US Pharm. 2012;37(10):HS2-HS8.
ABSTRACT: New molecular entities (NMEs), as
defined by the FDA, are drug products containing as their active
ingredient a chemical substance marketed for the first time in the
United States. The following descriptions of NMEs approved in 2011–2012
( TABLE 1) detail the basic clinical and
pharmacologic profiles for each new drug, as well as its
pharmacokinetics, adverse reactions, drug interactions, and dosing data.
Note that the information for each NME was obtained primarily from
sources published prior to FDA approval; thus, it is essential that
practitioners become aware of changes in a drug’s therapeutic profile as
reported by their own patients and in the pharmaceutical literature,
such as the emergence of additional adverse reactions and black box
Aflibercept (Eylea, Regeneron Pharmaceuticals, Inc.)
Indication and Clinical Profile1,2: Aflibercept
is approved to treat patients with wet (neovascular) age-related
macular degeneration (AMD), a leading cause of vision loss and blindness
in Americans aged 60 years and older. There are two forms of AMD, wet
and dry. The wet form involves the growth of abnormal blood vessels,
which can leak fluid into the central part of the retina, the macula.
With this fluid leakage, the macula thickens and vision loss occurs.
Other FDA-approved injectable treatment options for wet AMD include
verteporfin (Visudyne), pegaptanib (Macugen), and ranibizumab
Aflibercept’s efficacy was established in two clinical
trials (VIEW1, VIEW2) enrolling 2,412 patients with wet AMD. Patients
were randomly assigned to one of four dosing regimens: 1) aflibercept
administered 2 mg every 8 weeks following 3 initial monthly doses; 2)
aflibercept administered 2 mg every 4 weeks; 3) aflibercept 0.5 mg
administered every 4 weeks; or 4) ranibizumab administered 0.5 mg every 4
weeks. In both studies, the primary efficacy endpoint was the
proportion of patients who maintained vision, defined as losing fewer
than 15 letters of visual acuity at week 52 compared to baseline.
Aflibercept doses of 2 mg every 4 and 8 weeks were found to be as
efficacious and clinically equivalent to the ranibizumab regimen. In
VIEW1, this endpoint was reached by 94%, 95%, and 94% of subjects in the
aflibercept 2Q8, aflibercept 2Q4, and ranibizumab arms, respectively.
In VIEW2, this endpoint was reached by 95% of subjects in all three
Pharmacology and Pharmacokinetics1,2: Vascular
endothelial growth factor-A (VEGF-A) is a member of the VEGF family of
angiogenic factors that can act as mitogenic, chemotactic, and vascular
permeability factors for endothelial cells. Aflibercept, a recombinant
fusion protein, is a selective VEGF-A antagonist. It acts as a decoy
receptor by competing for binding and inhibiting the activation of
VEGF-A and other receptors responsible for neovascularization and
Some aflibercept bound to VEGF-A may be absorbed into the
systemic circulation. In plasma, aflibercept exists in equilibrium
between VEGF-bound and free form. The free form is digested by
proteolysis and cleared. The terminal elimination half-life of free
aflibercept in plasma was found to be 5 to 6 days after IV
administration at doses of 2 to 4 mg/kg.
Adverse Reactions and Drug Interactions1,2: The
most commonly reported side effects in patients receiving aflibercept
included conjunctival hemorrhage, eye pain, cataract, vitreous
detachment, vitreous floaters, and increased intraocular pressure.
Intravitreal injections have been associated with endophthalmitis and
retinal detachment; therefore, proper injection techniques must be used.
Patients should report any symptoms suggestive of endophthalmitis or
retinal detachment immediately and managed them accordingly. Elevated
intraocular pressure is common acutely following aflibercept injection.
Sustained increase in pressure should be monitored to avoid perfusion to
the optic nerve. Although uncommon (<2%) in clinical trials,
arterial thromboembolic events did occur following intravitreal use of
Aflibercept is contraindicated in patients with ocular or
periocular infections or active ocular inflammation. This drug has not
been studied in pregnant women, so the treatment should be used only in
pregnancy if the potential benefits outweigh any risks.
Dosage and Administration1,2: Aflibercept is available as a 40 mg/mL solution for intravitreal injection in a single-use vial (FIGURE 1).
Adequate anesthesia and topical broad-spectrum microbicide should be
given prior to injection. The recommended dosage is 2 mg (0.05 mL)
administered by intravitreal injection monthly for the first 3 months,
followed by 2 mg (0.05 mL) via intravitreal injection once every 2
months. Although aflibercept may be dosed as frequently as 2 mg every
month, additional efficacy was not demonstrated when aflibercept was
dosed every month compared to every 2 months.
Asparaginase Erwinia chrysanthemi (Erwinaze, EUSA Pharma [USA], Inc.)
Indication and Clinical Profile3,4: Asparaginase Erwinia chrysanthemi has been approved for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to Escherichia coli–derived
asparaginase and pegaspargase drugs used to treat ALL. ALL is the most
common malignancy in children and is characterized by an overproduction
of lymphocytes in bone marrow. Multidrug chemotherapy cures about 80% of
children with ALL. Inclusion of an asparaginase in ALL regimens
improves outcomes, but approximately 15% to 20% of patients treated with
E coli–derived asparaginase develop hypersensitivity to the drug.
Prior to Erwinaze’s approval, there were two
asparagine-specific enzyme products for ALL (asparaginase injection and
pegaspargase), both of which are E coli derived. Erwinaze has been designated as an orphan drug.
The approval of Erwinaze was based on one clinical trial
that enrolled 58 subjects with ALL who were unable to continue to
receive pegaspargase due to hypersensitivity reactions. The subjects
received 25,000 IU/m2 of Erwinaze intramuscularly (IM) for 2
weeks as a replacement for each scheduled dose of pegaspargase remaining
on their original treatment protocol. The main endpoint was
determination of the proportion of patients who achieved a serum trough
asparaginase level ≥0.1 IU/mL. More than 50% of the subjects reached
this endpoint at 48 or 72 hours following the third dose. In another
study, 42 E coli asparaginase–allergic children with ALL were switched to twice-weekly Erwinaze 25,000 IU/m2
to complete 30 weeks of asparaginase treatment. At a median follow-up
of 5.4 years, event-free survival in those children was similar to that
of children without E coli–asparaginase allergy (86% vs. 81%).
Pharmacology and Pharmacokinetics3,4: Erwinaze contains an asparaginase-specific enzyme derived from E chrysanthemi.
This enzyme catalyzes the hydrolysis of asparagine to aspartic acid and
ammonia, resulting in lower circulating levels of asparagine and
selective killing of leukemic cells that depend on an exogenous source
of asparagine for their survival. Normal human cells are able to make
asparagine through biosynthesis and are not affected by treatment with
The pharmacokinetics of Erwinaze have not been fully
determined. Serum asparaginase activity levels were >0.4 IU/mL for
80% of trial patients evaluated at 48 hours and 38% at 72 hours.
Adverse Reactions and Drug Interactions3,4: Adverse
effects associated with Erwinaze treatment include serious allergic
reactions (anaphylaxis), pancreatitis, abnormal transaminases and
bilirubin, blood clotting, hemorrhage, nausea, vomiting, and
hyperglycemia. Allergy to the drug was reported in 33% of trial
patients. Erwinaze is contraindicated in patients who have a history of
serious pancreatitis, thrombosis, or serious hemorrhagic events with
prior L-asparaginase therapy. Erwinaze is classified as a Pregnancy
Category C drug. No formal drug interaction studies have been performed.
Dosage and Administration3,4: Erwinaze
is supplied as a solution for IM administration. To substitute for a
dose of pegaspargase, the recommended dosage of Erwinaze is 25,000 IU/m2 IM three times a week for 6 doses for each planned dose of pegaspargase. To substitute for a dose of native E coli asparaginase, the recommended dosage is 25,000 IU/m2 IM for each scheduled dose of native E coli
asparaginase within a treatment. The volume of Erwinaze administered at
a single injection site should be limited to 2 mL; if the administered
dose is >2 mL, use multiple injection sites.
Brentuximab vedotin (Adcetris, Seattle Genetics, Inc.)
Indication and Clinical Profile5,6: Lymphoma
is a general term for a group of cancers that originate in the
lymphatic system. There are two major categories of lymphoma: Hodgkin’s
lymphoma (FIGURE 2) and non-Hodgkin’s lymphoma. Hodgkin’s
lymphoma is distinguished from other lymphomas by the presence of one
characteristic type of cell, known as the Reed-Sternberg cell, which generally expresses CD30.
Brentuximab vedotin is specifically approved for two
indications: 1) Hodgkin’s lymphoma after failure of autologous stem cell
transplantation (ASCT) or after failure of at least two prior
multi-agent chemotherapy regimens in patients who are not ASCT
candidates, and 2) systemic anaplastic large cell lymphoma (sALCL) after
failure of at least one prior multi-agent chemotherapy regimen.
The brentuximab approvals were based on data from two
pivotal trials in Hodgkin’s lymphoma patients who relapsed after ASCT (n
= 102) and in relapsed sALCL patients (n = 58). The primary endpoint of
both trials was overall response rate as assessed by an independent
review facility. In this study, 73% of patients achieved an objective
response following treatment with brentuximab, including 32% with
complete remissions and 40% with partial remissions. The median duration
of objective response was 6.7 months. There are no data available
demonstrating improvement in patient-reported outcomes or survival with
Pharmacology and Pharmacokinetics5,6: Brentuximab
vedotin is an antibody-drug conjugate (ADC) comprising an anti-CD30
monoclonal antibody attached by a protease-cleavable linker to a
microtubule-disrupting agent, monomethyl auristatin E (MMAE). The ADC
employs a linker system that is designed to be stable in the bloodstream
but to release MMAE upon internalization into CD30-expressing tumor
cells. sALCL is an aggressive type of T-cell
non-Hodgkin’s lymphoma that also expresses CD30.
Maximum concentrations of brentuximab are typically
observed immediately postinfusion, and serum concentrations decline in a
multiexponential manner with a terminal half-life of about 4 to 6 days.
Only a small fraction of MMAE released from brentuximab is metabolized,
primarily by oxidation of CYP3A4/5. The majority of the drug is
excreted in the feces as unchanged MMAE.
Adverse Reactions and Drug Interactions5,6: Adverse
events most commonly reported with brentuximab therapy (incidence ≥20%)
included neutropenia, peripheral sensory neuropathy, fatigue, nausea,
anemia, upper respiratory tract infection, diarrhea, fever, rash,
thrombocytopenia, cough, and vomiting. Infusion-related reactions,
including anaphylaxis, were also reported. If this occurs, interrupt the
infusion and institute appropriate medical management.
to the risk of tumor lysis syndrome, patients with rapidly
proliferating tumor and high tumor burden should be monitored closely.
Concomitant use of brentuximab with bleomycin is contraindicated due to
risk of pulmonary toxicity. Brentuximab is classified as a Pregnancy
Category D drug.
MMAE, the active component of brentuximab, is primarily
metabolized by CYP3A. Therefore, coadministration of brentuximab with a
potent CYP3A4 inhibitor or inducer may significantly increase or
decrease MMAE exposure, respectively. Patients who are receiving strong
CYP3A4 inhibitors or inducers concomitantly with brentuximab should be
closely monitored for adverse reactions or treatment failure.
Brentuximab does not inhibit CYP enzymes at relevant clinical
concentrations and thus is not expected to alter the exposure to drugs
that are metabolized by CYP isozymes.
Dosage and Administration5,6: Brentuximab
vedotin is supplied as a solution for IV infusion. The recommended
dosage is 1.8 mg/kg administered IV over 30 minutes every 3 weeks.
Treatment should be continued until a maximum of 16 cycles are completed
or disease progression or unacceptable toxicity occurs. The company has
established a patient assistance program (SeaGen Secure) that offers
patients and providers access to drug reimbursement support, benefit
investigations, and patient assistance programs.
Glucarpidase (Voraxaze, BTG International Inc.)
Indication and Clinical Profile7,8: Glucarpidase
is approved for the treatment of toxic plasma methotrexate (MTX)
concentrations (>1 µmol/L) in patients with delayed MTX clearance due
to impaired renal function. High-dose methotrexate (HD-MTX) is
frequently used in the treatment of various malignancies. However,
around 2% to 10% of patients experience grade ≥2 HD-MTX–related
nephrotoxicity and renal failure, which results in disruption of therapy
and may be life threatening. Precipitation of MTX in renal tubules is
thought to be the main mechanism of HD-MTX–induced renal failure and,
consequently, of prolonged exposure to toxic MTX levels. Prolonged
exposure can cause bone marrow suppression, oral and gastrointestinal
ulceration, and hepatic toxicity. Administration of leucovorin (folinic
acid) with aggressive IV hydration and alkalinization of urine can
reduce these toxicities.
The efficacy of glucarpidase was established in a
single-arm, open-label study in 22 patients with delayed MTX clearance
secondary to renal dysfunction. The main outcome of the study was the
proportion of patients who achieved a rapid and sustained clinically
important reduction (RSCIR) in MTX plasma concentration. Forty-five
percent of patients receiving glucarpidase achieved an RSCIR in MTX
concentrations (95% CI, 27%-65%). In the 9 patients with preglucarpidase
MTX concentrations >50 µmol/L, all achieved a >95% reduction in
MTX concentrations for up to 8 days following the initial injection.
None, however, achieved an RSCIR. Since glucarpidase does not reduce
intracellular concentrations of MTX, continuation of leucovorin is still
required during MTX therapy.
Pharmacology and Pharmacokinetics7,8:
Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the
carboxyl-terminal glutamate residue from folic acid and classical
antifolates such as MTX. This enzyme converts MTX to its inactive
metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA)
and glutamate. DAMPA and glutamate are further metabolized by the liver,
providing an alternative route of MTX elimination to renal clearance
during high-dose MTX treatment. Thus, glucarpidase lowers plasma levels
of MTX, reducing its concentration to below the threshold for serious
toxicity, without altering intracellular MTX levels.
In a pharmacokinetic study, IV administration of glucarpidase-produced mean concentration (Cmax) was 3.3 µg/mL and the mean AUC0-inf
was 23.3 µg·h/mL. Serum glucarpidase activity levels declined with a
mean elimination half-life of 5.6 hours. The mean systemic clearance
(CL) was 7.5 mL/min. The mean volume of distribution (Vd) was 3.6 L,
which suggests that glucarpidase distribution is restricted to plasma
Adverse Reactions and Drug Interactions7,8: The
most common adverse reactions (occurring in >1% of patients) in
glucarpidase clinical trials included paresthesia, flushing, nausea
and/or vomiting, hypotension, and headache. Serious allergic reactions,
including anaphylactic reactions, occurred in <1% of patients.
Glucarpidase is classified as Category C for use during pregnancy.
Leucovorin is a substrate for glucarpidase and should not
be administered within 2 hours before or after a dose of glucarpidase.
No dose adjustment is recommended for the continuing leucovorin regimen
because the dose is based on the patient’s preglucarpidase MTX
concentration. Other folates and folate antimetabolite drugs are also
potential substrates for glucarpidase and therefore may interact.
Dosage and Administration7,8: Glucarpidase
is supplied in single-use vials containing 1,000 U of the drug for
reconstitution and IV administration. It is administered as a bolus
injection over 5 minutes, at a dose of 50 U/kg. Monitoring levels of MTX
concentration during the initial 48 hours of treatment with
glucarpidase should be performed using chromatography, since immunoassay
will result in overestimations due to products formed from metabolized
MTX. Additional monitoring can resume using immunoassays following the
initial 48 hours of treatment. Therapy with leucovorin should be
continued until the MTX concentration has been maintained below the
leucovorin treatment threshold for a minimum of 3 days. However,
leucovorin should not be administered within 2 hours of a dose of
glucarpidase because it is a substrate for glucarpidase. For 48 hours
after glucarpidase administration, the leucovorin dose should be based
on the patient’s preglucarpidase MTX concentration. Even with
glucarpidase use, hydration and alkalinization of the urine should be
continued as indicated.
Ipilimumab (Yervoy, Bristol-Myers Squibb)
Indication and Clinical Profile9,10: Ipilimumab
is approved to treat patients with unresectable or metastatic melanoma.
Melanoma is the leading cause of death from skin disease. An estimated
68,130 new cases of melanoma were diagnosed in the U.S. during 2010 and
about 8,700 people died from the disease, according to the National
Cancer Institute. Current treatment options for metastatic melanoma
include dacarbazine (DTIC), high-dose interleukin-2, and gp100 peptide
vaccine with high-dose interleukin-2. However, none of these therapies
have been found to significantly delay disease progression or increase
overall survival in a significant number of patients.
Ipilimumab’s efficacy and safety were established in a
single international study involving 676 patients with melanoma. All
patients in the study had stopped responding to other FDA-approved or
commonly used treatments for melanoma. Participants had disease that had
spread or that could not be surgically removed. The study was designed
to measure overall survival, the length of time from when this treatment
started until a patient’s death. The randomly assigned patients
received ipilimumab plus an experimental tumor vaccine called gp100,
ipilimumab alone, or the gp100 vaccine alone. Survival rate at 1 year
was 46% in the ipilimumab arm versus 25% in the gp100 arm. The estimated
survival rate at 2 years was 24% in the ipilimumab arm versus 14% in
the gp100 arm. Subjects treated with ipilimumab had a 34% reduction in
the risk of death over the gp100 control arm, and those treated with
ipilimumab plus gp100 had a 32% reduction in the risk of death over the
gp100 control arm. Those who received the combination of ipilimumab plus
the vaccine or ipilimumab alone lived an average of about 10 months,
while those who received only the experimental vaccine lived an average
of 6.5 months.
Another trial in 502 patients with previously untreated
metastatic melanoma compared ipilimumab 10 mg/kg plus dacarbazine with
dacarbazine alone. Overall survival, which was the primary endpoint, was
significantly longer with ipilimumab plus dacarbazine (11.2 vs. 9.1
Pharmacology and Pharmacokinetics9,10: Ipilimumab
is a recombinant, human monoclonal antibody that binds to the cytotoxic
T-lymphocyte–associated antigen 4 (CTLA-4), a molecule on T cells that
suppresses the immune response. Ipilimumab binding blocks the
interaction of CTLA-4 with its ligands, enhancing T-cell activation and
proliferation. The mechanism of action of ipilimumab’s effect in
patients with melanoma is indirect, possibly through T-cell mediated
antitumor immune responses.
Peak concentration (Cmax), trough concentration (Cmin),
and AUC of ipilimumab appear to be dose proportional. The drug has a
terminal half-life of 14.7 days, systemic clearance (CL) of 15.3 mL/h,
and volume of distribution at steady state (Vss) of 7.21 L. The
pharmacokinetics of ipilimumab do not appear to be significantly altered
by renal or hepatic impairment.
Adverse Reactions and Drug Interactions9,10: In
clinical trials, the most common adverse effects of ipilimumab included
diarrhea, nausea, fatigue, pruritus, rash, and colitis. In the
controlled trial with gp100, severe or fatal (grade 3 or 4)
immune-related adverse reactions, mostly diarrhea, occurred in 10% to
15% of ipilimumab-treated patients, compared to 3% of patients receiving
gp100 alone. In the controlled trial with dacarbazine, grade 3 or 4
adverse effects occurred in 56.3% of patients treated with both drugs
and in 27.5% of those treated with dacarbazine alone. Immune-related
adverse effects of ipilimumab have included colitis, hepatitis, toxic
epidermal necrolysis, neuropathy, and endocrinopathy.
Due to the unusual and severe side effects associated with
this drug, it was approved with a black box warning concerning severe
immune-related adverse effects and a Risk Evaluation and Mitigation
Strategy (REMS) to inform health care professionals about these serious
risks. No formal drug-drug interaction studies have been conducted with
ipilimumab. It is classified as Category C for use during pregnancy.
Dosage and Administration9,10: Ipilimumab
is supplied as 5 mg/mL solutions (10 and 40 mL) for IV administration.
The recommended dosage is 3 mg/kg IV over 90 minutes every 3 weeks for a
total of four doses. The ipilimumab dose should be withheld for any
moderate immune-mediated adverse reactions or for symptomatic
endocrinopathy, and permanently discontinued if patients experience
serious immune-related reactions (skin or other organs), colitis,
neuropathies, or significantly elevated liver function enzymes (>5
times the upper limit of normal [ULN]).
Lucinactant (Surfaxin, Discovery Laboratories, Inc.)
Indication and Clinical Profile11,12: The FDA has approved lucinactant for the prevention of respiratory distress syndrome (RDS) in high-risk premature infants (FIGURE 3).
RDS is a condition in which premature infants are born with an
insufficient amount of pulmonary surfactant, a substance produced
naturally in the lungs and essential for breathing. Infants with RDS
often require animal-derived surfactant replacement therapy along with
mechanical ventilation to survive.
Approximately 90,000 premature infants in the U.S. are
treated annually with currently available animal-derived surfactants.
Lucinactant is the fifth surfactant approved in the U.S. to treat RDS in
premature infants; the others are Survanta (beractant), Curosurf
(poractant alfa), Infasurf (calfactant), and Exosurf (colfosceril
palmitate), which is no longer marketed.
The safety and efficacy of lucinactant were determined on
the basis of a large, multinational trial involving 1,294 premature
infants in Europe and Latin America. Within the first 30 minutes after
birth, infants were randomized to receive one of three surfactants,
lucinactant (5.8 mL/kg), colfosceril palmitate (5.0 mL/kg), or beractant
(4.0 mL/kg). Infants in the lucinactant and beractant groups could be
given up to three additional doses between 6 and 24 hours of birth, as
often as every 6 hours, if they subsequently developed RDS and required
mechanical ventilation. Infants in the colfosceril palmitate group could
receive up to two additional doses at least 12 hours apart if they met
the retreatment criteria. Some infants received placebo air to maintain
blinding of the study.
All dosages were calculated based on birth weight, and the
trial infants were followed through 12 months’ corrected age. Coprimary
endpoints were the incidence of RDS at 24 hours and RDS-related
mortality at 14 days, with the intent of demonstrating superiority over
colfosceril palmitate. Beractant served as an additional active
comparator. Compared to colfosceril palmitate, lucinactant demonstrated a
statistically significant improvement in both RDS at 24 hours (39% vs.
47%) and RDS-related mortality through day 14 (5% vs. 9%).
Pharmacology and Pharmacokinetics11,12: Lucinactant
is a synthetic formulation consisting of phospholipids, a fatty acid,
and sinapultide (KL4 peptide), a 21–amino acid hydrophobic synthetic
peptide. It functions as a nonpyrogenic pulmonary surfactant, thereby
lowering surface tension at the air-liquid interface of the alveolar
surfaces during respiration and stabilizing the alveoli against collapse
at resting transpulmonary pressures. Thus, lucinactant compensates for
the deficiency of surfactant and restores surface activity to the lungs
of these infants. Based on its route of administration and presumed lack
of absorption, no human pharmacokinetic studies have been performed to
characterize the absorption, distribution, metabolism, or elimination of
Adverse Reactions and Drug Interactions11,12: The
most common side effects of lucinactant are related to its
administration via an endotracheal tube and include endotracheal tube
reflux, skin paleness, endotracheal tube obstruction, and need for dose
interruption. If bradycardia, oxygen desaturation, endotracheal tube
reflux, or airway obstruction occurs during administration, therapy
should be interrupted and the infant’s clinical condition assessed and
stabilized. No significant drug interactions are expected with this drug
due to the anticipated lack of absorption from its site of
Dosage and Administration11,12: Lucinactant
is supplied as a solution for intratracheal administration only. The
recommended dosage is 5.8 mL per kg of birth weight. Up to four doses
can be administered in the first 48 hours of life, but doses should be
given no more frequently than every 6 hours. Lucinactant should be
administered only by clinicians trained and experienced with intubation,
ventilator management, and general care of premature infants in a
highly supervised clinical setting. Infants receiving the drug should
undergo frequent clinical assessments so that oxygen and ventilatory
support can be modified to respond to changes in respiratory status.
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12. Moya FR, Gadzinowski J, Bancalari E, et al;
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