The medical letter on drugs and therapeutics august 17 2015

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE
ISSUE
No.

1433
1475
Volume 56

August 17, 2015

IN THIS ISSUE

Alirocumab (Praluent) to Lower LDL-Cholesterol ..............................................................p 113
Palbociclib (Ibrance) for Metastatic Breast Cancer ...........................................................p 115
Brexpiprazole (Rexulti) for Schizophrenia and Depression ...............................................p 116
In Memoriam ........................................................................................................................p 118
Panobinostat (Farydak) for Multiple Myeloma ....................................................................online only
Lenvatinib (Lenvima) for Thyroid Cancer .......................................................................online only

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57

ISSUE

ISSUE No.

1433
1475
Volume 56

▶

August 17, 2015
Take CME Exams
ALSO IN THIS ISSUE

Palbociclib (Ibrance) for Metastatic Breast Cancer ...........................................................p 115
Brexpiprazole (Rexulti) for Schizophrenia and Depression ...............................................p 116
In Memoriam ........................................................................................................................p 118
Panobinostat (Farydak) for Multiple Myeloma ....................................................................online only
Lenvatinib (Lenvima) for Thyroid Cancer .......................................................................online only

Alirocumab (Praluent) to Lower
LDL-Cholesterol

The FDA has approved the subcutaneously injected
PCSK9 (proprotein convertase subtilisin kexin type 9)
inhibitor alirocumab (Praluent – Sanofi/Regeneron)
as an adjunct to diet and maximally tolerated
statin therapy for adults with heterozygous familial
hypercholesterolemia (HeFH) or clinical atherosclerotic
cardiovascular disease who require additional lowering
of LDL-cholesterol (LDL-C). It was not approved for
general use in statin-intolerant patients. Alirocumab
is the first PCSK9 inhibitor to be approved in the US.
Evolocumab (Repatha – Amgen), another PCSK9

inhibitor, was recently approved in Europe and has been
recommended for approval for the same indications in
the US by an FDA Advisory Committee.
Pronunciation Key
Alirocumab: al i rok' ue mab
Praluent: prahl' u ent

MECHANISM OF ACTION — PCSK9 binds to LDL receptors on hepatocytes, promoting receptor degradation,
preventing LDL-C clearance from blood, and increasing
serum concentrations of LDL-C. Alirocumab is a human
monoclonal antibody that targets PCSK9, prevents it
from binding to LDL receptors, and increases hepatic
uptake of LDL-C.
Table 1. Pharmacology
Class
Formulation

PCSK9 inhibitor
75, 150 mg/mL preservative-free solution in
single-use pen or prefilled syringe
Route
Subcutaneous injection
Tmax
3-7 days
Metabolism
Probably degradation to small peptides and
amino acids
Elimination
Low concentrations: saturable binding to PCSK9
Higher concentrations: nonsaturable proteolysis

Half-life (terminal) 12 days with statin coadministration

NEW GUIDELINES — The American College of
Cardiology and the American Heart Association
no longer recommend using specific cholesterol
targets in the treatment of hyperlipidemia. They
now recommend high-intensity statin therapy (e.g.,
atorvastatin 40-80 mg), which generally results in
LDL-C reductions of ≥50%, for patients with clinical
atherosclerotic cardiovascular disease.1 The National
Lipid Association has recommended use of statins
to achieve LDL-C reductions of ≥50% in patients with
familial hypercholesterolemia.2
CLINICAL STUDIES — Results of randomized,
double-blind clinical trials comparing alirocumab
75-150 mg injected subcutaneously every 2 weeks
to oral ezetimibe 10 mg/day or placebo in patients
already taking maximally tolerated statin therapy are
summarized in Table 2.
Table 2. Some Alirocumab Clinical Trials
Trial

Population

COMBO I1
(n=316)
COMBO II2
(n=720)
FH I3
(n=486)

FH II3
(n=249)

High CV Risk
High CV Risk
HeFH
HeFH

Mean LDL-C

Treatment
Arms

Change at
24 Weeks

Alirocumab
Placebo
Alirocumab
Ezetimibe
Alirocumab
Placebo
Alirocumab
Placebo

-48.2%
-2.3%
-50.6%
-20.7%
-48.8%

+9.1%
-48.7%
+2.8%

CV = cardiovascular; HeFH = heterozygous familial hypercholesterolemia
1. DJ Kereiakes et al. Am Heart J 2015; 169:906.
2. CP Cannon et al. Eur Heart J 2015; 36:1186.
3. Summarized in the FDA Clinical Review.

A randomized, double-blind trial (LONG TERM) in 2341
patients at high risk for cardiovascular events because
of HeFH, established coronary heart disease, or known
coronary disease risk factors and with LDL-C levels ≥70
mg/dL despite treatment with maximally tolerated statin
113

Published by The Medical Letter, Inc. • A Nonprofit Organization


The Medical Letter

Vol. 57 (1475)

®

August 17, 2015

Table 3. Some Drugs for Hypercholesterolemia
Drug
Cholesterol Absorption Inhibitor

Ezetimibe – Zetia (Merck)
HMG-CoA Reductase Inhibitors
Atorvastatin – generic
Lipitor (Pfizer)
Fluvastatin – generic
Lescol (Novartis)
extended-release – Lescol XL
Lovastatin – generic
extended-release – Altoprev (Covis)

Formulations

Usual Adult Dosage

10 mg tabs

10 mg PO once/d

10, 20, 40, 80 mg tabs

Initial: 10-20 mg PO once/d
Max: 80 mg PO once/d
Initial: 40 mg PO bid
Max: 40 mg PO bid
80 mg PO once/d
Initial: 20 mg PO once/d
Max: 80 mg PO once/d2
Initial: 20 mg PO once/d
Max: 60 mg PO once/d
Initial: 2 mg PO once/d

Max: 4 mg PO once/d
Initial: 40 mg PO once/d3
Max: 80 mg PO once/d
Initial: 10-20 mg PO once/d4,5
Max: 40 mg PO once/d6
Initial: 10-20 mg PO once/d7
Max: 40 mg PO once/d8,9

20, 40 mg caps
80 mg ER tabs
10, 20, 40 mg tabs
20, 40, 60 mg ER tabs

Pitavastatin – Livalo (Kowa)

1, 2, 4 mg tabs

Pravastatin – generic
Pravachol (BMS)
Rosuvastatin – Crestor (AstraZeneca)

10, 20, 40, 80 mg tabs

Simvastatin – generic
Zocor (Merck)
PCSK9 Inhibitor
Alirocumab – Praluent (Sanofi/Regeneron)

5, 10, 20, 40 mg tabs
5, 10, 20, 40, 80 mg tabs

75, 150 mg/mL single-use
pens, prefilled syringes

Initial: 75 mg SC q2 wks
Max: 150 mg SC q2 wks

Cost1
$236.50
9.50
190.70
105.30
153.00
233.70
10.10
546.70
189.30
20.10
169.70
216.10
3.50
123.50
1120.00

ER = extended release; SC = subcutaneously
1. Approximate WAC for 30 days’ treatment at the lowest initial dose. 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. August 5, 2015. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
2. Or 40 mg bid.
3. Patients with significant renal impairment should start with 10 mg/d.

4. Higher concentrations of rosuvastatin have been reported in Asian patients; an intial dosage of 5 mg once/d is recommended.
5. Patients with severe renal impairment not on hemodialysis should begin with 5 mg and not exceed 10 mg/d.
6. Maximum dose in Asian patients is 20 mg/d (E Lee et al. Clin Pharmacol 2005; 78:330).
7. Patients with severe renal impairment should begin with 5 mg/d.
8. Patients taking 80 mg/d for ≥12 months without evidence of myopathy can continue at this dosage.
9. The maximum daily dose of simvastatin should be 10 mg if taken with diltiazem (Cardizem), verapamil (Calan), or dronedarone (Multaq) and 20 mg if taken with
amlodipine (Norvasc), ranolazine (Ranexa), or amiodarone (Cordarone).

therapy compared alirocumab 150 mg with placebo, both
injected subcutaneously every 2 weeks for 78 weeks. The
mean change in LDL-C at 24 weeks (the primary endpoint)
was -61.0% with the active drug and +0.8% with placebo.
At 78 weeks of treatment, the mean change was -52.4%
with alirocumab and +3.6% with placebo. A post-hoc
analysis found that major cardiovascular events occurred
in 1.7% of patients treated with alirocumab and in 3.3% of
those treated with placebo (p=0.002).3
In an unpublished, randomized, double-blind trial
(HIGH FH, summarized in the package insert) in 107
patients with HeFH who had baseline LDL-C levels
≥160 mg/dL despite taking maximally tolerated statin
therapy, the mean reduction in LDL-C at 24 weeks
(the primary endpoint) was significantly greater with
alirocumab 150 mg given every 2 weeks than with
placebo (-43% vs -7%).
Two randomized, double-blind trials in a total of 660
high-risk patients taking atorvastatin 20 or 40 mg/day
(OPTIONS I) or rosuvastatin 10 or 20 mg/day (OPTIONS
II, summarized in the FDA clinical review) found that
114

adding biweekly 75-mg doses of alirocumab reduced
LDL-C significantly more than adding ezetimibe,
doubling the dose of the statin, or (in OPTIONS I)
switching from atorvastatin to a maximally tolerated
dose of rosuvastatin.4
ADVERSE EFFECTS — Most clinical trials of alirocumab
found no significant differences in adverse events
between the active drug and placebo. In the 78week trial, patients injected with alirocumab were
significantly more likely to experience injection-site
reactions (5.9% vs 4.2% with placebo) and myalgia
(5.4% vs 2.9% with placebo). Neurocognitive events
including amnesia, memory impairment, and confusion
occurred in some patients with use of alirocumab.1
Hypersensitivity reactions, including some that
required hospitalization, have also occurred.
PREGNANCY — Monoclonal antibodies are unlikely to
cross the placenta in the first trimester, but may do so
subsequently. Animal studies found that alirocumab
injections had no adverse effects on the fetus. The drug
has not been studied in pregnant women.


The Medical Letter

®

DOSAGE AND ADMINISTRATION — The recommended
starting dosage of alirocumab is 75 mg injected subcutaneously into the thigh, abdomen, or upper arm
every 2 weeks. It can be increased to a maximum

of 150 mg if necessary. The injection site should be
rotated with each use. If a dose is missed, it should
be administered only if the next dose is scheduled to
be given at least 7 days later. LDL-C levels should be
measured within 4-8 weeks after starting therapy with
alirocumab or changing the dose.
Alirocumab is supplied in prefilled pens or glass syringes
containing 75 or 150 mg of the drug in 1 mL of solution.
Dosage units must be refrigerated, but should be allowed
to warm to room temperature for 30-40 minutes before
injection. The drug should be discarded if exposed to
room-temperature conditions for ≥24 hours, or if the
solution is discolored or contains visible particulates.
CONCLUSION — The PCSK9 inhibitor alirocumab
(Praluent) given by subcutaneous injection every 2

▶

Palbociclib (Ibrance) for
Metastatic Breast Cancer

Palbociclib (Ibrance – Pfizer), an oral cyclin-dependent
kinase inhibitor, has been approved by the FDA for use
in combination with the aromatase inhibitor letrozole
(Femara, and generics) for first-line treatment of
postmenopausal women with estrogen receptor (ER)positive, human epidermal growth factor receptor 2
(HER2)-negative metastatic breast cancer. It is the
first cyclin-dependent kinase inhibitor to become
available in the US.
Pronunciation Key

Palbociclib: pal” boe sye’ klib
Ibrance: eye’ brans

STANDARD TREATMENT — The American Society of
Clinical Oncology (ASCO) recommends that postmenopausal women with ER-positive, HER2-negative
metastatic breast cancer be offered hormone therapy
(preferably an aromatase inhibitor) as standard firstline treatment.1,2 These patients often do well for many
years with hormone therapy alone; how to identify a
target population that could benefit from the addition
of other drugs is unclear.3
MECHANISM OF ACTION — Cyclin-dependent kinases
4 and 6 regulate the G1/S phase transition within the
cell cycle. This pathway may be hyperactivated in some
malignancies, including estrogen-dependent breast
cancer. Palbociclib inhibits CDK 4 and 6, which blocks
progression of the cell cycle and results in cell cycle
arrest or senescence.4

Vol. 57 (1475)

August 17, 2015

weeks can further lower LDL-cholesterol levels by
40% or more in patients with heterozygous familial
hypercholesterolemia or clinical atherosclerotic cardiovascular disease already taking maximally tolerated
doses of a statin. Limited post-hoc data suggest that
it may decrease the incidence of cardiovascular events
as well. The long-term efficacy and safety of alirocumab
are unknown, and it is expensive. ■
1. NJ Stone et al. 2013 ACC/AHA guideline on the treatment of

blood cholesterol to reduce atherosclerotic cardiovascular risk
in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am
Coll Cardiol 2014; 63:2889.
2. JG Robinson et al. Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations
from the National Lipid Association Expert Panel on Familial
Hypercholesterolemia. J Clin Lipidol 2011; 5(3 Suppl):S18.
3. JG Robinson et al. Efficacy and safety of alirocumab in reducing
lipids and cardiovascular events. N Engl J Med 2015; 372:1489.
4. H Bays et al. Alirocumab as add-on to atorvastatin versus other
lipid treatment strategies: ODYSSEY OPTIONS I randomized
trial. J Clin Endocrinol Metab 2015 June 1 (epub).

Table 1. Pharmacology
Class

CDK 4 and 6 inhibitor

Formulation

75, 100, 125 mg capsules

Route

Oral

Tmax

6-12 hours

Metabolism

Primarily by CYP3A and sulfotransferase SULT2A1

Elimination (healthy subjects)

Feces (~74%); urine (~18%)

Half-life (cancer patients)

~29 hours

CLINICAL STUDIES — Approval of palbociclib was
based on an open-label trial (PALOMA-1/TRIO-18)
that randomized 165 postmenopausal women
with ER-positive, HER2-negative advanced breast
cancer to letrozole 2.5 mg once daily for 28 days
alone or with palbociclib 125 mg once daily added
on days 1-21 of a 28-day treatment cycle. Median
progression-free survival, the primary endpoint,
was significantly longer in patients taking letrozole
plus palbociclib than in those taking letrozole alone
(20.2 vs 10.2 months).5
A randomized, double-blind trial (PALOMA3) in 521
women with ER-positive, HER2-negative advanced
breast cancer previously treated with hormonal
therapy found that palbociclib 125 mg/day for 3 weeks
every 28 days plus the estrogen receptor antagonist
fulvestrant (Faslodex) 500 mg IM every 14 days for the
first 3 injections and then every 28 days significantly
increased median progression-free survival compared

to fulvestrant alone (9.2 vs 3.8 months).6
115


The Medical Letter

®

ADVERSE EFFECTS — Grade 3 and 4 neutropenia
occurred in 48% and 6%, respectively, of patients
taking palbociclib plus letrozole. Grade 3 neutropenia
occurred in 1% of those taking letrozole alone. No
cases of febrile neutropenia were reported during
the first clinical trial; in the second trial, 0.6% of
patients treated with palbociclib developed febrile
neutropenia. Grade 3 leukopenia occurred in 19% of
those taking both drugs compared to none of those
taking letrozole alone. Pulmonary embolism, fatigue,
upper respiratory infection, nausea, stomatitis, anemia,
thrombocytopenia, peripheral neuropathy, and epistaxis
have also been reported in patients taking palbociclib.
DRUG INTERACTIONS — Palbociclib is a substrate of
CYP3A; concurrent administration of strong CYP3A
inhibitors or moderate or strong CYP3A inducers is not
recommended.7
DOSAGE, ADMINISTRATION, AND COST — The
recommended starting dosage of palbociclib is 125 mg
once daily with food for 21 days, followed by 7 days
off. Patients treated with the drug should also take
letrozole 2.5 mg once daily on all 28 days. Blood

counts should be monitored before starting therapy,
at the beginning of each treatment cycle, and on day
14 of the first 2 cycles. Both drugs should be continued
until disease progression occurs. The labeling specifies
a number of dosage adjustments that should be made
if adverse effects occur. The daily dose of palbociclib
should be reduced to 75 mg if coadministered with a
strong CYP3A inhibitor. The cost of palbociclib for one
28-day treatment cycle is $9850.8
CONCLUSION — Palbociclib (Ibrance), the first cyclindependent kinase 4 and 6 inhibitor to be approved in
the US, markedly extended median progression-free
survival when added to either letrozole (Femara, and
generics) or fulvestrant (Faslodex) in women with
estrogen receptor (ER)-positive, human epidermal
growth factor receptor 2 (HER2)-negative advanced
breast cancer. Serious adverse effects such as grade
3-4 neutropenia and grade 3 leukopenia can occur.
The drug's effect on overall survival remains to be
determined. How to identify patients whose prognosis
would justify the additional cost and toxicity of
palbociclib is unclear. ■
1. AH Partridge et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or
unknown) advanced breast cancer : American Society of Clinical
Oncology Clinical Practice Guideline. J Clin Oncol 2014; 32:3307.
2. Aromatase inhibitors for adjuvant treatment of postmenopausal breast cancer. Med Lett Drugs Ther 2011; 53:47.
3. LA Carey and CM Perou. Palbociclib–taking breast-cancer cells
out of gear. N Engl J Med 2015; 373:273.

116

August 17, 2015

Vol. 57 (1475)

4. CG Murphy and MN Dickler. The role of CDK4/6 inhibition in
breast cancer. Oncologist 2015; 20:483.
5. RS Finn et al. The cyclin-dependent kinase 4/6 inhibitor
palbociclib in combination with letrozole versus letrozole alone
as first-line treatment of oestrogen receptor-positive, HER2negative, advanced breast cancer (PALOMA-1/TRIO-18): a
randomised phase 2 study. Lancet Oncol 2015; 16:25.
6. NC Turner et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015; 373:209.
7. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
8. 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. August 5, 2015. Reprinted with
permission by First Databank, Inc. All rights reserved. ©2015.
www.fdbhealth.com/policies/drug-pricing-policy.

▶

Brexpiprazole (Rexulti) for
Schizophrenia and Depression

The FDA has approved the oral, once-daily, secondgeneration antipsychotic brexpiprazole (Rexulti –
Otsuka/Lundbeck) for treatment of schizophrenia
and as an adjunct to antidepressants for treatment
of major depressive disorder (MDD). Aripiprazole
(Abilify), a structurally similar second-generation

antipsychotic also comarketed by Otsuka (with BMS),
recently became available generically.
Pronunciation Key
Brexpiprazole: breks pip' ra zole
Rexulti: recks ul' tee

STANDARD TREATMENT – Schizophrenia - Secondgeneration antipsychotics are not clearly more
effective than first-generation drugs, but they have
a much lower risk of tardive dyskinesia. Clozapine
(Clozaril, and others) is the most effective secondgeneration antipsychotic drug, but it is usually
reserved for refractory disease because of its potential
for serious toxicity. Olanzapine (Zyprexa, and generics)
appears to have slight advantages over some other
drugs in efficacy, but its metabolic adverse effects
may be unacceptable for long-term use. Patients who
do not respond to one antipsychotic may respond to
another. Long-acting injectable antipsychotics may be
useful when adherence is a problem.1
Table 1. Pharmacology
Class

Second-generation antipsychotic

Mechanism of action

Dopamine (D2) and serotonin (5-HT1A )
partial agonist; 5-HT2A antagonist

Formulation

0.25, 0.5, 1, 2, 3, 4 mg tablets

Route

Oral

Tmax

Within 4 hours

Metabolism

Primarily hepatic by CYP3A4 and 2D6

Elimination

Feces (46%); urine (25%)

Half-life (terminal)

91 hours


The Medical Letter

Vol. 57 (1475)

®

August 17, 2015

Table 2. Some Oral Second-Generation Antipsychotics

Drug
Aripiprazole – generic
Abilify (BMS/Otsuka)
Asenapine – Saphris (Forest)
Brexpiprazole – Rexulti (Otsuka/Lundbeck)
Clozapine5 – generic
Clozaril (Novartis)
orally disintegrating – generic
FazaClo (Jazz)
suspension – Versacloz (Jazz)
Iloperidone – Fanapt (Novartis)
Lurasidone – Latuda (Sunovion)
Olanzapine3 – generic
Zyprexa (Lilly)
orally disintegrating – generic
Zyprexa Zydis
Paliperidone3 – Invega (Janssen)
Quetiapine – generic
Seroquel (AstraZeneca)
extended-release – Seroquel XR
Risperidone3 – generic
Risperdal (Janssen)
orally disintegrating – generic
Risperdal M-TAB
Ziprasidone – generic
Geodon3 (Pfizer)
3

Some Available
Oral Formulations

Usual Adult
Maintenance Dosage
in Schizophrenia1

Usual Adult
Maintenance
Dosage in MDD1

2, 5, 10, 15, 20, 30 mg tabs

10-30 mg once/d

2-15 mg once/d

2.5, 5, 10 mg sublingual tabs
0.25, 0.5, 1, 2, 3, 4 mg tabs
25, 50, 100, 200 mg tabs
25, 100 mg tabs
12.5, 25, 100, 150, 200 mg ODT

5-10 mg bid
2-4 mg once/d
100-300 mg tid

50 mg/mL susp
1, 2, 4, 6, 8, 10, 12 mg tabs

20, 40, 60, 80, 120 mg tabs
2.5, 5, 7.5, 10, 15, 20 mg tabs

6-12 mg bid
40-160 mg once/d
10-20 mg once/d

5, 10, 15, 20 mg ODT
1.5, 3, 6, 9 mg ER tabs
25, 50, 100, 200, 300,
400 mg tabs
50, 150, 200, 300, 400 mg ER tabs
0.25, 0.5, 1, 2, 3, 4, mg tabs;
1 mg/mL soln
0.25, 0.5, 1, 2, 3, 4 mg ODT
0.5, 1, 2, 3, 4 mg ODT
20, 40, 60, 80 mg caps

6-12 mg once/d
300-800 mg/d in 2 or
3 divided doses
400-800 mg once/d
4-8 mg/d in 1 or
2 doses
40-100 mg bid

Cost2

$765.00
892.00

See footnote 4
833.00
2 mg once/d
865.50
See footnote 4
217.50
1125.80
588.60
1321.20
1321.50
See footnote 4
1035.60
See footnote 4
838.80
See footnote 6
26.40
553.20
202.70
582.60
See footnote 4
849.90
See footnote 4
40.30
600.00
150-300 mg once/d 694.70
2 mg/d in 1 or
25.60
650.00
2 doses7
369.70

780.00
See footnote 4
171.00
804.50

MDD = major depressive disorder; ODT = orally disintegrating tablets; ER = extended-release
1. As an adjunct to antidepressant therapy.
2. Approximate WAC for 30 days’ treatment at the lowest usual maintenance dosage in schizophrenia. 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. August 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drugpricing-policy.
3. Also available parenterally.
4. Not FDA-approved for adjunctive treatment of MDD.
5. Clozapine is associated with seizures and agranulocytosis and should be reserved for patients with schizophrenia who fail to respond to other drugs.
6. A fixed-dose combination of olanzapine and fluoxetine (Symbyax - Lilly) is FDA-approved for use in treatment-resistant depression. The usual dosage in
adults is one 6/25 mg or 12/50 mg olanzapine/fluoxetine capsule every evening. The WAC for a 30-day supply of 6/25 mg capsules is $402.30.
7. Risperidone is used for adjunctive treatment of MDD by some clinicians, but is not FDA-approved for this indication.

MDD – A selective serotonin reuptake inhibitor
(SSRI) such as fluoxetine (Prozac, and generics), a
serotonin-norepinephrine reuptake inhibitor (SNRI)
such as venlafaxine (Effexor, and generics), bupropion
(Wellbutrin XL, and others), or mirtazapine (Remeron,
and generics) could be used for first-line treatment of
major depression. Most clinicians begin with an SSRI.
When an adequate trial of an SSRI produces little to
no response, another antidepressant can be tried, or
two antidepressants from different classes can be
combined. Augmentation with antipsychotic drugs
may be helpful when the response to antidepressant
agents is inadequate, but adverse effects such as

weight gain or extrapyramidal symptoms can occur.1
CLINICAL STUDIES – Schizophrenia - Brexpiprazole
was compared to placebo in two 6-week, randomized,
double-blind trials in a total of 1076 adults 18-65 years
old with schizophrenia. The primary endpoint in both
studies was mean improvement at 6 weeks in scores
on the 181-point Positive and Negative Syndrome
Scale (PANSS). In one study, mean improvements in
PANSS scores were significantly greater with both

2 mg/day (20.7 points) and 4 mg/day (19.7 points)
than with placebo (12.0 points).2 In the other study,
improvement was significantly greater with 4 mg/
day (20.0 points), but not with 2 mg/day (16.6 points),
compared to placebo (13.5 points).3
MDD - In two unpublished, 6-week, double-blind trials
(summarized in the package insert), a total of 980 adults
18-65 years old with MDD that had not responded
adequately to prior antidepressant therapy were
randomized to receive brexpiprazole or placebo as an
adjunct to an SSRI or SNRI. The primary endpoint in both
studies was mean improvement at 6 weeks in scores
on the clinician-rated 61-point Montgomery-Asberg
Depression Rating Scale (MADRS). In one study, mean
improvements in MADRS scores were significantly
greater with brexpiprazole 2 mg/day than with placebo
(8.4 vs 5.2 points). In the other study, improvement was
numerically greater with brexpiprazole 3 mg/day and 1
mg/day than with placebo (8.3 and 7.6 vs 6.3 points),
but statistical significance was not achieved (p=0.033

for 3 mg/day vs placebo; superiority criteria required
p<0.025).
117


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®

Table 3. Some Relative Adverse Effects of Second-Generation Antipsychotics
Drug

Diabetes

Weight Gain

Extrapyramidal
Symptoms

QTc Interval
Prolongation

Elevated
Prolactin

Aripiprazole

Asenapine
Brexpiprazole*
Clozapine
Iloperidone
Lurasidone
Olanzapine
Paliperidone
Quetiapine
Risperidone
Ziprasidone

+/–
+
+
++++
++
+/–
++++
++
++
++
+/–

+
++
++
++++
++
+/–
++++

+++
+++
+++
+/–

++
++
+
+/–
+/–
++
+
+++
+/–
+++
–

+/–
+
–
+
++
+/–
+
+
+
+
++

–

++
+/–
+/–
+/–
+/–
+
+++
+/–
+++
+

*

Limited experience

ADVERSE EFFECTS – Adverse effects occurring in ≥5% of
patients taking brexpiprazole and more frequently than
in those taking placebo in at least 1 clinical trial included
akathisia, weight gain, headache, and somnolence.
Mean weight gain over 6 weeks was 1.0-1.3 kg greater
with brexpiprazole 2 mg/day than with placebo.
PREGNANCY – There are no adequate studies of
brexpiprazole in pregnant women. Animal studies did
not find the drug to be teratogenic. Neonates whose
mothers were exposed to antipsychotic drugs during
the third trimester of pregnancy could be at risk for
extrapyramidal and/or withdrawal symptoms.
DOSAGE AND ADMINISTRATION – For treatment of
schizophrenia, the recommended starting dosage of
brexpiprazole is 1 mg once daily. The dose should be

increased to 2 mg/day on day 5 and can be further
increased to 4 mg/day on day 8, depending on clinical
response and tolerability.
For adjunctive treatment of MDD, patients should start
with 0.5-1 mg of brexpiprazole once daily. The dose
should be increased gradually to a target of 2 mg daily.
The maximum recommended dose of brexpiprazole
for treatment of MDD is 3 mg/day.
Patients with moderate to severe hepatic impairment
(Child-Pugh B/C) or renal impairment (CrCl <60 mL/min)
should take no more than 3 mg/day of brexpiprazole
for schizophrenia or 2 mg/day for MDD. The usual dose
should be halved in known CYP2D6 poor metabolizers.
Table 4. Brexpiprazole Dosage Adjustments with CYP
Inducers or Inhibitors
Coadministered Drug(s)

Dosage Adjustment

Strong 3A4 inducer
Strong 3A4 inhibitor
Strong 2D6 inhibitor
Strong/moderate 3A4 inhibitor
with strong/moderate 2D6 inhibitor
or in 2D6 poor metabolizers

Double over 1-2 weeks
Reduce by 50%
Reduce by 50%*
Reduce by 75%

*Patients taking brexpiprazole for MDD do not require dosage reduction with coadministration of a strong CYP2D6 inhibitor such as fluoxetine or paroxetine.

118

DRUG INTERACTIONS – Drugs that inhibit CYP3A4
(such as clarithromycin) or CYP2D6 (such as fluoxetine
or paroxetine) may increase serum concentrations
of brexpiprazole, and inducers of CYP3A4 (such as
rifampin) may reduce exposure to the drug.4 In patients
receiving drugs that alter CYP3A4- or 2D6-mediated
metabolism, the dosage of brexpiprazole should be
adjusted according to the recommendations in Table 4.
CONCLUSION – Brexpiprazole (Rexulti) was more
effective than placebo in short-term trials in reducing
symptoms of schizophrenia and depression. It appears
to be generally well tolerated with relatively mild
metabolic adverse effects, but direct comparisons with
other antipsychotics are lacking, and its long-term
safety is unknown. There is no reason to prescribe
brexpiprazole over generic aripiprazole, which has a
much longer record of efficacy and safety and should
soon cost much less. ■
1. Drugs for psychiatric disorders. Treat Guidel Med Lett 2013;
11:53.
2. CU Correll et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week, randomized, double-blind,
placebo-controlled trial. Am J Psychiatry 2015 April 16 (epub).
3. JM Kane et al. A multicenter, randomized, double-blind, controlled
phase 3 trial of fixed-dose brexpiprazole for the treatment of
adults with acute schizophrenia. Schizophr Res 2015; 164:127.

4. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.

In Memoriam
July was a sad month at The Medical Letter.
Hans Meinertz, M.D. of University Hospital in Copenhagen
died on July 21, 2015. Hans joined the Advisory Board of
The Medical Letter in 1994. He became a Contributing Editor
in 2009.
Jules Hirsch, M.D. of Rockefeller University died on July 23,
2015. His name has been on the masthead of The Medical
Letter, first as a member of the Editorial Board and then as a
Contributing Editor, since 1965.
We will miss their wise counsel and their friendship.


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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57 (Issue 1475)

▶

August 17, 2015

Panobinostat (Farydak) for
Multiple Myeloma

The FDA has approved panobinostat (Farydak –
Novartis), an oral histone deacetylase (HDAC) inhibitor,
for use in combination with bortezomib (Velcade) and
dexamethasone for treatment of patients with multiple
myeloma who have received at least 2 prior therapies
including bortezomib and an immunomodulatory
drug. It is the first HDAC inhibitor to be approved for
this indication.
Pronunciation Key
Panobinostat: pan" oh bin' oh stat
Farydak: fayr' ah dak

MULTIPLE MYELOMA — Use of drug regimens that
include the proteasome inhibitor bortezomib1 plus
thalidomide (Thalomid) or lenalidomide (Revlimid),2
a thalidomide analog, has led to improved response
rates and survival in patients with multiple myeloma.
Carfilzomib (Kyprolis),3 a second proteasome
inhibitor, is approved for treatment of refractory
multiple myeloma. Pomalidomide (Pomalyst), another
thalidomide analog, is an alternative for patients
whose disease has progressed on lenalidomide and
bortezomib.4 Many patients do not respond to these
drugs or discontinue them due to toxicity, and most

who do respond initially subsequently relapse. Median
survival is generally less than 5 years.
MECHANISM OF ACTION — Histones are charged
proteins that provide structural support for DNA
in eukaryotic chromosomes. HDACs catalyze the
removal of acetyl groups from lysine in histones and
Table 1. Pharmacology
Class

HDAC inhibitor

Formulation

10, 15, 20 mg capsules

Route

Oral

Metabolism

Primarily by CYP3A, and to a minor extent by
CYP2D6 and 2C19

Elimination

Feces (44-77%); urine (29-51%)

Half-life (terminal) 37 hrs

in some non-histone proteins. Inhibition of HDAC
activity results in increased acetylation of histone
proteins, leading to transcriptional activation. In vitro,
panobinostat inhibits HDAC, causing accumulation of
acetylated histones and other proteins, resulting in cell
cycle arrest and apoptosis.5
A CLINICAL STUDY — A randomized, double-blind
trial (PANORAMA1) in 768 patients with relapsed
or refractory multiple myeloma who had received
1-3 previous treatment regimens found that median
progression-free survival, the primary endpoint, was
significantly longer in patients taking panobinostat
in addition to bortezomib and dexamethasone
than in those taking placebo plus bortezomib and
dexamethasone (12.0 vs 8.1 months). Overall response
rates were similar (60.7% with panobinostat vs 54.6%
with placebo), but significantly more patients taking
panobinostat achieved a complete or near complete
response (27.6% vs 15.7% with placebo).6
ADVERSE EFFECTS — Severe diarrhea (grade 3/4)
and diarrhea of any grade occurred in 25% and 68%,
respectively, of patients taking panobinostat in
the clinical trial. Thrombocytopenia, lymphopenia,
leukopenia, neutropenia, and anemia occurred in ≥60%
of patients taking panobinostat. Hypophosphatemia,
hypokalemia, hyponatremia, and increased serum
creatinine were reported in ≥40% of patients. Other
common adverse effects of panobinostat (occurring
in ≥20% of patients) included peripheral neuropathy,
fatigue, nausea, peripheral edema, decreased appetite,

constipation, fever, vomiting, and cough. Severe and
fatal cardiac ischemic events, severe arrhythmias, and
ECG changes have occurred. Panobinostat may prolong the QT interval; patients with a QTcF ˃450 msec
or clinically significant baseline ST-segment or
T-wave abnormalities should not start treatment with
the drug. Hemorrhage, infections, and hepatotoxicity
have also been reported.
PREGNANCY — Panobinostat is teratogenic in rabbits
and rats. Women who could become pregnant should
e118

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August 17, 2015

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®

use an effective form of contraception during treatment
and for at least 1 month after stopping it. Men should
use a condom during treatment with panobinostat and
for 3 months after stopping the drug.
DRUG INTERACTIONS — Panobinostat is a substrate
of CYP3A and P-glycoprotein (P-gp) and an inhibitor
of CYP2D6. Coadministration with a strong CYP3A
inducer or a CYP2D6 substrate should be avoided.

The dose of panobinostat should be reduced when
coadministered with a strong CYP3A inhibitor.7
Concomitant use of drugs that prolong the QT interval
is not recommended (www.crediblemeds.org).
DOSAGE, ADMINISTRATION, AND COST — The
recommended starting dosage of panobinostat is
20 mg orally on days 1, 3, 5, 8, 10, and 12 of a 21-day
cycle. The drug should be continued for at least 8 cycles
or until disease progression or unacceptable toxicity
occurs (maximum 16 cycles). Panobinostat should be
administered with bortezomib and dexamethasone
(dosage schedule provided in the labeling). The
capsules should be taken with water, and should not
be opened, crushed, or chewed. Blood counts, serum
electrolyte levels, and an ECG should be obtained
before starting treatment; blood counts should be
monitored weekly, and serum electrolytes and an ECG
periodically during treatment. The labeling specifies a
number of dosage adjustments that should be made
when adverse effects occur. The dose of panobinostat
should be reduced to 15 mg in patients who have
mild hepatic impairment and to 10 mg in those with
moderate hepatic impairment or who are also taking a

strong CYP3A4 inhibitor; the drug should not be used
in patients with severe hepatic impairment. The cost
of one treatment cycle (six 20-mg capsules) is $6860.8
CONCLUSION — Panobinostat (Farydak), in combination with bortezomib (Velcade) and dexamethasone,
extended median progression-free survival in patients
with relapsed or refractory multiple myeloma, but it has

many adverse effects and it is expensive. ■
1. Bortezomib (Velcade) for multiple myeloma. Med Lett Drugs
Ther 2003; 45:57.
2. Lenalidomide (Revlimid) for anemia of myelodysplastic syndrome. Med Lett Drugs Ther 2006; 48:31.
3. Carfilzomib (Kyprolis) for multiple myeloma. Med Lett Drugs
Ther 2012; 54:103.
4. Pomalidomide (Pomalyst) for multiple myeloma. Med Lett
Drugs Ther 2015; 57:e66.
5. A Heinemann et al. Combining BET and HDAC inhibitors synergistically induces apoptosis of melanoma and suppresses AKT
and YAP signaling. Oncotarget 2015 Jun 5 (epub).
6. JF San-Miguel et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase
3 trial. Lancet Oncol 2014; 15:1195.
7. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
8. 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 actual
transactional prices. Source: AnalySource® Monthly. August
5, 2015. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2015. www.fdbhealth.com/policies/drugpricing-policy.

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EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical School;
Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N. Juurlink, BPhm, M.D., Ph.D.,
Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Franco M. Muggia, M.D., New York University Medical Center; Sandip K. Mukherjee,

M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School; F. Estelle
R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell
University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino;
VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without
prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage
resulting from any error, inaccuracy, or omission.

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 57 (Issue 1475)

▶

August 17, 2015

Lenvatinib (Lenvima) for Thyroid
Cancer

The FDA has approved the oral multikinase inhibitor
lenvatinib (Lenvima – Eisai) for treatment of locally
recurrent or metastatic, progressive, differentiated
thyroid cancer (papillary or follicular) refractory to
radioactive iodine treatment.
Pronunciation Key
Lenvatinib: len va' ti nib
Lenvima: len vee ma

STANDARD TREATMENT — Surgery and radioactive
iodine are the preferred treatments for differentiated
thyroid cancer. Cytotoxic agents such as doxorubicin
have not been shown to improve survival. Recently,
use of tyrosine kinase inhibitors has shown promising
results.1 The oral multikinase inhibitor sorafenib
(Nexavar), approved by the FDA in 2013 for treatment
of locally recurrent or metastatic, progressive,
radioiodine-refractory differentiated thyroid cancer,
has increased progression-free survival by about 5
months compared to placebo.2 In a small preliminary

trial, vandetanib (Caprelsa),3 a tyrosine kinase inhibitor
approved for treatment of advanced medullary thyroid
cancer, also increased progression-free survival in
patients with metastatic differentiated thyroid cancer,
particularly those with the papillary subtype.4
MECHANISM OF ACTION — Lenvatinib targets vascular
endothelial growth factor (VEGF) receptors, fibroblast
growth factor (FGF) receptors, and other receptor
tyrosine kinases that play a role in tumor proliferation
and angiogenesis.
CLINICAL STUDIES — In a double-blind trial, 392
patients with   locally recurrent or metastatic,
radioiodine-refractory differentiated thyroid cancer
and radiographic evidence of disease progression
within the previous 12 months were randomized in
a 2:1 ratio to receive lenvatinib 24 mg once daily or
placebo until disease progression occurred. Some of
the patients (n=93; 24%) had previously been treated
with a tyrosine kinase inhibitor. Median progression-

Table 1. Pharmacology
Class

Multikinase inhibitor

Route

Oral

Formulation

4, 10 mg capsules

Tmax

1-4 hrs

Metabolism

Enzymatic (CYP3A and aldehyde oxidase)
and non-enzymatic

Half-life (terminal)

28 hours

Excretion

Feces (64%); urine (25%)

free survival, the primary endpoint, was 18.3 months
with lenvatinib and 3.6 months with placebo.
Lenvatinib was effective both in patients who had
previously received a tyrosine kinase inhibitor and
in those who had not (median progression-free
survival 15.1 and 18.7 months, respectively). The
tumor response rate was 64.8% in the lenvatinib
group compared to 1.5% in the placebo group; there
were 4 complete responses with lenvatinib and none
with placebo.5

ADVERSE EFFECTS — Hypertension of any grade
occurred in 73% of patients treated with lenvatinib
and grade 3-4 hypertension occurred in 44%. Other
common adverse effects reported in more than 30%
of patients taking the drug included fatigue, diarrhea,
arthralgia/myalgia, decreased appetite, decreased
weight, nausea, stomatitis, headache, vomiting,
proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. Cardiac
dysfunction, thromboembolic events (including
fatal pulmonary embolism), hepatotoxicity and
fatal hepatic failure, renal impairment and failure,
gastrointestinal perforation and fistula, QT interval
prolongation, hypocalcemia, reversible posterior
leukoencephalopathy syndrome (RPLS), and hemorrhagic events (mainly epistaxis) also occurred.
Adverse effects resulted in dose reductions in 68% of
patients and treatment discontinuation in 18%.
Monitoring for proteinuria, hypertension, hepatotoxicity, and hypocalcemia is recommended during
treatment. Thyroid stimulating hormone (TSH) levels
increased in patients receiving lenvatinib; TSH levels
e120

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August 17, 2015

Vol. 57 (1475)

®

should be monitored monthly and the dose of thyroid
replacement medication adjusted as needed.

reactions or laboratory abnormalities. A 30-day supply
of lenvatinib costs $13,950.6

PREGNANCY — Lenvatinib is embryotoxic, fetotoxic,
and teratogenic in animals. Women who could become
pregnant should use effective contraception during
treatment with lenvatinib and for at least 2 weeks after
completing therapy. Use of lenvatinib may result in
reduced fertility in both males and females.

CONCLUSION — Lenvatinib (Lenvima) increases
progression-free survival in patients with radioiodinerefractory differentiated thyroid cancer, including
those previously treated with another tyrosine kinase
inhibitor. In separate clinical trials, progression-free
survival has been longer with lenvatinib than with
sorafenib (Nexavar), the other multikinase inhibitor
approved for this indication, but no head-to-head
comparisons are available. Like other tyrosine kinase
inhibitors, lenvatinib can cause serious adverse
effects, and it is expensive. ■

LACTATION — In animal studies, lenvatinib was
detected in milk at levels about twice as high as
those in maternal plasma; it is not known whether the
drug is present in human milk. Women should avoid

breastfeeding during treatment with lenvatinib.
DRUG INTERACTIONS – Lenvatinib is metabolized by
CYP3A and is a substrate of P-glycoprotein (P-gp) and
breast cancer resistance protein (BCRP), but no dose
adjustments are required when it is coadministered
with inhibitors or inducers of CYP3A, P-gp, or BCRP.
DOSAGE, ADMINISTRATION, AND COST — Lenvima is
available from two specialty pharmacies. The 4-mg
and 10-mg capsules are supplied in cartons of 6 blister
cards, each of which contains 5 doses of the drug.
The recommended dosage is 24 mg taken once daily
until disease progression or unacceptable toxicity
occurs. Patients with severe renal (CrCl <30 mL/min)
or hepatic impairment should take 14 mg once daily.
The labeling of lenvatinib provides recommendations
for treatment interruptions and dose adjustments
in patients who experience certain serious adverse

1. S Jasmin et al. Multikinase inhibitors use in differentiated thyroid carcinoma. Biologics 2014; 8:281.
2. Sorafenib (Nexavar) for thyroid cancer. Med Lett Drugs Ther
2014; 56:43.
3. Vandetanib (Caprelsa) for medullary thyroid cancer. Med Lett
Drugs Ther 2012; 54:3.
4. S Leboulleux et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind,
phase 2 trial. Lancet Oncol 2012; 13:897.
5. M Schlumberger et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372:621.
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. August 5, 2015. Reprinted with permission by First Databank, Inc.
All rights reserved. ©2015. www.fdbhealth.com/policies/drugpricing-policy.

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EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical School;
Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N. Juurlink, BPhm, M.D., Ph.D.,
Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Franco M. Muggia, M.D., New York University Medical Center; Sandip K. Mukherjee,
M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School; F. Estelle
R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell
University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino;
VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without
prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage
resulting from any error, inaccuracy, or omission.

Subscription Services
Address:
The Medical Letter, Inc.
145 Huguenot St. Ste. 312
New Rochelle, NY 10801-7537

www.medicalletter.org

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Copyright 2015. ISSN 1523-2859

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Review the efficacy and safety of alirocumab (Praluent) for treatment of hypercholesterolemia.
2.
Review the efficacy and safety of palbociclib (Ibrance) for treatment of estrogen receptor (ER)-positive, human epidermal growth factor 2 (HER2)-negative metastatic
breast cancer.
3.
Review the efficacy and safety of brexpiprazole (Rexulti) for treatment of schizophrenia and depression.

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Issue 1475 Questions
(Correspond to questions #31-40 in Comprehensive Exam #73, available January 2016)
Alirocumab (Praluent) to Lower LDL-Cholesterol
1. Which of the following is an FDA-approved indication for
alirocumab?
a. LDL-C ˃100 mg/dL
b. reduction of LDL-C in patients who cannot tolerate a statin
c. additional lowering of LDL-C as an adjunct to diet and statin
therapy in patients with clinical atherosclerotic disease
d. all of the above
2. Which one of the following statements about the mechanism of

action of alirocumab is true?
a. it inhibits the synthesis of LDL-C
b. it degrades LDL receptors
c. it increases clearing of LDL-C from blood
d. all of the above

6. In clinical trials, compared to placebo, palbociclib significantly
increased:
a. overall survival
b. progression-free survival
c. time to response
d. all of the above
7. A 44-year-old woman with metastatic breast cancer has been told
that she should be treated with palbociclib. She asks if it has any
side effects. You should tell her that palbociclib can cause:
a. neutropenia
b. pulmonary embolism
c. peripheral neuropathy
d. all of the above
Brexpiprazole (Rexulti) for Schizophrenia and Depression

3. In clinical trials, the reduction in LDL-C with alirocumab was
about:
a. 20-40%
b. 40-60%
c. 60-80%
d. 80-90%

8. Which of the following antipsychotic drugs is the most effective
for treatment of schizophrenia?

a. brexpiprazole
b. iloperidone
c. lurasidone
d. clozapine

4. A 52-year-old man has heterozygous familial hypercholesterolemia that has not responded adequately to diet and maximally
tolerated doses of a statin. You suggest a trial of alirocumab, but
he is concerned about the possible side effects of the new drug.
You could tell him that:
a. clinical trials have found the drug to be safe for up to 5 years
of use
b. hypersensitivity reactions have not been reported
c. in one large study only injection-site reactions and myalgia
occurred more frequently with the drug than with placebo
d. some patients treated with alirocumab have required liver
transplants

9. A 21-year-old man with schizophrenia complains that since
starting treatment with quetiapine 6 months ago, “I’ve gained 12
pounds and lost my sex drive.” He asks if there is another drug he
could take instead. Which of the following may be least likely to
cause weight gain or hyperprolactinemia?
a. risperidone
b. aripiprazole
c. olanzapine
d. asenapine

Palbociclib (Ibrance) for Metastatic Breast Cancer
5. Palbociclib is approved for use in postmenopausal women with:
a. ER-positive and HER2-negative metastatic breast cancer

b. ER-negative and HER2-negative metastatic breast cancer
c. ER-positive and HER2-positive metastatic breast cancer
d. all of the above

10. A 20-year-old woman who is taking brexpiprazole 4 mg/day for
schizophrenia is being treated for pneumonia with clarithromycin
(a strong CYP3A4 inhibitor). Which of the following dosage
adjustments is recommended while the patient is taking
clarithromycin concurrently?
a. the daily dose of brexpiprazole should be reduced to 2 mg
b. the daily dose of brexpiprazole should be reduced to 1 mg
c. brexpiprazole should be withheld because of a risk of QT
interval prolongation
d. no dosage adjustment is necessary because the patient is
not taking a strong CYP2D6 inhibitor

ACPE UPN: Per Issue Exam: 0379-0000-15-475-H01-P; Release: August 17, 2015, Expire: August 17, 2016
Comprehensive Exam 73: 0379-0000-16-073-H01-P; Release: January 2016, Expire: January 2017

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical School;
Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N. Juurlink, BPhm, M.D., Ph.D.,
Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Franco M. Muggia, M.D., New York University Medical Center; Sandip K. Mukherjee,
M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School; F. Estelle
R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell
University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino;

VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without
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