The medical letter on drugs and therapeutics may 9 2016

The Medical Letter

®

on Drugs and Therapeutics

Volume 58

ISSUE
ISSUE
No.

1433
1494
Volume 56

May 9, 2016

IN THIS ISSUE

Treatment of Lyme Disease ................................................................................................. p 57
Ixekizumab (Taltz) – A Second IL-17A Inhibitor for Psoriasis.......................................... p 59
Odefsey – Another NNRTI Combination for HIV ................................................................ p 60
BioThrax and Anthrasil for Anthrax ..................................................................................... p 62
In Brief: Two Drugs for Soft-Tissue Sarcoma............................................................. online only

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The Medical Letter

®

on Drugs and Therapeutics

Volume 58

May 9, 2016
Take CME Exams

ISSUE

ISSUE No.

1433
1494
Volume 56

▶

ALSO IN THIS ISSUE

Ixekizumab (Taltz) – A Second IL-17A Inhibitor for Psoriasis.......................................... p 59
Odefsey – Another NNRTI Combination for HIV ................................................................ p 60
BioThrax and Anthrasil for Anthrax ..................................................................................... p 62
In Brief: Two Drugs for Soft-Tissue Sarcoma............................................................. online only

Treatment of Lyme Disease
Note: An addendum to this article has been published

Most cases of Lyme disease in the US occur between
May and September in the Northeastern, Mid-Atlantic,
and North Central states.
THE DISEASE — Lyme disease in the US is caused by
the spirochete Borrelia burgdorferi, which is transmitted
to humans by Ixodes scapularis or I. pacificus ticks.1
The characteristic skin lesion, erythema migrans,
develops at the site of the tick bite 1-2 weeks after
the tick has detached (range 3-30 days) and expands
over days to weeks. The classic skin lesion has central
clearing with a bull’s-eye appearance, but more often
the rash is homogeneously erythematous and, rarely,
necrotic or vesicular. Erythema migrans may go
unnoticed because it often occurs in areas not readily

visible to the patient, such as the back, buttocks,
axillae or popliteal fossa, is often asymptomatic, and
resolves spontaneously within weeks.
Fever, headache, malaise, arthralgia, or myalgia may
accompany erythema migrans. A newly discovered
species of Borrelia, B. mayonii (found in the upper
Midwest), may cause nausea and vomiting as well.2,3
Weeks to months after initial infection, patients
with untreated Lyme disease may develop early
disseminated disease that can include migratory
musculoskeletal pain, carditis, facial nerve palsy,
ocular manifestations, or meningitis. Months to a few
years after initial infection (late disease), arthritis may
develop, typically of the knee.
PROPHYLAXIS — Avoidance of ticks and use of tick
repellents can reduce the risk of being bitten.4 Ticks
found on the skin should be removed promptly;
ticks must be attached for ≥36 hours to transmit the
disease. Within 72 hours after tick removal, antibiotic
prophylaxis with a single dose of doxycycline should
be considered; the strongest indication is when an

I. scapularis tick from a highly endemic area is partially
engorged or attached for ≥36 hours, but prophylaxis
would also be reasonable when the duration of tick
attachment or degree of engorgement is uncertain.5
ERYTHEMA MIGRANS — In patients with early Lyme
disease, treatment with oral doxycycline for 10 days
shortens the duration of the skin lesion and generally
prevents development of late sequelae. Doxycycline

is not recommended for children <8 years old or
for pregnant or lactating women; amoxicillin and
cefuroxime axetil (Ceftin, and generics) are effective
alternatives.
NEUROLOGIC DISEASE — Facial nerve palsy, which
may be bilateral, can be a presenting feature of early
disseminated Lyme disease. For patients with isolated
facial nerve palsy, oral doxycycline is effective.
Patients with other neurologic involvement such as
meningitis, other cranial nerve palsies, radiculopathy,
or cognitive deficits are usually treated with IV
ceftriaxone (Rocephin, and generics).
CARDIAC DISEASE — Cardiac conduction abnormalities associated with Lyme disease are generally
self-limited. Patients with minor cardiac involvement
(first-degree atrioventricular [AV] block with a PR
interval of <300 milliseconds) can be treated with
oral doxycycline, amoxicillin, or cefuroxime axetil.
Those with more severe cardiac involvement, such
as first-degree AV block with symptoms or a PR
interval ≥300 milliseconds, or second- or thirddegree AV block, should be hospitalized and treated
with IV ceftriaxone.
ARTHRITIS — Oral treatment with doxycycline,
amoxicillin, or cefuroxime axetil for 28 days is usually
effective for treatment of Lyme arthritis. Arthritis
that has only partially responded to oral treatment
may respond fully to a second month of oral therapy.
Refractory arthritis can be treated with IV ceftriaxone.
57

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

The Medical Letter

®

Vol. 58 (1494)

May 9, 2016

Table 1. Treatment of Lyme Disease1
Drug

Usual Adult Dosage (Range)2

Usual Pediatric Dosage3

Doxycycline4,5
and/or observation

200 mg PO x 1 dose

≥8 yrs: 4 mg/kg PO x 1 dose

Doxycycline5
Amoxicillin
Cefuroxime axetil
Azithromycin6

100 mg PO bid x 10 d

500 mg PO tid x 14 d
500 mg PO bid x 14 d
500 mg PO once/d x 7-10 d

≥8 yrs: 2 mg/kg PO bid
50 mg/kg/d PO divided tid
30 mg/kg/d PO divided bid
10 mg/kg/d PO

Doxycycline5,7
Amoxicillin
Doxycycline
Ceftriaxone

100 mg PO bid x 14 d
500 mg PO tid x 14 d
100 mg PO bid x 14 d
2 g q24h IV x 14 d

≥8 yrs: 2 mg/kg PO bid
50 mg/kg/d PO divided tid
≥8 yrs: 2 mg/kg PO bid
50-75 mg/kg/d IV

or
or

Doxycycline5
Amoxicillin
Cefuroxime axetil

Ceftriaxone

100 mg PO bid x 14 d (14-21)
500 mg PO tid x 14 d (14-21)
500 mg PO bid x 14 d (14-21)
2 g q24h IV x 14 d (14-21)

≥8 yrs: 2 mg/kg PO bid
50 mg/kg/d PO divided tid
30 mg/kg/d PO divided bid
50-75 mg/kg/d IV

or
or

Doxycycline5
Amoxicillin
Cefuroxime axetil
Ceftriaxone

100 mg PO bid x 28 d
500 mg PO tid x 28 d
500 mg PO bid x 28 d
2 g q24h IV x 14-28 d

≥8 yrs: 2 mg/kg PO bid
50 mg/kg/d PO divided tid
30 mg/kg/d PO divided bid
50-75 mg/kg/d IV

Tick Bite

Erythema Migrans
or
or
or
Neurologic Disease
Facial nerve palsy
or
Other neurologic disease8
or
Cardiac Disease
Mild (first-degree
AV block, PR <300 msec)
More serious9
Arthritis10
Arthritis without
neurologic disease11
Persistent or recurrent12
1.

Regardless of the clinical manifestation of Lyme disease, complete response to treatment may be delayed beyond the treatment duration. Relapse may occur
with all of these regimens; patients who relapse may need a second course of treatment. Excessively prolonged treatment or many repeat courses of therapy
are not recommended.
2. Based on severity and/or response.
3. Should not exceed adult dosage. Duration of therapy is the same as in adult patients.
4. The strongest indication for prophylaxis with doxycycline is when: a) the attached tick can be reliably identified as an Ixodes scapularis tick that is estimated
to have been attached for ≥36 hours based on the degree of engorgement of the tick or the time of exposure; b) it can be started within 72 hours after tick
removal and c) the local rate of infection of I. scapularis ticks with Borrelia burgdorferi is >20%.
5. Should generally not be used for children <8 years old or for pregnant or lactating women.

6. For patients unable to take beta-lactams or tetracyclines.
7. Cefuroxime axetil 500 mg bid can be substituted for patients unable to take tetracyclines.
8. Available data on European neuroborreliosis indicate that doxycycline 200 mg q24h and ceftriaxone are equally effective in Lyme meningitis. Data are
lacking on the efficacy of doxycycline in Lyme encephalitis or Lyme encephalopathy. In the absence of brain or spinal cord involvement, doxycycline may be
considered an acceptable treatment option if the illness is not severe.
9. Includes hospitalized patients with first-degree AV block with symptoms or with a PR interval ≥300 milliseconds, or second- or third-degree AV block. A
temporary pacemaker may be necessary. Oral treatment with doxycycline, amoxicillin, or cefuroxime axetil may be substituted for IV therapy after resolution
of heart block in a stable patient.
10. In late disease, the response to treatment may be delayed for several weeks or months.
11. Patients with Lyme arthritis and neurological symptoms should be treated with ceftriaxone 2g IV q24h x 28 days.
12. Patients with mild persistent or recurrent arthritis may be treated with a second course of oral antibiotics.

POST-TREATMENT LYME DISEASE SYMPTOMS —
Some patients whose objective manifestations of
Lyme disease resolved with antibiotic treatment
report persistent subjective symptoms such
as fatigue, musculoskeletal pain, or cognitive
difficulties. These long-standing symptoms have not
been associated with active infection and have not
responded to antibiotics.6-8 Recurrent symptoms in
previously treated patients may be due to new tick
bites and reinfection.9
CONCLUSION — Use of tick repellents and early removal
of ticks are the first steps in preventing Lyme disease.
After an I. scapularis tick bite in a highly endemic area,
prophylaxis with a single dose of doxycycline would be
reasonable for nonpregnant adults and children ≥8 years
old. Recommended doses of antibiotics cure almost all
patients with erythema migrans and can prevent more
serious manifestations of Lyme disease. ■

58

1. E Sanchez et al. Diagnosis, treatment, and prevention of Lyme
disease, human granulocytic anaplasmosis, and babesiosis: a
review. JAMA 2016; 315:1767.
2. BS Pritt et al. Identification of a novel pathogenic Borrelia species
causing Lyme borreliosis with unusually high spirochaetaemia: a
descriptive study. Lancet Infect Dis 2016 February 5 (epub).
3. P Wilhelmsson and PE Lindgren. Detection of a novel Lyme
borreliosis pathogen. Lancet Infect Dis 2016 February 5 (epub).
4. Insect repellents. Med Lett Drugs Ther 2012; 54:75.
5. S Warshafsky et al. Efficacy of antibiotic prophylaxis for the
prevention of Lyme disease: an updated systematic review and
meta-analysis. J Antimicrob Chemother 2010; 65:1137.
6. PM Lantos et al. Final report of the Lyme disease review panel
of the Infectious Diseases Society of America. Clin Infect Dis
2010; 51:1.
7. E Weitzer et al. Long-term assessment of post-treatment
symptoms in patients with culture-confirmed early Lyme disease. Clin Infect Dis 2015; 61:8100.
8. A Berende et al. Randomized trial of longer-term therapy
for symptoms related to Lyme disease. N Engl J Med 2016;
374:1209.
9. RB Nadelman et al. Differentiation of reinfection from relapse in
recurrent Lyme disease. N Engl J Med 2012; 367: 1883.


The Medical Letter

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®

Ixekizumab (Taltz) – A Second
IL-17A Inhibitor for Psoriasis

The FDA has approved ixekizumab (Taltz – Lilly), an
injectable humanized interleukin (IL)-17A antagonist,
for treatment of adults with moderate to severe plaque
psoriasis who are candidates for systemic therapy
or phototherapy. Ixekizumab is the second IL-17A
antagonist to be approved for this indication in the US;
secukinumab (Cosentyx – Novartis) was the first.1
Pronunciation Key
Ixekizumab : ix" ee kiz' ue mab
Taltz : tahltz

STANDARD TREATMENT — Psoriasis is a chronic
inflammatory, immune-mediated condition associated
with multiple comorbidities. Mild to moderate psoriasis
is generally treated with topical corticosteroids.
Topical vitamin D analogs and the retinoid tazarotene
(Tazorac) are alternatives that can be used alone
or in combination with topical corticosteroids.2
UVB phototherapy can be used for treatment of
widespread or unresponsive disease. For patients with
moderate to severe disease, systemic options include
methotrexate, cyclosporine, the oral retinoid acitretin
(Soriatane), the phosphodiesterase type-4 inhibitor
apremilast (Otezla), and biologic therapies such as
the TNF inhibitors etanercept (Enbrel), adalimumab

(Humira) and infliximab (Remicade, and others),
the human IL-12 and -23 antagonist ustekinumab
(Stelara), secukinumab, and now ixekizumab.3
MECHANISM OF ACTION — IL-17A is a naturally
occurring pro-inflammatory cytokine that plays
an important role in the pathogenesis of immunemediated diseases such as plaque psoriasis.
Ixekizumab is a recombinant, humanized IgG4
monoclonal antibody that selectively binds to and
neutralizes IL-17A. Secukinumab is a recombinant,
fully human, high-affinity IgG1 monoclonal antibody
that acts in the same way.4
CLINICAL STUDIES — In a 12-week, randomized,
double-blind trial (UNCOVER-1) available only as an
abstract, 1296 adults with moderate to severe plaque
psoriasis received ixekizumab every 2 or 4 weeks,
or placebo. Significantly more patients treated with
ixekizumab achieved the co-primary endpoints of a
≥75% reduction in the Psoriasis Area and Severity
Index score (PASI 75) and a score of 0 (clear) or 1
(minimal) with at least a 2-point reduction from
baseline on the static Physician Global Assessment
(sPGA) scale compared to those who received
placebo (see Table 1).5

Vol. 58 (1494)

May 9, 2016

In two other double-blind, placebo- and activecontrolled trials (UNCOVER-2 and UNCOVER-3), a
total of 2570 adults with moderate to severe plaque

psoriasis were randomized to receive ixekizumab
every 2 or 4 weeks, the TNF inhibitor etanercept, or
placebo. After 12 weeks of treatment, patients taking
ixekizumab in both trials were significantly more
likely than those taking placebo or etanercept to
achieve the co-primary endpoints of PASI 75 and an
sPGA score of 0 or 1. Differences from etanercept in
achievement of PASI 75 were significant within 1 week
after beginning treatment. In both trials, about 40% of
the patients treated with ixekizumab every 2 weeks
achieved a 100% reduction in PASI score (PASI 100)
after 12 weeks.6
Continued Treatment – After 12 weeks of treatment in
the UNCOVER-1 and UNCOVER-2 trials, responders to
ixekizumab were randomized to receive ixekizumab or
placebo for an additional 48 weeks. Among responders
who continued treatment with ixekizumab every 4
weeks, 75% maintained an sPGA score of 0 or 1 at
week 60 compared to 7% of those switched to placebo.
The median time to relapse was about 5 months in the
placebo group.
ADVERSE EFFECTS — The most common adverse
effects that occurred more often with ixekizumab
than with placebo were mild to moderate injectionsite reactions, which occurred in 10-15% of patients.
Vaginal and oral candidiasis also occurred more often
in patients treated with ixekizumab. No invasive fungal
infections were reported. Development of Crohn’s
Table 1. Results of Some Ixekizumab Clinical Trials
Study

PASI 751

sPGA2

UNCOVER-13 (n=1296)
Ixekizumab q2 wks4
Ixekizumab q4 wks4
Placebo

89.1%
82.6%
3.9%

81.8%
76.4%
3.2%

UNCOVER-25 (n=1224)
Ixekizumab q2 wks4
Ixekizumab q4 wks4
Etanercept6
Placebo

89.7%
77.5%
41.6%
2.4%

83.2%
72.9%

36.0%
2.4%

UNCOVER-35 (n=1346)
Ixekizumab q2 wks4
Ixekizumab q4 wks4
Etanercept6
Placebo

87.3%
84.2%
53.4%
7.3%

80.5%
75.4%
41.6%
6.7%

1. Proportion of patients achieving a ≥75% reduction in Psoriasis Area and
Severity Index (PASI) score from baseline to week 12, a primary endpoint.
2. Proportion of patients achieving a score of 0 (clear) or 1 (minimal) with
at least a 2-point reduction from baseline on the static Physician Global
Assessment (sPGA) scale at week 12, a primary endpoint.
3. K Gordon et al. Presented at the 73rd Annual Meeting of the American Academy of Dermatology, San Francisco, March 20-24, 2015. Session F010.
4. Patients received a 160-mg starting dose of ixekizumab. All other doses
were 80 mg.
5. CEM Griffiths et al. Lancet 2015; 386:541.
6. Patients received etanercept 50 mg twice weekly.

59


The Medical Letter

Vol. 58 (1494)

®

Table 2. Dosage and Cost of IL-17A Antagonists
Drug

Usual Adult Dosage

Cost

Ixekizumab –
Taltz (Lilly)

160 mg2 SC at wk 0, followed
by 80 mg at wks 2, 4, 6, 8, 10,
and 12, then every 4 wks

$12,311.00

Secukinumab –
300 mg3 SC at wks 0, 1,
Cosentyx (Novartis) 2, 3, and 4, then every 4 wks

1

11,724.704

1. Approximate WAC for 12 weeks’ treatment with the lowest 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. Two 80-mg injections.
3. Two 150-mg injections. For some patients a dose of 150 mg may be
acceptable.
4. A carton containing a 300-mg dose (two 150-mg pens or syringes) costs the
same as a carton containing a 150-mg dose (one 150-mg pen or syringe).

disease and ulcerative colitis and exacerbations of
existing disease have been reported during clinical
trials in patients taking ixekizumab.
PREGNANCY — No data are available on the use of
ixekizumab in pregnant women.
DRUG INTERACTIONS — No adverse drug interactions
have been reported with use of ixekizumab. The
labeling recommends avoiding use of live vaccines
during treatment with ixekizumab.
DOSAGE AND ADMINISTRATION — Taltz is supplied in
cartons containing prefilled, single-use autoinjectors
or syringes that each deliver a single 80-mg dose of
ixekizumab. The recommended dosage of ixekizumab is
two injections (160 mg) administered subcutaneously
at week 0, followed by one injection (80 mg) at weeks 2,

4, 6, 8, 10, and 12, and then every 4 weeks.
CONCLUSION — Ixekizumab (Taltz), like secukinumab
(Cosentyx), has been shown to be highly effective
and, in the short term, safe for treatment of patients
with moderate to severe plaque psoriasis. Both of
these agents presumably would have to be continued
indefinitely. Both are very expensive, and their longterm safety is unknown. ■
1. Secukinumab (Cosentyx) for psoriasis. Med Lett Drugs Ther
2015; 57:45.
2. Calcipotriene/betamethasone foam (Enstilar) for psoriasis.
Med Lett Drugs Ther 2016; 58:48.
3. Drugs for psoriasis. Med Lett Drugs Ther 2015; 57:81.
4. TN Canavan et al. Anti-IL-17 medications used in the treatment
of plaque psoriasis and psoriatic arthritis: a comprehensive review. Am J Clin Dermatol 2016; 17:33.
5. K Gordon et al. Ixekizumab for treatment of moderate-to-severe
plaque psoriasis: 60-week results from a double-blind phase 3 induction and randomized withdrawal study (UNCOVER-1). Presented
at the 73rd Annual Meeting of the American Academy of Dermatology, San Francisco, March 20-24, 2015. Session F010. Available at:
www.aad.org/Symposium/LBAM2015. Accessed April 28, 2016.
6. CE Griffiths et al. Comparison of ixekizumab with etanercept or
placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet
2015; 386:541.

60

▶

May 9, 2016

Odefsey – Another NNRTI
Combination for HIV

The FDA has approved Odefsey (Gilead), a oncedaily, fixed-dose combination of the non-nucleoside
reverse transcriptase inhibitor (NNRTI) rilpivirine
and the nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs) emtricitabine and tenofovir
alafenamide, for initial treatment of HIV-1 infection in
patients with HIV-1 RNA (viral load) ≤100,000 copies/
mL or to replace a stable antiretroviral regimen in
patients who have been virologically suppressed
(viral load <50 copies/mL) for at least six months with
no history of treatment failure.
Complera, a fixed-dose combination of rilpivirine,
emtricitabine, and tenofovir disoproxil fumarate
(TDF), was approved in 2011 for the same indications.
Tenofovir alafenamide (TAF), a tenofovir prodrug, is
also available in a 2-drug combination (Descovy) with
emtricitabine and as part of a 4-drug combination
(Genvoya) with emtricitabine, the integrase strand
transfer inhibitor (INSTI) elvitegravir, and the pharmacokinetic enhancer cobicistat.
Pronunciation Key
Emtricitabine : em" trye sye' ta been
Odefsey : oh def' see
Rilpivirine: ril" pi vir' een
Tenofovir alafenamide: ten of' oh veer al" a fen' a mide

STANDARD TREATMENT — Recently updated
guidelines recommend that antiretroviral-naive
patients infected with HIV-1 receive an INSTI-based
regimen or a regimen including the protease inhibitor
(PI) darunavir boosted with ritonavir. NNRTI-based

regimens like Odefsey are now considered alternative
rather than recommended options for initial treatment.1
In patients with a viral load ≤100,000 copies/mL, NNRTI
regimens containing rilpivirine are similar in efficacy
to those containing efavirenz and are better tolerated.2
Virologically suppressed patients switched from a
PI-based regimen to a rilpivirine-based regimen have
maintained virologic suppression.3
CLINICAL STUDIES — Approval of Odefsey was based
on the results of earlier clinical trials that established
the efficacy of rilpivirine-based treatment and on
comparative trials that found antiretroviral regimens
containing emtricitabine/TAF to be similar in efficacy
to those containing emtricitabine/TDF.4,5
ADVERSE EFFECTS — The most common moderate
to severe adverse effects of rilpivirine have been
depression, insomnia, and headache. Severe skin and
hypersensitivity reactions and hepatotoxicity have been
reported. Higher-than-recommended doses of rilpivirine


The Medical Letter

Vol. 58 (1494)

®

Table 1. Fixed-Dose NNRTI/NRTI Combinations for HIV
Drug

Formulations

Dosage

Cost1

Efavirenz/emtricitabine/TDF –
Atripla
600/200/300 mg
(Gilead/BMS)
tabs

1 tab once/d2,3 $2391.60

Rilpivirine/emtricitabine/TDF –
Complera
25/200/300 mg
(Gilead)
tabs

1 tab once/d3,4

2345.90

Rilpivirine/emtricitabine/TAF –
Odefsey
25/200/25 mg
(Gilead)
tabs

1 tab once/d4,5

2345.90

TDF = tenofovir disoproxil fumarate; TAF = tenofovir alafenamide
1. Approximate WAC for 30 days’ treatment. 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. Without food. Taking at bedtime may diminish CNS effects.
3. Not recommended for patients with moderate or severe renal impairment
(CrCl <50 mL/min).
4. With food.
5. Not recommended for patients with severe renal impairment (CrCl <30 mL/min).

(≥75 mg) can prolong the QTc interval. The most
common adverse effect of emtricitabine/TAF (taken
with elvitegravir and cobicistat) was nausea (10%).
Immune reconstitution syndrome can occur with use
of any antiretroviral regimen. Since both emtricitabine
and tenofovir are active against the hepatitis B
virus (HBV), patients co-infected with HIV and HBV
may experience a flare of hepatitis if Odefsey is
discontinued.
TDF vs TAF — Use of TDF has been associated with
renal toxicity, decreased bone mineral density (BMD),
and osteomalacia. In trials comparing TAF and TDF,
renal laboratory abnormalities were less likely to

occur with TAF. In a clinical trial that included TDFtreated patients who were switched to TAF, mean
BMD increased after 48 weeks of treatment with
TAF. No cases of Fanconi syndrome, proximal renal
tubulopathy, or osteomalacia have been reported
in patients taking TAF in clinical trials through 96
weeks. More patients taking TAF have developed LDLcholesterol levels >190 mg/dL.
PREGNANCY — No evidence of embryofetal toxicity
was found in animal studies with any of the 3 drugs
in Odefsey. There are no adequate studies of TAF or
rilpivirine in pregnant women. Based on reports to
the Antiretroviral Pregnancy Registry, emtricitabine
does not appear to increase the risk of major birth
defects.
DRUG INTERACTIONS — Coadministration with drugs
that increase gastric pH may decrease rilpivirine
concentrations. Use of Odefsey with proton pump
inhibitors is contraindicated. Antacids should be
administered at least 2 hours before or 4 hours after

May 9, 2016

Odefsey and H2-receptor antagonists at least 12 hours
before or 4 hours after the combination.
Rilpivirine is primarily metabolized by CYP3A; concurrent
administration of drugs that induce CYP3A may cause
significant reductions in rilpivirine serum concentrations
and is contraindicated. Concomitant use of rilpivirine
with an inhibitor of CYP3A may increase its serum
concentrations.6 Rilpivirine should be used cautiously
with drugs that are known to cause torsades de pointes.7

TAF is a substrate of P-glycoprotein (P-gp), breast
cancer resistance protein (BCRP), and organic anion
transporting polypeptide (OATP) 1B1 and 1B3. Its use
with P-gp inducers such as rifabutin could lead to
loss of efficacy, and use with P-gp inhibitors such as
cyclosporine could increase the risk of adverse effects.6
RESISTANCE — Resistance to NNRTIs develops rapidly
if they are used in combinations that do not completely
suppress viral replication. NNRTI-resistance mutations
develop more often with rilpivirine than with efavirenz.
Mutations conferring resistance to rilpivirine are likely
to confer cross-resistance to all other NNRTIs.8
DOSAGE AND ADMINISTRATION — The recommended
dosage of Odefsey is one tablet once daily with a meal.
It should only be used in patients ≥12 years old who
weigh ≥35 kg and have a CrCl ≥30 mL/min.
CONCLUSION — Odefsey, a fixed-dose combination
of rilpivirine, emtricitabine, and tenofovir alafenamide
(TAF), is expected to be as effective as Complera, a similar 3-drug combination containing tenofovir disoproxil
fumarate (TDF), and it is less likely to adversely affect
renal function or bone mineral density. ■
1. Panel on Antiretroviral Guidelines for Adults and Adolescents.
Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Department of Health and Human Services. Available at: aidsinfo.nih.gov. Accessed April 28, 2016.
2. C Cohen et al. Week 48 results from a randomized clinical trial
of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs.
efavirenz/emtricitabine/tenofovir dsoproxil fumarate in treatment-naïve HIV-1-infected adults. AIDS 2014; 28:989.
3. FJ Palella Jr et al. Simplification to rilpivirine/emtricitabine/
tenofovir disoproxil fumarate from ritonavir-boosted protease
inhibitor antiretroviral therapy in a randomized trial of HIV-1

RNA-suppressed participants. AIDS 2014; 28:335.
4. Genvoya – a new 4-drug combination for HIV. Med Lett Drugs
Ther 2016; 58:19.
5. D Wohl et al. Brief report: a randomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: week 96 results. J Acquir
Immune Defic Syndr 2016; 72:58.
6. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2016; 58:e46.
7. RL Woosley and KA Romero. QT drugs list. Available at www.
crediblemeds.org. Accessed April 28, 2016.
8. Drugs for HIV infection. Treat Guidel Med Lett 2014; 12:7.

61


The Medical Letter

▶

®

BioThrax and Anthrasil for Anthrax

The FDA has approved anthrax vaccine adsorbed (AVA;
BioThrax – Emergent BioSolutions) for prevention of
anthrax disease in adults following exposure to Bacillus
anthracis and intravenous anthrax immune globulin
(Anthrasil – Emergent BioSolutions) for treatment of
inhalation anthrax in adults and children. AVA has been
available since 1970 for prevention of anthrax disease
in persons at high risk of exposure.

Pronunciation Key
BioThrax : bye' oh thrax"
Anthrasil : an' thra sil

STANDARD TREATMENT — Management of a known
or suspected inhalation exposure to anthrax in adults
includes administration of three 0.5-mL subcutaneous
injections of AVA at 2-week intervals and 60 days'
treatment with an appropriate oral antibiotic such
as ciprofloxacin or doxycycline.1,2 Raxibacumab, an
intravenous human monoclonal antibody available
only from the CDC, can be used for treatment of
inhalation anthrax in combination with appropriate
antibiotics, and for prophylaxis of inhalation anthrax
when alternative therapies are not available or are not
appropriate.3 The monoclonal antibody obiltoxaximab
(Anthim) has recently been approved by the FDA for
both prevention and treatment of inhalation anthrax; it
will be reviewed in a future issue.
EFFICACY — Both AVA and anthrax immune globulin
were approved under the Animal Efficacy Rule, which
allows the FDA to approve drugs that demonstrate
efficacy in animals if they are reasonably likely to
produce a clinical benefit in humans and are safe for
human use.
Approval of AVA for post-exposure prophylaxis was
based on the results of two unpublished trials (summarized in the package insert) in which the survival rate
was 70-100% (depending on the dose) among rabbits
that received the vaccine and antibiotics, compared to
23% and 44% in those that received antibiotics alone.

Approval of anthrax immune globulin for treatment
of inhalation anthrax was based on the results of five
unpublished trials (summarized in the package insert)
in animals exposed to lethal aerosolized doses of B.
anthracis. In one trial in monkeys, the survival rate was
36-70% (depending on the dose) in those treated with
anthrax immune globulin and 0% in those who received
placebo.
ADVERSE EFFECTS — Among healthy human subjects,
injection-site reactions were the most common
62

Vol. 58 (1494)

May 9, 2016

adverse effect of AVA. Malaise, headache, fever, and
myalgia also occurred.4
The most common adverse effects of anthrax immune
globulin in healthy volunteers were headache, infusionsite pain and swelling, nausea, and back pain. More
severe adverse effects such as thrombosis, hemolysis,
and renal impairment have been reported with
administration of other immune globulin products and
can also occur with anthrax immune globulin. Anthrasil
contains maltose, which can cause falsely elevated
blood glucose levels. It also contains trace amounts of
IgA and is contraindicated in IgA-deficient patients with
antibodies to IgA and a history of IgA hypersensitivity.
DOSAGE AND ADMINISTRATION — Both Anthrasil and
BioThrax are available only through the US Strategic

National Stockpile. They should both be administered
in combination with appropriate antibiotic therapy.
BioThrax is available in 5-mL vials. The recommended
dosage is 0.5 mL administered by subcutaneous
injection 0, 2, and 4 weeks following exposure to B.
anthracis.
Anthrasil is available in 50-mL single-use vials
containing ≥60 units of toxin neutralizing activity. The
recommended dose for adults is 420 units (7 vials)
administered by slow intravenous infusion using an
infusion pump; 840 units can be used for more severe
disease. Additional doses can be given if needed. For
children, the dose is based on weight (60-420 units); it
can be doubled for children who weigh >5 kg and have
severe disease.
CONCLUSION — Patients who are exposed to Bacillus
anthracis should receive three doses of anthrax
vaccine adsorbed (AVA; BioThrax) and 60 days
of appropriate antibiotic therapy. In patients with
systemic anthrax infection, administration of anthrax
immune globulin (Anthrasil) should be considered in
addition to appropriate antibiotic therapy. ■
1. JG Wright et al. Use of anthrax vaccine in the United States:
recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2010;
59(RR-6):1.
2. KA Hendricks et al. Centers for Disease Control and Prevention
expert panel meetings on prevention and treatment of anthrax
in adults. Emerg Infect Dis 2014; 20:e130687.
3. Raxibacumab for anthrax. Med Lett Drugs Ther 2013; 55:27.
4. RJ Hopkins et al. Phase 3 trial evaluating the immunogenicity

and safety of a three-dose BioThrax regimen for post-exposure
prophylaxis in healthy adults. Vaccine 2014; 32:2217.

Online Only Article
In Brief: Two Drugs for Soft-Tissue Sarcoma
www.medicalletter.org/TML-article-1494e


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The Medical Letter

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on Drugs and Therapeutics

Volume 58 (Issue 1494)

May 9, 2016

IN BRIEF

Two Drugs for Soft-Tissue Sarcoma
The anthracycline doxorubicin with or without the alkylating agent ifosfamide is the standard first-line treatment
for advanced soft-tissue sarcomas. The FDA recently
approved the minor groove DNA intercalator trabectedin
(Yondelis – Janssen) for treatment of unresectable or
metastatic liposarcoma or leiomyosarcoma in patients

previously treated with an anthracycline. Trabectedin
has been available for years in Europe for treatment
of advanced soft-tissue sarcoma. The FDA has also
approved the microtubule inhibitor eribulin mesylate
(Halaven – Eisai), which was approved earlier for treatment
of metastatic breast cancer,1 for treatment of unresectable
or metastatic liposarcoma, but not for leiomyosarcoma, in
patients previously treated with an anthracycline.
Trabectedin binds guanine residues in the minor groove
of DNA, which inhibits active transcription and blocks
DNA repair proteins to achieve an antiproliferative effect.2
It has not been shown to be superior to doxorubicin for
first-line treatment of advanced soft-tissue sarcomas,3
but has shown activity in anthracycline- and alkylating
agent-resistant soft tissue sarcomas.4 FDA approval of
trabectedin was based on a randomized, open-label trial
comparing it to dacarbazine in 518 heavily pretreated
patients with metastatic or recurrent leiomyosarcoma
or liposarcoma. Median progression-free survival was
significantly longer with trabectedin (4.2 months vs
1.5 months with dacarbazine). Median overall survival,
however, was not significantly different (12.4 months with
trabectedin vs 12.9 months with dacarbazine).5 Adverse
effects of trabectedin include nausea, fatigue, neutropenia,
and transient hepatic enzyme elevations.6 Trabectedin is
administered over 24 hours through a central venous line
every 3 weeks until disease progression or unacceptable
toxicity occurs.

overall survival in patients with advanced liposarcoma.

The incidence of grade 3 or 4 adverse effects, particularly
leukopenia and neutropenia, was higher with eribulin
(67%) than with dacarbazine (56%). Fatigue, alopecia,
peripheral neuropathy, nausea, and constipation also
occurred. Eribulin is administered IV over 2 to 5 minutes
on days 1 and 8 of a 3-week cycle.
1. Eribulin mesylate (Halaven) for breast cancer. Med Lett Drugs
Ther 2011; 53:30.
2. AK Larsen et al. Unique features of trabectedin mechanism of
action. Cancer Chemother Pharmacol 2015; 77:663.
3. B Bui-Nguyen et al. A phase IIb multicentre study comparing the
efficacy of trabectedin to doxorubicin in patients with advanced
or metastatic untreated soft tissue sarcoma: the TRUSTS trial.
Eur J Cancer 2015; 51:1312.
4. BJ Petek et al. Trabectedin in soft tissue sarcomas. Mar Drugs
2015; 13:974.
5. GD Demetri et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure
of conventional chemotherapy: results of a phase III randomized
multicenter clinical trial. J Clin Oncol 2016; 34:786.
6. C Leporini et al. A comprehensive safety evaluation of trabectedin and drug-drug interactions of trabectedin-based combinations. BioDrugs 2014; 28:499.
7. NF Dybdal-Hargreaves et al. Eribulin mesylate: mechanism of
action of a unique microtubule-targeting agent. Clin Cancer Res
2015; 21:2445.
8. P Schöffski et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a
randomised, open-label, multicentre, phase 3 trial. Lancet 2016
February 10 (epub).

Eribulin mesylate is a microtubule-polymerizing drug that
sequesters tubulin into nonfunctional aggregates.7 FDA
approval of eribulin for treatment of advanced liposarcoma

was based on a randomized, open-label trial comparing
it to dacarbazine in 452 patients with unresectable or
metastatic liposarcoma or leiomyosarcoma previously
treated with an anthracycline. Median progression-free
survival was 2.6 months in both groups, but overall survival
was significantly longer with eribulin (13.5 months vs
11.5 months with dacarbazine). A pre-planned subgroup
analysis found that the benefit was limited to patients with
liposarcoma.8 Eribulin is the first drug shown to prolong

e62

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The Medical Letter publications are protected by US and international copyright laws.
Forwarding, copying or any other distribution of this material is strictly prohibited.
For further information call: 800-211-2769

The Medical Letter

®

on Drugs and Therapeutics

Volume 58 (Issue 1497)

June 20, 2016
Take CME Exams

Addendum: Doxycycline for Young Children?
A reader commenting on our Treatment of Lyme Disease
article (Med Lett Drugs Ther 2016; 58:57) objected to a
footnote in the table advising against use of doxycycline
in children <8 years old. This warning has been included
in the labeling of all tetracyclines since 1970 when it was
recognized, after decades of use, that these drugs caused
permanent staining and enamel hypoplasia of developing
teeth. The CDC recently stated that short courses of
doxycycline, which was first marketed in the US in 1967 and
has less affinity for calcium than other tetracyclines, have
not been shown to cause tooth staining.1 That statement
was prompted by the discovery that children <10 years old
have a disproportionately high fatality rate from rickettsial
diseases, particularly Rocky Mountain spotted fever, for
which doxycycline is the drug of choice and chloramphenicol
is the only proven alternative.
The main evidence supporting the CDC's statement was
a retrospective cohort study consisting of a record review
and dental examination of 271 children living on a Native
American reservation. No staining was detected in any of the
58 children who had been treated with doxycycline before
the age of 8 years or in any of the 213 children who had not
been exposed to the drug. Enamel hypoplasia was present in
4% of children in both cohorts.2
Lyme disease, unlike Rocky Mountain spotted fever, is
seldom fatal and can be treated with antibiotics other than
doxycycline. A single dose of doxycycline is recommended
for prophylaxis after a tick bite. Given the CDC’s statement
about its safety, it would seem reasonable to use doxycycline

for prophylaxis in all age groups. When longer treatment
courses (10, 14, or 28 days) are recommended for the various
clinical manifestations of Lyme disease in children <8 years
old, alternative antibiotics generally could be used instead. ■
1. HM Biggs et al. Diagnosis and management of tickborne rickettsial
diseases: Rocky Mountain spotted fever and other spotted fever
group Rickettsioses, Ehrlichioses, and Anaplasmosis – United
States. MMWR Recomm Rep 2016; 65:1.
2. SR Todd et al. No visible dental staining in children treated with
doxycycline for suspected Rocky Mountain spotted fever. J Pediatr 2015; 166:1246.

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Issue 1494 Questions
(Correspond to questions #91-100 in Comprehensive Exam #74, available July 2016)
Treatment of Lyme Disease
1. The characteristic skin lesion of Lyme disease usually develops
at the site of a tick bite how long after the tick has detached?
a. 1-2 hours
b. 1-2 days
c. 1-2 weeks
d. 1-2 months
2. Which of the following is recommended for antibiotic
prophylaxis after removal of the tick?
a. a single dose of doxycycline
b. doxycycline for 10 days
c. a single dose of ceftriaxone
d. azithromycin for 7-10 days
3. A 31-year-old man presents with left-sided facial nerve palsy. He
had gone camping at a site near Old Lyme, Connecticut 4 weeks
earlier and remembers having a fever for a few days and a headache about a week later, but he is certain that he never saw a tick

on his skin and never developed a rash. You could tell him that:
a. facial palsy can be a sign of early disseminated Lyme
disease
b. the typical rash of Lyme disease may go unnoticed
c. oral doxycycline for 2 weeks is an effective treatment for
isolated facial nerve palsy in early disseminated Lyme
disease
d. all of the above
4. Oral treatment for Lyme arthritis should be continued for:
a. 10 days
b. 14 days
c. 28 days
d. 6 months

6. Mild to moderate psoriasis is generally treated with:
a. topical corticosteroids
b. a retinoid
c. a vitamin D analog
d. methotrexate
7. A 36-year-old woman who has had severe plaque psoriasis
since childhood is currently being treated with a TNF inhibitor,
but she is unhappy with its effectiveness. She asks if she
should switch to ixekizumab. You could tell her that:
a. ixekizumab has been shown to be highly effective for
treatment of moderate to severe plaque psoriasis
b. ixekizumab has been shown to be more effective than
secukinumab for severe psoriasis
c. ixekizumab has caused life-threatening fungal infections
d. all of the above
Odefsey – Another NNRTI Combination for HIV

8. Compared to Complera, Odefsey is expected to be:
a. more effective
b. less likely to cause nausea
c. less likely to affect renal function
d. all of the above
9. Which of the following is recommended for initial treatment of
antiretroviral-naive patients with HIV?
a. a CCR5-based regimen
b. an INSTI-based regimen
c. an NNRTI-based regimen
d. none of the above
BioThrax and Anthrasil for Anthrax

Ixekizumab (Taltz) – A Second IL-17A Inhibitor for Psoriasis
5. In clinical trials in adults with moderate to severe plaque
psoriasis treated with ixekizumab every 2 weeks for 12 weeks,
approximately what percentage of patients achieved a 100%
reduction in their Psoriasis Area and Severity Index (PASI) score?
a. 5%
b. 20%
c. 40%
d. 60%

10. A 45-year-old man opens a letter that contains a white powder
that is strongly believed to contain Bacillus anthracis. Which of
the following regimens would you recommend for patients with
suspected inhalation exposure to anthrax?
a. 3 doses of anthrax vaccine adsorbed administered at
2-week intervals
b. 60 days’ treatment with an appropriate antibiotic

c. both a and b
d. none of the above

ACPE UPN: Per Issue Exam: 0379-0000-16-494-H01-P; Release: May 9, 2016, Expire: May 9, 2017
Comprehensive Exam 74: 0379-0000-16-074-H01-P; Release: July 2016, Expire: July 2017

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,
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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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