The medical letter on drugs and therapeutics march 27 2017

The Medical Letter

®

on Drugs and Therapeutics
Volume 59

ISSUE
ISSUE
No.

1433
1517
Volume 56

March 27, 2017

IN THIS ISSUE

Bezlotoxumab (Zinplava) for Prevention of Recurrent Clostridium Difficile Infection ................... p 49
Nusinersen (Spinraza) for Spinal Muscular Atrophy ................................................................... p 51
Exablate Neuro for Essential Tremor ......................................................................................... p 52
Obeticholic Acid (Ocaliva) for Primary Biliary Cholangitis .......................................................... p 54
Triferic for Iron Replacement .................................................................................................... p 55
Inhibitors and Inducers of CYP Enzymes and P-glycoprotein .............................................online only

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The Medical Letter

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on Drugs and Therapeutics
Volume 59

March 27, 2017
Take CME Exams

ISSUE

ISSUE No.

1433

1517
Volume 56

▶

ALSO IN THIS ISSUE

Nusinersen (Spinraza) for Spinal Muscular Atrophy ................................................................... p 50
Exablate Neuro for Essential Tremor ......................................................................................... p 52
Obeticholic Acid (Ocaliva) for Primary Biliary Cholangitis .......................................................... p 53
Triferic for Iron Replacement .................................................................................................... p 55
Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein .............................................online only

Bezlotoxumab (Zinplava)
for Prevention of Recurrent
Clostridium difficile Infection

The FDA has approved the fully human monoclonal
antibody bezlotoxumab (Zinplava – Merck) for use
with antibacterial drug treatment to reduce recurrence
of Clostridium difficile infection (CDI) in adults with
CDI at high risk for recurrence. It is the first drug to be
approved for this indication.
Pronunciation Key
Bezlotoxumab: bez’’ loe tox’ ue mab Zinplava: zin plah’ va

CDI — CDI is the most common infectious cause
of healthcare-associated diarrhea in adults. The
incidence and severity of CDI have increased in recent
years with the emergence of an epidemic hypervirulent

strain (NAP1/B1/027).1 The recurrence rate after an
initial episode of CDI is typically 20-25%. Patients
who develop one recurrent episode have up to a 35%
chance of having another one, and patients with at
least three CDI episodes have up to a 65% chance of
additional recurrences.2
STANDARD TREATMENT — Oral metronidazole (Flagyl,
and generics) and oral vancomycin (Vancocin, and
generics) have been the drugs of choice for treatment
of an initial episode of CDI for several years. Recent
data suggest that oral vancomycin is more effective
than oral metronidazole in preventing death in patients
with CDI.3 Fidaxomicin (Dificid) appears to be at least as
effective as oral vancomycin for first-line treatment of
CDI with fewer recurrences in patients not infected with
the hypervirulent strain.4,5
Fecal microbiota transplantation (FMT) is an
investigational therapy that has been highly effective in
treating CDI and preventing recurrences. It is generally

used only in patients with severe, refractory CDI or in
those who have had multiple recurrences. More data
from randomized, controlled trials are needed and its
long-term safety is unknown.6 One randomized, openlabel trial found that oral vancomycin followed by FMT
was not more effective than tapered oral vancomycin
alone in reducing recurrent CDI.7
MECHANISM OF ACTION — Pathogenic strains of
C. difficile can express two exotoxins, A and/or B. These
toxins damage the epithelial cells of the gut wall, resulting in an increase in gut wall permeability and induction
of an acute inflammatory response.8 Toxin B is more

virulent than toxin A. Bezlotoxumab binds to and
neutralizes C. difficile toxin B. It does not bind to toxin A.
Table 1. Pharmacology
Formulation

1000 mg/40 mL vial

Route

IV infusion

Metabolism

Protein catabolism

Half-life

19 days

CLINICAL STUDIES — Approval of bezlotoxumab was
based on the results of two randomized, doubleblind, placebo-controlled trials (MODIFY I and II) in
1554 adults with a positive stool test for toxigenic C.
difficile.9 MODIFY I included some patients who were
treated with actoxumab, a drug that neutralizes toxin
A, and both trials included groups that were treated
with actoxumab in combination with bezlotoxumab.
Actoxumab alone was not effective, and the drug did
not provide any additional benefit when used with
bezlotoxumab.
A majority (77%) of the patients in the trials had

one or more risk factor for CDI recurrence; these
included: age ≥65 years, >1 previous CDI episode,
immunosuppression, clinically severe CDI at study
entry, infection with a hypervirulent strain, use of
other antibacterial drugs during or after standard CDI
49

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therapy, and renal impairment. A single infusion of
bezlotoxumab 10 mg/kg or placebo was administered
to patients receiving 10-14 days of treatment with
metronidazole, vancomycin, or fidaxomicin.
A clinical cure of the initial episode of CDI occurred in
about 80% of patients treated with bezlotoxumab or
placebo in the two trials. The CDI recurrence rate (new
episode following initial clinical cure within 12 weeks
after infusion of bezlotoxumab or placebo) in patients
who started CDI antibacterial therapy before or within
one day after receiving a study infusion was significantly
lower with bezlotoxumab than with placebo (22% vs
33% in MODIFY I and 19% vs 33% in MODIFY II). The
incidence of sustained cure through 12 weeks after
infusion was significantly higher with bezlotoxumab
than with placebo in MODIFY II (67% vs 52%), but not in

MODIFY I (60% vs 55%). The efficacy of bezlotoxumab
was not affected by the choice of antibacterial therapy.
A post-hoc analysis of European inpatients enrolled in
the trials found that the rate of CDI-associated hospital
readmissions within 30 days following discharge was
lower in those treated with bezlotoxumab than in those
who received placebo (4.5% vs 13.3%).10
ADVERSE EFFECTS — Nausea, pyrexia, and
headache were the most common adverse effects
of bezlotoxumab reported within 4 weeks of infusion
and more often than with placebo. Infusion-related
reactions reported in 1-3% of patients treated with
bezlotoxumab included nausea, fatigue, pyrexia,
dizziness, dyspnea, headache, and hypertension. In
patients with a history of congestive heart failure, use
of bezlotoxumab was associated with higher rates of
heart failure (12.7% vs 4.8% with placebo) and death
(19.5% vs 12.5% with placebo). Overall rates of death
among patients treated with bezlotoxumab or placebo
were similar (7.1% and 7.5%).
PREGNANCY — Bezlotoxumab has not been studied in
pregnant women or animals.
IMMUNOGENICITY — None of the patients who
received bezlotoxumab in the clinical trials tested
positive for anti-drug antibodies after completing
treatment.
DOSAGE, ADMINISTRATION AND COST — Zinplava is
available in 40-mL single-dose vials containing 1000 mg
of bezlotoxumab. Prior to administration, the solution
must be diluted in 0.9% sodium chloride or 5% dextrose

to a final concentration of 1-10 mg/mL. Bezlotoxumab
must be administered during antibacterial treatment of
CDI. The recommended dosage is 10 mg/kg IV infused
once over 60 minutes. The cost for one vial is $3800.11
50

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March 27, 2017

CONCLUSION — A single IV infusion of bezlotoxumab
(Zinplava) in combination with standard antibacterial
therapy significantly reduced post-treatment recurrence of Clostridium difficile infection (CDI). Use of
bezlotoxumab in patients with a history of heart failure
may increase the risk of heart failure and death. ■
1. I See et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis 2014; 58:1394.
2. DN Gerding et al. Treatment of clostridium difficile infection.
Clin Infect Dis 2008; 46 Suppl 1 :S32.
3. VW Stevens et al. Comparative effectiveness of vancomycin
and metronidazole for the prevention of recurrence and death
in patients with Clostridium difficile infection. JAMA Intern Med
2017 Feb 6 (epub).
4. Fidaxomicin (Dificid) for Clostridium difficile infection. Med Lett
Drugs Ther 2011; 53:73.
5. SD Goldenberg et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven
NHS secondary care hospitals in England: a series of local service evaluations. Eur J Clin Microbiol Infect Dis 2016; 35:251.
6. K Rao and N Safdar. Fecal microbiota transplantation for the
treatment of Clostridium difficile infection. J Hosp Med 2016;
11:56.
7. SS Hota et al. Oral vancomycin followed by fecal transplantation versus tapering oral vancomycin treatment for recurrent

Clostridium difficile infection: an open-label, randomized, controlled trial. Clin Infect Dis 2017; 64:265.
8. Z Yang et al. Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab. Infect Immun 2015; 83:822.
9. MH Wilcox et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med 2017; 376:305.
10. V Prabhu et al. Bezlotoxumab decreases CDI recurrence and is
associated with a reduction in 30-day readmissions: European
analysis. Presented at European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Amsterdam, The Netherland, April 9-12, 2016. Abstract P1340.
11. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a
published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. March
5, 2017. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2017. www.fdbhealth.com/policies/drugpricing-policy.

▶

Nusinersen (Spinraza) for Spinal
Muscular Atrophy

The FDA has approved nusinersen (Spinraza – Biogen)
for treatment of spinal muscular atrophy (SMA), a
hereditary neurodegenerative disease that occurs in
about one in every 10,000 births.1 It is the first drug to
be approved in the US for this indication.
Pronunciation Key
Nusinersen: nue” si ner’ sen
Spinraza: spin rah' zah

SPINAL MUSCULAR ATROPHY — SMA is an
autosomal recessive neuromuscular disorder in which
degeneration of alpha motor neurons in the anterior
horn cells of the spinal cord leads to muscle weakness
and atrophy. Most cases are caused by a homozygous

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deletion or mutation in the 5q13 survival of motor
neuron 1 (SMN1) gene, which leads to SMN protein
deficiency. Mutations in a similar gene, SMN2, are
correlated with a milder SMA phenotype.2
SMA is classified based on the age of symptom onset
and motor function achieved. Infants with type 1 SMA
(age of onset 0-6 months) are unable to sit unassisted;
without respiratory support, they often die by 2 years
of age. Children with type 2 SMA (age of onset <18
months) can sit unassisted, but are unable to stand
or walk independently. Patients with type 3 SMA
(age of onset >18 months) initially have the ability to
walk, but eventually require assistance with mobility.
Patients with type 4 SMA (age of onset >21 years) are
ambulatory with only mild weakness.3
Before approval of nusinersen, management of SMA
consisted of supportive measures to address the
respiratory, nutritional, and orthopedic/muscular
complications of the disease.
MECHANISM OF ACTION — Nusinersen is an SMN2directed antisense oligonucleotide. It acts by increasing
exon 7 inclusion in SMN2 messenger RNA transcripts,
which increases the gene’s production of SMN protein.
Nusinersen is administered intrathecally, which allows
the drug to be distributed from the cerebrospinal fluid

to the target central nervous system tissues.
CLINICAL STUDIES — Approval of nusinersen was
based on the results of an unpublished, randomized,
double-blind, sham-controlled trial, summarized in the
package insert, in 121 infants with type 1 SMA who
received their first dose at ≤7 months of age. Among
82 infants included in an interim analysis, 40% of those
in the active-treatment group showed improvement in
motor milestones on Section 2 of the Hammersmith
Infant Neurologic Exam (HINE-2), the primary endpoint,
compared to none of the infants who received a sham
injection. Motor milestones include ability to kick, head
control, rolling, sitting, crawling, standing, and walking.
Patients were also evaluated using the Children’s
Hospital of Philadelphia Infant Test of Neuromuscular
Disorders (CHOP-INTEND); more patients in the
active-treatment group had a ≥4-point improvement
from baseline (63% vs 3%) and fewer had a ≥4-point
worsening (4% vs 40%).
Several open-label trials also provided data for
approval of nusinersen for treatment of SMA. Two of
these studies were published: a phase 2 trial in 20
patients with infantile-onset SMA4 and a phase 1 trial
in 28 patients 2-14 years old with type 2 or 3 SMA.5

Vol. 59 (1517)

March 27, 2017

Table 1. Pharmacology

Class
Route
Formulation
Metabolism
Elimination
Half-life (terminal)

Antisense oligonucleotide
Intrathecal
12 mg/5 mL single-dose vials
Exonuclease (3'- and 5')-mediated
hydrolysis
Probably renal
~135-177 days (CSF); 63-87 days
(plasma)

In the phase 2 trial, nusinersen significantly increased
HINE-2 and CHOP-INTEND scores compared to
baseline. In the phase 1 trial, nusinersen increased
scores on the Hammersmith Functional Motor Scale
Expanded (HFMSE) at 3 months and 9-14 months
post-dose with no reports of serious adverse events.
ADVERSE EFFECTS — In the sham-controlled trial,
the most common adverse effects of nusinersen
were lower respiratory infection, upper respiratory
infection, and constipation. Observations made
during the trial suggest that nusinersen may cause
growth retardation. Adverse events related to
lumbar puncture, including headache, back pain, and
post-lumbar puncture syndrome, have occurred.6

Hyponatremia and rash have also been reported.
Thrombocytopenia, coagulation abnormalities, and
renal toxicity have occurred following administration
of some antisense oligonucleotides, and decreased
platelet levels and elevated urine protein were
observed in some nusinersen-treated patients during
clinical trials.
PREGNANCY AND LACTATION — There are no adequate
studies of nusinersen in pregnant women. No adverse
embryofetal effects were observed in mice and rabbits
given subcutaneous injections of the drug. There are
no data on the presence of nusinersen in breast milk.
DOSAGE, ADMINISTRATION, AND COST — Spinraza
is available in single-dose vials containing 12 mg/
5 mL. The recommended dosage is 12 mg
administered intrathecally; 5 mL of cerebrospinal fluid
should be removed prior to administration. Patients
may be sedated before treatment. Use of imaging
techniques (e.g., fluoroscopy) can be considered to
guide the intrathecal injection, particularly in patients
with prominent scoliosis or surgical hardware. When
starting treatment with nusinersen, the first 3 doses
should be given 14 days apart and the fourth dose 30
days after the third dose. Maintenance doses should
be administered once every 4 months thereafter.
Spinraza is only available through one specialty pharmacy. The cost of one 5-mL vial of nusinersen is
51


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®

$125,000.7 The drug's website (www.spinraza-hcp.com)
includes a 73-page guide to drug reimbursement.
The manufacturer offers a $0 drug copay and $0
procedure copay program for most patients with
nongovernmental insurance. For those who are not
eligible for the drug copay program, the manufacturer
says it will help find a charitable organization that can
provide third-party assistance.
CONCLUSION — The antisense oligonucleotide
nusinersen (Spinraza) is the first drug to improve
motor function in infants and children with spinal
muscular atrophy (SMA). Whether it can prevent
respiratory failure and death in infantile-onset SMA
and to what extent it can improve disability in older
children remain to be determined. The cost of the
drug may limit its use. ■

▶

Exablate Neuro for Essential Tremor

The FDA has approved use of Exablate Neuro (Insightec)
for unilateral thalamotomy to treat medicationrefractory essential tremor in patients ≥22 years old.
Exablate Neuro uses magnetic resonance-guided
focused ultrasound (MRgFUS) to create lesions in the
ventral intermediate nucleus of the thalamus. MRgFUS
is also approved in the US for treatment of uterine

fibroids and for pain palliation of bone metastases.
TREATMENT OF ESSENTIAL TREMOR — Essential
tremor is a common neurological disorder that
causes involuntary and rhythmic shaking, especially
of the hand, head, neck, and voice. The tremor is not
life threatening, but it can be distressing and make
performance of everyday activities difficult. The most
effective drugs used to treat essential tremor are the
beta blocker propranolol (Inderal, and others) and
(off-label) the anticonvulsant primidone (Mysoline,
and generics); they reduce tremor by about 60% in
about 50% of patients. The anticonvulsant topiramate
(Topamax, and others) is a commonly used alternative.
Botulinum toxin injections have been used to treat
head and voice tremor.1,2
Surgical ablation of the ventral intermediate nucleus
of the thalamus is an option for drug-refractory
cases. Both deep brain stimulation from implanted
electrodes and radiofrequency thalamotomy have
been highly effective in suppressing tremor and do
so immediately. Both methods require a craniotomy.
Deep brain stimulation causes fewer side effects
such as speech, gait, and cognition disturbances, and
it is reversible.
52

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March 27, 2017

1. TW Prior et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A 2010; 152A:1608.
2. MA Farrar et al. Emerging therapies and challenges in spinal
muscular atrophy. Ann Neurol 2016 Dec 27 (epub).
3. SJ Kolb and JT Kissel. Spinal muscular atrophy. Neurol Clin
2015; 33: 831.
4. RS Finkel et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation
study. Lancet 2016; 388:3017.
5. CA Chiriboga et al. Results from a phase 1 study of nusinersen
(ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology 2016; 86:890.
6. M Haché et al. Intrathecal injections in children with spinal
muscular atrophy: nusinersen clinical trial experience. J Child
Neurol 2016; 31:899.
7. WAC = wholesaler acquisition cost or manufacturer’s published
price to wholesalers; WAC represents a published catalogue or
list price and may not represent an actual transactional price.
Source: AnalySource® Monthly. March 5, 2017. Reprinted with
permission by First Databank, Inc. All rights reserved. ©2017.
www.fdbhealth.com/policies/drug-pricing-policy.

Gamma knife thalamotomy uses radiation to ablate
the ventral intermediate nucleus and does not require
a craniotomy. It has improved tremor in several
studies, but its benefits may take weeks to months to
become apparent and serious delayed adverse effects
have been reported.1
MRgFUS THALAMOTOMY — Exablate Neuro uses
magnetic resonance-guided high-intensity focused
ultrasound waves to heat focal areas in the ventral
intermediate nucleus of the thalamus to approximately
130-140°F (~55-60°C) and ablate them.3,4

THE PROCEDURE — Prior to treatment, CT and MRI
scans of the patient’s head are taken to determine
skull thickness and density and to locate the target
area. The patient’s head is shaved, treated with a
local anesthetic, and immobilized with a stereotactic frame.
During the procedure, cold water circulates around the
head to keep the skull cool because bone temperature
can rise during application of ultrasound energy.3 Sublethal low-energy sonications are delivered initially
to test targeting accuracy and patient response.
Once targeting accuracy is confirmed, the energy is
gradually increased to temperatures sufficient for
tissue ablation (~55-60° C) and the patient is assessed
for reduction in tremor. The patient remains awake and
can respond to questions during treatment.
CLINICAL STUDIES — Approval of Exablate Neuro was
based on the results of a randomized, double-blind,
sham-controlled trial in 76 patients with moderate
to severe essential tremor that had not responded to
treatment with at least two drug regimens. Patients


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were randomized to unilateral focused ultrasound
thalamotomy or to sham treatment. Three months
after the procedure, mean contralateral hand-tremor
scores improved from baseline by 47% in patients who
received unilateral focused ultrasound thalamotomy

and by 0.1% in those who received sham treatment;
a 40% improvement in hand-tremor scores in treated
patients was maintained at 12 months after the
procedure. Total disability scores decreased by 62%
from baseline and quality-of-life scores decreased
by 46% at 3 months in patients who received the
active treatment compared to a 3% reduction for
both measures in the sham group. Only minimal
improvements were observed in head, neck, and voice
tremors and no improvement was seen in ipsilateral
hand tremors.5
MRgFUS fails to achieve adequate heating for
successful treatment in some patients, which may
be related to skull characteristics. In a retrospective
study of 25 patients who had undergone MRgFUS,
skull volume was negatively correlated with maximal
temperatures while skull density ratio (the ratio
of cortical to cancellous bone) was positively
correlated with maximal temperatures.6 In the pivotal
trial, a criterion for enrollment was a skull density
ratio ≥0.45.
ADVERSE EFFECTS — Exablate Neuro is only approved
for unilateral thalamotomy. Bilateral thalamotomy
has been associated with a higher rate of adverse
effects.1
In the double-blind trial, the most common adverse
effects reported during the procedure were head
discomfort (30%), dizziness (21%), and nausea (20%).
The most common postoperative adverse effects were
paresthesias and gait disturbances, which occurred

in 38% and 36% of patients, respectively, in the active
treatment group, and these effects persisted at 12
months in 14% and 9% of patients.
Other possible side effects of MRgFUS include damage
to areas surrounding the focal point, hemorrhage
requiring emergency treatment, skin ulceration, scar
formation, and blood clots.7
Treatment with Exablate Neuro is contraindicated in
patients who cannot undergo an MRI scan, such as
those with implanted metallic devices. Pregnancy,
advanced kidney disease, severe hypertension, and
a history of bleeding abnormalities also preclude
treatment with the device. It is not recommended for
patients with a history of stroke or brain tumors or in
those taking an anticoagulant.

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March 27, 2017

CONCLUSION — Magnetic resonance-guided
focused ultrasound unilateral thalamotomy using
Exablate Neuro significantly improved contralateral
hand tremor in patients with drug-refractory
essential tremor, but postoperative paresthesias and
gait disturbances were common and persisted for
at least one year in some patients. This procedure
has not been compared to deep brain stimulation,
which is also effective in reducing tremor and, unlike
thalamotomy, is reversible. ■

1. TA Zesiewicz et al. Practice parameter: therapies for essential
tremor: report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 2005; 64:2008.
2. TA Zesiewicz et al. Evidence-based guideline update: treatment
of essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2011;
77:1752.
3. P Ghanouni et al. Transcranial MRI-guided focused ultrasound:
a review of the technologic and neurologic applications. AJR
Am J Roentgenol 2015; 205:150.
4. Exablate Model 4000 Type 1. Information for prescribers. Available at: www.accessdata.fda.gov/cdrh_docs/pdf15/p150038c.
pdf. Accessed March 16, 2017.
5. WJ Elias. A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med 2016; 375:730.
6. WS Chang et al. Factors associated with successful magnetic
resonance-guided focused ultrasound treatment: efficiency of
acoustic energy delivery through the skull. J Neurosurg 2016;
124:411.
7. FDA. Summary of safety and effectiveness data (SSED). Available at www.accessdata.fda.gov/cdrh_docs/pdf15/P150038B.
pdf. Accessed March 16, 2017.

▶

Obeticholic Acid (Ocaliva) for
Primary Biliary Cholangitis

Obeticholic acid (Ocaliva – Intercept), a farnesoid X
receptor agonist, has been approved by the FDA for
treatment of primary biliary cholangitis; it is indicated
for use in combination with ursodeoxycholic acid
(ursodiol, UDCA; Urso, and others) in adults with an
inadequate response to UDCA and as monotherapy in

adults unable to tolerate UDCA. Obeticholic acid is the
second drug to be approved for this indication; UDCA
was the first.
Ocaliva: oh cal' i va

Pronunciation Key
Obeticholic acid: oh bet" i koe' lik as' id

PRIMARY BILIARY CHOLANGITIS — Primary biliary
cholangitis, formerly called primary biliary cirrhosis,
is a rare progressive autoimmune disease of the
intralobular bile ducts that can lead to fibrosis,
cirrhosis, and liver failure.1 It most commonly affects
women >40 years old.
STANDARD TREATMENT — UDCA, a naturally
occurring hydrophilic bile acid, replaces toxic
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hydrophobic bile acids that accumulate in the
liver, promotes choleresis, inhibits apoptosis of
hepatocytes, and has immunomodulatory effects. It
has been shown to reduce the risk of cirrhosis and
liver transplantation and improve survival, but about
one-third of patients have an inadequate response.
Budesonide, methotrexate, rituximab, fibrates, and

other drugs have been added to UDCA when monotherapy fails, but the benefits are unclear.2
MECHANISM OF ACTION — Obeticholic acid
is a derivative of the primary human bile acid
chenodeoxycholic acid (CDCA); it is a more potent
agonist of the farnesoid X receptor (FXR) than
CDCA. Stimulation of FXRs, which are expressed in
enterohepatic tissue, suppresses bile acid synthesis
and promotes bile acid transport out of hepatocytes.
Table 1. Pharmacology
Class
Formulation
Route
Tmax
Metabolism
Elimination

Farnesoid X receptor (FXR) agonist
5, 10 mg tablets
Oral
1.5 hours, active conjugates 10 hours
Conjugated with taurine and glycine and
secreted into bile
In feces (87%) after deconjugation in the
ileum and colon

CLINICAL STUDIES — Approval of obeticholic acid
was based on studies using alkaline phosphatase
(ALP) levels as a surrogate endpoint.3 Obeticholic
acid has not yet been shown to improve clinical
outcomes in patients with primary biliary cholangitis.

In a 12-month, double-blind, phase 3 trial, 216
patients with primary biliary cholangitis and an ALP
level ≥1.67 times the upper limit of normal (ULN) or
an abnormal total bilirubin level <2 times the ULN
were randomized to receive obeticholic acid 5 or 10
mg or placebo once daily. Patients in the 5-mg group
could be titrated to the 10-mg dose after 6 months
if necessary. Most patients were taking UDCA at the
time of enrollment and continued taking the drug
throughout the trial. Treatment response, the primary
endpoint, was a composite of an ALP level <1.67
times the ULN with a reduction of ≥15% from baseline,
and a normal total bilirubin level at 12 months. The
response rate was 47% with the 10-mg dose, 46%
in the titration group, and 10% with placebo. There
was no change in liver fibrosis score (measured
noninvasively) in any group at 12 months.4
In an earlier trial, 165 patients with primary biliary
cholangitis inadequately controlled with UDCA and
with ALP levels 1.5-10 times the ULN were randomized
to receive obeticholic acid 10, 25, or 50 mg, or placebo
54

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March 27, 2017

once daily for 3 months. Patients maintained their
dose of UDCA throughout the trial. Compared to
placebo, the average reduction from baseline in ALP

levels was significantly greater with obeticholic acid
(21-25% vs 3%), and significantly more patients taking
obeticholic acid had a ≥20% reduction in ALP level
(69% vs 8%).5
In another study, available only as an abstract, 59
patients with primary biliary cholangitis and ALP
levels 1.5-10 times the ULN were randomized to
monotherapy with obeticholic acid 10 or 50 mg or
placebo once daily for 12 weeks. Patients in the 10and 50-mg groups had improvement in ALP levels
(-44.5% and -37.6%, respectively) compared to those
taking placebo (+0.4%). ALP levels decreased from 3.9
to 1.9 times the ULN by the end of the trial in patients
taking the 10-mg dose.6
ADVERSE EFFECTS — The most common adverse
effect of obeticholic acid is pruritus, which is also
a common clinical manifestation of primary biliary
cholangitis. In the phase 3 trial, pruritus occurred
in 68% of patients taking the 10-mg dose, in 56% of
those taking the 5-mg (titrated to 10-mg) dose, and in
38% of those taking placebo; 59% of trial participants
reported pruritus at baseline. Other adverse effects
that occurred in ≥10% of patients taking either dose
of obeticholic acid were fatigue, abdominal pain,
rash, and arthralgia. Reductions in high density
lipoprotein-cholesterol (HDL-C) and increases in
low density lipoprotein-cholesterol (LDL-C) were
also reported.
In a pooled analysis of three placebo-controlled trials,
rates of liver-related adverse effects were higher
in obeticholic acid-treated patients (5.2 events per

100 patient-exposure years with 10 mg daily, 19.8
with 25 mg daily, and 54.5 with 50 mg daily vs 2.4
with placebo).
DRUG INTERACTIONS — Bile acid sequestrants can
decrease systemic absorption of obeticholic acid; it
should be taken at least 4 hours before or 4 hours after
a bile acid sequestrant.
Obeticholic acid may increase the INR in patients
taking warfarin. It is an inhibitor of CYP1A2 and may
increase concentrations of drugs metabolized by
CYP1A2, such as theophylline.7
PREGNANCY AND LACTATION — There are no
adequate studies of obeticholic acid in pregnant
women. No adverse fetal effects were observed in
animal studies using higher-than-recommended


The Medical Letter

®

Vol. 59 (1517)

March 27, 2017

Table 2. Drugs for Primary Biliary Cholangitis
Drug
Obeticholic acid – Ocaliva (Intercept)

Formulations

5, 10 mg tabs

Daily Dosage
5-10 mg once

Ursodiol (UDCA)2 – generic
Urso (Actavis)
Urso Forte (Actavis)

250, 500 mg tabs
250 mg tabs
500 mg scored tabs

13-15 mg/kg in 2-4
divided doses

Adverse Effects
Pruritus, fatigue, abdominal
pain, rash, arthralgia
Abdominal discomfort and
pain, alopecia, diarrhea,
nausea, pruritus, rash

Cost1
$5700.00
228.00
575.40
509.80

UDCA = Ursodeoxycholic acid

1. Approximate WAC for 30 days’ treatment with obeticholic acid 5 mg daily or ursodiol 1000 mg daily. WAC = wholesaler acquisition cost or manufacturer’s
published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource®
Monthly. March 5, 2017. Reprinted with permission by First Databank, Inc. All rights reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.
2. Ursodiol is also marketed in 300-mg capsules (Actigall, and generic) for dissolution of gallbladder stones.

human doses of obeticholic acid. There are no data
on the presence of the drug in breast milk.
DOSAGE AND ADMINISTRATION — The recommended
starting dosage of Ocaliva in patients who have had
an inadequate response to treatment with UDCA for at
least 1 year or are intolerant to UDCA is 5 mg daily.
If adequate reductions in ALP or total bilirubin levels
have not been achieved after 3 months, the dosage
can be increased to 10 mg once daily.
If intolerable pruritus occurs, an antihistamine or
bile acid sequestrant can be added. The dosage of
Ocaliva may be reduced to 5 mg every other day in
patients taking 5 mg once daily, or to 5 mg once daily
in those taking 10 mg once daily; treatment may also
be interrupted for 2 weeks and then restarted at a
lower dosage.
CONCLUSION — Treatment with obeticholic acid
(Ocaliva) alone or with ursodeoxycholic acid (UDCA)

▶

Triferic for Iron Replacement

The FDA has approved ferric pyrophosphate
citrate solution (Triferic – Rockwell Medical) to

maintain hemoglobin concentrations in adults with
hemodialysis-dependent chronic kidney disease.
Triferic is the first iron replacement product that is
added into the hemodialysis solution at each dialysis
procedure.
Pronunciation Key
Ferric pyrophosphate citrate: fer’ ik pye” roe fos’ fate si’ trate
Triferic: trye fer’ ik

IRON SUPPLEMENTATION — Iron deficiency anemia
is common in patients with chronic kidney disease
who require hemodialysis; contributing factors
include gastrointestinal bleeding, blood draws, use
of erythropoiesis-stimulating agents (ESAs), and
hemodialysis itself. In these patients, IV iron is

can lower alkaline phosphatase and bilirubin levels
in patients with primarily biliary cholangitis. Unlike
UDCA, which is much cheaper, obeticholic acid has not
yet been shown to improve clinical outcomes. ■
1. PJ Trivedi et al. Obeticholic acid for the treatment of primary
biliary cirrhosis. Expert Rev Clin Pharmacol 2016; 9:13.
2. YQ Huang. Recent advances in the diagnosis and treatment of
primary biliary cholangitis. World J Hepatol 2016; 8:1419.
3. WJ Lammers et al. Levels of alkaline phosphatase and bilirubin
are surrogate end points of outcomes of patients with primary
biliary cirrhosis: an international follow-up study. Gastroenterology 2014; 147:1338.
4. F Nevens et al. A placebo-controlled trial of obeticholic acid in
primary biliary cholangitis. N Engl J Med 2016; 375:631.
5. GM Hirschfield et al. Efficacy of obeticholic acid in patients with

primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148:751.
6. KV Kowdley et al. An international study evaluating the farnesoid X receptor agonist obeticholic acid as monotherapy in
PBC. J Hepatol 2011; 54:S13 abstract 28.
7. Inhibitors and inducers of CYP enzymes and p-glycoprotein. Med
Lett Drugs Ther 2017. March 27 (epub). Available at: medicalletter.
org/TML-article-1517f. Accessed March 16, 2017.

preferred over oral iron for supplementation because
oral formulations are poorly absorbed.1 IV iron
preparations approved for use in patients requiring
hemodialysis include iron dextran (Dexferrum; INFeD),
sodium ferric gluconate (Ferrlecit, and generic), iron
sucrose (Venofer), and ferumoxytol (Feraheme). Most
IV iron preparations are given in 3-10 infusions over
multiple weeks; ferumoxytol requires only two IV
doses over 3-8 days.
Iron accumulation leading to iron overload is a serious
potential adverse effect of IV iron replacement
therapy, and high IV iron doses have been associated
with increased mortality.2 Anaphylactic reactions
can occur; the incidence has been higher with iron
dextran products than with other parenteral iron
products.3
THE NEW PRODUCT — Ferric pyrophosphate citrate
(FPC) is a carbohydrate-free, water-soluble complex
55


The Medical Letter

®

Vol. 59 (1517)

March 27, 2017

iron salt that is added to the bicarbonate concentrate
used to make the hemodialysate and transferred to the
patient’s blood through the dialyzer membrane. Unlike
other parenteral iron products, Triferic binds directly
to transferrin for transport to erythroid precursor
cells, bypassing the reticuloendothelial system; as a
result, progressive iron accumulation does not occur.
According to the manufacturer, use of FPC solution
replaces the 5-7 mg of iron lost during a typical
hemodialysis treatment.

27.2 mg and 272 mg, respectively, of iron (5.44 mg/
mL of solution), and in powder packets containing
272 mg of iron. For treatment of a single patient,
one 5-mL ampule should be added to 2.5 gallons
of the bicarbonate concentrate used to make the
hemodialysate (50-mL ampules and powder packets
can be used to treat multiple patients). The final
concentration is 110 mcg (2 micromoles) of iron per
liter of hemodialysate. The cost for a 50-mL ampule of
Triferic is $61 and for a powder packet is $192.6

CLINICAL STUDIES — Approval of FPC solution was
based on the results of two identically designed,

single-blind trials (CRUISE 1 and 2) in a total of
599 hemodialysis-dependent patients who were
randomized to receive treatment with either FPC
dialysate or standard dialysate (placebo) 3 or 4 times
per week.4 Use of oral or IV iron replacement products
and changes to baseline ESA doses were not allowed.
Patients were treated for 48 weeks or until prespecified
hemoglobin or serum ferritin values indicated a need
for changes in anemia management. The combined
results of both trials showed that patients given FPC
dialysate had significantly smaller reductions from
baseline in hemoglobin concentrations, the primary
endpoint, than those receiving standard dialysate
(-0.1 g/dL vs -0.4 g/dL).

CONCLUSION — Ferric pyrophosphate citrate (Triferic)
solution is the first iron replacement product available
in the US that is added into the hemodialysis solution.
It appears to be effective in maintaining hemoglobin
levels and reducing use of erythropoiesis stimulating
agents (ESAs) in patients with hemodialysisdependent chronic kidney disease. Some patients
may require additional IV iron supplementation. Use
of Triferic could theoretically reduce the risk of iron
overload that has been associated with administration
of IV iron replacement products. ■

A randomized, double-blind trial (PRIME) compared
the effect of FPC dialysate with that of standard
dialysate (placebo) on the prescribed dose of ESAs in
103 patients receiving 3-4 hemodialysis treatments

weekly.5 After 9 months, the prescribed ESA dose had
increased by 4.9% in patients receiving FPC dialysate
and by 39.8% in those receiving standard dialysate, a
statistically significant difference.
ADVERSE EFFECTS — The risks, if any, of bypassing
the reticuloendothelial system are not known. In the
CRUISE trials, common adverse events that occurred
at a >1% higher incidence in FPC-treated patients
than in placebo-treated patients included procedural
hypotension (21.6% vs 19.3%), muscle spasms (9.6%
vs 8.1%), headache (9.2% vs 5.4%), peripheral edema
(6.8% vs 3.7%), extremity pain (6.8% vs 5.7%), and urinary
tract infection (4.5% vs 1.4%). One hypersensitivity
reaction was reported in the FPC group compared to
none in the control group. In the CRUISE and PRIME
trials, use of FPC dialysate did not result in significant
changes in biomarkers of inflammation compared to
use of standard dialysate.
DOSAGE, ADMINISTRATION, AND COST — Triferic
is available in 5-mL and 50-mL ampules containing
56

1. J Albaramki et al. Parenteral versus oral iron therapy for adults
and children with chronic kidney disease. Cochrane Database
Syst Rev 2012; 1:CD007857.
2. GR Bailie et al. Data from the dialysis outcomes and practice
patterns study validate an association between high intravenous iron doses and mortality. Kidney Int 2015; 87:162.
3. Ferric carboxymaltose (Injectafer) for iron deficiency anemia.
Med Lett Drugs Ther 2013; 55:99.
4. SN Fishbane et al. Ferric pyrophosphate citrate (Triferic) administration via the dialysate maintains hemoglobin and iron

balance in chronic hemodialysis patients. Nephrol Dial Transplant 2015; 30:2019.
5. A Gupta et al. Ferric pyrophosphate citrate administered via
dialysate reduces erythropoiesis-stimulating agent use and
maintains hemoglobin in hemodialysis patients Kidney Int
2015; 88:1187.
6. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual
transactional price. Source: AnalySource® Monthly. March 5,
2017. Reprinted with permission by First Databank, Inc. All rights
reserved. ©2017. www.fdbhealth.com/policies/drug-pricingpolicy.

Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein
(online only)
www.medicalletter.org/TML-article-1517f

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Review the efficacy and safety of bezlotoxumab (Zinplava) for use in the patients with Clostridium difficile infection.
Review the efficacy and safety of nusinersen (Spinraza) for treatment of spinal muscular atrophy.
Review the efficacy and safety of Exablate Neuro for treatment of essential tremor.
Review the efficacy and safety of obeticholic acid (Ocaliva) for treatment of primary biliary cholangitis.

Review the efficacy and safety of ferric pyrophosphate citrate solution (Triferic) for maintenance of hemoglobin concentrations in patients on hemodialysis.

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Issue 1517 Questions
(Correspond to questions #61-70 in Comprehensive Exam #76, available July 2017)
Bezlotoxumab (Zinplava) for Prevention of Recurrent
Clostridium difficile Infection
1. Bezlotoxumab:
a. is bactericidal against Clostridium difficile
b. binds to and neutralizes Clostridium difficile toxin B
c. is used in place of antibacterial treatment for CDI
d. all of the above
2. The clinical trials that led to FDA approval of bezlotoxumab showed

that:
a. the rate of clinical cure of the initial episode of CDI was
significantly higher with bezlotoxumab than with placebo
b. the rate of clinical cure of the initial episode of CDI was
significantly lower with bezlotoxumab than with placebo
c. bezlotoxumab significantly reduced the rate of CDI recurrence
compared to placebo
d. CDI recurrence rates with bezlotoxumab were higher in
patients receiving vancomycin than in those receiving
fidaxomicin
Nusinersen (Spinraza) for Spinal Muscular Atrophy
3. The clinical trial that led to FDA approval of nusinersen showed that:
a. 40% of treated infants had an improvement in motor milestones
b. 45% of treated infants were able to sit unassisted
c. 80% of treated infants survived beyond their second birthday
d. all of the above
4. The mother of a 6-month-old boy with type 1 spinal muscular
atrophy is anxious for her son to begin treatment with nusinersen.
You should tell her:
a. the drug is administered intrathecally
b. the first 4 doses are given over a period of about 2 months and
then maintenance doses are given once every 4 months
c. whether nusinersen can prevent respiratory failure is not
known
d. all of the above
Exablate Neuro for Essential Tremor
5. Which of the following are contraindications to the use of Exablate
Neuro?
a history of concussion
b. diabetes

c. presence of an implanted metallic device
d. all of the above

6. A 58-year-old man with medication-refractory essential tremor is
experiencing severe bilateral tremor of both of his hands. He has
read about Exablate Neuro and asks whether it would be suitable for
him. You could tell him that:
a. this device uses high-intensity focused ultrasound waves
to destroy the parts of the brain that are responsible for his
tremor
b. it can only be used to treat the tremor in one hand
c. the procedure could leave him with some difficulty in walking
d. all of the above
Obeticholic Acid (Ocaliva) for Primary Biliary Cholangitis
7. In clinical trials in patients with primary biliary cholangitis, use of
obeticholic acid:
a. reduced the risk of liver transplantation
b. reduced the risk of cirrhosis
c. improved survival
d. lowered alkaline phosphatase and bilirubin levels
8. The most common adverse effect of obeticholic acid is:
a. fatigue
b. abdominal pain
c. pruritus
d. arthralgia
Triferic for Iron Replacement
9. The theoretical advantage of an iron replacement product like
Triferic, which is added into the hemodialysis solution, is that:
a. it may be possible to give it only once a month
b. it may not increase the risk of developing leukemia

c. it may not cause iron overload
d. all of the above
10. In clinical trials, patients treated with Triferic:
a. had an increase from baseline in serum hemoglobin
concentrations
b. had significantly smaller reductions from baseline in
hemoglobin concentrations than patients treated with placebo
c. required larger increases in ESA doses than those treated with
placebo
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-17-517-H01-P; Release: March 27, 2017, Expire: March 27, 2018
Comprehensive Exam 76: 0379-0000-17-076-H01-P; Release: July 2017, Expire: July 2018
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