US Pharm. 2013;38(10):27-34.
New molecular entities (NMEs), as defined by the FDA, are new 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 2012–2013 (TABLE 1) detail the basic
clinical and pharmacologic profiles of each new drug, as well as key
precautions and warnings. Also included is a brief summary of selected
pharmacokinetic, adverse-reaction (AR), drug-interaction, and dosing
data submitted to the FDA in support of the manufacturer’s new drug
application. This review is intended to be objective rather than
evaluative in content. The information for each NME was obtained
primarily from sources published prior to FDA approval. Experience
clearly demonstrates that many aspects of a new drug’s therapeutic
profile are not detected in premarketing studies and emerge after the
drug is used in large numbers of patients. Studies have demonstrated the
appearance of “new” ARs for many NMEs within 2 to 3 years after they
first become available. Some of these drugs may eventually acquire at
least one Black Box Warning for serious ARs or are withdrawn from the
market for safety reasons not recognized at the time of approval. Hence,
while this review offers a starting point for learning about new drugs,
it is essential that practitioners be aware of changes in a drug’s
therapeutic profile as reported in the pharmaceutical literature and by
their own patients.
Alogliptin (Nesina, Takeda Pharmaceuticals America)
Indication and Clinical Profile1,2: Alogliptin
is a new dipeptidyl peptidase-4 (DPP-4) inhibitor approved as an
adjunct to diet and exercise to improve glycemic control in patients
with type 2 diabetes mellitus (DM2). DM2 is a chronic, progressive
disease affecting more than 23 million people in the United States. Even
with diet and exercise, patients often must take multiple medications
to help manage their blood glucose levels. Alogliptin is the fifth DPP-4
inhibitor approved by the FDA since 2006 (the others being linagliptin,
saxagliptin, vildagliptin, and sitagliptin).
Approval of alogliptin was based on three 26-week, double-blind,
randomized, placebo- and active-controlled studies involving more than
1,768 patients with inadequate glycemic control through diet and
exercise. Alogliptin 25 mg once daily was superior to placebo in
improvements from baseline to week 26 for glycosylated hemoglobin (A1C)
and fasting plasma glucose (FPG). Compared with the respective
monotherapies, alogliptin coadministered with either pioglitazone or
metformin produced significant improvements in A1C and FPG from
baseline. Based on these studies, alogliptin also was approved in
combination with pioglitazone (as Oseni) and metformin HCl (as Kazano).
Pharmacology and Pharmacokinetics1,2: Alogliptin is a dihydropyrimidinedione (FIGURE 1)
that functions as a DPP-4 inhibitor. DPP-4 is involved in the
inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic peptide (GIP), each of which enables glucose-dependent
insulin secretion from the pancreas. By functioning as a DPP-4
inhibitor, alogliptin slows GLP-1 and GIP inactivation, thereby reducing
blood glucose levels.
The absolute bioavailability of alogliptin is 100% when the drug is
taken with or without food. Alogliptin has a peak plasma concentration
of 1 to 2 hours and a half-life of 21 hours. It undergoes minimal CYP450
metabolism, resulting in formation of an active N-demethylated
metabolite (1%) and some conjugation yielding an inactive metabolite.
Alogliptin does not appear to significantly induce or inhibit metabolism
by any major cytochrome isozyme. Alogliptin is eliminated primarily via
renal excretion (76%), along with some fecal elimination (13%).
Adverse Reactions (ARs) and Drug Interactions1,2: The
most common ARs reported in clinical trials were nasopharyngitis,
headache, and upper respiratory tract infection. Alogliptin produced
hypoglycemia at a rate comparable to that for placebo. There have been
postmarketing reports of acute pancreatitis, severe hypersensitivity
reactions (anaphylaxis, angioedema, and cutaneous ARs), and hepatic
failure (sometimes fatal) in patients taking alogliptin. Alogliptin is
not predicted to increase the risk of fetal developmental abnormalities,
but in the absence of more concrete data, consideration should be given
to whether the potential benefits of treatment outweigh the potential
risks (Pregnancy Category B).
Alogliptin has no significant interactions with drugs that are CYP
substrates or inhibitors, or with drugs excreted renally. Patients
taking insulin or an insulin secretagogue in combination with alogliptin
may have to lower the insulin or insulin secretagogue dosage to reduce
the risk of hypoglycemia.
Dosage and Administration1,2: Alogliptin
is supplied as 6.25-mg, 12.5-mg, and 25-mg tablets. The recommended
dosage is 25 mg once daily, with or without food. Patients with moderate
renal impairment should take 12.5 mg once daily, and those with severe
renal impairment or end-stage renal disease should take 6.25 mg once
daily. No initial dosage adjustment is recommended for patients who are
elderly or who have mild renal or mild-to-moderate hepatic impairment.
Alogliptin has not been studied in patients with severe hepatic
impairment. Alogliptin is also available as combination therapy under
the names Kazano (alogliptin + metformin HCl) and Oseni (alogliptin +
Tofacitinib (Xeljanz, Pfizer)
Indication and Clinical Profile3,4: Tofacitinib,
a novel Janus kinase (Jak) 3 inhibitor, is approved to treat adults
with moderately to severely active rheumatoid arthritis (RA) who have
had an inadequate response or are intolerant to methotrexate (MTX).
Ruxolitinib (Jakafi), the only other Jak inhibitor available in
the United States, is approved to treat myelofibrosis. RA, an autoimmune
disease that causes inflammation of the joints and surrounding tissues,
affects about 1.5 million Americans. Initial treatment typically
includes a disease-modifying antirheumatic drug (DMARD) and a
nonsteroidal anti-inflammatory drug or corticosteroid to control
symptoms. MTX is generally the DMARD of choice; hydroxychloroquine is a
safer alternative that may be appropriate in milder cases. Tumor
necrosis factor inhibitors (TNFIs) are usually the first-line biologic
agents prescribed after inadequate response to a DMARD; they may be
given as monotherapy or in combination with MTX. For patients with an
inadequate response to a TNFI, it may be effective to switch to a second
TNFI or to a non-TNF biologic agent with a different mechanism of
action. Tofacitinib is a new biologic treatment option for adults with
RA who have a poor response to MTX. It may be used as monotherapy or in
combination with MTX or other nonbiologic DMARDs.
FDA approval of tofacitinib was based on two dose-ranging trials and
five confirmatory trials in more than 3,300 patients with
moderate-to-severe RA who did not respond to previous treatment with MTX
or another nonbiologic DMARD, or with a TNFI or another biologic DMARD.
In all trials, compared with patients taking placebo, patients taking
tofacitinib 5 mg or 10 mg twice daily—with or without background DMARD
treatment—had higher ACR20, ACR50, and ACR70 response rates (RRs) (20%,
50%, and 70% improvement on the American College of Rheumatology [ACR]
scale, respectively) at months 3 and 6. Higher ACR20 RRs were observed
within 2 weeks versus placebo. In the 12-month trials, ACR RRs in
tofacitinib-treated patients were consistent at 6 and 12 months. In
these trials, a greater proportion of patients taking tofacitinib 5 mg
or 10 mg twice daily plus MTX achieved a low level of disease activity,
as measured by a Disease Activity Score (DAS28-4 [erythrocyte
sedimentation rate]) <2.6, at 6 months, versus patients taking MTX
alone; they also showed significant improvement on the Health Assessment
Questionnaire Disability Index.
Pharmacology and Pharmacokinetics3,4: Tofacitinib is a pyrrolopyrimidine (FIGURE 2)
that acts as a Jak3 inhibitor. Jaks are intracellular enzymes that
transmit signals arising from cytokine or growth factor receptor
interactions on the cellular membrane to influence cellular processes of
hematopoiesis and immune-cell function. Within the signaling pathway,
Jaks phosphorylate and activate signal transducers and activators of
transcription (STATs), which modulate intracellular activity, including
gene expression. Tofacitinib modulates the signaling pathway at the
point of Jaks, preventing phosphorylation and activation of STATs. In a
murine model of established arthritis, tofacitinib rapidly improved
disease by inhibiting the production of inflammatory mediators and
suppressing STAT1-dependent genes in joint tissue. The efficacy of this
disease model correlated with inhibition of both Jak1 and Jak3 signaling
pathways, suggesting that tofacitinib may exert therapeutic benefit via
pathways that are not exclusive to Jak3 inhibition.
Adverse Reactions (ARs) and Drug Interactions3,4:
The most common ARs associated with tofacitinib in clinical trials were
upper respiratory tract infections, headache, diarrhea,
nasopharyngitis, and hypertension. Tofacitinib also was associated with
an increased risk of serious infections, including tuberculosis (TB) and
other opportunistic infections, and with lymphoma and other cancers.
The product labeling has a Black Box Warning regarding these safety
risks. Patients should be tested for latent or active TB before starting
tofacitinib. Eleven solid cancers and one lymphoma were diagnosed in
3,328 patients taking tofacitinib with or without a DMARD for ≤12
months, versus no solid cancers or lymphoma in 809 patients taking
placebo with or without a DMARD for 3 to 6 months. The significance of
this finding is unclear.
Tofacitinib treatment is associated with gastrointestinal perforation
(especially in patients with diverticulitis), increases in cholesterol
and liver-enzyme tests, and reductions in blood counts (lymphocytopenia,
neutropenia, hemoglobin levels). Tofacitinib was approved with a Risk
Evaluation and Mitigation Strategy, which consists of a Medication Guide
advising patients about important safety information and a
communication plan informing health care providers about the serious
risks associated with tofacitinib and advising regular monitoring. The
FDA is also requiring a postmarketing study to evaluate the long-term
effects of tofacitinib with regard to heart disease, cancer, and serious
infections. Tofacitinib has demonstrated feticidal and teratogenic
effects in animals and is classified as Pregnancy Category C.
Tofacitinib is metabolized by CYP3A4. Thus, potent inhibitors of
CYP3A4, (e.g., ketoconazole) can increase serum concentrations of
tofacitinib, and the tofacitinib dosage should be reduced to 5 mg once
daily if these drugs are taken concurrently. Drugs that are both
moderate CYP3A4 inhibitors and potent CYP2C19 inhibitors (e.g.,
fluconazole) also increase serum concentrations of tofacitinib;
concurrent use requires a reduction in tofacitinib dosage. Potent
inducers of CYP3A4 (e.g., rifampin) decrease tofacitinib levels and
should be avoided. Tofacitinib should not be coadministered with other
biologic agents or potent immunosuppressive drugs. Live vaccines should
not be given to patients taking tofacitinib; immunizations should be
updated before tofacitinib is initiated.
Dosage and Administration3,4: Tofacitinib
is supplied as 5-mg tablets. The recommended initial dosage is 5 mg
twice daily, with or without food. The dosage should be reduced to 5 mg
once daily in patients with moderate hepatic impairment or
moderate-to-severe renal impairment. The drug is not recommended for
patients with severe hepatic impairment or for those with a low
lymphocyte count (<500 cells/mm3), a low absolute neutrophil count (<1,000 cells/mm3), or low hemoglobin levels (<9 g/dL).
Apixaban (Eliquis, Bristol-Myers Squibb, Pfizer)
Indication and Clinical Profile5,6: Apixaban
is the newest anticoagulant approved by the FDA to reduce the risk of
stroke and systemic embolism in patients with nonvalvular atrial
fibrillation (AF). AF, which affects approximately 3 million people in
the United States, causes the heart to beat with less strength and
regularity, resulting in blood pooling in the atria. This results in a
greater likelihood of clot formation, which increases the risk of stroke
and systemic embolism. Anticoagulant therapy is recommended for
patients with AF and a CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, or stroke
× 2) score ≥1. For years, the anticoagulant of choice for AF patients
has been warfarin; however, warfarin has multiple drug and food
interactions and requires regular international normalized ratio (INR)
monitoring. Apixaban is the third anticoagulant since 2010 to be
approved as an alternative to warfarin (the others are rivaroxaban and
dabigatran) for patients who are nonadherent to routine INR monitoring
or did not achieve clinical benefit from warfarin.
Approval of apixaban was based on two 2-year, multicenter,
randomized, head-to-head, double-blind studies that involved more than
23,000 patients with AF. These studies demonstrated that, at endpoint,
apixaban was statistically superior to placebo and active comparators
(warfarin and aspirin) for reducing stroke and systemic embolism in
patients who have nonvalvular AF.
Pharmacology and Pharmacokinetics5,6: Apixaban is a pyrazolopyridinone (FIGURE 3)
that indirectly decreases platelet aggregation by reversibly inhibiting
free and clot-bound factor Xa (FXa) at the active site. FXa antagonism
results in reduced prothrombinase activity, causing a decrease in
thrombin generation. This mechanism inhibits development of thrombi that
are induced by thrombin.
The estimated absolute bioavailability of apixaban is 50% when the
drug is taken with or without food. Apixaban undergoes prolonged
absorption, with a half-life of 12 hours, and it is approximately 87%
plasma protein bound. Apixaban is metabolized by O-demethylation
and hydroxylation to inactive metabolites, mainly by CYP3A4, with minor
contributions from other cytochrome isozymes. The drug is eliminated in
the urine and feces, 25% of it as inactive metabolites.
Adverse Reactions (ARs) and Drug Interactions5,6:
In clinical trials, ARs were similar to those reported in patients
taking other anticoagulants. The most frequent ARs reported in clinical
trials were increased bleeding and symptoms of increased bleeding
(paleness, fatigue). Major bleeding events (intracranial, intraspinal,
intraocular, pericardial, intra-articular, intramuscular, severe
retroperitoneal), some of them fatal, have occurred; the risk is
increased in patients aged >75 years and in patients whose INR with
warfarin was within goal (2.0-3.0). Any patient exhibiting signs of
active pathologic bleeding should not take apixaban. Apixaban increases
the risk of bleeding during labor and pregnancy; therefore, in pregnant
patients, consideration should be given to whether the potential
benefits outweigh the potential risks (Pregnancy Category B). Apixaban
should not be taken by patients who are breastfeeding, as it is
currently unknown whether the drug is excreted in breast milk. The
safety and efficacy of apixaban have not been established in patients
with prosthetic heart valves, so the drug should be avoided in this
Coadministration of drugs affecting hemostasis (selective serotonin
reuptake inhibitors, serotonin norepinephrine reuptake inhibitors,
fibrinolytics, heparin, aspirin, nonsteroidal anti-inflammatory drugs)
will result in an increased risk of bleeding. The apixaban dosage should
be reduced when the drug is coadministered with strong dual inhibitors
of CYP3A4 and P-glycoprotein (Pgp) (ketoconazole, itraconazole,
ritonavir, clarithromycin). Concomitant use of apixaban with strong dual
inducers of CYP3A4 and Pgp (rifampin, carbamazepine, phenytoin, St.
John’s wort) should be avoided, as this can result in inadequate drug
concentrations. Procoagulant reversal agents (prothrombin complex
concentrate, recombinant factor VIIa) may potentially reverse the
effects of apixaban, but this has not been evaluated.
Dosage and Administration5,6: Apixaban
is available as capsules of 2.5 mg and 5 mg. The recommended dosage for
most patients is 5 mg twice daily. No dosage adjustment is required for
patients with mild hepatic impairment, but because of insufficient
clinical data, a dosage adjustment for moderate hepatic impairment is
not available. Apixaban should be reduced to 2.5 mg twice daily when
coadministered with strong dual inhibitors of CYP3A4 and Pgp or when
used in patients with at least two of the following characteristics: age
>80 years, body weight <60 kg, and serum creatinine >1.5
Apixaban should be temporarily discontinued ≥24 hours prior to
surgery or invasive procedures with a low risk of bleeding, and 48 hours
prior to procedures with a moderate or high risk of unacceptable or
clinically significant bleeding. Apixaban should not be permanently
discontinued without starting an alternative anticoagulant, as doing so
incurs an increased risk of stroke or other thrombotic events.
Perampanel (Fycompa, Eisai)
Indication and Clinical Profile7,8: Perampanel
is approved to treat partial-onset seizures in epilepsy patients aged
≥12 years. Partial-onset seizures, the most common type of seizure in
patients with epilepsy, affect only a limited or localized area of the
brain at onset, but they can spread to other parts of the brain.
Seizures cause a wide range of symptoms, including repetitive limb
movements (spasms), unusual behavior, and generalized convulsions with
loss of consciousness. Many epilepsy patients do not achieve
satisfactory seizure control with the treatments currently available;
thus, it is important to have a variety of options.
FDA approval of perampanel was based on three randomized,
double-blind, placebo-controlled, multicenter trials involving 1,037
patients aged ≥12 years. All trials had a 6-week baseline period during
which patients needed to have more than five seizures in order to be
randomized. Median baseline seizure frequency ranged from 9.3 to 14.3
seizures per 28 days. The baseline period was followed by a 19-week
treatment period consisting of a 6-week titration phase and a 13-week
maintenance phase. The primary endpoint in all trials was the percentage
change in seizure frequency per 28 days during the treatment period
compared with the baseline period. A statistically significant decrease
in seizure rate was observed at dosages of 4 mg to 8 mg/day, with little
additional reduction in frequency at 12 mg/day. Proportions of patients
with a ≥50% reduction in seizure frequency were 19.3%, 28.5%, 35.3%,
and 35.0% for placebo, 4 mg, 8 mg, and 12 mg, respectively.
Pharmacology and Pharmacokinetics7,8: Perampanel is a pyridopyridone (FIGURE 4)
that acts as a selective, noncompetitive antagonist of the ionotropic
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor
on postsynaptic central nervous system (CNS) neurons. Glutamate is the
primary excitatory neurotransmitter in the CNS and is implicated in a
number of neurologic disorders caused by neuronal overexcitation.
Perampanel has high potency and a prolonged terminal half-life of
approximately 70 hours. The drug is 95% bound to plasma protein, and its
primary route of metabolism is via CYP3A4. Perampanel does not induce
or inhibit any CYP isoenzymes. About 70% of the dose is excreted in the
feces, and 30% is excreted in the urine; less than 2% is excreted
unchanged in the urine.
Adverse Reactions (ARs) and Drug Interaction7,8:
In clinical trials, the most common ARs reported with perampanel were
dizziness, drowsiness, fatigue, irritability, falls, upper respiratory
tract infection, weight increase, vertigo, ataxia, gait disturbance,
balance disorder, anxiety, blurred vision, dysarthria, asthenia,
aggression, and hypersomnia. The drug has a Black Box Warning concerning
the risk of serious neuropsychiatric events, including irritability,
aggression, anger, anxiety, paranoia, euphoric mood, agitation, and
mental status changes. Some of these events were serious and
life-threatening. Health care providers should be alerted immediately if
changes in mood or behavior that are atypical for the patient are
observed. Patients should also be closely monitored during the titration
period, when higher dosages are used.
Dosage and Administration7,8: Perampanel
is supplied as 2-, 4-, 6-, 8-, 10-, and 12-mg tablets. The minimum
effective dosage is 4 mg once daily. Dosages of 8 mg and 12 mg confer a
greater therapeutic benefit, but also an increase in ARs. In the absence
of enzyme-inducing antiepileptic drugs (AEDs), the recommended starting
dose is 2 mg once daily at bedtime. The dosage is then increased by
increments of 2 mg/day, no more frequently than every week, to a total
of 4 mg to 8 mg once daily at bedtime. In elderly patients, dosage
increases during titration are recommended no more frequently than every
2 weeks. The recommended maximum dosage is 12 mg once daily. In the
presence of enzyme-inducing AEDs (e.g., phenytoin, carbamazepine,
oxcarbazepine), the recommended starting dose is 4 mg, and patients
should be monitored closely for response.
Pasireotide (Signifor, Novartis)
Indication and Clinical Profile9,10: Pasireotide diaspartate is
specifically indicated for the treatment of Cushing’s disease in adults
for whom pituitary surgery is not an option or has not been curative.
In Cushing’s disease, a tumor in the pituitary gland leads to
overproduction and release of adrenocorticotropic hormone (ACTH),
resulting in hyperstimulation of the adrenal gland and overproduction of
cortisol. Cortisol regulates many important bodily functions, including
response to stress and injury. Patients with Cushing’s disease may have
increased weight, glucose intolerance or diabetes, high blood pressure,
easy bruising, and increased risk of infections. Although pituitary
surgery tends to be first-line therapy for Cushing’s disease, it is not
always successful, and some patients refuse to undergo the procedure.
The safety and effectiveness of pasireotide were evaluated in a
multicenter, randomized clinical trial involving 162 patients. Most
patients had persistent or recurrent Cushing’s disease despite pituitary
surgery; the rest were de novo patients for whom surgery was not
indicated or who had refused surgery. Patients were assigned to one of
two pasireotide regimens (0.6 mg subcutaneously [SC] twice daily [bid]
or 0.9 mg SC bid) for a 6-month period. The dosage could be reduced by
0.3 mg bid for intolerability at any time, and some patients who safely
responded to the medication were allowed to continue treatment. The
primary efficacy endpoint was the proportion of patients who achieved
normalization of mean 24-hour urinary free cortisol (UFC) levels after 6
months and did not dose-increase during this period. At month 6,
percentages of responders for the primary endpoint were 15% and 26% in
the 0.6 mg bid and 0.9 mg bid groups, respectively, with some reductions
observed as early as 1 month after treatment initiation. For patients
who remained in the trial (n = 78), similar UFC-lowering was observed at
the end of 1 year.
Pharmacology and Pharmacokinetics9,10: Pasireotide is a somatostatin-based cyclohexapeptide somatostatin analogue (FIGURE 5)
that exerts its pharmacologic activity via binding to somatostatin
receptor (SSTS) subtypes 1 through 5. In Cushing’s disease, pituitary
corticotroph tumor cells frequently overexpress SSTS-5, whereas the
other receptor subtypes often are not expressed or are expressed at
lower levels. Pasireotide has a 40-fold increased affinity for SSTS-5,
and binding to this receptor leads to inhibition of ACTH secretion,
which in turn results in reduced adrenal cortisol secretion.
Pasireotide gives peak plasma concentrations within 30 minutes
postadministration and is widely distributed. It is not significantly
metabolized, but somatostatin analogues (including pasireotide) may
decrease the metabolic clearance of compounds metabolized by CYP450
enzymes. Pasireotide is a substrate for P-glycoprotein pumps, but no
other known transporter. The drug is cleared primarily hepatically and
appears to have a half-life of about 12 hours.
Adverse Reactions (ARs) and Drug Interactions9,10: The
most common ARs observed in clinical trials with pasireotide were
hyperglycemia, diarrhea, nausea, abdominal pain, and gallstones.
Hyperglycemia could be detected as early as 2 weeks after treatment
initiation, and continued treatment caused or worsened diabetes in some
patients. Therefore, patients should be carefully monitored and treated
appropriately with antidiabetic therapies, including insulin. Also,
based on its mechanism, pasireotide may cause biochemical and/or
clinical hypocortisolism. If this occurs, it may be necessary to reduce
or interrupt the dosage and/or add a low-dose short-term glucocorticoid.
The FDA is requiring several postmarketing studies for pasireotide
that focus on safety monitoring for serious hyperglycemia, acute liver
injury, and adrenal insufficiency. Pasireotide is Pregnancy Category C,
and it should not be used while nursing since it is excreted in breast
milk. The safety and effectiveness of pasireotide have not been
established in pediatric patients.
Concurrent use of cyclosporine with pasireotide may decrease the
relative bioavailability of cyclosporine; therefore, dosage adjustment
of cyclosporine to maintain therapeutic levels may be necessary. Caution
is required when pasireotide is coadministered with antiarrhythmic
agents and other drugs that may prolong the QT interval. No significant
interactions have been observed between pasireotide and drugs used to
manage hyperglycemia (metformin, nateglinide, liraglutide).
Dosage and Administration9,10: Pasireotide
is supplied as a solution for SC injection. The recommended initial
dose is either 0.6 mg or 0.9 mg SC twice daily. Patients should be
evaluated for treatment response, including a clinically significant
reduction in 24-hour urinary free cortisol levels and/or improvement in
disease signs or symptoms. Patients should continue pasireotide therapy
as long as benefit is derived. The drug is dispensed with a Medication
Guide, including instructions for patients and caregivers that describe
the risks and ARs to be mindful of when using pasireotide. See the
prescription label for any dosing modifications.
1. Nesina (alogliptin) product information. Deerfield, IL: Takeda Pharmaceuticals America, Inc; January 2013.
2. DeFronzo RA, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 010
Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor
alogliptin in patients with type 2 diabetes and inadequate glycemic
control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31:2315-2317.
3. Xeljanz (tofacitinib) product information. New York, NY: Pfizer Inc; November 2012.
4. Fleischmann R, Kremer J, Cush J, et al; ORAL Solo Investigators.
Placebo-controlled trial of tofacitinib monotherapy in rheumatoid
arthritis. N Engl J Med. 2012;367:495-507.
5. Eliquis (apixaban) product information. Princeton, NJ: Bristol-Myers Squibb Co, and New York, NY: Pfizer Inc; December 2012.
6. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees
and Investigators. Apixaban versus warfarin in patients with atrial
fibrillation. N Engl J Med. 2011;365:981-992.
7. Fycompa (perampanel) product information. Woodcliff Lake, NJ: Eisai Inc; October 2012.
8. French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for
refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79:589-596.
9. Signifor (pasireotide diaspartate) product information. East Hanover, NJ: Novartis Pharmaceuticals Corp; December 2012.
10. Colao A, Petersenn S, Newell-Price J, et al; Pasireotide B2305
Study Group. A 12-month phase 3 study of pasireotide in Cushing’s
disease. N Engl J Med. 2012;366:914-924.
To comment on this article, contact email@example.com.