure was achieved in 55% and 53% of the patients
treated with the drug in the two studies, compared with 17%
and 17% of those treated with the vehicle.
Although efinaconazole has not been directly compared
with ciclopirox in clinical studies, the new drug may be more
effective and attain a higher cure rate. However, the labeled
indication for efinaconazole is only for the treatment of the
toenails, whereas ciclopirox nail lacquer is indicated for the
treatment of onychomycosis of the toenails and fingernails.
Efinaconazole is well tolerated, and the adverse events
reported most often in the clinical studies include ingrown
toenail (2%), application site dermatitis (2%), and application
site vesicles (2%). The drug is classified in Pregnancy Category C. Effectiveness and safety of efinaconazole in pediatric
patients have not been established.
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NEW THERAPEUTIC AGENTS MARKETED IN 2014: PART 3
Efinaconazole is supplied in a topical solution in a 10%
concentration. The product is flammable and should be kept
away from flame and heat. The toenails should be clean and
dry before application, and patients should wait at least 10
minutes after showering, bathing, or washing before applying the solution. One drop of the solution is applied onto the
affected toenail once a day for 48 weeks. For the big toenail,
a second drop is also applied to the end of the toenail. The
brush applicator supplied with the product is used to spread
the solution around the entire toenail, ensuring that the toenail, toenail folds, toenail bed, hyponychium, and undersurface of the toenail plate are completely covered.
Tavaborole
Tavaborole (Kerydin—PharmaDerm), an oxaborole antifungal agent that inhibits fungal protein synthesis, is indicated
for the topical treatment of onychomycosis of the toenails
caused by T. rubrum or T. mentagrophytes. Its effectiveness
has been demonstrated in two vehicle-controlled studies
in which a larger number of patients (7%; 9%) treated with
tavaborole achieved a complete cure, compared with 0.5%
and 2% of those treated with the vehicle. A mycologic cure
was achieved in 31% and 36% of the patients treated with the
drug in the two studies, compared with 7% and 12% of those
treated with the vehicle.
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Tavaborole has not been directly compared with other
antifungal agents in clinical studies. However, results of
studies of the individual agents suggest that it may be less effective than efinaconazole. Like efinaconazole, it is indicated
for treatment of onychomycosis of the toenails, whereas ciclopirox nail lacquer is indicated for treatment of onychomycosis of the toenails and fingernails.
The most commonly reported adverse events in the clinical studies of tavaborole included application site exfoliation
(3%), ingrown toenail (3%), and application site erythema
(2%). Tavaborole is classified in Pregnancy Category C. Its
effectiveness and safety in pediatric patients have not been
established.
Tavaborole is supplied in a topical solution in a concentration of 5%. The product is flammable and should be kept
away from flame and heat. The toenails should be clean
and dry before application of the solution. Enough solution
should be applied to completely cover the toenail; more than
one drop may be needed. The dropper tip should be used to
spread the solution over the entire toenail up to the edges
and under the entire tip of the toenail. The solution is applied
once a day for 48 weeks. If the solution comes in contact with
the surrounding skin, a tissue should be used to remove excess solution from the skin. The solution should not be wiped
off the toenails.
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CPE
NEW THERAPEUTIC AGENTS MARKETED IN 2014: PART 3
CPE assessment
Instructions: To view the assessment questions, please see the online version of this article. See “CPE information” sidebar
below for further instructions.
1. Which of the following drug : classification pairings is
correct?
a. Dulaglutide : sodium–glucose cotransporter-2 inhibitor
b. Olodaterol : beta-2-adrenergic receptor antagonist
c. Netupitant : serotonin-3 receptor antagonist
d. Peramivir : neuraminidase inhibitor
2. Which of the following drug : use pairings is correct?
a. Peginterferon beta-1a : chronic hepatitis C virus
infection
b. Luliconazole : onychomycosis of the toenails
c. Olodaterol : chronic obstructive pulmonary disease
d. Ceftolozane : acute bacterial skin infections
3. Which of the following agents is administered subcutaneously?
a. Dulaglutide
c. Ceftolozane
b. Peramivir
d. Netupitant
4. Which of the following agents is administered twice a
day?
a. Efinaconazole
c. Ledipasvir
b. Dasabuvir
d. Ceftolozane
5. With the use of which of the following agents do approximately one-half of patients experience influenzalike symptoms as adverse events?
a. Ombitasvir
c. Peginterferon beta-1a
b. Netupitant
d. Dulaglutide
6. The administration of which of the following agents
should be separated from the administration of an
antacid by a 4-hour period?
a. Dasabuvir
c. Netupitant
b. Ledipasvir
d. Ceftolozane
7. Ritonavir is used to inhibit the metabolism and
increase the concentration of which of the following
agents?
a. Ombitasvir
c. Dasabuvir
b. Ledipasvir
d. Paritaprevir
8. Which of the following agents is administered as a
single-dose treatment?
a. Peramivir
c. Peginterferon beta-1a
b. Ceftolozane
d. Tavaborole
88
PharmacyToday • APRIL 2015
9. Which of the following statements is correct regarding
dulaglutide?
a. Hypoglycemia is a common adverse event.
b. Many patients gain weight during treatment.
c. It is administered once a week.
d. It is available in a combination formulation with
metformin.
10. Which of the following statements is correct regarding
olodaterol?
a. It is classified as a muscarinic antagonist.
b. Its indications include the treatment of acute episodes of bronchospasm.
c. It is administered by nasal inhalation.
d. It is administered once a day.
11. Which of the following statements is correct regarding
peginterferon beta-1a?
a. It is administered intramuscularly.
b. Most patients experience injection site reactions.
c. It is administered every 4 weeks.
d. Its use is contraindicated in patients with impaired
renal function.
12. Which of the following statements is correct regarding
netupitant/palonosetron?
a. It is used in a regimen that also includes dexamethasone.
b. Its labeled indications include the prevention of postoperative nausea and vomiting.
c. It is effective in preventing nausea and vomiting
during the acute phase after cancer chemotherapy
but not during the delayed phase.
d. Its use is contraindicated in patients with impaired
renal function.
13. Which of the following statements is correct regarding
ledipasvir/sofosbuvir?
a. It is the first regimen demonstrated to be effective for
the treatment of all genotypes of chronic HCV infection.
b. It is the first regimen demonstrated to be effective in
a 4-week course of treatment for some patients with
chronic HCV infection.
c. It is the first regimen demonstrated to be effective for
the treatment of HCV infection that does not require
administration with either interferon or ribavirin.
d. In patients with chronic HCV genotype 1 infection,
treatment should be continued for at least 24 weeks.
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NEW THERAPEUTIC AGENTS MARKETED IN 2014: PART 3
14. Which of the following statements is correct regarding
ledipasvir/sofosbuvir?
a. It should be administered with food.
b. Both drugs are extensively metabolized via the
CYP3A4 pathway.
c. Its concentration and activity may be increased by
rifampin, and concurrent use is not recommended.
d. It may increase the concentration and activity of rosuvastatin, and concurrent use is not recommended.
15. Which of the following agents has activity that is most
similar to that of sofosbuvir?
a. Ombitasvir
c. Paritaprevir
b. Dasabuvir
d. Ledipasvir
16. Which of the following statements is correct regarding
Viekira Pak?
a. It is supplied in a tablet formulation that includes a
combination of ombitasvir, paritaprevir, dasabuvir,
and ritonavir.
b. Renal adverse events are the most important risk,
and renal function determinations should be regularly monitored.
c. The concurrent use of an ethinyl estradiol–containing product is contraindicated.
d. The concurrent use of gemfibrozil may reduce the
action of dasabuvir.
17. Which of the following statements is correct regarding
peramivir?
a. It is most effective in patients who have been symptomatic for no more than 2 days.
b. Its use should be reserved for the treatment of hospitalized patients with complicated influenza.
c. It has been demonstrated to be most effective in
patients with infection caused by influenza B virus.
d. Most patients experience injection site reactions following administration.
CPE
18. Which of the following statements is correct regarding
ceftolozane?
a. Its properties and spectrum of action are most similar to those of cefazolin.
b. Its spectrum of action includes Pseudomonas aeruginosa.
c. It has a long duration of action and is administered
once a day.
d. It is extensively metabolized and dosage adjustment
is not necessary in patients with impaired renal
function.
19. Which of the following statements is correct?
a. Tazobactam is used in combination with ceftolozane
to provide greater coverage against Gram-positive
bacteria.
b. Ceftolozane/tazobactam has been demonstrated to
be noninferior to levofloxacin in the treatment of
complicated intra-abdominal infections.
c. Ceftolozane/tazobactam has been demonstrated to
be more effective than meropenem in the treatment
of complicated urinary tract infections.
d. Ceftolozane/tazobactam should be used in a regimen with metronidazole in the treatment of complicated intra-abdominal infections.
20. Which of the following statements is correct?
a. The labeled indication for efinaconazole is the topical treatment of onychomycosis of the toenails.
b. Luliconazole is indicated for the topical treatment of
tinea pedis and is available without a prescription.
c. Tavaborole is classified as an imidazole antifungal
agent.
d. The duration of treatment of luliconazole and efinaconazole is 48 weeks.
CPE information To obtain 2.0 contact hours of continuing pharmacy education credit (0.2 CEUs) for this activity, you must complete the online assessment and
evaluation. A Statement of Credit will be awarded for a passing grade of 70% or better. Pharmacists who successfully complete this activity before
April 1, 2018, can receive CPE credit. Your Statement of Credit will be available upon successful completion of the assessment and evaluation and
will be stored in your My Training Page and on CPE Monitor for future viewing/printing.
CPE instructions:
1. Log in or create an account at pharmacist.com and select LEARN from the top of the page; select Continuing Education, then Home Study CPE
to access the Library.
2. Enter the title of this article or the ACPE number to search for the article and click on the title of the article to start the home study.
3. To receive CPE credit, select Enroll Now or Add to Cart from the left navigation and successfully complete the Assessment (with randomized
questions), Learning Evaluation, and Activity Evaluation.
4. To get your Statement of Credit, click “Claim” on the right side of the page. You will need to provide your NABP e-profile ID number to obtain
and print your Statement of Credit.
Live step-by-step assistance is available Monday through Friday from 8:30 am to 5:00 pm ET at APhA Member Services at 800-237-APhA (2742)
or by e-mailing [email protected].
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APRIL 2015 •
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