The medical letter on drugs and therapeutics jun 6 2016

The Medical Letter

®

on Drugs and Therapeutics
Volume 58

ISSUE
ISSUE
No.

1433
1496
Volume 56

June 6, 2016

IN THIS ISSUE

Drugs for Multiple Sclerosis ................................................................................................ p 71
Pimavanserin (Nuplazid) for Parkinson’s Disease Psychosis ........................................... p 74
Alternatives to Fluoroquinolones ........................................................................................ p 75
In Brief: New Indications for Secukinumab (Cosentyx) ..................................................... p 76
In Brief: Liposomal Irinotecan (Onivyde) for Pancreatic Cancer ............................... online only
In Brief: Trifluridine/Tipiracil (Lonsurf) for Metastatic Colorectal Cancer ............... online only

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The Medical Letter

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on Drugs and Therapeutics
Volume 58

June 6, 2016
Take CME Exams

ISSUE

ISSUE No.

1433

1496
Volume 56

▶

ALSO IN THIS ISSUE

Pimavanserin (Nuplazid) for Parkinson's Disease Psychosis ........................................... p 74
Alternatives to Fluoroquinolones ........................................................................................ p 75
In Brief: New Indications for Secukinumab (Cosentyx) ..................................................... p 76
In Brief: Liposomal Irinotecan (Onivyde) for Pancreatic Cancer ............................... online only
In Brief: Trifluridine/Tipiracil (Lonsurf) for Metastatic Colorectal Cancer ............... online only

Drugs for Multiple Sclerosis

Most patients with multiple sclerosis (MS) present
with the relapsing-remitting form of the disease.1
Treatment usually includes disease-modifying drugs,
various other drugs for managing symptoms such as
fatigue, depression, and pain, and corticosteroids for
acute exacerbations.
INJECTABLE AGENTS — Interferons – Interferon beta
was the first disease-modifying drug approved for
treatment of MS. Interferons have several immunemodulating and anti-inflammatory effects. They can
reduce clinical relapse rates by 30-35% and decrease
the number of new T2 or gadolinium-enhancing brain
lesions seen on MRI. Whether these effects delay or
prevent long-term disability is unclear.2,3 Interferons
frequently cause injection-site reactions and a flu-like
syndrome.4 Pegylated interferon beta-1a (Plegridy)

injected SC every 2 weeks appears to be similar in efficacy and adverse effects to older interferon formulations
that must be injected every-other-day SC or weekly IM.5
Pregnancy – Interferons are classified as category C
(abortifacient activity in animals at 2.8-40 times the
recommended human dose; no adequate studies in
pregnant women) for use during pregnancy. Extensive
data available on exposure of pregnant women to
interferon beta suggest that it is safe to use.6
Glatiramer Acetate (Copaxone, Glatopa) – Glatiramer
acetate is a mixture of synthetic polypeptides
containing four naturally occurring amino acids
(glutamic acid, alanine, tyrosine, and lysine). Its
exact mechanism of action is unknown, but the drug
has several immune-modulating effects including
suppression of T-cell activation, and induction and
activation of suppressor T-cells. Glatiramer acetate
can reduce clinical relapse rates by about 30% and

Recommendations for Treatment of Multiple Sclerosis

▶ Interferon beta (Avonex, Plegridy, and others) and glatiramer
acetate (Copaxone, Glatopa), both given by injection, have
been used for first-line treatment.
▶ Glatiramer acetate is better tolerated than interferon and
equally effective, but it requires more frequent injections.
▶ Use of oral agents or IV natalizumab (Tysabri) for first-line
treatment is increasing.
▶ Natalizumab is highly effective and needs to be infused only
every 4 weeks, but its adverse effects, especially progressive
multifocal leukoencephalopathy (PML), are a concern.

▶ Among the oral drugs, fingolimod (Gilenya) and dimethyl
fumarate (Tecfidera) appear to be more effective than
teriflunomide (Aubagio), but head-to-head trials are
lacking.

decrease the number of new T2 or gadoliniumenhancing brain lesions seen on MRI.7 Glatiramer may
be the safest of all the drugs used to treat MS, but it
must be injected daily or three times a week SC.
Pregnancy – Glatiramer acetate is classified as category
B (no adverse effects in animals; no adequate studies in
pregnant women) for use during pregnancy. Extensive
data available on exposure of pregnant women to
glatiramer acetate suggest that it is safe to use.6
Natalizumab (Tysabri) – A recombinant humanized
monoclonal antibody, natalizumab prevents leukocyte
migration across the blood-brain barrier, which may
interrupt the inflammatory cascade in MS. Natalizumab
has decreased relapse rates by 68%, new or enlarging
T2 brain lesion development by 83%, and disease
progression rates by 42%,8,9 but progressive multifocal
leukoencephalopathy (PML), a potentially fatal infection
caused by the JC virus, has occurred in about 0.2% of
patients; those who have anti-JC virus antibodies or
are immunosuppressed have the highest risk. The risk
increases with the duration of treatment; it is very low
during the first 2 years of treatment in patients without
anti-JC virus antibodies.10 Natalizumab was voluntarily
71

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The Medical Letter

Vol. 58 (1496)

®

June 6, 2016

Table 1. FDA-Approved Drugs for Relapsing-Remitting Multiple Sclerosis
Drug

Reduction
in Clinical
Relapse Rate

Usual
Maintenance
Dosage

Frequent or Serious Adverse Effects

Cost1

Injectable
Interferon beta-1a –
30%-35%2
Avonex (Biogen-Idec)
Rebif (EMD Serono)

Pegylated interferon beta-1a–
Plegridy (Biogen-Idec)
Interferon beta-1b –
Betaseron (Bayer)
Extavia (Novartis)
Glatiramer acetate –
Copaxone (Teva)

30 mcg IM once/wk
44 mcg SC 3x/wk
125 mcg SC q2 wks

Injection-site reactions, flu-like
symptoms, depression, transaminase
elevations, possible cardiac toxicity,
autoimmune disorders, allergic reactions,
hepatotoxicity, seizures, suicidal ideation,
lymphopenia with interferon beta-1b

250 mcg SC every
other day
~30%2
20 mg SC once/d
or 40 mg 3x/wk
20 mg SC once/d

Glatopa (Sandoz)

$72,072.00
77,797.20

72,072.00
78,920.60
65,902.00

Injection-site reactions, transient
post-injection systemic reactions
(flushing, chest pain, palpitations,
and dyspnea)

80,216.10
70,251.50
63,192.50

Natalizumab – Tysabri
(Biogen-Idec)

68%3

300 mg IV q4 wks

Headache, fatigue, arthralgia, depression,
infections, hypersensitivity reactions,
hepatotoxicity, PML

71,773.00

Alemtuzumab – Lemtrada
(Genzyme)

50-55%4

12 mg IV once/d x 5d
followed 1 year later by
12 mg IV once/d x 3d

Infusion reactions (rash, headache, pyrexia,
nausea, urticaria), nasopharyngitis, autoimmune disorders (immune cytopenias
[especially thrombocytopenia], glomerular
nephropathies, thyroid disorders), infections,
pneumonitis, malignancies

59,250.005

Mitoxantrone – generic

~60%6

12 mg/m2 IV q3 mos

Nausea, alopecia, amenorrhea,
cardiotoxicity at cumulative
doses >100 mg/m2, myelosuppression,
acute and chronic myeloid leukemia

Fingolimod – Gilenya
(Novartis)

~55%8

0.5 mg PO once/d

Transaminase elevations, bradycardia,
AV block, macular edema, mild
hypertension, lymphopenia, decreased
pulmonary function, hypersensitivity
reactions, malignancies, serious viral
and fungal infections, PML

78,135.60

Teriflunomide – Aubagio
(Genzyme)

~30%9

7 or 14 mg PO once/d

Diarrhea, nausea, alopecia, transaminase
elevations, neutropenia, leukopenia,
peripheral neuropathy, hyperkalemia,
hypophosphatemia, hypertension,
hepatic failure, acute renal failure,
Stevens-Johnson syndrome, toxic
epidermal necrolysis

74,379.70

Dimethyl fumarate –
Tecfidera (Biogen-Idec)

~50%10

240 mg PO bid

Flushing, abdominal pain, nausea, vomiting,
diarrhea, lymphopenia, anaphylaxis, angioedema, PML

73,168.00

1330.407

Oral

PML = progressive multifocal leukoencephalopathy
1. Approximate WAC for 1 year’s treatment at the usual maintenance dosage. 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. April 5, 2016. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
2. Med Lett Drugs Ther 2015; 57:67.
3. CH Polman et al. N Engl J Med 2006; 354:899.
4. Compared to interferon beta-1a (JA Cohen et al. Lancet 2012; 380:1819; AJ Coles et al. Lancet 2012; 380:1829).
5. Cost for second year of treatment; cost for first year’s treatment is $98,750.
6. HP Hartung et al. Lancet 2002; 360:9018.
7. Cost for treatment of a patient with a body surface area of 1.7 m2 using 12.5-mL multi-dose vials containing 25 mg (2 mg/mL).
8. Med Lett Drugs Ther 2010; 52:98.
9. Med Lett Drugs Ther 2012; 54:89.
10. Med Lett Drugs Ther 2013; 55:45.

withdrawn from the market in 2005 and re-introduced
in 2006 with a Risk Evaluation and Mitigation Strategy
(REMS) program which restricts its use to certified

healthcare providers and settings.11 Based on crosstrial comparisons, it appears to be the most effective
drug currently available for treatment of MS, but its
safety remains a concern.
72

Pregnancy – Natalizumab is classified as category
C (fetotoxicity in animals; no adequate studies in
pregnant women) for use during pregnancy. An
observational study in pregnant women found that
exposure to natalizumab during the first trimester
of pregnancy did not increase the risk of adverse
pregnancy outcomes.12


The Medical Letter

®

Alemtuzumab (Lemtrada) – A humanized monoclonal
antibody directed against the lymphocyte cell surface
molecule CD52, alemtuzumab causes rapid depletion
of CD52-positive B- and T-cells. It has been shown to
be more effective than subcutaneous interferon beta1a in preventing relapses.13 The drug has an attractive
dosing schedule; it is given as a daily IV infusion for
5 consecutive days, followed 12 months later by an
additional 3 days of treatment. However, because of
the occurrence of serious autoimmune effects, infusion
reactions, and malignancies, the FDA has approved
labeling recommending that alemtuzumab generally
be used only for patients who have had a suboptimal

response to at least two other disease-modifying
drugs for MS and has restricted its availability with a
REMS program.
Pregnancy – Alemtuzumab is classified as category
C (embryolethality in animals; no adequate studies
in pregnant women) for use during pregnancy. It
can induce thyroid disorders; placental transfer of
anti-thyroid antibodies resulting in neonatal Graves’
disease has been reported. The manufacturer
recommends that women of childbearing age use
effective contraception while taking the drug and for
four months after stopping it.
Mitoxantrone – An anthracenedione also used to
treat cancer, mitoxantrone inhibits DNA replication.
It has decreased relapse frequency and slowed
progression of disability in patients with severe MS,
but it is potentially cardiotoxic, it can cause persistent
amenorrhea in women, and it has been associated
with a risk of developing acute or chronic myeloid
leukemia, particularly with higher cumulative doses.14
Use of mitoxantrone for treatment of MS has declined
because of concerns about its long-term risks.
Pregnancy – Mitoxantrone is classified as category D
(may cause fetal harm) for use during pregnancy.
ORAL AGENTS — Fingolimod (Gilenya) – The first oral
drug approved for treatment of MS, fingolimod blocks
lymphocyte egress from lymph nodes, reducing the
number of lymphocytes in peripheral blood and the
central nervous system.15 A one-year study found
that fingolimod was more effective than IM interferon

beta-1a in reducing relapse rates and decreasing
the number of new or enlarging brain lesions seen
on MRI.16 PML has occurred in patients treated with
fingolimod for 2 years or more.
Pregnancy – Fingolimod is classified as category
C (developmental toxicity in animals; no adequate

Vol. 58 (1496)

June 6, 2016

studies in pregnant women) for use during pregnancy.
The manufacturer recommends that women of
childbearing age use effective contraception while
taking the drug and for two months after stopping it.
Teriflunomide (Aubagio) – A pyrimidine synthesis
inhibitor, teriflunomide reduces T- and B-cell activation,
proliferation, and function. Teriflunomide has significantly reduced some MRI measures of disease activity
(lesion volume, number of gadolinium-enhancing and
unique active lesions), but cross-trial comparisons
suggest that it is less effective than fingolimod or
dimethyl fumarate in decreasing relapse rates.13
Pregnancy – Teriflunomide is teratogenic in animals
and is contraindicated for use during pregnancy. It is
eliminated very slowly; women who wish to become
pregnant and men wishing to father a child should
discontinue the drug and undergo an accelerated
elimination procedure (cholestyramine or activated
charcoal for 11 days).
Dimethyl Fumarate (Tecfidera) – An antioxidant that

induces expression of anti-inflammatory proteins,
dimethyl fumarate has significantly reduced relapse
rates and development of new or enlarging T2 brain
lesions. In cross-trial comparisons, it appears to be
more effective than teriflunomide.17 An increasing
number of cases of PML have been reported following
use of dimethyl fumarate, particularly in patients with
lymphopenia for more than 6 months.
Pregnancy – Dimethyl fumarate is classified as
category C (embryofetal toxicity in animals at doses
twice the approved human dose; no adequate studies
in pregnant women) for use during pregnancy. ■
1. FD Lublin et al. Defining the clinical course of multiple sclerosis:
the 2013 revisions. Neurology 2014; 83:278.
2. A Shirani et al. Association between use of interferon beta and
progression of disability in patients with relapsing-remitting
multiple sclerosis. JAMA 2012; 308:247.
3. T Derfuss and L Kappos. Evaluating the potential benefit of interferon treatment in multiple sclerosis. JAMA 2012; 308:290.
4. V Annibali et al. IFN-β and multiple sclerosis: from etiology to
therapy and back. Cytokine Growth Factor Rev 2015; 26:221.
5. Peginterferon beta-1a (Plegridy) for multiple sclerosis. Med
Lett Drugs Ther 2015; 57:67.
6. PK Coyle. Management of women with multiple sclerosis
through pregnancy and after childbirth. Ther Adv Neurol Disord
2016; 9:198.
7. Glatiramer acetate for relapsing multiple sclerosis. Med Lett
Drugs Ther 1997; 39:61.
8. Natalizumab (Tysabri) for relapsing multiple sclerosis. Med Lett
Drugs Ther 2005; 47:13.
9. CH Polman et al. A randomized placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;

354:899.
10. PS Sørensen et al. Risk stratification for progressive multifo-

73


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®

cal leukoencephalopathy in patients treated with natalizumab.
Mult Scler 2012; 18:143.
11. In brief: Natalizumab (Tysabri) returns. Med Lett Drugs Ther
2006; 48:76.
12. N Ebrahimi et al. Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study. Mult Scler 2015; 21:198.
13. New drugs for multiple sclerosis. Med Lett Drugs Ther 2012;
54:89.
14. VM Rivera et al. Results from the 5-year, phase IV RENEW
(Registry to Evaluate Novantrone Effects in Worsening Multiple
Sclerosis) study. BMC Neurol 2013; 13:80.
15. Oral fingolimod (Gilenya) for multiple sclerosis. Med Lett Drugs
Ther 2010; 52:98.
16. JA Cohen et al. Oral fingolimod or intramuscular interferon for
relapsing multiple sclerosis. N Engl J Med 2010; 362:402.
17. Dimethyl fumarate (Tecfidera) for multiple sclerosis. Med Lett
Drugs Ther 2013; 55:45.

▶

Pimavanserin (Nuplazid) for

Parkinson’s Disease Psychosis

The FDA has approved the atypical antipsychotic
pimavanserin (Nuplazid – Acadia) for treatment
of hallucinations and delusions associated with
Parkinson’s disease. It is the first drug to be approved
in the US for this indication.
Pronunciation Key
Pimavanserin : pim" a van' ser in
Nuplazid : new plahz' id

PARKINSON’S DISEASE PSYCHOSIS — Hallucinations
and delusions occur in up to 60% of patients with
Parkinson’s disease.1 Low doses of clozapine
(Clozaril, and others) have been effective for treatment
of these symptoms, but even in low doses clozapine
can cause agranulocytosis, somnolence, and other
significant toxicity.2,3 Low-dose quetiapine has been
used off-label to treat Parkinson’s disease psychosis,
but it has not been effective in controlled trials.4,5 Both
clozapine and quetiapine block dopamine receptors
and could exacerbate the motor symptoms of
Parkinson's disease.
MECHANISM OF ACTION — Pimavanserin has no
structural resemblance to other antipsychotic drugs
and has no clinically significant effect on dopaminergic,
Table 1. Pharmacology
Class
Mechanism
of action

Formulation
Route
Tmax (median)
Metabolism
Elimination
Half-life

74

Atypical antipsychotic
Inverse agonist and antagonist at serotonin
5-HT2A receptors
17 mg tablets
Oral
6 hours
Primarily by CYP3A4 and 3A5
Urine (<1%); feces (1.53%)
~57 hours (pimavanserin); 200 hours (active
metabolite)

Vol. 58 (1496)

June 6, 2016

adrenergic, histaminergic, or muscarinic receptors.
It is an inverse agonist and antagonist at serotonin
5-HT2A receptors, which have been implicated in
the development of hallucinations and delusions in
patients with Parkinson’s disease.6
CLINICAL STUDIES — FDA approval of pimavanserin

was based on the results of a 6-week, randomized,
double-blind, placebo-controlled trial in 199 patients
with Parkinson’s disease psychosis. The primary
outcome was the change in score on the Parkinson’s
disease-adapted scale for assessment of positive
symptoms (SAPS-PD). The change in score on
the SAPS-PD (a lower score is associated with an
antipsychotic benefit) was -5.79 with pimavanserin
and -2.73 with placebo, a statistically significant
difference. There was no indication that pimavanserin
exacerbated the motor symptoms of Parkinson’s
disease.7 A meta-analysis of four randomized,
controlled trials reported similar results.8
ADVERSE EFFECTS — Peripheral edema occurred
in 7% of patients taking pimavanserin in the clinical
trial and a confusional state was reported in 6%.
Pimavanserin prolongs the QT interval; it should not
be used in patients with QT interval prolongation or
in those at increased risk of a cardiac arrhythmia.
Pimavanserin should not be used in patients with
hepatic impairment or severe renal impairment. The
FDA requires that the labels of all antipsychotics,
including pimavanserin, contain a boxed warning
about an increased risk of death in elderly patients
with dementia-related psychosis treated with these
drugs.
DRUG INTERACTIONS — Pimavanserin prolongs the
QT interval and should not be used with other QTprolonging drugs.9 Pimavanserin is metabolized
primarily by CYP3A; concurrent administration with
CYP3A inducers can decrease serum concentrations

of pimavanserin and inhibitors of CYP3A can increase
them.10 Pharmacokinetic studies have found no
interaction between pimavanserin and levodopa/
carbidopa.
DOSAGE, ADMINISTRATION, AND COST — Nuplazid
is available as 17-mg tablets. The recommended
dosage is 34 mg once daily with or without food. If a
strong CYP3A4 inhibitor must be used concurrently,
the dosage of pimavanserin should be reduced to
17 mg per day. If a strong CYP3A4 inducer must be
used, an increase in the dose of pimavanserin may be
needed. The cost for 30 days’ treatment with Nuplazid
is $1,950.11


The Medical Letter

®

CONCLUSION — Pimavanserin (Nuplazid) appears
to be effective in the short term for treatment
of hallucinations and delusions that occur in
many patients with Parkinson’s disease, without
exacerbating the motor symptoms of the disease. It
can prolong the QT interval, and it is expensive. ■
1. EB Forsaa et al. A 12-year population-based study of psychosis
in Parkinson disease. Arch Neurol 2010; 67:996.
2. The Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl
J Med 1999; 340: 757.
3. The French Clozapine Parkinson Study Group. Clozapine in

drug-induced psychosis in Parkinson’s disease. Lancet 1999;
353:2041.
4. P Shotbolt et al. Quetiapine in the treatment of psychosis in
Parkinson’s disease. Ther Adv Neurol Disord 2010; 3:339.
5. P Desmarais et al. Quetiapine for psychosis in Parkinson disease and neurodegenerative Parkinsonian disorders: a systematic review. J Geriatr Psychiatry Neurol 2016 April 6 (epub).

▶

Alternatives to Fluoroquinolones

The FDA has announced that it is requiring changes in
the labeling of systemic fluoroquinolones to warn that
the risk of serious adverse effects, including tendinitis,
peripheral neuropathy and CNS effects, generally outweighs their benefit for the treatment of acute sinusitis,
acute exacerbations of chronic bronchitis, and uncomplicated urinary tract infections. For these infections, the
new labels will recommend reserving fluoroquinolones
for patients with no other treatment options.1
Table 1. Systemic Fluoroquinolones Available in the US
Ciprofloxacin (Cipro)
Gemifloxacin (Factive)
Levofloxacin (Levaquin)

Moxifloxacin (Avelox)
Ofloxacin (Floxin)1

1. Only available generically.

SINUSITIS — Acute sinusitis in adults is often viral
and symptoms can be managed with analgesics, a
nasal corticosteroid, and/or nasal saline irrigation.

When it is bacterial, it is generally caused by
Streptococcus pneumoniae, Haemophilus influenzae,
or Moraxella catarrhalis and can be treated with
amoxicillin or amoxicillin/clavulanate.2 The addition
of clavulanate improves coverage of beta-lactamaseproducing strains of H. influenzae and M. catarrhalis.
Doxycycline is an option for adults who are allergic to
penicillin, but resistance to doxycycline has increased,
particularly among isolates of S. pneumoniae with
reduced susceptibility to penicillin.2-4 A respiratory
fluoroquinolone (levofloxacin or moxifloxacin) is an
alternative for penicillin-allergic patients. Monotherapy
with a macrolide (erythromycin, clarithromycin, or
azithromycin) or trimethoprim/sulfamethoxazole is
generally not recommended because of increasing
resistance among pneumococci.

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June 6, 2016

6. U Hacksell et al. On the discovery and development of pimavanserin: a novel drug candidate for Parkinson’s psychosis. Neurochem Res 2014; 39:2008.
7. J Cummings et al. Pimavanserin for patients with Parkinson’s
disease psychosis: a randomised, placebo-controlled phase 3
trial. Lancet 2014; 383:533.
8. I Yasue et al. Serotonin 2A receptor inverse agonist as a treatment for Parkinson’s disease psychosis: a systematic review
and meta-analysis of serotonin 2A receptor negative modulators. J Alzheimers Dis 2016; 50:733.
9. RL Woosley and KA Romero. QT drugs list. Available at www.
crediblemeds.org. Accessed May 25, 2016.
10. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2016; 58:e46.

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. May
5, 2016. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2016. www.fdbhealth.com/policies/drugpricing-policy.

Table 2. Alternatives to Fluoroquinolones
Drug
Acute Sinusitis and AECB3
Amoxicillin – generic
Amoxicillin/clavulanate –
generic
Augmentin
Doxycycline6 – generic
Acute Uncomplicated Cystitis
Trimethoprim/
sulfamethoxazole – generic
Bactrim DS, Septra DS
Nitrofurantoin monohydrate/
macrocrystals – generic
Macrobid
Fosfomycin tromethamine –
Monurol

Usual Adult Dosage1

Cost2

500 mg PO tid
x 5-7 days4
875 mg/125 mg PO

bid x 5-7 days4,5

$3.20

100 mg PO bid7
x 5-7 days

32.20

160/800 mg PO
bid x 3 days

1.00

100 mg PO bid
x 5 days

25.60

3 g PO once

66.50

23.50

AECB = acute exacerbation of chronic bronchitis
1. Dosage adjustment may be needed for renal or hepatic impairment.
2. Approximate WAC for 7 days’ treatment with the generic product (when
available) for acute sinusitis and AECB; for UTI, cost is for recommended
treatment course. 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. May 5, 2016. Reprinted with permission by First
Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/
drug-pricing-policy.
3. Acute sinusitis and AECB due to a bacterial pathogen.
4. A higher dose of amoxicillin (2 g/day) should be considered for patients
with severe disease and those at risk of infection with S. pneumoniae with
reduced susceptibility to penicillin.
5. 500 mg/125 mg is an alternative.
6. For use in penicillin-allergic patients.
7. 200 mg once/d is an alternative.

BRONCHITIS — Acute exacerbation of chronic bronchitis
(AECB) is often viral. Bacterial AECB is generally caused
by H. influenzae, S. pneumoniae, or M. catarrhalis
and can be treated with the same antibacterial drugs
used to treat acute bacterial sinusitis. In patients
with severe COPD, Pseudomonas aeruginosa can
be a cause of AECB and use of an intravenous
antipseudomonal agent, such as cefepime or piperacillin/
tazobactam, should be considered.5
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URINARY TRACT INFECTION — Most episodes of

uncomplicated cystitis are caused by Escherichia
coli. The remaining cases are generally caused by
Staphylococcus saprophyticus, Klebsiella pneumoniae,
Proteus spp., other gram-negative rods, or enterococci.
The drug of choice for empiric treatment of acute
uncomplicated cystitis in non-pregnant women is
trimethoprim/sulfamethoxazole, as long as the local
rate of resistance to trimethoprim/sulfamethoxazole
among urinary pathogens is <20%.6,7 An equally effective
alternative with a low rate of resistance among E. coli
is nitrofurantoin. A single dose of fosfomycin, which
has a broad spectrum of activity against the usual
uropathogens, is another alternative. Beta-lactams
such as amoxicillin/clavulanate, cefdinir, cefpodoxime,
or ceftibuten are second-line alternatives.8
In pregnant women, nitrofurantoin, amoxicillin, or a
cephalosporin could be used to treat uncomplicated
cystitis based on the results of susceptibility testing,
but nitrofurantoin should not be given in the third
trimester or during labor because it can cause
hemolytic anemia in the newborn. ■
1. FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections;
warns about disabling side effects that can occur together.
Available at: www.fda.gov/Drugs/DrugSafety/ucm500143.htm.
Accessed May 26, 2016.
2. AM Harris et al. Appropriate antibiotic use for acute respiratory tract infection in adults: advice for high-value care from
the American College of Physicians and the Centers for Disease
Control and Prevention. Ann Intern Med 2016; 164:425.
3. AW Chow et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis 2012;
54:e72.

4. RM Rosenfeld et al. Clinical practice guideline (update): adult
sinusitis executive summary. Otolaryngol Head Neck Surg
2015; 152:598.
5. Drugs for bacterial infections. Treat Guidel Med Lett 2013;
11:65.
6. K Gupta et al. International clinical practice guidelines for the
treatment of acute uncomplicated cystitis and pyelonephritis
in women: A 2010 update by the Infectious Diseases Society of
America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 2011; 52:e103.
7. Drugs for urinary tract infections. Med Let Drugs Ther 2012;
54:57.
8. TM Hooton. Clinical practice. Uncomplicated urinary tract infection. N Engl J Med 2012; 366:1028.

Online Only Articles
In Brief: Liposomal Irinotecan (Onivyde) for Pancreatic Cancer
www.medicalletter.org/TML-article-1496e
In Brief: Trifluridine/Tipiracil (Lonsurf) for Metastatic Colorectal Cancer
www.medicalletter.org/TML-article-1496f
76

Vol. 58 (1496)

June 6, 2016

IN BRIEF

New Indications for Secukinumab
(Cosentyx)
The FDA has approved the subcutaneous IL-17A antagonist
secukinumab (Cosentyx - Novartis), which was first

approved in 2015 for treatment of plaque psoriasis, for
treatment of psoriatic arthritis and ankylosing spondylitis
in adults.1 Secukinumab is one of the most effective drugs
available for treatment of plaque psoriasis.2
FDA approval of secukinumab for treatment of psoriatic
arthritis was based on two randomized, double-blind trials
with a primary endpoint of at least a 20% improvement in
the American College of Rheumatology response criteria
(ACR20) at 24 weeks. In both trials, ACR20 response rates
were significantly higher in patients receiving secukinumab
than in those receiving placebo.3,4 Secukinumab was
effective in both TNF inhibitor-naive and TNF inhibitorexperienced patients.
Approval of secukinumab for ankylosing spondylitis
was based on two double-blind trials in which the
primary endpoint was the percentage of patients who
achieved at least a 20% improvement in Assessment of
Spondyloarthritis International Society response criteria
(ASA20) at 16 weeks. In both trials, ASA20 response
rates were significantly higher in patients receiving
secukinumab than in those receiving placebo.5
The most common adverse effects of secukinumab in
clinical trials were nasopharyngitis, diarrhea, and upper
respiratory infection. In general, infections occurred at
a higher rate in secukinumab-treated patients than in
those who received placebo. Patients should be screened
for tuberculosis before starting therapy. Exacerbations
of Crohn’s disease were reported during clinical trials in
patients taking secukinumab. Urticaria and anaphylaxis
have occurred.
The recommended dosage of secukinumab for patients

with psoriatic arthritis (without concomitant moderate
to severe plaque psoriasis) or ankylosing spondylitis is
150 mg injected subcutaneously at weeks 0, 1, 2, 3, and
4, then every 4 weeks. The drug can also be given every
4 weeks without the weekly loading doses. The dose can
be increased to 300 mg in patients who continue to have
active psoriatic arthritis. The cost for one 150 mg/mL
single-use pen is $1954.10.6
1. Secukinumab (Cosentyx) for psoriasis. Med Lett Drugs Ther 2015;
57:45.
2. Drugs for psoriasis. Med Lett Drugs Ther 2015; 57:81.
3. IB McInnes et al. Secukinumab, a human anti-interleukin-17A
monoclonal antibody, in patients with psoriatic arthritis (FUTURE-2): a randomised, double-blind, placebo-controlled, phase 3
trial. Lancet 2015; 386:1137.
4. PJ Mease et al. Secukinumab inhibition of interleukin-17A in
patients with psoriatic arthritis. N Engl J Med 2015; 373:1329.
5. D Baeten et al. Secukinumab, an interleukin-17A inhibitor, in
ankylosing spondylitis. N Engl J Med 2015; 373:2534.
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. May 5, 2016.
Reprinted with permission by First Databank, Inc. All rights reserved.
©2016. www.fdbhealth.com/policies/drug-pricing-policy.


The Medical Letter

®

on Drugs and Therapeutics
Volume 58 (Issue 1496)

June 6, 2016

IN BRIEF

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Liposomal Irinotecan (Onivyde) for
Pancreatic Cancer
A liposomal formulation of irinotecan (Onivyde –
Merrimack) has been approved by the FDA for use in
combination with fluorouracil and leucovorin for treatment
of metastatic pancreatic cancer that has progressed after
gemcitabine-based therapy. A non-liposomal formulation
of irinotecan (Camptosar, and generics) has been available
in the US for many years. The liposomal carrier prolongs
exposure to irinotecan and improves the cellular uptake
and cytotoxic effect of the drug.1
FDA approval of liposomal irinotecan was based on the
results of an open-label trial (NAPOLI-1) in 417 patients
with metastatic pancreatic ductal adenocarcinoma whose
disease progressed after gemcitabine-based therapy.
Patients were randomized to receive either liposomal
irinotecan alone, fluorouracil and leucovorin alone, or
liposomal irinotecan in combination with fluorouracil
and leucovorin. Median overall survival, the primary

endpoint, was significantly longer with all three drugs
(6.1 months), compared to fluorouracil and leucovorin
alone (4.2 months) and liposomal irinotecan alone (4.9
months). The most frequent severe (grade 3 or 4) adverse
effects of the liposomal irinotecan-containing regimen
were neutropenia, diarrhea, vomiting, and fatigue.2
Life-threatening diarrhea has also occurred in patients
receiving the 3-drug combination.
Onivyde is available in 43 mg/10 mL single-dose vials.
The recommended dosage is 70 mg/m2 administered
intravenously over 90 minutes every 2 weeks; leucovorin
and fluorouracil should be administered after liposomal
irinotecan. The recommended starting dose of Onivyde for
patients who are homozygous for the UGT1A1*28 allele
is 50 mg/m2; the dose can be increased to 70 mg/m2
as tolerated. The labeling specifies a number of dosage
adjustments that should be made when adverse effects
occur. One dose of Onivyde costs $4860.3
1. A Casadó et al. Formulation and in vitro characterization of thermosensitive liposomes for the delivery of irinotecan. J Pharm Sci
2014; 103:3127.
2. A Wang-Gillam et al. Nanoliposomal irinotecan with fluorouracil
and folinic acid in metastatic pancreatic cancer after previous
gemcitabine-based therapy (NAPOLI-1): a global, randomised,
open-label, phase 3 trial. Lancet 2016; 387:545.
3. Approximate WAC for a patient with a 1.7 m2 surface area. 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. May 5, 2016. Reprinted with permission
by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.

e76

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


The Medical Letter

®

on Drugs and Therapeutics
Volume 58 (Issue 1496)

June 6, 2016

Follow us on Twitter

IN BRIEF

Like us on Facebook

Trifluridine/Tipiracil (Lonsurf) for
Metastatic Colorectal Cancer
The FDA has approved Lonsurf (Taiho Oncology), a
combination of the thymidine-based nucleoside analog
trifluridine and the thymidine phosphorylase inhibitor
tipiracil, for oral treatment of metastatic colorectal cancer.
Trifluridine is incorporated into DNA, interfering with DNA
synthesis and inhibiting cell proliferation. Tipiracil inhibits
the metabolism of trifluridine. The combination is only

approved for use in patients who were previously treated
with a fluoropyrimidine (fluorouracil or capecitabine),
oxaliplatin, irinotecan, an anti-VEGF biological such as
bevacizumab, and, if the tumor is RAS wild-type, an antiEGFR agent (cetuximab or panitumumab). The median
survival of patients with metastatic colorectal cancer
treated with these drugs is about 30 months.
FDA approval of trifluridine/tipiracil was based on the results
of a randomized, double-blind, placebo-controlled trial in
800 patients with metastatic colorectal cancer who had
previously been treated with chemotherapy and biological
therapy. Median overall survival, the primary endpoint, was
significantly longer with trifluridine/tipiracil compared to
placebo (7.1 months vs 5.3 months). Median progressionfree survival, a secondary endpoint, was 1.7 months with
placebo and 2.0 months with trifluridine/tipiracil. The most
common adverse effects of the combination included
nausea, vomiting, diarrhea, fatigue, neutropenia, anemia,
and leukopenia. Among 533 patients treated with the
combination, only one treatment-related death occurred
(from septic shock).1
Lonsurf is available in tablets containing 15 mg of
trifluridine and 6.14 mg of tipiracil or 20 mg of trifluridine
and 8.19 mg of tipiracil. The recommended dosage is 35
mg/m2 (based on the trifluridine component) orally twice
daily on days 1-5 and 8-12 of each 28-day cycle until
disease progression or unacceptable toxicity occurs.
Lonsurf should be taken within one hour after meals. The
cost of one treatment cycle (sixty 20 mg/8.19 mg tablets)
is $10,947.70.2
1. RJ Mayer et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015; 372:1909.
2. Approximate WAC for a patient with a 1.7 m2 surface area. 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. May 5, 2016. Reprinted with permission
by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.
com/policies/drug-pricing-policy.

e77

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


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Issue 1496 Questions
(Correspond to questions #111-120 in Comprehensive Exam #74, available July 2016)
Drugs for Multiple Sclerosis

Pimavanserin (Nuplazid) for Parkinson's Disease Psychosis

1. Which of the following do interferons and glatiramer acetate have in
common in the treatment of multiple sclerosis?
a. frequent injections
b. 30% reduction in clinical relapse rates
c. reduction in new brain lesions seen on MRI
d. all of the above

6. One particular concern about treating the hallucinations and delusions
that occur in some patients with Parkinson’s disease with clozapine or
quetiapine is that they could:
a. cause urinary retention
b. cause severe hepatotoxicity
c. exacerbate the motor symptoms of the disease
d. all of the above

2. A 31-year-old woman presents with a severe form of relapsing-remitting
multiple sclerosis. Because of the severity of her symptoms, you would like
to begin treatment with natalizumab, but she is reluctant because of the
possibility of JC virus infection. She has not previously received treatment for

MS and testing reveals no anti-JC virus antibodies. You could tell her that:
a. the risk of JC virus infection is highest at the beginning of treatment
b. the risk would indeed be high for her because she has no anti-JC
virus antibodies
c. starting treatment with immunosuppressants and then adding
natalizumab would lower the risk
d. the risk is very low during the first 2 years of treatment in patients
without anti-JC virus antibodies
3. Head-to-head trials comparing drugs used to treat multiple sclerosis
are rare, but one such trial comparing IM interferon beta-1a with oral
fingolimod found that:
a. interferon was more effective in reducing relapse rates and new
brain lesions
b. fingolimod was more effective in reducing relapse rates and new
brain lesions
c. interferon was more effective in reducing relapse rates but not new
brain lesions
d. fingolimod was more effective in reducing relapse rates but not new
brain lesions
4. Progressive multifocal leukoencephalopathy (PML) has occurred with
which of the following?
a. interferon beta-1a
b. fingolimod
c. teriflunomide
d. all of the above
5. Most drugs available for treatment of relapsing-remitting multiple
sclerosis cost about:
a. $20,000/yr
b. $50,000/yr
c. $70,000/yr

d. $110,000/yr

7. Clinically significant drug interactions could occur if pimavanserin is
taken with:
a. a CYP3A inducer
b. another QT-prolonging drug
c. a strong CYP3A inhibitor
d. all of the above
Alternatives to Fluoroquinolones
8. The FDA has advised against use of a fluoroquinolone to treat acute
sinusitis, acute exacerbation of chronic bronchitis, and uncomplicated
urinary tract infection because:
a. they are not effective for treatment of these infections
b. they can cause serious adverse effects
c. they increase bacterial resistance to antibiotics
d. none of the above
9. A 35-year-old, otherwise healthy man is complaining of purulent nasal
discharge, fever, and facial pain. He says his symptoms began about 2
weeks ago and have gotten worse over the past 2 days despite using a
nasal steroid. He has no known drug allergies. Which antibiotic would you
recommend for treatment of acute bacterial sinusitis in this patient?
a. amoxicillin/clavulanate
b. erythromycin
c. trimethoprim/sulfamethoxazole
d. ciprofloxacin
10. Which of the following antibiotics can be used for empiric treatment of
acute uncomplicated cystitis in non-pregnant women?
a. trimethoprim/sulfamethoxazole
b. fosfomycin
c. nitrofurantoin monohydrate macrocrystals

d. all of the above

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PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm,
Pharm.D.; ASSOCIATE EDITORS: Susan M. Daron, Pharm.D., Amy Faucard, MLS, Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah,
Pharm.D., F. Peter Swanson, M.D.
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;
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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
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Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
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