1. health and fitness
2. disease
3. cancer

CPE
New therapeutic agents marketed
in the second half of 2012: Part 2
Daniel A. Hussar
Abstract
Objective: To provide information regarding the most important properties of
the new therapeutic agents marketed in the second half of 2012.
Data sources: Product labeling supplemented selectively with published studies and drug information reference sources.
Data synthesis: 13 new therapeutic agents were marketed in the United States
during the second half of 2012, 6 of which were considered in part 1 of this two-part
series. The other seven agents are considered in this article: sodium picosulfate,
regorafenib, enzalutamide, carfilzomib, bosutinib, omacetaxine mepesuccinate,
and ponatinib. 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 the use of these
new agents also are discussed. When possible, the properties of the new drugs are
compared with those of the older agents marketed for the same indications.
Conclusion: Sodium picosulfate is a stimulant laxative that is supplied in a combination formulation that also contains magnesium oxide and anhydrous citric
acid. When dissolved in water, the latter two agents form magnesium citrate, an
osmotic laxative. The product is used for cleansing of the colon as a preparation
for colonoscopy and may be administered in a smaller volume of liquid than is
needed for other products. The other six drugs considered in this article are antineoplastic agents that have been approved for the treatment of patients who are refractory to or intolerant of the first-line and other treatment regimens. Regorafenib
is indicated for the treatment of patients with metastatic colorectal cancer who
have been previously treated with other regimens. It is effective in some patients,
but its benefit is usually of brief duration. Enzalutamide has been approved for the
treatment of patients with metastatic castration-resistant prostate cancer who have
previously received docetaxel and has increased median survival by approximately 5 months. Carfilzomib is indicated for treating patients with multiple myeloma
who have received at least two previous therapies, including bortezomib and an
immunomodulatory agent such as lenalidomide. Bosutinib, ponatinib, and omacetaxine have been approved for treating patients with chronic myeloid leukemia
(CML) with resistance or intolerance to prior therapies. Ponatinib exhibits activity
against CML cells with the T315I mutation, which is associated with resistance to
the first-line treatment imatinib.
Keywords: New drugs, Food and Drug Administration, drug development,
pharmaceutical marketing, risk assessment.
Pharmacy Today. 2013(Mar);19(3):73–84.
Accreditation information
Provider: American Pharmacists Association
Target audience: Pharmacists
Release date: March 1, 2013
Expiration date: March 1, 2016
Learning level: 2
ACPE number:
0202-0000-13-108-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 $15 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 0202-0000-13-108-H01-P.
Disclosure: Dr. Hussar 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.
www.pharmacist.com
Daniel A. Hussar, PhD, is Remington
Professor of Pharmacy, Philadelphia College
of Pharmacy, University of the Sciences in
Philadelphia.
Development: This home-study CPE activity
was developed by the American Pharmacists
Association.
Learning objectives
At the conclusion of this knowledge-based
activity, the pharmacist will be able to:
■■ Identify the new therapeutic agents
marketed July to December 2012 that
are considered and explain their appropriate use.
■■ Identify the indications and most important adverse events and other risks
of each of the new therapeutic agents.
■■ State the route of administration for
each new drug and the important
considerations regarding dosage and
administration.
■■ Demonstrate appropriate patient
counseling regarding the use of the new
medications and the precautions to be
observed.
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CPE new drugs
Preassessment questions
Before participating in this activity, test your knowledge by answering
the following questions. These questions also will be part of the CPE
exam.
1. Which of the following drug : use pairings is correct?
a. Regorafenib : prostate cancer
b. Enzalutamide : chronic myeloid leukemia
c. Carfilzomib : multiple myeloma
d. Bosutinib : colorectal cancer
2. With which of the following agents should the concurrent use
of a proton pump inhibitor be avoided?
a.Ponatinib
b.Regorafenib
c.Enzalutamide
d.Omacetaxine
3. Which of the following statements is correct regarding
enzalutamide?
a. Its action is increased by the concurrent use of gemfibrozil.
b. It must be administered apart from food.
c. Most of a dose is excreted in the urine in unchanged form.
d. The dosage should be reduced by one-half in patients with
impaired kidney function.
Laxative
Colon cancer is the second leading cause of cancer death in
the United States. Colonoscopy has been of value in reducing the incidence and subsequent deaths from colon cancer
by permitting early identification of precancerous lesions, as
well as other gastrointestinal (GI) diseases. Various laxatives
such as bisacodyl, polyethylene glycol (PEG) 3350, and certain salt/electrolyte formulations have been used to cleanse
the bowel to permit optimal visualization during the colonoscopy procedure. However, some patients have difficulty
consuming the large volumes of liquids needed in the bowelcleansing preparation for the colonoscopy and/or consider
the flavor/taste of the product to be objectionable. The result
is that some may not successfully complete the prep regimen.
Sodium picosulfate is a stimulant laxative that is supplied in a combination formulation (Prepopik—Ferring)
with magnesium oxide and anhydrous citric acid. Although
the new drug was recently approved in the United States, it
has been available in some other countries since 1980. Sodium picosulfate is a prodrug that is hydrolyzed by colonic
bacteria to an active metabolite, bis-(p-hydroxy-phenyl)-pyridyl-2-methane, which acts on the colonic mucosa to stimulate colonic peristalsis. The Prepopik formulation is supplied
as a powder, and when it is reconstituted, magnesium oxide
and citric acid react in solution to form magnesium citrate,
which is an osmotic laxative that causes water to be retained
within the GI tract. The combined actions of sodium picosulfate and magnesium citrate cause a laxative effect that when
used in conjunction with additional fluids, produces watery
diarrhea.
Prepopik for oral solution is indicated for cleansing of the
colon as a preparation for colonoscopy in adults. Its effectiveness was evaluated in two studies in which it was compared
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with another colon-cleansing regimen that included a 2-L
solution of PEG plus electrolytes and two 5-mg bisacodyl
tablets. The primary efficacy endpoint was the proportion
of patients with successful colon cleansing as determined
by blinded colonoscopists using the Aronchick scale, which
is used to assess overall colon cleansing. Prepopik was determined to be noninferior to the comparator regimen, and
when the new product was used in a “split dose” (one dose
on the evening before and the second dose on the day of the
colonoscopy), it was considered superior to the comparator
regimen (administered entirely on the day prior to colonoscopy).
The Prepopik formulation is contraindicated in patients
with severely reduced renal function (creatinine clearance
<30 mL/min) because of the risk of accumulation of magnesium. Caution also must be exercised in other patients
with impaired renal function and in those also taking other
medications that may affect renal function (e.g., diuretics).
Patients must be advised of the importance of adequate hydration before, during, and after use of the regimen. The use
of the new regimen also is contraindicated in patients with
GI obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, or gastric retention.
Fluid and electrolyte changes may increase the risk of
certain serious adverse events such as cardiac dysrhythmias
and seizures. Caution must be exercised in using the new
regimen in patients with a previous history of these conditions, and preexisting fluid and electrolyte abnormalities
should be corrected before using Prepopik. The consumption
of the recommended quantities of additional liquids reduces
the risk of certain problems, though patients with congestive
heart failure should be monitored closely when replacing fluids. Approximately 20% of the patients in both arms of the
studies experienced changes in blood pressure and/or heart
rate on the day of colonoscopy, and postcolonoscopy lab tests
(electrolytes, creatinine, and blood urea nitrogen) should be
considered if a patient develops serious vomiting or signs of
dehydration, including orthostatic hypotension.
Use of the Prepopik regimen can exacerbate certain GI
problems. If GI obstruction or perforation is suspected, diagnostic studies should be conducted to rule out these conditions before use. Caution should be observed when using
the product in patients with severe active ulcerative colitis.
The combined use of an osmotic laxative and stimulant laxative may increase the potential for mucosal ulcerations, and
this should be considered when interpreting colonoscopy
findings in patients with known or suspected inflammatory
bowel disease. Patients with impaired gag reflex and patients
prone to regurgitation or aspiration should be observed during the administration of the Prepopik regimen.
The adverse events most often reported with the Prepopik regimen in the clinical studies included nausea (3%),
headache (2%), and vomiting (1%). In general, the new regimen was associated with higher rates of abnormal electrolyte
shifts on the day of colonoscopy than were observed with the
comparator regimen. However, these shifts were transient in
www.pharmacytoday.org
CPE new drugs
Table 1. New therapeutic agents marketed in the United States from July to December 2012a
Generic name
Bosutinib
Carfilzomib
Enzalutamide
Omacetaxine
mepesuccinate
Ponatinib
Regorafenib
Sodium picosulfate
a
Trade name
Bosulif
Kyprolis
Xtandi
Manufacturer
Pfizer
Onyx
Astellas; Medivation
Therapeutic classification
Antineoplastic agent
Antineoplastic agent
Antineoplastic agent
Route of
administration
Oral
Intravenous
Oral
FDA
classificationb
1-S
1-S
1-P
Synribo
Iclusig
Stivarga
Prepopik
Teva
Ariad
Bayer; Onyx
Ferring
Antineoplastic agent
Antineoplastic agent
Antineoplastic agent
Laxative
Subcutaneous
Oral
Oral
Oral
1-S
1-P
1-P
1-S
Additional agents marketed in this time period are considered in part 1 of this two-part series (Pharmacy Today. 2013[Feb];19[2]61–71).
FDA classification of new drugs: 1 = new molecular entity; P = priority review; S = standard review.
b
nature.
The Prepopik formulation is classified in Pregnancy
Category B. Whether the ingredients are excreted in human
milk is unknown, and caution should be exercised when the
product is used by a woman who is breast-feeding. The effectiveness and safety in pediatric patients have not been
established.
The use of the Prepopik formulation may alter the absorption of other medications that are administered during
the same time period. Oral medications administered within
1 hour of the start of administration of the new formulation
may be eliminated from the GI tract at a faster rate, resulting
in a reduction in the amount of the medication that is absorbed. To avoid complexation with magnesium, tetracycline
and fluoroquinolone antimicrobial agents, digoxin, iron,
chlorpromazine, and penicillamine should be taken at least 2
hours before and not less than 6 hours after administration of
the Prepopik formulation. Because the conversion of sodium
picosulfate to its active metabolite is mediated by colonic bacteria, prior or concurrent use of antibiotics with the Prepopik
formulation may reduce its effectiveness. Caution also must
be observed when the new product is used in patients who
are taking medications (e.g., diuretics, corticosteroids) that
increase the risk of problems associated with fluid and electrolyte changes.
Prepopik is supplied in a carton containing two packets
of powder for oral solution, along with a premarked dosing
cup. Each packet contains 10 mg sodium picosulfate, 3.5 g
magnesium oxide, and 12 g anhydrous citric acid. Two doses
are administered and the powder from one of the packets
is reconstituted just before administering a dose. The dosing cup that is supplied should be filled with cold water up
to the lower (5-oz) line on the cup and the contents of one
packet of powder are poured into the cup and stirred for 2 to
3 minutes, during which time the reconstituted solution may
become slightly warm as the powder dissolves. The resulting
solution has an orange flavor.
Two dosing regimens can be used, with the “Split-Dose”
regimen being the preferred method. In this method, the
first dose is taken during the evening (e.g., 5:00 to 9:00 pm)
of the day before the colonoscopy. This dose should be followed by five 8-oz drinks (upper line on the dosing cup) of
clear liquids before bed and within 5 hours following administration of the dose. Examples of clear liquids include
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water, clear broth, apple juice, white cranberry juice, white
grape juice, ginger ale, and plain jello. Red or purple liquids
should not be consumed, neither should milk or solid foods.
The second dose is taken on the next day approximately 5
hours before the colonoscopy, followed by at least three 8-oz
drinks of clear liquids before the colonoscopy. These liquids
should be consumed within 5 hours up until 2 hours before
the colonoscopy.
The alternate dosing regimen is designated as the “DayBefore” regimen and is used for patients for whom the SplitDose method is not appropriate. The first dose is taken in
the afternoon or early evening (e.g., 4:00 to 6:00 pm) of the
day before the colonoscopy, followed by five 8-oz drinks of
clear liquids before the next dose, and within 5 hours following administration of the dose. The second dose is taken approximately 6 hours later in the late evening (e.g., 10:00 pm
to 12:00 am), followed by three 8-oz drinks of clear liquids
before bed, and within 5 hours following administration of
the dose.
The new regimen has an advantage over other coloncleansing regimens in having the lowest volume (i.e., two
5-oz doses) of liquid containing the active ingredients/electrolytes. Although additional quantities of clear liquids must
be consumed, these are of the patient’s choosing. If patients
experience bloating, distention, or abdominal pain following
the first dose, the second dose should be delayed until the
symptoms resolve.
Antineoplastic agents
Regorafenib
Before 2002, the options for treating colorectal cancer were
very limited and primarily consisted of regimens based on
fluorouracil/leucovorin and irinotecan (Camptosar). In the
following 5-year period, four new agents were approved for
treating colorectal cancer, including oxaliplatin (Eloxatin);
bevacizumab (Avastin), which exhibits anti–vascular endothelial growth factor (anti-VEGF) activity; and cetuximab
(Erbitux) and panitumumab (Vectibix), which exhibit anti–
epidermal growth factor receptor (anti-EGFR) activity. However, many patients with metastatic colorectal cancer are or
have become refractory to all of these agents and/or have
experienced intolerance.
Regorafenib (Stivarga—Bayer; Onyx) is a small-molecule
inhibitor of multiple membrane-bound and intracellular
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new drugs
kinases involved in normal cellular functions but also in
pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In
animal models, it exhibited antiangiogenic activity, inhibition of tumor growth, and antimetastatic activity that may
extend beyond that provided by other antineoplastic agents.
It is indicated for treating patients with metastatic colorectal
cancer who have been previously treated with fluoropyrimidine- (i.e., fluorouracil), oxaliplatin-, and irinotecan-based
chemotherapy, an anti-VEGF therapy, and if KRAS wild type,
an anti-EGFR therapy. The KRAS gene is a tumor marker
in colorectal cancer, and patients with the KRAS wild-type
gene—the normal, unchanged form of the gene—often benefit from the use of an EGFR inhibitor.
The effectiveness of regorafenib was demonstrated in
a randomized (2:1) placebo-controlled trial in 760 patients
who had received prior treatment with the antineoplastic
agents identified above. Patients were randomly assigned to
receive regorafenib or placebo in addition to best supportive
care (i.e., treatments to help manage adverse events or symptoms of cancer). Patients who were treated with regorafenib
lived a median of 6.4 months compared with a median of 5
months in patients receiving placebo. The study results also
showed that patients treated with regorafenib experienced a
delay in tumor growth (progression-free survival) for a median of 2 months compared with a median of 1.7 months in
those receiving placebo. Although the benefit attributed to
regorafenib is of short duration, the new agent represents an
advance for patients with no other options. In mid-2012, FDA
also approved the angiogenesis inhibitor ziv-aflibercept (Zaltrap) for use in combination with fluorouracil, leucovorin,
and irinotecan in patients with metastatic colorectal cancer
that is resistant to or has progressed following an oxaliplatin-containing regimen.
Regorafenib also is being evaluated for the treatment of
patients with GI stromal tumors. However, this is not a labeled indication at the present time.
Numerous serious adverse events have been associated
with the use of regorafenib. Fatal hepatotoxicity is the subject of a boxed warning in the labeling, and liver function
tests (e.g., alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin) should be determined before
initiating treatment, at least every 2 weeks during the first
2 months of treatment, and at least monthly thereafter. Liver
function tests should be monitored weekly in patients experiencing elevated liver function tests until improvement to
less than three times the upper limit of normal or baseline.
The incidence of hemorrhage in patients treated with
regorafenib is 21%, with a fatal outcome in 0.8%. The international normalized ratio (INR) should be monitored more
frequently in patients treated with warfarin, and the drug
should be permanently discontinued in patients who experience severe or life-threatening hemorrhage.
Hypertension is a common (30%) adverse event with the
use of regorafenib, and blood pressure should be adequately
controlled in patients for whom treatment with the new drug
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is to be initiated. Blood pressure should be monitored weekly for the first 6 weeks of treatment and then at least every
cycle of treatment. In addition, hand–foot skin reaction, also
designated as palmar–plantar erythrodysesthesia, has been
commonly experienced (45%), with the onset of symptoms
usually occurring in the first cycle of treatment and dosage
modification often being necessary.
GI perforation or fistula, myocardial ischemia and infarction, and reversible posterior leukoencephalopathy syndrome have been reported infrequently in patients treated
with regorafenib. Because regorafenib and other agents that
are VEGF inhibitors can impair wound healing, treatment
with the new drug should be stopped at least 2 weeks before
scheduled surgery.
In addition to hypertension and hand–foot skin reactions,
the other adverse events most often experienced with the use
of regorafenib include asthenia/fatigue (64%), decreased
appetite and food intake (47%), weight loss (32%), diarrhea (43%), mucositis (33%), infection (31%), and dysphonia
(30%). Liver function tests often are elevated, and decreased
electrolyte concentrations (e.g., calcium, potassium, sodium)
and blood cell counts (e.g., anemia, thrombocytopenia) are
commonly reported.
Regorafenib may cause fetal harm if administered to a
pregnant woman, and it is classified in Pregnancy Category
D. Both women and men must use effective contraception
during treatment and for 2 months following the discontinuation of treatment. Whether regorafenib is excreted in breast
milk is not known, and a decision should be made to discontinue nursing or not use the drug. The effectiveness and
safety of regorafenib in patients younger than 18 years have
not been established.
Regorafenib is administered once a day with a low-fat
breakfast that contains less than 30% fat (e.g., two slices of
white toast with 1 tbsp low-fat margarine and 1 tbsp jelly, 8
oz skim milk). The drug is primarily metabolized via the cytochrome P450 (CYP)3A4 and UDP-glucuronosyltransferase
1A9 pathways, and the M-2 and M-5 metabolites each have
pharmacological activity and steady-state concentrations
that are similar to those of the parent compound. Approximately 71% of a dose of the drug is excreted in the feces (47%
as parent compound and 24% as metabolites) and 19% is
excreted in the urine (17% as glucuronides). Clinically important changes in the activity of the drugs and its active
metabolites are not anticipated in patients with mild to moderate hepatic or renal impairment. Regorafenib has not been
studied in patients with severe hepatic or renal impairment.
The bioavailability of regorafenib and its active metabolites may be altered by strong CYP3A4 inhibitors (e.g.,
ketoconazole, clarithromycin, grapefruit juice) and strong
CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John’s
wort), and concurrent use of the new drug with any of these
agents should be avoided.
The recommended dosage of regorafenib is 160 mg once
a day with a low-fat breakfast for the first 21 days of each 28day cycle. Treatment should be continued until disease prowww.pharmacytoday.org
CPE
gression or unacceptable toxicity. The occurrence of adverse
events may necessitate a reduction in dosage, interruption
of treatment, or discontinuation of therapy, and the product
labeling should be consulted for the specific recommendations.
Regorafenib film-coated tablets are supplied in a 40-mg
potency. The tablets should be swallowed whole. The tablets
should be dispensed and stored in the original bottle, and
the desiccant should not be removed. The bottle should be
tightly closed after each opening. Tablets that are not used
within 28 days after first opening the bottle should be discarded.
Enzalutamide
According to statistics from the National Cancer Institute,
more than 28,000 men died from prostate cancer in 2012. The
treatment of prostate cancer may include surgery, radiation,
and/or medications. Because testosterone stimulates the
growth of prostate tumors, the goal of drug therapy is to reduce the production of testosterone and block its effects (i.e.,
androgen deprivation therapy, medical castration). Medical
castration (i.e., hormonal treatment) blocks androgen production in the testes and, at least initially, often provides effective treatment. However, many patients continue to produce androgens in the adrenal glands and prostate tumor
and subsequently experience castration-resistant (hormonerefractory) prostate cancer.
Until recently, a regimen based on docetaxel (e.g., Taxotere) was the only treatment that had been demonstrated
to prolong survival in men with castration-resistant prostate
cancer. However, in a period of approximately 2 years, four
new drugs have been approved for the treatment of metastatic prostate cancer. In 2010, sipuleucel-T (Provenge), an autologous cellular immunotherapy, was approved for the treatment of asymptomatic or minimally symptomatic metastatic
castration-resistant prostate cancer, and cabazitaxel (Jevtana), a taxane antineoplastic agent, was approved for use in
combination with prednisone for the treatment of metastatic
castration-resistant prostate cancer previously treated with
a docetaxel-containing regimen. In 2011, abiraterone acetate
(Zytiga) was approved for the same indication for which
cabazitaxel is approved. Abiraterone acetate is converted to
abiraterone that is an androgen biosynthesis inhibitor that
reduces the formation of testosterone precursors in multiple
tissues (e.g., testicular, adrenal, prostatic tumor).
Enzalutamide (Xtandi—Astellas; Medivation) is an androgen receptor inhibitor that acts on multiple steps in the
androgen receptor signaling pathway. Its properties are
generally similar to those of flutamide (e.g., Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron). However, the
new drug appears to bind the androgen receptors with greater affinity and it inhibits the translocation of the androgen
receptor complex into the nuclei of prostate cancer cells and
inhibits its interaction with DNA. It has been demonstrated
to decrease proliferation and induce cell death of prostate
cancer cells in vitro. Enzalutamide is indicated for the treatwww.pharmacist.com
new drugs
ment of patients with metastatic castration-resistant prostate
cancer who have previously received docetaxel. Its labeled
indication and use can best be compared with those for abiraterone, although abiraterone must be used in combination
with prednisone. In late 2012, subsequent to the approval of
enzalutamide, FDA approved the revision of the labeled indication for abiraterone to delete the phrase regarding previous treatment with a docetaxel-containing regimen.
The effectiveness of enzalutamide was evaluated in a
placebo-controlled study in approximately 1,200 patients in
which all patients continued androgen deprivation therapy.
The primary endpoint was overall survival, and in the patients treated with enzalutamide, the median survival was
18.4 months compared with 13.6 months for patients receiving placebo. The mechanism of action and safety profile of
enzalutamide have prompted interest in prescribing it in earlier stages of prostate cancer. However, this is not a labeled
indication currently.
The occurrence of seizure is the risk associated with
the use of enzalutamide that is of greatest concern. A seizure was experienced by 0.9% of the patients treated with
enzalutamide in the clinical study and treatment was permanently discontinued. The safety of the drug in patients with
predisposing factors for seizure is not known because these
patients were excluded from the study. Patients for whom
enzalutamide is prescribed should be cautioned about the
risk of engaging in activities in which the sudden loss of consciousness could cause harm to themselves and others.
The most commonly reported adverse events with
enzalutamide in the clinical trial were asthenia/fatigue
(51%), back pain (26%), diarrhea (22%), arthralgia (21%), hot
flush (20%), peripheral edema (15%), musculoskeletal pain
(15%), headache (12%), upper respiratory infection (11%),
muscular weakness (10%), and dizziness (10%). However, the
incidence of these events was not much lower in the patients
receiving placebo with only asthenia/fatigue (44%), hot flush
(10%), and headache (6%) occurring at an incidence that was
more than 5% less than that experienced in patients treated
with enzalutamide. Falls or injuries related to falls occurred
in 5% of the patients treated with enzalutamide compared
with 1% of those receiving placebo.
The only labeled indication for enzalutamide is prostate
cancer; therefore, it is not indicated for use in women. The
drug may cause fetal harm and is classified in Pregnancy
Category X, and its use during pregnancy is contraindicated.
Men who are sexually active with a pregnant woman or a
woman who may become pregnant must use a condom and
another form of birth control during treatment and for 3
months after treatment is discontinued.
Enzalutamide may be administered with or without
food. It is primarily metabolized via the CYP2C8 pathway to
a major metabolite that has activity similar to that of the parent compound. Approximately 71% of a dose is recovered as
inactive metabolites in the urine and 14% in the feces. Dosage
adjustment is not necessary in patients with mild or moderate hepatic or renal impairment. The drug has not been studmarch 2013 •
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ied in patients with severe hepatic or renal impairment.
The bioavailability and activity of enzalutamide may be
increased by strong CYP2C8 inhibitors (e.g., gemfibrozil),
and concurrent use is best avoided. To a lesser extent, enzalutamide also is a substrate for the CYP3A4 metabolic pathway,
and the concurrent use of a strong or moderate CYP3A4 or
CYP2C8 inducer (e.g., rifampin, carbamazepine, St. John’s
wort) also should be avoided if possible. Enzalutamide is a
strong CYP3A4 inducer and a moderate inducer of the CYP2C9 and CYP2C19 pathways. Concomitant use with narrow
therapeutic index drugs that are substrates for the CYP3A4
(e.g., cyclosporine, fentanyl) and CYP2C9 pathways (e.g., phenytoin, warfarin) should be avoided.
The recommended dosage of enzalutamide is 160 mg
once a day. If avoiding the concurrent use of a strong CYP2C8
inhibitor is not possible, the dosage should be reduced to 80
mg once a day. If a patient experiences toxicity of a severity
of grade 3 or greater or an intolerable adverse event, enzalutamide should be withheld for 1 week or until the symptoms
improve to grade 2 or lesser severity, then resumed at the
same or a reduced dosage (120 or 80 mg), if warranted.
Enzalutamide capsules are supplied in a 40-mg potency.
The capsules should be swallowed whole and should not be
opened, chewed, or dissolved. If a dose is missed, it may be
taken later the same day as soon as it is remembered. If the
daily dose is missed, the prescribed dose should be taken at
the regular time the next day.
Carfilzomib
Multiple myeloma is one of the most common hematologic
cancers and usually develops in the bone marrow, resulting in the formation of abnormal blood cells. In 2012, the
American Cancer Society estimated that 22,000 Americans
were diagnosed with multiple myeloma and approximately
11,000 individuals died from the disease. Recent advances in
the treatment of multiple myeloma include the marketing of
the proteasome inhibitor bortezomib (Velcade) and the immunomodulatory agents lenalidomide (Revlimid) and thalidomide (Thalomid).
Carfilzomib (Kyprolis—Onyx) is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to active
sites in the proteolytic core particle within the 26S proteasome. It exhibits antiproliferative and proapoptotic activities
in vitro in hematologic and solid tumor cells, and its properties and use are most similar to those for bortezomib.
Carfilzomib is indicated for intravenous administration for the treatment of patients with multiple myeloma
who have received at least two previous therapies, including bortezomib and an immunomodulatory agent, and have
demonstrated disease progression on or within 60 days of
completion of the last therapy. The new drug was evaluated
in a study of 266 patients with relapsed multiple myeloma
who had received at least two previous therapies, including bortezomib and thalidomide and/or lenalidomide. The
overall response rate (complete and partial responses) was
23%, and the median duration of response was 7.8 months.
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Although clinical benefit, such as improvement in survival
or symptoms, has not been documented, the response to the
drug in many patients who have experienced disease progression following use of the current standards for treatment
represents an important advance in treatment.
Most of the more serious risks associated with the use of
carfilzomib are similar to those experienced with bortezomib and include cardiac adverse events (e.g., cardiac arrest,
congestive heart failure, myocardial ischemia), pulmonary
complications (e.g., pulmonary hypertension, duspnea), tumor lysis syndrome, thrombocytopenia, and hepatic toxicity.
Patients should be well hydrated to reduce the risk of tumor
lysis syndrome and should be monitored for cardiac and
pulmonary symptoms. In addition, platelet counts and liver
enzymes should be monitored frequently. Depending on the
severity and evaluation of the adverse events, withholding or
discontinuing treatment may be necessary.
Infusion reactions may occur immediately following or
up to 24 hours after administration of carfilzomib and may
include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. Dexamethasone
is used to reduce the incidence and severity of infusion reactions during the first cycle of treatment, the first cycle of
dosage escalation, and if reactions occur with subsequent
cycles of treatment. Infusion reactions are more likely to be
experienced compared with bortezomib, which can be administered subcutaneously as well as intravenously.
Pulmonary arterial hypertension was reported in 2% of
patients treated with carfilzomib. Overall, serious adverse
events were reported in 45% of patients, with pneumonia
(10%), acute renal failure (4%), pyrexia (3%), and congestive
heart failure (3%) being the most common serious events.
Although some patients in the clinical study experienced peripheral neuropathy and hypotension, the new drug appears
less likely than bortezomib to cause these adverse events.
The most frequently reported adverse events reported
with the use of carfilzomib included fatigue (56%), anemia
(47%), nausea (45%), thrombocytopenia (36%), dyspnea
(35%), diarrhea (33%), and pyrexia (30%). Increases in blood
creatinine were reported in 24% of patients and renal failure
in 9%; although most of these events were grade 1 or grade
2 in severity, each of these responses was responsible for 1%
of patients discontinuing treatment. Herpes zoster reactivation was reported in 2% of patients, and antiviral prophylaxis should be considered for patients who have a history of
herpes zoster infection.
Carfilzomib may cause harm to the fetus if administered during pregnancy, and it is classified in Pregnancy
Category D. Women of reproductive potential should be advised to avoid becoming pregnant while being treated with
the drug. Whether the new drug is excreted in human milk
is unknown, and a decision should be made to discontinue
nursing or not use the drug. The effectiveness and safety of
carfilzomib in pediatric patients have not been established.
Carfilzomib is rapidly and extensively metabolized to
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inactive derivatives. Peptidase cleavage and epoxide hydrolysis are thought to be the primary pathways of metabolism,
and CYP-mediated mechanisms have only a small role in
its metabolism. Unlike bortezomib, it is not likely to interact
with other medications that inhibit or induce the CYP3A4
pathway.
Impairment of renal function does not affect the clearance or exposure of carfilzomib. The drug has not been studied in patients on dialysis, and it should be administered
after the dialysis procedure. Because carfilzomib may cause
hepatic adverse events, including hepatic failure, it must be
used with caution in patients with impaired hepatic function.
The dosage of carfilzomib is calculated using the patient’s actual body surface area at baseline. Patients with a
body surface area greater than 2.2 m2 should receive a dose
based on a body surface area of 2.2 m2.
Carfilzomib is administered intravenously over 2 to 10
minutes but must not be administered as a bolus. Each 28day period is considered one treatment cycle. In cycle 1, the
recommended dose is 20 mg/m2 on 2 consecutive days, each
week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by a
12-day rest period (days 17–28). If tolerated in cycle 1, the
dosage should be increased to 27 mg/m2 beginning in cycle
2, administered on the same days as cycle 1, and continued
at this higher dose in subsequent cycles. Treatment may be
continued until disease progression or until unacceptable
toxicity occurs.
To reduce the risk of renal toxicity and of tumor lysis syndrome, patients should be hydrated with 250 to 500 mL intravenous normal saline or other appropriate intravenous fluid
before each dose of carfilzomib in cycle 1. Following administration of the drug, an additional 250 to 500 mL intravenous
fluid can be administered as needed. Intravenous hydration
should be continued, as needed, in subsequent cycles.
Patients should be premedicated with dexamethasone
4 mg orally or intravenously before all doses of carfilzomib
during cycle 1 and before all doses during the first cycle of
dose escalation to 27 mg/m2, in order to reduce the incidence
and severity of infusion reactions. If symptoms of infusion
reactions occur during subsequent cycles, dexamethasone
premedication should be reinstated.
The use of carfilzomib is associated with the occurrence
of a number of adverse events that may necessitate a reduction in dosage, or withholding or discontinuing treatment,
and the product labeling should be consulted for the specific
recommendations.
Carfilzomib is supplied as a lyophilized cake or powder
in single-use vials containing 60 mg of the drug. The vials
should be stored in a refrigerator. The contents of a vial are
reconstituted by slowly injecting 29 mL Sterile Water for Injection onto the inside wall of the vial to minimize foaming.
The vial should be swirled or inverted, but not shaken, for
about 1 minute or until complete dissolution occurs. The reconstituted solution contains the drug in a concentration of 2
mg/mL. If the drug is to be administered in an intravenous
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bag, the calculated dose should be withdrawn from the vial
and diluted into 50 mL of 5% Dextrose Injection in an intravenous bag. The intravenous administration line should be
flushed with normal saline or 5% Dextrose Injection immediately before and after carfilzomib administration.
Bosutinib
According to the National Cancer Institute, approximately
5,400 Americans were diagnosed with chronic myeloid leukemia (CML) in 2012. It most often occurs in older adults,
and the median age of diagnosis is 67 years. CML is a slowgrowing disease that is characterized by three distinct
phases (chronic, accelerated, and blast) that are marked by
a progressive increase in abnormal white blood cells. As the
disease moves through these phases, it usually becomes increasingly resistant to therapy.
Most patients with CML have a cytogenetic abnormality
designated as the Philadelphia chromosome. This is characterized by an abnormal translocation from chromosome 9 to
an area on chromosome 22 known as the breakpoint cluster region (BCR). The consequence of this genetic change is
the formation of an abnormal fusion protein, BCR-ABL, that
contains an activated tyrosine kinase domain that promotes
cell reproduction and growth. The overall effect is a cascade
of cellular events and uncontrolled proliferation of abnormal
white blood cells.
The marketing of imatinib (Gleevec) in 2001 represented
an important advance in the treatment of CML. Imatinib is a
tyrosine kinase inhibitor that blocks the abnormal BCR-ABL
tyrosine kinase, thereby inhibiting the proliferation of white
blood cells. Many patients with CML have experienced an
excellent response with imatinib, and it has been a first-line
treatment. However, some patients have experienced resistance or intolerance that preclude the continuation of treatment. In 2006 and 2007, dasatinib (Sprycel) and nilotinib
(Tasigna), respectively, were marketed. These agents also are
tyrosine kinase inhibitors, but their activity includes some of
the BCR-ABL mutations that are associated with resistance to
imatinib. These agents were initially approved for the treatment of patients with CML with resistance or intolerance to
prior therapy including imatinib, but both drugs have been
subsequently approved for treating selected patients with
CML that is newly diagnosed.
Bosutinib (Bosulif—Pfizer) is a tyrosine kinase inhibitor
that inhibits the BCR-ABL kinase that promotes CML, as well
as the SRC family kinases. The new drug inhibited 16 of 18
imatinib-resistant forms of BCR-ABL expressed in murine
myeloid cell lines. It has been approved for the treatment of
adult patients with chronic, accelerated, or blast-phase Philadelphia chromosome–positive (Ph+) chronic myelogenous
leukemia with resistance or intolerance to prior therapy.
The effectiveness of bosutinib was demonstrated in a
clinical trial involving more than 500 patients with CML that
had worsened after treatment with imatinib or imatinib followed by dasatinib and/or nilotinib or who could not tolerate
the previous therapy. In patients with chronic phase CML,
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efficacy was determined by the number of patients who experienced a major cytogenetic response (MCyR) within the
first 24 weeks of treatment. Of the patients who had been previously treated with imatinib, 34% achieved a MCyR after 24
weeks. Of the patients who achieved a MCyR at any time,
53% had their response last at least 18 months. Among patients previously treated with imatinib followed by dasatinib
and/or nilotinib, 27% achieved a MCyR within the first 24
weeks of treatment. Of those who achieved a MCyR at any
time, 51% had their MCyR last at least 9 months.
In patients with accelerated CML previously treated
with at least imatinib, 30% had their blood counts return
to normal range (complete hematologic response) and 55%
achieved normal blood counts with no evidence of leukemia
(overall hematologic response) within the first 48 weeks of
treatment. In the patients with blast-phase CML, 15% of patients achieved a complete hematologic response and 28% an
overall hematologic response.
The labeled indication for bosutinib differs in several
ways from those for dasatinib and nilotinib. The latter two
agents are indicated for Ph+ CML with resistance or intolerance to previous therapy, including imatinib, but nilotinib
is indicated for patients with chronic- or accelerated-phase
disease, whereas dasatinib also is indicated for blast-phase
disease. Both dasatinib and nilotinib are indicated for newly
diagnosed patients with Ph+ CML in chronic phase, and
dasatinib also is indicated for the treatment of patients with
Ph+ acute lymphoblastic leukemia (ALL) with resistance or
intolerance to prior therapy. Imatinib has numerous additional labeled indications, such as patients with myelodysplastic/myeloproliferative diseases and GI stromal tumors.
Treatment with bosutinib is frequently associated with
myelosuppression (e.g., thrombocytopenia, anemia), and
complete blood counts should be performed weekly for the
first month of therapy and at least monthly thereafter. Some
patients experience ALT and AST elevations, and hepatic
enzyme tests should be performed at least monthly during
the first 3 months of treatment and as clinically indicated
thereafter. Other risks with the use of bosutinib include fluid
retention (e.g., pericardial and/or pleural effusion, pulmonary and/or peripheral edema) and GI toxicity. In patients in
whom these events are severe, interrupting or discontinuing
treatment may be necessary.
Although bosutinib has not been directly compared with
dasatinib or nilotinib in clinical studies, the new drug may
be less likely to cause severe adverse events. For example, the
labeling for nilotinib includes a boxed warning regarding
QT prolongation and sudden deaths, as well as warnings regarding electrolyte abnormalities, elevated serum lipase, and
tumor lysis syndrome. The labeling for dasatinib includes
warnings regarding QT prolongation, congestive heart failure and myocardial infarction, pulmonary arterial hypertension, and bleeding events.
The adverse events reported most frequently (incidence
>20%) with the use of bosutinib included diarrhea (82%),
nausea (46%), thrombocytopenia (41%), vomiting (39%), ab80
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dominal pain (37%), rash (35%), anemia (27%), pyrexia (26%),
and fatigue (24%).
Bosutinib may cause harm to the fetus if administered
during pregnancy, and it is classified in Pregnancy Category
D. Women of reproductive potential should be advised to use
contraceptive measures during treatment and for at least 30
days following discontinuation of treatment. Whether the
new drug is excreted in human milk is not known, and a decision should be made to discontinue nursing or not use the
drug. The effectiveness and safety of bosutinib in patients
younger than 18 years have not been evaluated.
The aqueous solubility of bosutinib is pH dependent, and
its plasma concentration and bioavailability are reduced by
the concurrent use of lansoprazole. The use of lansoprazole
or another proton pump inhibitor should be avoided. For patients who need to use an acid-reducing agent, an antacid or
histamine H2 receptor blocker (e.g., famotidine) can be used,
but an interval of at least 2 hours should separate the administration of one of these agents from the dose of bosutinib.
Bosutinib is metabolized primarily via the CYP3A4 pathway to derivatives that are not pharmacologically active.
More than 90% of a dose is recovered in the feces and approximately 3% in the urine. The dosage should be reduced
in patients with hepatic impairment, but dosage adjustment
is not necessary in patients with impaired renal function.
The action of bosutinib may be increased by the concurrent use of strong or moderate CYP3A inhibitors (e.g., clarithromycin, itraconazole, grapefruit products) and/or P-glycoprotein (P-gp) inhibitors. Conversely, the action of the new
drug may be reduced by the concomitant use of a strong or
moderate CYP3A inducer (e.g., rifampin, carbamazepine, St.
John’s wort). The use of any of these agents should be avoided in patients treated with bosutinib. The new drug may increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin.
Bosutinib should be administered with food, and the recommended dosage is 500 mg once a day. Treatment should
be continued until disease progression or patient intolerance.
An increase in dosage to 600 mg once a day with food should
be considered for patients who do not reach a complete hematological response by week 8 or a complete cytogenetic
response by week 12 and who do not have grade 3 or higher
adverse events. The product labeling should be consulted for
recommendations for dosage adjustments or interruption of
treatment in patients who experience serious adverse events.
In patients with preexisting hepatic impairment, the recommended dosage is 200 mg once a day with food.
Bosutinib film-coated tablets are supplied in 100 and 500
mg potencies. The tablets should be swallowed whole, and
patients should be advised to not crush or cut the tablets and
not handle crushed or broken tablets. If a dose is missed and
not taken within the next 12 hours, the patient should skip
that dose and take the next usual dose on the following day.
Omacetaxine mepesuccinate
Omacetaxine mepesuccinate (Synribo—Teva) was the secwww.pharmacytoday.org
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ond drug to be approved and marketed in late 2012 for the
treatment of patients with CML, following bosutinib (Bosulif). It is prepared by a semisynthetic process from cephalotaxine, which is derived from the leaves of evergreen trees.
Omacetaxine has a unique mechanism of action that includes inhibition of protein synthesis and is independent of
direct BCR-ABL binding. Some data suggest that it may have
activity against the BCR-ABL T315I genetic mutation that is
thought to be associated with treatment resistance.
Omacetaxine is administered subcutaneously and is indicated for the treatment of adult patients with chronic- or
accelerated-phase CML with resistance and/or intolerance
to two or more tyrosine kinase inhibitors (i.e., imatinib, dasatinib, nilotinib, bosutinib). The approval of this indication
is based on response rate, and no studies of the drug at the
present time confirm improvement in disease-related symptoms or increased survival.
The activity of omacetaxine was demonstrated in patients with chronic-phase CML by a reduction in the percentage of cells expressing the Philadelphia chromosome genetic
mutation that is identified in most patients with CML. This
MCyR occurred in 18% of the patients. The mean time to
MCyR onset was 3.5 months and the median duration was
12.5 months. In patients with accelerated-phase CML, the response was determined by the number of patients who experienced a normalization of white blood cell counts or had no
evidence of leukemia (major hematologic response [MaHR]).
This response occurred in 14% of patients in an average of 2.3
months, with a median duration of response of 4.7 months.
Although omacetaxine and bosutinib have not been directly compared in clinical trials, the data from the studies
in which they have been evaluated individually suggest that
bosutinib is more effective. Unlike the labeled indication for
bosutinib, the indication for omacetaxine does not include
use in patients with blast-phase CML.
Most patients treated with omacetaxine experience myelosuppression (thrombocytopenia, neutropenia, anemia),
and in some patients, this has resulted in fatal consequences.
Complete blood counts and platelet counts should be monitored weekly during induction and initial maintenance
cycles of treatment and every 2 weeks during later maintenance cycles, as clinically indicated. Bleeding events also are
possible; these are most often associated with severe thrombocytopenia, and some patients have experienced cerebral
hemorrhage and GI hemorrhage. Use of anticoagulants, aspirin, and nonsteroidal anti-inflammatory drugs should be
avoided by patients whose platelet counts are less than 50,000
per µL. Patients with neutropenia are at increased risk of infections, and they should be advised to contact their physician if they experience fever or other symptoms of infection.
Omacetaxine may cause glucose intolerance, and blood
glucose concentrations should be monitored frequently, particularly in patients with diabetes or risk factors for diabetes. Treatment with the new drug should not be initiated in
patients with poorly controlled diabetes until good glycemic
control has been established.
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The adverse events experienced most frequently in the
clinical study with omacetaxine (and the incidence reported
in patients with chronic-phase CML) included thrombocytopenia (74%), anemia (61%), neutropenia (50%), infection
(46%), diarrhea (42%), injection site reaction (34%), nausea
(32%), fatigue (26%), pyrexia (24%), and asthenia (23%).
Omacetaxine may cause harm to the fetus if administered during pregnancy and is classified in Pregnancy Category D. Whether it is excreted in human milk is not known,
and a decision should be made to discontinue nursing or not
use the drug. The effectiveness and safety of omacetaxine in
pediatric patients have not been established.
Following subcutaneous administration, maximum concentrations of omacetaxine are achieved in approximately 30
minutes. The drug is hydrolyzed via plasma esterases, and
less than 15% of a dose of the drug is excreted unchanged
in the urine. Omacetaxine is not likely to interact with other
medications.
The recommended initial dosage of omacetaxine for induction is 1.25 mg/m2 twice a day for 14 consecutive days every 28 days, during a 28-day cycle. Cycles should be repeated
every 28 days until patients achieve a hematologic response.
The recommended maintenance schedule is 1.25 mg/m2,
administered twice a day for 7 consecutive days every 28
days, during a 28-day cycle. Treatment should continue as
long as patients are experiencing clinical benefit. If hematologic toxicity occurs, treatment cycles may be delayed and/or
the number of days of dosing during the cycle reduced. The
product labeling should be consulted for the specific recommendations for dosage modification if hematologic or nonhematologic toxicity occurs.
Omacetaxine mepesuccinate is supplied as a lyophilized
powder in single-use vials containing 3.5 mg of the drug.
The drug should be reconstituted with 1 mL of 0.9% Sodium
Chloride Injection. The vial should be gently swirled, and
the powder should completely dissolve in less than 1 minute. The drug should be administered within 12 hours of reconstitution when stored at room temperature and within 24
hours if stored in a refrigerator. The reconstituted solution
should be protected from light. If omacetaxine comes in contact with the skin, the affected area should be immediately
and thoroughly washed with soap and water.
Ponatinib
Ponatinib (Iclusig—Ariad) was the third drug to be approved
and marketed in late 2012 for the treatment of patients with
CML, following bosutinib (Bosulif) and omacetaxine (Synribo). Like imatinib (Gleevec), dasatinib (Sprycel), nilotinib
(Tasigna), and bosutinib, ponatinib inhibits tyrosine kinases
that promote the proliferation of cancer cells. However, many
patients are now resistant to the action of the older tyrosine
kinase inhibitors (imatinib, dasatinib, and nilotinib), resulting in the need for options that address the mechanisms
through which resistance occurs. Some CML cells have a
mutation designated as the T315I mutation that represents
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sistant to certain of the tyrosine kinase inhibitors. Studies of
ponatinib have demonstrated important activity against the
cells with the T315I mutation and other mutations that are
associated with resistance to imatinib.
Ponatinib is indicated for the treatment of adult patients
with chronic-, accelerated-, or blast-phase CML that is resistant or intolerant to previous tyrosine kinase inhibitor therapy. It also is indicated for the treatment of patients with Ph+
ALL that is resistant to or intolerant of prior tyrosine kinase
inhibitor therapy. The approval of these indications is based
on response rate, and no studies of the drug at the present
time confirm improvement in disease-related symptoms or
increased survival.
In patients with chronic-phase CML, the effectiveness of
ponatinib was demonstrated by a reduction in the percentage of cells expressing the Philadelphia chromosome genetic
mutation, representing a MCyR. More than one-half (54%) of
the 267 patients in the study and 70% of the 64 patients with
the T315I mutation achieved a MCyR. In patients with accelerated CML (83 patients), blast-phase CML (62 patients), and
Ph+ ALL (32 patients), the effectiveness of ponatinib was determined by the number of patients who experienced a normalization of white blood cell counts or had no evidence of
leukemia (MaHR). In patients with accelerated-phase CML,
blast-phase CML, and Ph+ ALL, 52%, 31%, and 41%, respectively, experienced a MaHR for a median duration of 9.5 , 4.7,
and 3.2 months, respectively.
Use of ponatinib is associated with numerous serious
risks. Arterial thrombosis (i.e., cardiovascular, cerebrovascular, peripheral vascular), including fatal myocardial infarction and stroke, is the subject of a boxed warning in the
product labeling. In the clinical studies, 8% of the patients
experienced serious arterial thrombosis. Hepatotoxicity
also is the subject of a boxed warning. The incidence of ALT
and AST elevation in the clinical studies was 56%, and liver
function tests should be determined at baseline and at least
monthly during treatment.
Severe myelosuppression (e.g., thrombocytopenia, neutropenia, anemia) occurred in 48% of the patients treated
with ponatinib in the clinical studies, and complete blood
counts and platelet counts should be obtained every 2 weeks
for the first 3 months of treatment and at least monthly thereafter. Hemorrhagic events were reported in 24% of patients
and most often occurred in patients with grade 4 thrombocytopenia. Cerebral hemorrhage and GI hemorrhage were the
most commonly reported serious bleeding events.
Treatment-emergent hypertension occurred in most patients, and blood pressure should be monitored closely. Lipase elevation was reported in 41% of patients, and clinical
pancreatitis occurred in 6%. Serum lipase concentrations
should be determined every 2 weeks for the first 2 months
of treatment and at least monthly thereafter. Other serious
adverse events that have been reported with the use of ponatinib included cardiac dysrhythmias, congestive heart fail-
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ure, fluid retention, and tumor lysis syndrome, and patients
should be monitored accordingly. Ponatinib may compromise wound healing, and treatment should be interrupted
for at least 1 week before major surgery.
The adverse events experienced most frequently in the
clinical study with ponatinib (and the incidence reported
in patients with chronic-phase CML) included hypertension (68%), rash (54%), abdominal pain (49%), fatigue (39%),
headache (39%), dry skin (39%), constipation (37%), arthralgia (26%), nausea (23%), and pyrexia (23%). Hematologic
abnormalities (and the incidence at grade 3 or 4 severity) included thrombocytopenia (36%), neutropenia (24%), leukopenia (14%), lymphopenia (10%), and anemia (9%).
Ponatinib may cause harm to the fetus if administered
during pregnancy, and it is classified in Pregnancy Category
D. Whether the drug is excreted in human milk is not known,
and a decision should be made to discontinue nursing or not
use the drug. The effectiveness and safety of ponatinib in patients younger than 18 years have not been established.
Ponatinib may be administered with or without food, but
its aqueous solubility is pH dependent, with higher pH resulting in lower solubility. Because proton pump inhibitors
(e.g., omeprazole), histamine H2 receptor antagonists (e.g.,
famotidine), and antacids elevate gastric pH, their concurrent use with ponatinib should be avoided.
Ponatinib is extensively metabolized, primarily via the
CYP3A4 pathway. Almost 90% of a dose is recovered in the
feces and approximately 5% in the urine. The concentration
and activity of ponatinib may be increased in patients with
moderate to severe hepatic impairment, and its use in these
patients should be avoided unless the anticipated benefit
outweighs the risk. Strong inhibitors of the CYP3A4 pathway
(e.g., ketoconazole, clarithromycin) may increase the action
of ponatinib, and the dosage of the new drug should be reduced when it is used concurrently with one of these agents.
Conversely, the concomitant use of a strong CYP3A4 inducer
(e.g., carbamazepine, St. John’s wort) would be expected to
reduce the action of ponatinib, and concurrent use should be
avoided. Ponatinib inhibits the transporter P-gp and may increase the action of agents such as digoxin that are substrates
for P-gp.
The recommended dosage of ponatinib is 45 mg once a
day, and treatment should be continued for as long as the
patient does not show evidence of disease progression or
unacceptable toxicity. The dosage should be reduced to 30
mg once a day in patients who also are being treated with
a strong CYP3A4 inhibitor. The product labeling should be
consulted for the recommendations for dosage modifications
in patients who experience myelosuppression, hepatic toxicity, pancreatitis, or other serious adverse events.
Ponatinib tablets are supplied in 15 and 45 mg potencies.
The tablets should be swallowed whole. The tablets contain
lactose; therefore, patients who are lactose intolerant should
observe caution.
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CPE assessment
Instructions: This exam must be taken online; please see “CPE information” for further instructions. The online system
will present these questions in random order to help reinforce the learning opportunity. There is only one correct answer to
each question.
1. Which of the following drug : use pairings is correct?
a. Regorafenib : prostate cancer
b. Enzalutamide : chronic myeloid leukemia (CML)
c. Carfilzomib : multiple myeloma
d. Bosutinib : colorectal cancer
2. Which of the following drug : classification pairings is
correct?
a. Regorafenib : proteasome inhibitor
b. Enzalutamide : androgen receptor inhibitor
c. Carfilzomib : vascular endothelial growth factor inhibitor
d. Omacetaxine : tyrosine kinase inhibitor
3. Which of the following drug : route of administration
pairings is correct?
a. Enzalutamide : intramuscular
b. Carfilzomib : subcutaneous
c. Omacetaxine : intravenous
d. Bosutinib : oral
4. Which of the following agents should be administered
with a low-fat breakfast?
a.Regorafenib
b.Enzalutamide
c.Ponatinib
d. Sodium picosulfate
5. Which of the following agents is associated with a risk
of seizure?
a.Carfilzomib
b.Regorafenib
c.Bosutinib
d.Enzalutamide
6. Which of the following agents is associated with a risk
of arterial thrombosis?
a.Bosutinib
b.Ponatinib
c.Regorafenib
d.Omacetaxine
7. Which of the following agents is converted to an active
metabolite by colonic bacteria?
a.Enzalutamide
b.Regorafenib
c. Sodium picosulfate
d.Bosutinib
8. With which of the following agents should the concurrent use of a proton pump inhibitor be avoided?
a.Ponatinib
b.Regorafenib
c.Enzalutamide
d.Omacetaxine
9. Which of the following statements is correct regarding
sodium picosulfate?
a. It is classified as an osmotic laxative.
b. It is used in combination with magnesium hydroxide.
c. It is used in combination with polyethylene glycol
3350.
d. It is supplied as a powder in combination with magnesium oxide and anhydrous citric acid.
CPE information
To obtain 2.0 contact hours (0.2 CEUs) of CPE credit for this activity, you must complete the online Assessment, the Learning Evaluation, and
Activity Evaluation. A Statement of Credit will be awarded for a passing grade of 70% or better on the Assessment. You will have two opportunities
to successfully complete the CPE Assessment. Pharmacists who successfully complete this activity before March 1, 2016, can receive CPE credit.
Your Statement of Credit will be available upon successful completion of the Assessment, Learning Evaluation, and Activity Evaluations 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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10. Which of the following statements is correct regarding
the Prepopik formulation?
a. It is contraindicated in patients with severely reduced
renal function.
b. The “Day-Before” regimen is more effective than the
“Split-Dose” regimen.
c. The administration of each dose should be followed
by five 8-oz drinks of electrolyte solution.
d. It may increase the absorption of other medications
that are administered at the same time.
16. Which of the following statements is correct regarding
carfilzomib?
a. It is administered once a day for the first 14 days of a
28-day treatment cycle.
b. Dexamethasone is used to reduce the frequency and
severity of infusion reactions.
c. It is extensively metabolized by the cytochrome P450
(CYP)3A4 metabolic pathway.
d. Its action is increased by the concurrent use of ketoconazole.
11. Which of the following statements is correct regarding
regorafenib?
a. It is indicated for first-line treatment of prostate cancer.
b. It is indicated for use in combination with bevacizumab.
c. Hypertension is a common adverse event and blood
pressure should be monitored during treatment.
d. Nephrotoxicity is the subject of a boxed warning in
its labeling.
17. Which of the following statements is correct regarding
bosutinib?
a. Its labeled indications include acute lymphoblastic
leukemia.
b. Myelosuppression is a common adverse event, and
complete blood counts should be monitored frequently.
c. It is administered twice a day.
d. It should be administered at least 1 hour before or 2
hours after food.
12. Which of the following statements is correct regarding
regorafenib?
a. Myelosuppression occurs in most patients and complete blood counts should be monitored frequently.
b. Hand–foot skin reactions are experienced by many
patients.
c. Most of a dose is excreted in the urine in unchanged
form.
d. It is administered twice a day.
18. Which of the following statements is correct regarding
bosutinib?
a. It is a prodrug that is converted to an active metabolite.
b. Its absorption and activity are increased by medications that increase gastric pH.
c. It is extensively metabolized by the CYP3A4 metabolic pathway.
d. Its action is increased by the concurrent use of carbamazepine.
13. Which of the following statements is correct regarding
enzalutamide?
a. It is indicated for first-line use in the treatment of
metastatic castration-resistant prostate cancer.
b. It must be used in combination with prednisone.
c. It may cause harm to a fetus and is classified in Pregnancy Category X.
d. It is administered twice a day.
14. Which of the following statements is correct regarding
enzalutamide?
a. Its action is increased by the concurrent use of gemfibrozil.
b. It must be administered apart from food.
c. Most of a dose is excreted in the urine in unchanged
form.
d. The dosage should be reduced by one-half in patients
with impaired kidney function.
19. Which of the following statements is correct regarding
omacetaxine?
a. It is classified as a tyrosine kinase inhibitor.
b. It was demonstrated in comparative clinical studies
to be more effective than bosutinib.
c. It is extensively metabolized via the CYP2D6 metabolic pathway.
d. It is administered twice a day.
20. Which of the following statements is correct regarding
ponatinib?
a. It is active against CML cells that have the T315I mutation that is usually resistant to other agents.
b. It increases blood glucose concentrations and should
not be used in patients with diabetes.
c. Most of a dose is excreted in the urine in unchanged
form.
d. It is administered twice a day.
15. Which of the following statements is correct regarding
carfilzomib?
a. It is classified as a tyrosine kinase inhibitor.
b. It is used in combination with lenalidomide.
c. It is used in combination with bortezomib.
d. Its use is associated with the occurrence of cardiac
adverse events.
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PharmacyToday • march 2013
www.pharmacytoday.org