The medical letter on drugs and therapeutics jun 6 2016

1496 on Drugs and Therapeutics Drugs for Multiple Sclerosis ...p 71 Pimavanserin Nuplazid for Parkinson’s Disease Psychosis ...p 74 Alternatives to Fluoroquinolones ...p 75 In Brief: Ne

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IN THIS ISSUE

ISSUE

1433

Volume 56

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

ISSUE No

1496

on Drugs and Therapeutics

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

71

on Drugs and Therapeutics

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

ISSUE

1433

Volume 56

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1496 Pimavanserin (Nuplazid) for Parkinson's Disease Psychosis Alternatives to Fluoroquinolones p 74p 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

ALSO IN THIS ISSUE

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 fi rst disease-modifying drug approved for

treatment of MS Interferons have several

immune-modulating 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 effi

-cacy and adverse effects to older interferon formulations

that must be injected every-other-day SC or weekly IM.5

Pregnancy – Interferons are classifi ed 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

Drugs for Multiple Sclerosis

▶ Interferon beta (Avonex, Plegridy, and others) and glatiramer acetate (Copaxone, Glatopa), both given by injection, have

been used for fi rst-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 fi rst-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, fi ngolimod (Gilenya) and dimethyl fumarate (Tecfi dera) appear to be more effective than teriflunomide (Aubagio), but head-to-head trials are

lacking.

decrease the number of new T2 or gadolinium-enhancing 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 classifi ed 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 fi rst 2 years of treatment in patients without anti-JC virus antibodies.10 Natalizumab was voluntarily

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

Reduction Usual

in Clinical Maintenance Drug Relapse Rate Dosage Frequent or Serious Adverse Effects Cost 1

Injectable

Interferon beta-1a – 30%-35% 2 Injection-site reactions, flu-like

Avonex (Biogen-Idec) 30 mcg IM once/wk symptoms, depression, transaminase $72,072.00

Rebif (EMD Serono) 44 mcg SC 3x/wk elevations, possible cardiac toxicity, 77,797.20 Pegylated interferon beta-1a– autoimmune disorders, allergic reactions,

Plegridy (Biogen-Idec) 125 mcg SC q2 wks hepatotoxicity, seizures, suicidal ideation, 72,072.00

lymphopenia with interferon beta-1b Interferon beta-1b – 250 mcg SC every

Glatiramer acetate – ~30% 2 Injection-site reactions, transient

or 40 mg 3x/wk (flushing, chest pain, palpitations, 70,251.50

Glatopa (Sandoz) 20 mg SC once/d and dyspnea) 63,192.50

Natalizumab – Tysabri 68%3 300 mg IV q4 wks Headache, fatigue, arthralgia, depression, 71,773.00 (Biogen-Idec) infections, hypersensitivity reactions,

hepatotoxicity, PML

Alemtuzumab – Lemtrada 50-55%4 12 mg IV once/d x 5d Infusion reactions (rash, headache, pyrexia, 59,250.00 5

(Genzyme) followed 1 year later by nausea, urticaria), nasopharyngitis, auto-

12 mg IV once/d x 3d immune disorders (immune cytopenias

[especially thrombocytopenia], glomerular nephropathies, thyroid disorders), infections, pneumonitis, malignancies

Mitoxantrone – generic ~60% 6 12 mg/m 2 IV q3 mos Nausea, alopecia, amenorrhea, 1330.40 7

cardiotoxicity at cumulative doses >100 mg/m 2 , myelosuppression,

acute and chronic myeloid leukemia

Oral

Fingolimod – Gilenya ~55%8 0.5 mg PO once/d Transaminase elevations, bradycardia, 78,135.60 (Novartis) AV block, macular edema, mild

hypertension, lymphopenia, decreased pulmonary function, hypersensitivity reactions, malignancies, serious viral and fungal infections, PML

Teriflunomide – Aubagio ~30%9 7 or 14 mg PO once/d Diarrhea, nausea, alopecia, transaminase 74,379.70 (Genzyme) elevations, neutropenia, leukopenia,

peripheral neuropathy, hyperkalemia, hypophosphatemia, hypertension, hepatic failure, acute renal failure, Stevens-Johnson syndrome, toxic epidermal necrolysis

Dimethyl fumarate – ~50% 10 240 mg PO bid Flushing, abdominal pain, nausea, vomiting, 73,168.00

Tecfi dera (Biogen-Idec) diarrhea, lymphopenia, anaphylaxis,

edema, PML 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 fi rst 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 m 2 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 certifi ed

healthcare providers and settings.11 Based on

cross-trial comparisons, it appears to be the most effective

drug currently available for treatment of MS, but its

safety remains a concern

Pregnancy – Natalizumab is classifi ed 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 fi rst trimester

of pregnancy did not increase the risk of adverse pregnancy outcomes.12

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

beta-1a 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 classifi ed 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 classifi ed as category D

(may cause fetal harm) for use during pregnancy

ORAL AGENTS — Fingolimod (Gilenya) – The fi rst oral

drug approved for treatment of MS, fi ngolimod 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 fi ngolimod 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

fi ngolimod for 2 years or more

Pregnancy – Fingolimod is classifi ed as category

C (developmental toxicity in animals; no adequate

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 signifi -cantly 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 fi ngolimod 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 (Tecfi dera) – An antioxidant that

induces expression of anti-inflammatory proteins, dimethyl fumarate has signifi cantly 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 classifi ed 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 Defi ning 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 benefi t of in-terferon 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 na-talizumab for relapsing multiple sclerosis N Engl J Med 2006; 354:899.

10 PS Sørensen et al Risk stratifi cation for progressive

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

na-talizumab exposure in pregnancy A prospective, controlled

ob-servational 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 fi ngolimod (Gilenya) for multiple sclerosis Med Lett Drugs

Ther 2010; 52:98.

16 JA Cohen et al Oral fi ngolimod or intramuscular interferon for

relapsing multiple sclerosis N Engl J Med 2010; 362:402.

17 Dimethyl fumarate (Tecfi dera) 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 fi rst 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

signifi cant 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 signifi cant effect on dopaminergic,

Table 1 Pharmacology

Class Atypical antipsychotic

Mechanism Inverse agonist and antagonist at serotonin

of action 5-HT2A receptors

Formulation 17 mg tablets

Route Oral

Tmax (median) 6 hours

Metabolism Primarily by CYP3A4 and 3A5

Elimination Urine (<1%); feces (1.53%)

Half-life ~57 hours (pimavanserin); 200 hours (active

metabolite)

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 benefi t) was -5.79 with pimavanserin and -2.73 with placebo, a statistically signifi cant 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 QT-prolong ing 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 Pharmaco kinetic 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

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

treat-ment 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

dis-ease and neurodegenerative Parkinsonian disorders: a

system-atic review J Geriatr Psychiatry Neurol 2016 April 6 (epub).

6 U Hacksell et al On the discovery and development of pimavan-serin: a novel drug candidate for Parkinson’s psychosis Neuro-chem 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 treat-ment for Parkinson’s disease psychosis: a systematic review and meta-analysis of serotonin 2A receptor negative modula-tors 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 man-ufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an ac-tual 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

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

out-weighs their benefi t for the treatment of acute sinusitis,

acute exacerbations of chronic bronchitis, and

uncom-plicated 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) Moxifloxacin (Avelox)

Gemifloxacin (Factive) Ofloxacin (Floxin)1

Levofloxacin (Levaquin)

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-lactamase-producing 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

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

Table 2 Alternatives to Fluoroquinolones

Drug Usual Adult Dosage 1 Cost 2

Acute Sinusitis and AECB 3

Amoxicillin – generic 500 mg PO tid $3.20

x 5-7 days 4

Amoxicillin/clavulanate – 875 mg/125 mg PO 23.50 generic bid x 5-7 days 4,5

Augmentin

Doxycycline 6 – generic 100 mg PO bid 7 32.20

x 5-7 days

Acute Uncomplicated Cystitis

Trimethoprim/ 160/800 mg PO 1.00 sulfamethoxazole – generic bid x 3 days

Bact rim DS, Septra DS Nitrofurantoin monohydrate/ 100 mg PO bid 25.60 macrocrystals – generic x 5 days

Macrobid

Fosfomycin tromethamine – 3 g PO once 66.50

Monurol

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.

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

fluo-roquinolone 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

respira-tory 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

bacte-rial 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

Infec-tious 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

in-fection N Engl J Med 2012; 366:1028

IN BRIEF New Indications for Secukinumab

(Cosentyx)

The FDA has approved the subcutaneous IL-17A antagonist

secukinumab (Cosentyx - Novartis), which was fi rst

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 signifi cantly higher in patients receiving secukinumab than in those receiving placebo 3,4 Secukinumab was effective in both TNF naive and TNF inhibitor-experienced 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 signifi cantly 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 (FU-TURE-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.

Online Only Articles

In Brief: Liposomal Irinotecan (Onivyde) for Pancreatic Cancer

www.medicalletter.org/TML-article-1496e

In Brief: Trifluridine/Tipiracil (Lonsurf) for Metastatic

Colorec-tal Cancer

www.medicalletter.org/TML-article-1496f

e76

on Drugs and Therapeutics

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

IN BRIEF

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 signifi cantly 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/m 2 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/m 2 ; the dose can be increased to 70 mg/m 2

as tolerated The labeling specifi es 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

ther-mosensitive 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 m 2 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.fdb-health.com/policies/drug-pricing-policy.

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on Drugs and Therapeutics

IN BRIEF

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

anti-EGFR 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

signifi cantly longer with trifluridine/tipiracil compared to

placebo (7.1 months vs 5.3 months) Median

progression-free 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/m 2 (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

meta-static colorectal cancer N Engl J Med 2015; 372:1909.

2 Approximate WAC for a patient with a 1.7 m 2 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

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