US Pharm. 2012;37(10):46-55.
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
Abiraterone (Zytiga, Janssen Biotech, Inc.)
Indication and Clinical Profile1,2:
Abiraterone acetate is the first oral, once-daily medication indicated
for use in combination with prednisone for the treatment of men with
metastatic castration-resistant prostate cancer (CRPC) who have received
prior chemotherapy containing docetaxel.
Other than skin cancers, prostate cancer is the most
frequently diagnosed cancer in men in the United States. In 2010, more
than 217,000 new cases of prostate cancer were estimated and more than
32,000 men died from the disease. In prostate cancer, the male sex
hormone testosterone stimulates prostate tumors to grow. Drugs or
surgery are used to reduce testosterone production or to block
testosterone’s effects. However, prostate cancer can sometimes continue
to grow and metastasize beyond the prostate despite serum testosterone
below castration levels. Men with these cancers are said to have CRPC.
FDA approval was based on a controlled, multicenter study
involving 1,195 patients. These patients received either abiraterone
orally at a dose of 1,000 mg once daily in combination with prednisone 5
mg orally twice daily or placebo once daily plus prednisone 5 mg orally
twice daily. Treatment was administered until disease progression
(defined as a 25% increase in prostate-specific antigen [PSA] over the
patient’s baseline), initiation of new treatment, unacceptable toxicity,
The prespecified interim analysis was conducted after 552
deaths and showed a statistically significant improvement in overall
survival in subjects treated with abiraterone compared to placebo. An
updated survival analysis was conducted when 775 deaths occurred.
Results from this analysis were consistent with those from the interim
analysis. In the interim analysis, the median survival was 14.8 months
for the abiraterone arm and 10.9 months for the placebo arm. In the
updated analysis, the median survival was 15.8 months and 11.2 months,
Pharmacology and Pharmacokinetics1,2: Abiraterone acetate is a pyridine-steroidal prodrug that is hydrolyzed in vivo to abiraterone (FIGURE 1).
Abiraterone inhibits 17α-hydroxylase/C17,20-lyase, a CYP450 complex
(CYP17) that is involved in testosterone production. This enzyme is
expressed in testicular, adrenal, and prostatic tumor tissues and is
required for androgen biosynthesis.
After oral administration, abiraterone reaches maximum concentrations (Cmax) in about 2 hours. Taking the drug with food results in a significant increase in Cmax
and area under the curve (AUC). Abiraterone is partly metabolized in
the liver by CYP3A4 to inactive metabolites and is excreted primarily in
the feces, with a terminal half-life of about 12 hours.
Adverse Reactions and Drug Interactions1,2: The
most commonly reported side effects (>5%) in patients receiving
abiraterone include joint swelling or discomfort, hypo-kalemia, edema,
muscle discomfort, hot flush, diarrhea, urinary tract infection (UTI),
cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia,
and upper respiratory tract infection. Abiraterone should be used with
caution in patients with a history of cardiovascular disease or with
medical conditions that might be compromised by increases in
hypertension, hypokalemia, and fluid retention. Hypertension and
hypokalemia should be corrected before and during treatment, and blood
pressure, serum potassium, and symptoms of fluid retention should be
monitored at least monthly.
CYP17 inhibition also causes adrenocortical insufficiency,
hypertension, hypokalemia, and fluid retention. Coadministration of
prednisone reduces the severity of these effects, which have led to drug
interruption, dose modification, and/or discontinuation. Liver function
should also be monitored since increases in liver enzymes have been
Abiraterone is an inhibitor of the hepatic
drug-metabolizing enzyme CYP2D6; thus, coadministration with CYP2D6
substrates that have a narrow therapeutic index should be avoided. If an
alternative cannot be used, exercise caution and consider a dose
reduction of the CYP2D6 substrate. Additionally, abiraterone is a
substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4
should be avoided or used with caution.
Dosage and Administration1,2: Abiraterone
is supplied as 250-mg tablets for oral administration. It should be
taken with water and swallowed whole. Patients should not eat for 2
hours before taking the drug or for 1 hour afterwards. The recommended
dosage is 1,000 mg administered orally once daily in combination with
prednisone 5 mg administered orally twice daily.
The dosage should be decreased to 250 mg once daily in
patients with moderate hepatic impairment; it should not be used in
patients with severe hepatic impairment. If alanine aminotransferase
(ALT) and/or aspartate aminotransferase (AST) increases to five times
the upper limit of normal (ULN) or bilirubin increases to three times
the ULN, the drug should be stopped and restarted at a lower dose.
Avanafil (Stendra, Vivus, Inc.)
Indication and Clinical Profile3: Avanafil
is a new phosphodiesterase type 5 (PDE5) inhibitor approved to treat
erectile dysfunction (ED). This common condition affects an estimated 30
million men in the U.S., and its incidence increases with age.
The drug’s safety and efficacy were established in three
placebo-controlled clinical studies. A total of 1,923 patients were
randomly assigned to the drug for up to 12 weeks at doses of 50 mg, 100
mg, or 200 mg, or to a placebo as needed about 30 minutes before sexual
activity. The primary outcome measures were the erectile function domain
of the International Index of Erectile Function (IIEF) and questions 2
and 3 from the Sexual Encounter Profile (SEP). Avanafil demonstrated
statistically significant improvement from baseline in all three dose
arms against placebo.
A subset of patients from two of these trials were
enrolled in an extension trial of 3 months’ duration to evaluate
avanafil (100 or 200 mg) in ED patients with type 1 or type 2 diabetes
mellitus. In this study, patients in the avanafil treatment groups
demonstrated statistically significant improvement from baseline against
placebo based on the IIEF and SEP measures.
Pharmacology and Pharmacokinetics3: Avanafil is a highly selective pyrimidinecarboxamide PDE5 inhibitor (FIGURE 2).
PDE5 is responsible for the degradation of cyclic guanosine
monophosphate (cGMP), which produces smooth-muscle relaxation in the
corpus cavernosum and allows inflow of blood. Erection of the penis
involves release of nitric oxide (NO) in the corpus cavernosum during
sexual stimulation. NO then activates the enzyme guanylate cyclase,
which results in increased levels of cGMP, producing smooth-muscle
relaxation in the corpus cavernosum and allowing inflow of blood.
Avanafil enhances the effect of NO by inhibiting PDE5. Because sexual
stimulation is required to initiate the local release of nitric oxide,
the inhibition of PDE5 has no effect in the absence of sexual
Oral avanafil is rapidly absorbed, and food does not
significantly reduce bioavailability. The drug is extensively
metabolized, primarily by CYP3A4, and the metabolites have significantly
reduced ED activity. Avanafil is excreted as metabolites predominantly
in the feces (62%) and to a lesser extent in the urine (21%). The drug
has a terminal elimination half-life of approximately 5 hours.
Adverse Reactions and Drug Interactions3: The
most common side effects reported in >2% of patients in the clinical
studies of avanafil include headache, flushing, nasal congestion,
nasopharyngitis, and back pain.
In rare cases, patients taking avanafil and other PDE5
inhibitors may get an erection lasting 4 hours or longer (priapism).
When this occurs, patients should seek immediate medical care. In
addition, PDE5 inhibitors rarely may cause color vision changes, even
sudden loss of vision in one or both eyes and sudden loss or decrease in
hearing. Patients who experience a sudden loss of vision or hearing
should stop taking PDE5 inhibitors and immediately seek medical
As with other PDE5 inhibitors, administration of avanafil
is contraindicated with organic nitrates. Avanafil can potentiate the
hypotensive effect of nitrates, alpha-blockers, antihypertensives, and
alcohol. Avanafil is a CYP3A4 substrate that should not be used with
strong CYP3A4 inhibitors and only used in reduced doses with moderate
Dosage and Administration3: Avanafil
is supplied as 50-, 100-, and 200-mg tablets for oral administration.
The recommended initial dosage is 100 mg taken approximately 30 minutes
before sexual activity with or without food. The dosage may be increased
to 200 mg or decreased to 50 mg. The lowest dose that provides benefit
should be used as needed no more than once per day. If used with a
moderate CYP3A4 inhibitor, the dose should not exceed 50 mg in a 24-hour
period. For patients on stable alpha-blocker therapy, the recommended
starting dose is 50 mg.
Clobazam (Onfi, Lundbeck Inc.)
Indication and Clinical Profile4,5: Clobazam
has been approved as an adjunctive treatment for seizures associated
with Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older.
LGS is a severe form of epilepsy that usually begins before 4 years of
age. It can be caused by a number of conditions, including brain
malformations, severe head injuries, central nervous system (CNS)
infections, and inherited degenerative or metabolic conditions. In 30%
to 35% of patients, no cause can be found.
Patients commonly have frequent seizures of a wide
variety, including tonic, atonic, atypical absence, and myoclonic. Most
children with LGS experience some degree of impaired intellectual
functioning or information processing, as well as developmental delays
and behavioral disturbances. Since this disease affects fewer than
200,000 people in the U.S., clobazam was granted orphan drug designation
by the FDA.
The efficacy of clobazam, when added to ongoing seizure
medication, was established in two multicenter controlled studies of
patients aged ≥2 years. In each study, the drug was tested for the
amount of reduction in the weekly frequency of drop seizures (atonic,
tonic, or myoclonic seizures resulting in a fall or loss of posture)
from the 4-week baseline period to a maintenance period. In both
studies, patients taking clobazam had improved seizure control when
compared to those taking placebo or low-dose clobazam.
Pharmacology and Pharmacokinetics4,5: Clobazam is an antiepileptic drug of the 1,5-benzodiazepine class (FIGURE 3).
The exact mechanism of action is not completely understood, although it
likely involves potentiation of GABA-ergic neurotransmission, which
results from binding at the benzodiazepine site of the GABAA receptor.
Clobazam is rapidly and extensively absorbed following
oral administration and readily distributes to the CNS due to its
lipophilicity. It is extensively metabolized in the liver, and the major
metabolic pathway involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6.
N-desmethylclobazam, an active metabolite, is the
major circulating metabolite in humans, and at therapeutic doses, plasma
concentrations are three to five times higher than those of the parent
compound. N-desmethylclobazam is extensively metabolized, primarily by CYP2C19. N-desmethyl-clobazam and its metabolites constitute approximately 94% of the total drug-related components in urine.
Adverse Reactions and Drug Interactions4,5: Common
adverse reactions reported by patients taking clobazam include
somnolence, sedation, fever, drooling, cough, constipation, insomnia,
aggression, fatigue, UTI, upper respiratory tract infection,
irritability, vomiting, dysphagia, ataxia, bronchitis, and pneumonia.
Like other drugs of its class, clobazam should not be discontinued
suddenly. Clobazam may slow thinking and impair motor skills; thus,
patients should be cautioned against engaging in hazardous activities
until its effects are known. It can also cause abuse and dependence and
has been categorized as a Schedule IV drug.
As with other antiepileptics, clobazam may increase the
risk of suicidal thoughts or behaviors in a small number of people
taking the drug, so patients should be monitored for depression,
suicidal thoughts or behavior, and unusual changes in mood or behavior.
Clobazam is classified as a Pregnancy Category C drug.
CYP3A4 is the predominant enzyme that forms the active
metabolite of clobazam, which is further metabolized by CYP2C19.
Therefore, concurrent use of drugs that inhibit CYP2C19 (e.g.,
fluconazole or omeprazole) can increase serum concentrations of the
active metabolite and possibly its toxicity. Similarly, patients with
the “poor metabolizing” CYP2C19 polymorph may be at a greater risk for
Clobazam inhibits CYP2D6; thus, drugs that are metabolized
by 2D6 (e.g., fluoxetine or paroxetine) may require a dosage reduction
if taken concomitantly with clobazam. Clobazam is also a mild inducer of
CYP3A4 and may reduce serum concentrations of drugs metabolized by this
pathway, including hormonal contraceptives.
Alcohol and clobazam have additive effects on CNS
depression. In addition, alcohol can significantly increase plasma
levels of clobazam.
Dosage and Administration4,5: Clobazam
is supplied as 5-, 10-, and 20-mg tablets. The tablets can be
administered whole or crushed and mixed in applesauce, and should be
administered in divided doses twice daily. The recommended starting
dosage for patients who weigh ≤30 kg is 5 mg once daily for at least 1
week. The dose can be titrated to 5 mg twice daily and then to 10 mg
twice daily; the patient should take each dose for at least 1 week
before increasing it. For patients weighing >30 kg, the recommended
initial dosage is 5 mg twice daily for at least 1 week, followed by an
increase to 10 mg twice daily and then to a maintenance dose of 20 mg
Patients ≥65 years, those with mild-to-moderate hepatic
impairment, and those who are poor CYP2C19 metabolizers should take 5 mg
once daily initially. To avoid withdrawal symptoms or exacerbation of
seizures when discontinuing the drug, the daily dose should be reduced
weekly by 5 to 10 mg.
Tafluprost (Zioptan, Merck & Co., Inc.)
Indication and Clinical Profile6,7: Glaucoma
is an eye disease associated with increased fluid pressure in the eye,
eventually causing permanent damage to the optic nerve, impairing the
field of vision, and ultimately leading to blindness. Glaucomas are
subclassified as open-angle glaucoma (OAG) and closed-angle glaucoma
(CAG). CAG is an acute disease with rapid progression, while OAG is a
slowly progressive disease responsible for about 90% of glaucoma cases
in the U.S. Management of OAG typically includes medication to lower
intraocular pressure (IOP) and surgery.
Tafluprost is the newest ophthalmic prostaglandin approved
for reducing elevated IOP in patients with OAG or ocular hypertension.
It is an analogue of prostaglandin F2α, similar to other
antiglaucoma drugs. Prostaglandin analogues, including latanoprost,
bimatoprost, and travo-prost, are often used as first-line treatment to
lower IOP in patients with OAG. However, unlike other prostaglandin
drugs, tafluprost is preservative free; it does not contain benzalkonium
chloride, which may be irritating to some patients’ eyes.
The FDA approval of tafluprost was based on results from
five controlled clinical studies of up to 2 years in 905 patients. Both
preservative-containing and preservative-free formulations of tafluprost
were used. In clinical studies of up to 2 years in duration,
tafluprost, dosed once daily in the evening, lowered IOP at 3 and 6
months by 6 to 8 mmHg and 5 to 8 mmHg, respectively, from a baseline
pressure of 23 to 26 mmHg. Tafluprost, under other trademarks, has been
marketed outside the U.S. since 2008.
Pharmacology and Pharmacokinetics6,7: Tafluprost is a fluorinated analogue of prostaglandin F2α and an ester prodrug (FIGURE 4).
Ester-ification facilitates corneal permeation. Esterases in the eye
convert the drug to the active prosta-glandin acid form. The active acid
is a selective FP prostanoid receptor agonist that is believed to
reduce IOP by increasing uveoscleral outflow. The exact mechanism of
action is unknown at this time. Mean plasma Cmax is about 26 to 27 pg/mL, and mean plasma AUC is 394 to 432 pg*min/mL.
Adverse Reactions and Drug Interactions6,7: In
clinical trials of patients receiving either preservative-containing or
preservative-free tafluprost, the most common (4%-20%) pooled adverse
reaction observed was conjunctival hyperemia. Tafluprost may gradually
change eyelashes and vellus hair in the treated eye. These changes
include increased length, color, thickness, shape, and number of lashes
and are usually reversible upon discontinuation of treatment.
Tafluprost also has been reported to cause increased
pigmentation of the iris, periorbital tissue (eyelid), and eyelashes.
After discontinuation, pigmentation of the iris is likely to be
permanent, while pigmentation of the periorbital tissue and eyelash
changes have been reported to be reversible in some patients.
Tafluprost should be used with caution in patients with
active intraocular inflammation because the inflammation may be
exacerbated. Macular edema, including cystoid macular edema, has been
reported during treatment with prostaglandin F2α analogues.
Tafluprost should also be used with caution in aphakic patients (i.e.,
lacking a lens in the eye), in pseudophakic patients with a torn
posterior lens capsule, or in patients with known risk factors for
Tafluprost should not be used during pregnancy unless the
potential benefit justifies the potential risk to the fetus, and caution
should be exercised when it is administered during nursing (Pregnancy
Category B). No significant drug interactions are anticipated.
Dosage and Administration6,7: Tafluprost
is provided in 0.3 mL single-use containers containing 0.015 mg/mL of
the drug. The product does not contain preservatives, is a sterile
solution for single use only, and is of sufficient quantity to treat one
or both eyes. The recommended dosage is one drop in the conjunctival
sac of the affected eye(s) once daily in the evening. The dose should
not exceed once daily, as more frequent administration of prostaglandin
analogues may lessen the IOP-lowering effect. Since tafluprost does not
contain preservatives, any unused solution should be discarded
Tafluprost may be used concomitantly with other ophthalmic
products that lower IOP. If more than one topical ophthalmic product is
being used, they should be administered at least 5 minutes apart from
1. Zytiga (abiraterone acetate) package insert. Horsham, PA: Janssen Biotech, Inc; April 2011.
2. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
3. Stendra (avanafil) package insert. Mountain View, CA: Vivus, Inc; April 2012.
4. Onfi (clobazam) package insert. Deerfield, IL: Lundbeck Inc; October 2011.
5. Ng YT, Conry JA, Drummond R, et al; OV-1012 Study
Investigators. Randomized, phase III study results of clobazam in
Lennox-Gastaut syndrome. Neurology. 2011;77:1473-1481.
6. Zioptan (tafluprost) package insert. Whitehouse Station, NJ: Merck & Co., Inc; January 2012.
7. Erb C, Lanzl I, Seidova SF, Kimmich F.
Preservative-free tafluprost 0.0015% in the treatment of patients with
glaucoma and ocular hypertension. Adv Therapy. 2011;28:575-585.
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