US Pharm. 2013;38(10):HS4-HS10.
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. 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Warning for serious ARs or are withdrawn from the market for safety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.
Teduglutide (Gattex, NPS Pharmaceuticals)
Indication and Clinical Profile1,2: Teduglutide,
an analogue of glucagon-like peptide-2, is approved for the treatment
of short bowel syndrome (SBS) in adults requiring parenteral nutrition
(PN). Teduglutide is the third drug approved by the FDA to treat SBS in
adults receiving nutritional support (Zorbtive [somatropin] and
Nutrestore [glutamine] were approved in 2003 and 2004, respectively). In
adults, SBS most often results from partial or complete surgical
removal of the small and/or large intestine for disorders such as
Crohn’s disease. Patients with SBS-associated intestinal failure are
unable to absorb sufficient quantities of protein, calories, fluids,
electrolytes, and micronutrients, and they often experience diarrhea,
weight loss, malnutrition, and dehydration. Accordingly, PN is often
necessary in SBS patients; in fact, SBS is the most common diagnosis
requiring home PN. Patients with intestinal failure may need PN 5 to 7
days/week for ≥10 hours/day. Unfortunately, PN can lead to serious
complications, including hepatobiliary disease, bacteremia, and central
The safety and efficacy of teduglutide were evaluated in two clinical
trials and two extension studies that randomized patients to
teduglutide treatment or placebo. Clinical response was measured by the
number of patients who achieved ≥20% reduction in volume of weekly PN at
treatment weeks 20 and 24. In the two clinical trials, 63% and 46% of
teduglutide-treated patients achieved clinical response, versus 6% and
30% of placebo patients. After 24 weeks, teduglutide patients had mean
PN reductions of 2.5 L/week and 4.4 L/week, compared with 0.9 L/week and
2.3 L/week in placebo patients. The extension studies followed patients
who received teduglutide in the initial trials for an additional 28
weeks. These patients experienced mean PN reductions of 4.9 L/week and
5.2 L/week after 1 year of continuous teduglutide treatment, and six
patients were weaned off PN while taking teduglutide.
Pharmacology and Pharmacokinetics1,2: Endogenous
glucagon-like peptide-2 (GLP-2) is secreted in response to food by
intestinal L-cells located primarily in the terminal ileum and the
colon. GLP-2 promotes mucosal growth in the small bowel through
stimulation of crypt cell proliferation and inhibition of enterocyte
apoptosis. It also inhibits gastric acid secretion, reduces gastric
motility, enhances mucosal hexose transport, and increases portal and
intestinal blood flow. Teduglutide is a 36-membered polypeptide GLP-2
analogue with a longer half-life than that of endogenous GLP-2. It binds
to GLP-2 receptors located in intestinal subpopulations of
enteroendocrine cells, subepithelial myofibroblasts, and enteric neurons
of the submucosal and myenteric plexuses. Activation of these receptors
results in local release of multiple mediators, including insulin-like
growth factor-1, nitric oxide, and keratinocyte growth factor, resulting
in increased villus height and crypt depth of the intestinal mucosa and
enhanced gastrointestinal (GI) fluid absorption.
Subcutaneous (SC) teduglutide has an absolute bioavailability of 88%
and provides maximum plasma concentrations at 3 to 5 hours after
administration. Although the metabolism of teduglutide has not been
fully elucidated, the drug appears to be degraded into small peptides
and amino acids, similarly to the catabolism of endogenous GLP-2.
Teduglutide’s plasma clearance, which is approximately 123 mL/h/kg, is
similar to the glomerular filtration rate, suggesting that teduglutide
is cleared primarily renally. Teduglutide has a mean terminal half-life
of approximately 2 hours in healthy patients and 1.3 hours in SBS
patients. In patients with moderate-to-severe renal impairment or
end-stage renal disease (ESRD), the maximum concentration of drug and
AUC0-inf of teduglutide are significantly increased (>2-fold), suggesting the need for dosage reductions in these patients.
Adverse Reactions (ARs) and Drug Interactions1,2: The
most common ARs in clinical trials were abdominal pain, injection-site
reactions, nausea, headaches, stoma complication, and abdominal
distention. Antiteduglutide antibodies developed in a few patients, but
did not appear to reduce the drug’s effect. Other ARs included
intestinal obstruction, biliary-tract disorders, and increased incidence
of upper respiratory tract infection. Because teduglutide may
accelerate the growth of GI cancers, colonoscopy should be performed
before teduglutide initiation and repeated after 1 year, with subsequent
examinations as needed but no less frequently than every 5 years. To
ensure that the benefits of teduglutide outweigh the potential risks,
the drug was approved with a Risk Evaluation and Mitigation Strategy
consisting of a communication plan and training for prescribers.
Furthermore, the FDA is requiring a postmarketing study of SBS patients
receiving teduglutide in a routine clinical setting to further evaluate
the drug’s potential to increase the risk of colorectal cancer and other
conditions. Teduglutide is classified as Pregnancy Category B.
Based on teduglutide’s mechanism, there is a potential for increased
absorption of concomitant oral medications that should be considered if
these drugs require titration or have a narrow therapeutic index (e.g.,
benzodiazepines, phenothiazines). No inhibition or induction of CYP450
has been observed in in vitro studies.
Dosage and Administration1,2: Teduglutide
is supplied in single-use glass vials containing 5 mg of the drug as a
lyophilized powder. Upon reconstitution with the 0.5 mL Sterile Water
for Injection provided in the prefilled syringe, the solution delivers a
maximum of 3.8 mg of teduglutide. The recommended daily dosage is 0.05
mg/kg body weight administered by SC injection once daily. A 50% dosage
reduction is recommended in patients with moderate-to-severe renal
impairment (creatinine clearance <50 mL/min) or ESRD. It is
recommended to alternate sites for SC injection. Possible sites include
the thighs, arms, and abdominal quadrants. Teduglutide should not be
administered IV or intramuscularly. If a dose is missed, it should be
administered as soon as possible that day, but two doses should not be
administered on the same day.
Colonoscopy (or alternative imaging) of the entire colon, with
removal of polyps, should be performed within 6 months prior to
teduglutide initiation, and follow-up colonoscopy is recommended as
described above. Patients should also undergo initial laboratory
assessments (bilirubin, alkaline phosphatase, lipase, and amylase)
within 6 months prior to treatment initiation and every 6 months
thereafter. If clinically meaningful elevation of these values occurs,
further imaging of the biliary tract, liver, or pancreas may be
necessary. Discontinuation of teduglutide may result in fluid and
electrolyte imbalance; therefore, patients’ fluid and electrolyte status
should be carefully monitored.
Ponatinib (Iclusig, Ariad Pharmaceuticals)
Indication and Clinical Profile3,4:
Ponatinib is a new multitargeted tyrosine kinase inhibitor (TKI)
approved as an orphan drug under the FDA’s accelerated approval program.
It is indicated to treat patients with chronic-, accelerated-, or
blast-phase chronic myeloid leukemia (CML) or Philadelphia
chromosome–positive acute lymphoblastic leukemia (Ph+ALL) that is
resistant or intolerant to prior TKI therapy. CML and Ph+ALL are WBC
cancers that affect more than 20,000 people in the United States. They
are typically asymptomatic initially, but an enlarged spleen, fatigue,
paleness from anemia, and disrupted thermoregulation may develop.
Ponatinib is the third drug approved for CML treatment since 2012; the
others are bosutinib (Bosulif) and omacetaxine (Synribo).
Approval of ponatinib was based on a single-arm, open-label,
multicenter, phase II trial involving >449 patients with CML or
Ph+ALL whose disease was resistant or intolerant to prior TKI therapy.
Ponatinib 45 mg once daily resulted in a reduction in the percentage of
cells expressing the Philadelphia chromosome genetic mutation (major
cytogenetic response) in 54% of patients, including 70% of patients who
also had a T315I mutation. Ponatinib also resulted in a normalization of
WBC counts or no evidence of leukemia (major hematologic response) in
52% of accelerated-phase CML patients, 31% of blast-phase CML patients,
and 41% of Ph+ALL patients.
Pharmacology and Pharmacokinetics3,4: Ponatinib is an imidazo[1,2-b]pyridazine benzamide (FIGURE 1)
that functions as a TKI. Its primary target is the breakpoint cluster
region–Abelson (Bcr-Abl) tyrosine kinase expressed by CML and Ph+ALL,
but it also targets Bcr-Abl isoforms that carry mutations, including the
T315I mutation. Ponatinib also binds to members of the VEGFR, PDGFR,
FGFR, and EPH receptors and SRC families of kinases, and to KIT, RET,
TIE2, and FLT3.
The absolute bioavailability of ponatinib is unknown. The drug has a
half-life of 24 hours, and it is >99% plasma protein bound. Ponatinib
is metabolized by CYP3A4 and, to a lesser extent, by CYP2C8, 2D6, 3A5,
and esterases and amidases. Approximately 64% of ponatinib is excreted
as metabolites, primarily in the feces. Ponatinib does not inhibit
metabolism of other CYP-substrate drugs, nor does it appear to induce
CYP metabolism. It does, however, inhibit adenosine triphosphate–binding
cassette (ABC) G2, the bile salt export pump, and the P-glycoprotein
Adverse Reactions (ARs) and Drug Interactions3,4:
The most common ARs (≥20%) reported in clinical trials were
myelosuppression (thrombocytopenia, neutropenia, leukopenia, anemia, and
lymphopenia), hypertension, rash, abdominal pain, fatigue, headache,
dry skin, constipation, arthralgia, nausea, and pyrexia. Ponatinib also
carries a Black Box Warning that the drug may cause arterial thrombosis
and hepatotoxicity. The drug should be avoided in pregnancy because of
its potential for fetal harm (Pregnancy Category D). Patients who
breastfeed or intend to breastfeed should not use ponatinib.
The ponatinib dosage should be reduced when the drug is
coadministered with CYP3A inhibitors. Coadministration of ponatinib with
strong CYP3A inducers or drugs that elevate gastric pH (proton pump
inhibitors, H2 blockers, antacids) may lead to inadequate
drug concentration. Because of its inhibition of Pgp and ABC, ponatinib
may result in altered efficacy of drugs that are sensitive substrates of
these pumps; however, formal studies have not been conducted to
determine the severity of this interaction.
Dosage and Administration3,4: Ponatinib is
supplied as 15-mg and 45-mg tablets. The recommended dosage is 45 mg
once daily with or without food. The dosage should be reduced to 30 mg
once daily when the drug is administered with strong CYP3A inhibitors.
Ponatinib has not been studied in pediatric patients or in hepatically
or renally impaired patients. Ponatinib therapy should be interrupted
for 1 week prior to major surgery to avoid an increased bleeding risk.
Patients taking ponatinib who experience myelosuppression, hepatic
toxicity, asymptomatic lipase elevation (grade 3-4), or pancreatitis
(grade 2-3) should interrupt therapy until toxicity subsides, then
resume therapy at the dosage recommended by the manufacturer.
Omacetaxine (Synribo, Teva Pharmaceuticals USA)
Indication and Clinical Profile5,6: Omacetaxine
mepesuccinate is a protein synthesis inhibitor approved as an orphan
drug under the FDA’s accelerated approval program. It is indicated for
the treatment of chronic myelogenous leukemia (CML) (see discussion in
Ponatinib section) that is resistant or intolerant to two or more
tyrosine kinase inhibitors (TKIs). Omacetaxine is one of three drugs
approved for the treatment of CML since 2012; the others are bosutinib
(Bosulif) and ponatinib (Iclusig).
Approval of omacetaxine was based on research involving a combined
cohort of patients whose cancer progressed after previous treatment with
two or more TKIs. Omacetaxine’s effectiveness against chronic-phase CML
was demonstrated by a reduction in the percentage of cells expressing
the Philadelphia chromosome genetic mutation found in most CML patients.
Fourteen of 76 patients (18.4%) achieved reduction in an average of 3.5
months. Median length of reduction was 12.5 months. In
accelerated-phase CML, omacetaxine’s effectiveness was determined by the
number of patients who experienced WBC-count normalization or had no
evidence of leukemia (major hematologic response [MaHR]). Five of 35
patients (14.3%) achieved MaHR in an average of 2.3 months. Median MaHR
duration in these patients was 4.7 months.
Pharmacology and Pharmacokinetics5,6: Omacetaxine is a cephalotaxine ester (FIGURE 2) prepared by a semisynthetic process from the leaves of Cephalotaxus harringtonia.
It functions as a protein translation inhibitor by preventing the
initial elongation step of protein synthesis through binding to the
large ribosomal subunit A-site cleft. This prevents correct positioning
of amino acid side chains of aminoacyl-tRNAs. In vitro, omacetaxine has
been shown to reduce protein levels of the Bcr-Abl oncoprotein and the
Mcl-1 antiapoptotic protein. Because it acts at the initial stage of
protein synthesis, however, omacetaxine has no effect on protein
synthesis from mRNAs already undergoing translation.
The absolute bioavailability of omacetaxine is unknown. The drug has a
steady-state volume of distribution of about 140 L and a half-life of 6
hours, and it is ≤50% plasma protein bound. Omacetaxine’s primary route
of metabolism is hydrolysis to 4´-DMHHT via plasma esterases, with
little hepatic microsomal oxidative or esterase-mediated metabolism. The
major route of elimination is currently unknown; however, an average of
15% is excreted unchanged in the urine. Omacetaxine does not inhibit
metabolism of CYP450 substrates, and its ability to induce CYP450
enzymes has not been determined.
Adverse Reactions (ARs) and Drug Interactions5,6: The
most common ARs (≥20%) reported in clinical trials were
myelosuppression (thrombocytopenia, anemia, neutropenia, lymphopenia),
diarrhea, nausea, fatigue, pyrexia, asthenia, infection, and
injection-site reactions. The package insert includes a warning about
omacetaxine’s ability to induce hyperglycemia, although less common
(11%), and a precaution about its use in diabetic patients without good
glycemic control. Omacetaxine should be avoided in pregnant women
because of its potential for fetal harm (Pregnancy Category D). Also,
women who breastfeed or intend to breastfeed should not use omacetaxine.
In vitro drug-interaction studies with omacetaxine revealed no
significant interactions. However, concomitant use of anticoagulants,
aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs) may increase
the risk of bleeding.
Dosage and Administration5,6: Omacetaxine
is supplied in 3.5-mg single-use vials as a lyophilized powder to be
dissolved into solution for subcutaneous administration. The induction
dosage of omacetaxine is 1.25 mg/m2 twice daily for 14 consecutive days over a 28-day cycle, followed by a maintenance dosage of 1.25 mg/m2
twice daily for 7 consecutive days over a 28-day cycle, which should be
repeated as long as the patient continues to benefit from therapy.
Because of insufficient clinical data, there is no recommended dosage
adjustment for renally or hepatically impaired patients or for pediatric
patients. There is no recommended dosage adjustment for elderly
Cabozantinib (Cometriq, Exelixis)
Indication and Clinical Profile7,8: Cabozantinib
is a new tyrosine kinase inhibitor (TKI) approved to treat metastatic
medullary thyroid cancer (MTC). The National Cancer Institute estimated
that, in 2012, 56,460 people in the United States would be diagnosed
with thyroid cancer and nearly 2,000 would die from it. Only about 4% of
thyroid cancers are MTC. MTC develops in thyroid parafollicular cells,
which produce calcitonin (which regulates plasma calcium levels). MTC
appears to occur spontaneously or in families with certain genetic
mutations that lead to one or more cancers of the endocrine system.
Cabozantinib is the second drug approved to treat MTC in the past 2
years; vandetanib (Caprelsa) was approved in April 2011. Cabozantinib
was approved in 6 months under the FDA’s priority review program, which
allows an expedited review for drugs that offer major advances in
treatment or provide a treatment where no adequate therapy exists.
Cabozantinib also was designated an orphan product because it was
developed to treat a rare disease.
The safety and effectiveness of cabozantinib were established in an
international randomized, controlled trial involving 330 subjects with
MTC. Subjects were required to have evidence of actively progressive
disease within 14 months prior to study entry that was confirmed by an
Independent Radiology Review Committee or the treating physician.
Subjects received cabozantinib 140 mg or placebo orally once daily
without food until disease progression or intolerable toxicity.
Randomization was stratified by age (<65 years vs. >65 years) and
prior TKI use. The main efficacy outcome measures were progression-free
survival (PFS), objective response (OR), and response duration. The
cabozantinib arm had a statistically significant prolongation of PFS
compared with the placebo arm (median PFS of 11.2 months and 4.0 months,
respectively). Partial responses were observed only in the cabozantinib
arm (27% vs. 0%). Median duration of OR was 14.7 months for subjects
treated with cabozantinib, and there was no statistically significant
difference in overall survival between the treatment arms at the planned
Pharmacology and Pharmacokinetics7,8: Cabozantinib is a small-molecule inhibitor (FIGURE 3)
of tyrosine kinases (TKs), including RET; MET; VEGFR-1, -2, and -3;
KIT; TRKB; FLT-3; AXL; and TIE-2. These receptor TKs are involved in
both normal cellular function and pathologic processes such as
oncogenesis, metastasis, tumor angiogenesis, and maintenance of the
tumor microenvironment. Treatment with cabozantinib has been shown to
reduce tumor growth, metastasis, and angiogenesis.
Following oral administration, median time to peak cabozantinib plasma concentrations (Tmax)
ranges from 2 to 5 hours. The drug is metabolized by CYP3A4 and is
eliminated primarily in the feces. Because of the narrow therapeutic
window and this clearance profile, CYP3A4 inducers and inhibitors should
be avoided. The predicted effective half-life is approximately 55
hours, oral volume of distribution is approximately 349 L, and clearance
at steady state is estimated to be 4.4 L/h.
Adverse Reactions (ARs) and Drug Interactions7,8: The
most common ARs reported with cabozantinib include diarrhea; mouth
sores; redness, pain, or swelling of the digits; loss of appetite and
weight loss; nausea; fatigue; graying or loss of hair color; taste
alteration; hypertension; abdominal pain; and constipation. The package
insert for cabozantinib includes a Black Box Warning concerning severe
and fatal bleeding and perforations and fistula in the colon, which
occurred in some trial patients. The most common laboratory
abnormalities are increased liver enzymes and decreased calcium,
phosphorus, WBCs, and platelets. Cabozantinib can cause fetal harm and
thus is Pregnancy Category D. A decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Based on the clearance profile, strong CYP3A4 inhibitors (azole
antifungals, protease inhibitors, clarithromycin, telithromycin) should
be avoided with cabozantinib. Chronic coadministration of strong CYP3A4
inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin,
rifabutin, rifapentine, phenobarbital, St. John’s wort) should also be
avoided. Cabozantinib is an inhibitor, but not a substrate, of
P-glycoprotein (Pgp) transport; thus, it has the potential to increase
plasma concentrations of coadministered Pgp substrates.
Dosage and Administration7,8: Cabozantinib
is supplied as 20-mg and 80-mg capsules. The recommended daily dosage is
140 mg (one 80-mg and three 20-mg capsules). Capsules should be
swallowed whole. Patients should not eat ≥2 hours before and ≥1 hour
after taking cabozantinib. Treatment should be continued until disease
progression or unacceptable toxicity occurs. Foods (e.g., grapefruit
products), nutritional supplements, and drugs known to inhibit or induce
CYP450 should be avoided. Cabozantinib use is not recommended in
moderate-to-severe hepatic impairment.
Bedaquiline (Sirturo, Janssen Therapeutics)
Indication and Clinical Profile9,10: Bedaquiline
was approved as part of combination therapy for adults with
multidrug-resistant pulmonary tuberculosis (MDR-TB) when other
alternatives are not available. TB, which is caused by Mycobacterium tuberculosis,
is one of the world’s deadliest diseases. The first drug approved to
treat MDR-TB, bedaquiline should be used in combination with other
antituberculars. The FDA granted bedaquiline fast-track,
priority-review, and orphan-product status because the drug could fill
an unmet medical need, could potentially provide safe and effective
treatment where no satisfactory alternative therapy exists, and was
developed to treat a rare disease. Bedaquiline is not indicated to treat
latent, extrapulmonary, or drug-sensitive TB.
Bedaquiline’s safety and effectiveness were established in 440
patients in two phase II clinical trials. Patients in the first trial
were randomized either to bedaquiline plus other drugs used to treat TB
or to placebo plus other drugs used to treat TB. All patients in the
second trial, which is ongoing, received bedaquiline plus other TB
drugs. Both trials measured the length of time it took for a patient’s
sputum to be free of M tuberculosis (sputum culture conversion
[SCC]). In the first trial, patients receiving bedaquiline combination
therapy achieved SCC in a median of 83 days, compared with 125 days in
patients receiving placebo combination therapy. In the second trial, the
median time to SCC was 57 days, supporting the efficacy findings of the
first trial. There are no clinical data on the combined use of
antiretroviral agents and bedaquiline in HIV/MDR-TB–coinfected patients.
Pharmacology and Pharmacokinetics9,10: Bedaquiline is a diarylquinoline (FIGURE 4)
that inhibits mycobacterial adenosine 5´-triphosphate synthase, an
enzyme that regulates the proton pump of adenosine triphosphate synthase
and is essential for the generation of energy and mycobacterial
Bedaquiline is slowly absorbed from the gastrointestinal tract and
should be taken with food to enhance its oral bioavailability. It is
highly bound by plasma proteins and is widely distributed (volume of
distribution 164 L). CYP3A4 is the major isoenzyme involved in the
metabolism of bedaquiline, and the primary metabolite formed, N-monodesmethyl-bedaquiline,
has significantly reduced antimycobacterial activity. Bedaquiline and
its metabolites are eliminated primarily in feces. Based on this
clearance profile, bedaquiline should be used with caution in patients
with severe hepatic impairment and only when the benefits outweigh the
risks. Also, since bedaquiline is highly bound to plasma proteins, it is
unlikely that it will be significantly removed from plasma by
hemodialysis (HD) or peritoneal dialysis (PD). Therefore, it should be
used with caution in patients with severe renal impairment or end-stage
renal disease requiring HD or PD.
Adverse Reactions (ARs) and Drug Interactions9,10: The
most common ARs in clinical studies were nausea, joint and chest pain,
and headache. Some liver-related ARs were also reported in clinical
trials; thus, alcohol and other hepatotoxic drugs should be avoided,
especially in patients with diminished hepatic reserve. Bedaquiline has a
Black Box Warning about its potential to cause fatal arrhythmias, since
it may induce long QT syndrome by blocking the hERG channel. The
manufacturer is distributing the drug from a single source and is
providing educational materials to help ensure that it is used
appropriately. Bedaquiline is Pregnancy Category B, and animal studies
have shown it to be concentrated in breast milk. Because of the
potential for ARs in nursing infants, a decision should be made whether
to discontinue nursing or to discontinue the drug.
Because bedaquiline is metabolized by CYP3A4, its systemic exposure
and therapeutic efficacy may be reduced if it is coadministered with
CYP3A4 inducers, including rifamycins (e.g., rifampin, rifapentine,
rifabutin). Therefore, strong CYP3A4 inducers should be avoided in
patients taking bedaquiline. Also, coadministration of bedaquiline with
strong CYP3A4 inhibitors may increase systemic exposure to bedaquiline,
which can potentially increase the risk of ARs. Therefore, the use of
strong CYP3A4 inhibitors for >14 consecutive days should be avoided
with bedaquiline, unless the benefit of treatment with the drug
combination outweighs the risk.
Dosage and Administration9,10: Bedaquiline
is supplied as a 100-mg tablet. It should be used only in combination
with at least three other drugs to which the patient’s MDR-TB isolate
has been shown to be susceptible in vitro. If in vitro testing results
are unavailable, treatment may be initiated with bedaquiline in
combination with at least four other drugs to which the patient’s MDR-TB
isolate is likely to be susceptible. The recommended dosage for the
first 2 weeks is 400 mg once daily with food. This is followed, in weeks
3 to 24, with a dosage of 200 mg three times per week with food, for a
total of 600 mg per week.
1. Gattex (teduglutide [rDNA origin]) product information. Bedminster, NJ: NPS Pharmaceuticals; December 2012.
2. Jeppesen PB, Pertkiewicz M, Messing B, et al. Teduglutide reduces
need for parenteral support among patients with short bowel syndrome
with intestinal failure. Gastroenterology. 2012;143:1473-1481.
3. Iclusig (ponatinib) product information. Cambridge, MA: Ariad Pharmaceuticals, Inc; December 2012.
4. Zhou T, Commodore L, Huang WS, et al. Structural mechanism of the
Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase
inhibitor resistance. Chem Biol Drug Des. 2011;77:1-11.
5. Synribo (omacetaxine mepesuccinate) product information. North Wales, PA: Teva Pharmaceuticals USA, Inc; October 2012.
6. Cortes J, Lipton JH, Rea D; Omacetaxine 202 Study Group. Phase 2
study of subcutaneous omacetaxine mepesuccinate after TKI failure in
patients with chronic-phase CML with T315I mutation. Blood. 2012;120:2573-2580.
7. Cometriq (cabozantinib) product information. San Francisco, CA: Exelixis, Inc; November 2012.
8. Sherman SI, Cohen EE, Schöffski P, et al. Efficacy of cabozantinib
(Cabo) in medullary thyroid cancer (MTC) in patients with RAS or RET mutations: results from a phase III study. J Clin Oncol. 2013;31(suppl) [abstract 6000].
9. Sirturo (bedaquiline) product information. Titusville, NJ: Janssen Therapeutics; December 2012.
10. Diacon AH, Donald PR, Pym A, et al. Randomized pilot trial of
eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant
tuberculosis: long-term outcome, tolerability, and effect on emergence
of drug resistance. Antimicrob Agents Chemother. 2012;56:3271-3276.
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