The medical letter on drugs and therapeutics may 9 2016

1494 The Medical Letter on Drugs and Therapeutics Treatment of Lyme Disease ...p 57 Ixekizumab Taltz – A Second IL-17A Inhibitor for Psoriasis ...p 59 Odefsey – Another NNRTI Combination

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IN THIS ISSUE

ISSUE

1433

Volume 56

Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE No

1494

The Medical Letter

on Drugs and Therapeutics

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

57

on Drugs and Therapeutics

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Published by The Medical Letter, Inc • A Nonprofi t Organization

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Volume 56

ISSUE No

1494 Ixekizumab (Taltz) – A Second IL-17A Inhibitor for Psoriasis Odefsey – Another NNRTI Combination for HIV p 59p 60

BioThrax and Anthrasil for Anthrax p 62

In Brief: Two Drugs for Soft-Tissue Sarcoma online only

ALSO IN THIS ISSUE

Treatment of Lyme Disease

▶

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 pacifi cus 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 defi cits are usually treated with IV

ceftriaxone (Rocephin, and generics)

CARDIAC DISEASE — Cardiac conduction

abnor-malities associated with Lyme disease are generally self-limited Patients with minor cardiac involvement (fi rst-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 fi rst-degree AV block with symptoms or a PR interval ≥300 milliseconds, or second- or third-degree 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 treat ment 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

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Note: An addendum to this article has been published

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

diffi culties 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 fi rst 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 ■

Tick Bite

Doxycycline 4,5 200 mg PO x 1 dose ≥8 yrs: 4 mg/kg PO x 1 dose and/or observation

Erythema Migrans

Doxycycline 5 100 mg PO bid x 10 d ≥8 yrs: 2 mg/kg PO bid

or Amoxicillin 500 mg PO tid x 14 d 50 mg/kg/d PO divided tid

or Cefuroxime axetil 500 mg PO bid x 14 d 30 mg/kg/d PO divided bid

or Azithromycin 6 500 mg PO once/d x 7-10 d 10 mg/kg/d PO

Neurologic Disease

Facial nerve palsy Doxycycline 5,7 100 mg PO bid x 14 d ≥8 yrs: 2 mg/kg PO bid

or Amoxicillin 500 mg PO tid x 14 d 50 mg/kg/d PO divided tid Other neurologic disease 8 Doxycycline 100 mg PO bid x 14 d ≥8 yrs: 2 mg/kg PO bid

or Ceftriaxone 2 g q24h IV x 14 d 50-75 mg/kg/d IV

Cardiac Disease

Mild (fi rst-degree Doxycycline 5 100 mg PO bid x 14 d (14-21) ≥8 yrs: 2 mg/kg PO bid

AV block, PR <300 msec) or Amoxicillin 500 mg PO tid x 14 d (14-21) 50 mg/kg/d PO divided tid

or Cefuroxime axetil 500 mg PO bid x 14 d (14-21) 30 mg/kg/d PO divided bid More serious 9 Ceftriaxone 2 g q24h IV x 14 d (14-21) 50-75 mg/kg/d IV

Arthritis 10

Arthritis without Doxycycline 5 100 mg PO bid x 28 d ≥8 yrs: 2 mg/kg PO bid neurologic disease 11 or Amoxicillin 500 mg PO tid x 28 d 50 mg/kg/d PO divided tid

or Cefuroxime axetil 500 mg PO bid x 28 d 30 mg/kg/d PO divided bid Persistent or recurrent 12 Ceftriaxone 2 g q24h IV x 14-28 d 50-75 mg/kg/d IV

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 identifi ed 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 effi cacy 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 fi rst-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.

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 Identifi cation 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 Effi cacy 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-confi rmed early Lyme dis-ease 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 ® Vol 58 (1494) May 9, 2016

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 fi rst.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

immune-mediated 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-affi nity 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 Signifi cantly 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

In two other double-blind, placebo- and active-controlled 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 signifi cantly 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 signifi cant 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 injection- site 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 75 1 sPGA 2

UNCOVER-1 3 (n=1296) Ixekizumab q2 wks 4 89.1% 81.8% Ixekizumab q4 wks 4 82.6% 76.4%

UNCOVER-2 5 (n=1224) Ixekizumab q2 wks 4 89.7% 83.2% Ixekizumab q4 wks 4 77.5% 72.9% Etanercept 6 41.6% 36.0%

UNCOVER-3 5 (n=1346) Ixekizumab q2 wks 4 87.3% 80.5% Ixekizumab q4 wks 4 84.2% 75.4% Etanercept 6 53.4% 41.6%

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 Acad-emy 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 Griffi ths et al Lancet 2015; 386:541.

6 Patients received etanercept 50 mg twice weekly.

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 prefi lled, 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

indefi nitely Both are very expensive, and their

long-term 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

re-view 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

in-duction and randomized withdrawal study (UNCOVER-1) Presented

at the 73 rd Annual Meeting of the American Academy of

Dermatol-ogy, San Francisco, March 20-24, 2015 Session F010 Available at:

www.aad.org/Symposium/LBAM2015 Accessed April 28, 2016.

6 CE Griffi ths et al Comparison of ixekizumab with etanercept or

placebo in moderate-to-severe psoriasis (UNCOVER-2 and

UN-COVER-3): results from two phase 3 randomised trials Lancet

2015; 386:541.

Table 2 Dosage and Cost of IL-17A Antagonists

Drug Usual Adult Dosage Cost 1

Ixekizumab – 160 mg 2 SC at wk 0, followed

Taltz (Lilly) by 80 mg at wks 2, 4, 6, 8, 10, $12,311.00

and 12, then every 4 wks

Secukinumab – 300 mg 3 SC at wks 0, 1,

Cosentyx (Novartis) 2, 3, and 4, then every 4 wks 11,724.70 4

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).

Odefsey – Another NNRTI

Combination for HIV

▶

The FDA has approved Odefsey (Gilead), a

once-daily, fi xed-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 fi xed-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 pharma-cokinetic 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 effi cacy

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 effi cacy of rilpivirine-based treatment and on comparative trials that found antiretroviral regimens containing emtricitabine/TAF to be similar in effi cacy

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) May 9, 2016

(≥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

TDF-treated 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

LDL-cholesterol 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

Table 1 Fixed-Dose NNRTI/NRTI Combinations for HIV

Efavirenz/emtricitabine/TDF –

Atripla 600/200/300 mg 1 tab once/d 2,3 $2391.60

(Gilead/BMS) tabs

Rilpivirine/emtricitabine/TDF –

Complera 25/200/300 mg 1 tab once/d 3,4 2345.90

(Gilead) tabs

Rilpivirine/emtricitabine/TAF –

Odefsey 25/200/25 mg 1 tab once/d 4,5 2345.90

(Gilead) tabs

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).

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 signifi cant 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 effi cacy, 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 fi xed-dose combination

of rilpivirine, emtricitabine, and tenofovir alafenamide

(TAF), is expected to be as effective as Complera, a

sim-ilar 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 Ser-vices 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 treat-ment-nạve HIV-1-infected adults AIDS 2014; 28:989.

3 FJ Palella Jr et al Simplifi cation 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 compari-son of tenofovir alafenamide versus tenofovir disoproxil fuma-rate, each coformulated with elvitegravir, cobicistat, and em-tricitabine for initial HIV-1 treatment: week 96 results J Acquir Immune Defi c 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.

1 JG Wright et al Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immuni-zation 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.

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

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,

infusion-site 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-defi cient 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 ■

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 Effi cacy Rule, which

allows the FDA to approve drugs that demonstrate

effi cacy in animals if they are reasonably likely to

produce a clinical benefi t in humans and are safe for

human use

Approval of AVA for post-exposure prophylaxis was

based on the results of two unpublished trials

(sum-marized 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 fi ve

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

Online Only Article

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

e62

on Drugs and Therapeutics

Published by The Medical Letter, Inc • A Nonprofi t Organization

IN BRIEF

Two Drugs for Soft-Tissue Sarcoma

The anthracycline doxorubicin with or without the

alky-lating agent ifosfamide is the standard fi rst-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

but has shown activity in anthracycline- and alkylating

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

signifi cantly longer with trabectedin (4.2 months vs

1.5 months with dacarbazine) Median overall survival,

however, was not signifi cantly different (12.4 months with

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

Eribulin mesylate is a microtubule-polymerizing drug that

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 signifi cantly longer with eribulin (13.5 months vs

11.5 months with dacarbazine) A pre-planned subgroup

analysis found that the benefi t was limited to patients with

liposarcoma 8 Eribulin is the fi rst drug shown to prolong

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 effi cacy 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 Effi cacy and safety of trabectedin or dacarba-zine 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 trabect-edin and drug-drug interactions of trabecttrabect-edin-based combina-tions 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

treat-ed patients with advanctreat-ed liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial Lancet 2016 February 10 (epub).

The Medical Letter publications are protected by US and international copyright laws.

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on Drugs and Therapeutics

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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 fi rst marketed in the US in 1967 and

has less affi nity for calcium than other tetracyclines, have

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

Pedi-atr 2015; 166:1246.

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4 Review the effi cacy and safety of anthrax vaccine adsorbed (BioThrax) and anthrax immune globulin (Anthrasil) for post-exposure prophylaxis or treatment of inhalation

anthrax

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