The medical letter on drugs and therapeutics janurary 30 2017

1513 The Medical Letter on Drugs and Therapeutics Lixisenatide for Type 2 Diabetes ...p 19 Pembrolizumab Keytruda for First-Line Treatment of Metastatic NSCLC ...p 22 Inflectra — An Infl

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IN THIS ISSUE

ISSUE

1433

Volume 56

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

ISSUE No

1513

The Medical Letter

on Drugs and Therapeutics

Lixisenatide for Type 2 Diabetes p 19

Pembrolizumab (Keytruda) for First-Line Treatment of Metastatic NSCLC p 22

Inflectra — An Infliximab Biosimilar p 23

Yosprala — A Combination of Aspirin and Omeprazole p 25

Drug Interaction: Dabigatran (Pradaxa) and Statins p 26

Corrections p 26

Comparison Chart of SGLT2 Inhibitors online only

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19

on Drugs and Therapeutics

Take CME Exams

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

ISSUE

1433

Volume 56

ISSUE No

1513

IN THIS ISSUE

Pembrolizumab (Keytruda) for First-Line Treatment of Metastatic NSCLC p 22

Inflectra — An Infliximab Biosimilar p 23

Yosprala — A Combination of Aspirin and Omeprazole p 25

Drug Interaction: Dabigatran (Pradaxa) and Statins p 26

Corrections p 26

Comparison Chart of SGLT2 Inhibitors online only

The FDA has approved lixisenatide (Sanofi ), a

short-acting injectable GLP-1 (glucagon-like peptide-1)

receptor agonist, for once-daily treatment of adults

with type 2 diabetes, both alone (Adlyxin) and in a

fi xed-ratio combination with insulin glargine (Soliqua

100/33) Lixisenatide has been available since 2013 in

many other countries as Lyxumia It is the fi fth GLP-1

receptor agonist to be approved in the US

daily exenatide in reducing A1C, but exenatide caused

In a randomized, 26-week trial comparing once-daily lixisenatide 20 mcg with once-daily liraglutide 1.8 mg

as add-ons to metformin, sponsored by Novo Nordisk, lixisenatide was signifi cantly less effective than

In a randomized, double-blind trial in 6068 patients with type 2 diabetes who had had either a myocardial infarction or an unstable angina event within the last

6 months, rates of major cardiovascular events over

a median follow-up of 25 months were similar with

addition of lixisenatide or placebo to conventional

Insulin Glargine/Lixisenatide – Approval of insulin

glargine/lixisenatide was based on the results of an open-label trial in 736 patients with type 2 diabetes inadequately controlled on basal insulin and one or two oral antihyperglycemic drugs After a 6-week run-in period, patients stabilized on a daily dose of 20-50 units

of insulin glargine, with an A1C of 7-10% and fasting blood glucose ≤140 mg/dL, were randomized to receive insulin glargine/lixisenatide or continue on insulin glargine alone for 30 weeks; oral antihyperglycemic drugs other then metformin were discontinued The daily dose ranged from 10 to 60 units of insulin glargine and from 5 to 20 mcg of lixisenatide At week 30, there

combination than with insulin glargine alone (-1.1%

vs -0.6%) Mean body weight decreased by 0.7 kg with

Lixisenatide for Type 2 Diabetes

▶

Pronunciation Key

Lixisenatide: lix" i sen' a tide Adlyxin: ad lix' in

Soliqua: so lee' kwa

GLP-1 RECEPTOR AGONISTS — GLP-1 receptor

agonists lower glucose levels by potentiating

glucose-dependent secretion of insulin, suppressing

postpran-dial glucagon secretion, slowing gastric emptying, and

promoting satiety They lower glycated hemoglobin

(A1C) by about 1-1.5%, have been associated with

average weight loss of 1.5-2.8 kg, and rarely cause

(Victoza) has been shown to reduce the overall risk of

a major cardiovascular event and the risk of death from

cardiovascular causes in patients with type 2 diabetes

basal insulin such as insulin glargine, which primarily

targets fasting plasma glucose, may benefi t from

addi-tion of a short-acting GLP-1 receptor agonist such as

lixisenatide, liraglutide, or exenatide (Byetta) to control

CLINICAL STUDIES — Lixisenatide – In randomized

trials in patients with type 2 diabetes, use of

lixisenatide alone and in combination with metformin,

a sulfonylurea, pioglitazone, or insulin lowered

A1C and reduced weight (see Table 2) In one study

in patients inadequately controlled on metformin

(GetGoal-X), sponsored by Sanofi , addition of

once-daily lixisenatide was noninferior to addition of

twice-Table 1 Pharmacology of Lixisenatide

Class GLP-1 receptor agonist Route SC injection

Tmax (median) 1-3.5 hours Elimination Renal; glomerular fi ltration and proteolytic

degradation Half-life (terminal) ~3 hours

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the combination and increased by 0.7 kg with insulin

glargine alone.7

An open-label, 30-week trial in 1170 patients with

type 2 diabetes inadequately controlled on metformin

compared insulin glargine 10-60 units/lixisenatide

5-20 mcg daily to insulin glargine 10-60 units/day

alone and to lixisenatide 10-20 mcg/day alone

than with either component alone (-1.6% vs -1.3% with

insulin glargine and -0.9% with lixisenatide) Mean

body weight decreased by 2.3 kg with lixisenatide alone

and by 0.3 kg with the combination, and increased by

ADVERSE EFFECTS — Nausea, vomiting, and other GI

adverse effects occurred in 39.7% of patients treated with lixisenatide in clinical trials, which is similar to the rate with other GLP-1 receptor agonists; 4.3% of pa-tients discontinued the drug because of GI symptoms GLP-1 receptor agonists slow gastric emptying and should not be used in patients with severe gastroparesis Other common adverse effects of lixisenatide were headache (9%) and dizziness (7%)

Anaphylaxis occurred in 0.1% of lixisenatide-treated patients Other serious hypersensitivity reactions such

as angioedema have also been reported Antibodies to lixisenatide developed in 70% of patients; these patients were more likely to experience allergic or injection-site reactions and those with the highest antibody concentrations had a reduced glycemic response Use of GLP-1 receptor agonists has been associated with renal insuffi ciency and worsening of chronic renal failure Their use may also be associated with a risk

of acute pancreatitis, but a causal relationship has not

The most common adverse effect of the insulin glargine/lixisenatide combination is hypoglycemia Allergic and injection-site reactions, lipodystrophy, weight gain, and peripheral edema can occur The incidence of GI adverse effects with the combination was lower than with lixisenatide alone (possibly as a result of more gradual dose titration), but higher than with insulin glargine alone

DRUG INTERACTIONS — Since lixisenatide slows

gastric emptying, it may decrease the rate and extent

of absorption of oral medications taken concomitantly Oral contraceptives should be taken 1 hour before

or 11 hours after lixisenatide Lixisenatide does not signifi cantly inhibit or induce any CYP isozymes

PREGNANCY AND LACTATION — Lixisenatide has

not been studied in pregnant women Administration

of lixisenatide to pregnant animals during organogenesis was associated with visceral closure and skeletal defects at systemic exposures 1-6 times higher than those achieved in humans at the recommended dose Low levels of lixisenatide have been detected in rat milk

DOSAGE AND ADMINISTRATION — Adlyxin is available

in prefi lled pens containing 14 preset 10-mcg or 20-mcg doses The recommended starting dosage is

10 mcg SC once daily for 14 days; on day 15, the daily dosage should be increased to 20 mcg

Table 2 Some Lixisenatide Clinical Trials

Study Drug Regimen (%) 1 (kg) 1

Monotherapy

Get Goal-Mono 2 Lixisenatide 20 mcg/d 3 -0.7 -2.0

12 wks Lixisenatide 20 mcg/d 4 -0.9 -2.0

(n=361) Placebo -0.2 -2.0

Add-on Therapy

Get Goal-X 5 Metformin

24 wks + Lixisenatide 20 mcg/d 3 -0.8 -3.0

(n=634) + Exenatide 10 mcg bid -1.0 -4.0

Get Goal-F1 6 Metformin

(n=484) + Lixisenatide 20 mcg/d 4 -0.9 -2.6

+ Placebo -0.4 -1.6

Get Goal-M-Asia 7 Metformin ± sulfonylurea

24 wks 5 + Lixisenatide 20 mcg/d 4 -0.8 -1.5

(n=391) + Placebo -0.5 -1.2

Get Goal-S 8 Sulfonylurea ± metformin

(n=859) + Placebo -0.1 -0.9

Get Goal-P 9 Pioglitazone ± metformin

(n=484) + Placebo -0.3 +0.2

Get Goal-L 10 Basal insulin ± metformin

(n=495) + Placebo -0.4 -0.5

Get Goal-Duo 1 11 Insulin glargine ± metformin ± thiazolidinedione

24 wks + Lixisenatide 20 mcg/d 3 -0.7 +0.3

(n=446) + Placebo -0.4 +1.2

Get Goal Duo-2 12 Insulin glargine ± metformin

(n=894) + Insulin glulisine once/d -0.6 +1.0

+ Insulin glulisine tid -0.8 +1.4 Get Goal-L Asia 13 Basal insulin ± sulfonylurea

(n=311) + Placebo +0.11 +0.1

1 Least squares (LS) mean change from baseline.

2 VA Fonseca et al Diabetes Care 2012; 35:1225.

3 Lixisenatide 10 mcg once daily for 1 week, 15 mcg once daily for 1 week, and

then 20 mcg once daily.

4 Lixisenatide 10 mcg once daily for 2 weeks, and then 20 mcg once daily.

5 J Rosenstock et al Diabetes Care 2013; 36:2945.

6 GB Bolli et al Diabet Med 2014; 31:176.

7 Study in Asian patients C Yu Pan et al Diabetes Metab Res Rev 2014; 30:726.

8 J Rosenstock et al J Diabetes Complications 2014; 28:386.

9 M Pinget et al Diabetes Obes Metab 2013; 15:1000.

10 MC Riddle et al Diabetes Care 2013; 36:2489.

11 MC Riddle et al Diabetes Care 2013; 36:2497.

12 J Rosenstock et al Diabetes Care 2016; 39:1318.

13 Study in Asian patients Y Seino et al Diabetes Obes Metab 2012; 14:90

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Soliqua 100/33 is available in packages of fi ve 3-mL

prefi lled pens, each containing 100 units/mL of insulin

glargine and 33 mcg/mL of lixisenatide The

recom-mended starting dosage is insulin glargine 15 units/

lixisenatide 5 mcg SC once daily in patients inadequately

controlled on <30 units of basal insulin or on lixisenatide,

and 30 units/10 mcg in those inadequately controlled on

30-60 units of basal insulin The dose can then be titrated

up or down by 2-4 units per week to achieve the desired

fasting plasma glucose concentrations; the maximum

daily dosage is 60 units/20 mcg

For both products, unused pens should be stored in the

refrigerator; after fi rst use, the pen can be kept at room

temperature for up to 14 days, but must be protected

from light A new needle (purchased separately)

should be attached for each injection Adlyxin and

Soliqua 100/33 are injected subcutaneously in the

abdomen, thigh, or upper arm within one hour before

the fi rst meal of the day

CONCLUSION — Lixisenatide (Adlyxin), a new

once-daily injectable GLP-1 receptor agonist, reduces A1C

and weight in patients with type 2 diabetes As

add-on treatment to metformin, its effi cacy appears to be

similar to that of twice-daily exenatide (Byetta), but

less than that of once-daily liraglutide (Victoza)

The fi xed-ratio combination of insulin glargine and

lixisenatide (Soliqua 100/33) reduces A1C more than

either of its components alone, but it carries a greater risk of hypoglycemia and weight gain than lixisenatide alone and a greater risk of nausea and vomiting than insulin glargine alone ■

Table 3 GLP-1 Receptor Agonists

Albiglutide – Tanzeum (GSK) 30, 50 mg single-dose pen 2 30 or 50 mg SC once/wk 3 $478.90

Dulaglutide – Trulicity (Lilly) 0.75 mg/0.5 mL, 1.5 mg/0.5 mL 0.75 or 1.5 mg SC once/wk 3 626.00 single-dose pen or syringe

Exenatide –

immediate-release

Byetta (AstraZeneca) 250 mcg/mL 5 or 10 mcg SC bid 4,5 668.30 (1.2, 2.4 mL prefi lled pen)

extended-release

Bydureon (AstraZeneca) 2 mg single-dose pen or powder 2 mg SC once/wk 3,5 622.80 for injectable suspension 2

Liraglutide – Victoza (Novo Nordisk) 6 mg/mL (3 mL prefi lled pen) 1.2 or 1.8 mg SC once/d 3,6 498.40

Lixisenatide – Adlyxin (Sanofi ) 50 mcg/mL, 100 mcg/mL 20 mcg SC once/d 7,8 557.20

(3 mL prefi lled pen)

Combinations with Long-Acting Insulin Analogs

Insulin glargine/lixisenatide – 100 units/33 mcg/mL 15 units/5 mcg-60 units/ 20 mcg 508.00 10

Soliqua 100/33 (Sanofi ) (3 mL prefi lled pen) SC once/d 7,9

Insulin degludec/liraglutide – 100 units/3.6 mg/mL 16 units/0.58 mg-50 units/1.8 mg 762.40 10

Xultophy 100/3.6 (Novo Nordisk) (3 mL prefi lled pen) SC once/d 11

1 Approximate WAC for 4 weeks’ or 30 days’ treatment at the lowest usual adult 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 January 5,

2 Requires reconstitution before injection.

3 Can be given at any time of day, with or without food.

4 Starting dosage is 5 mcg twice daily After one month, the dose can be increased to 10 mcg twice daily Should be given within 60 minutes before morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart).

5 Not recommended for patients with a CrCl <30 mL/min.

6 Starting dosage is 0.6 mg once daily for 7 days.

7 Should be given within 60 minutes before the fi rst meal of the day.

8 Starting dosage is 10 mcg once daily for 14 days.

9 Starting dosage is 15 units/5 mcg in patients inadequately controlled on <30 units of basal insulin or on lixisenatide and is 30 units/10 mcg in those inad-equately controlled on 30-60 units of basal insulin; titrate up or down by 2-4 units/week to achieve desired fasting plasma glucose.

10 Cost of 30 days’ treatment for a patient using Soliqua 40 units/13.3 mcg daily or Xultophy 40 units/1.44 mg daily

11 Starting dosage is 16 units/0.58 mg; titrate up or down by 2 units every 3-4 days to achieve desired fasting plasma glucose Should be given at the same time each day with or without food.

1 Drugs for type 2 diabetes Med Lett Drugs Ther 2017; 59:9.

2 SP Marso et al Liraglutide and cardiovascular outcomes in type 2 diabetes N Engl J Med 2016; 375:311

3 T Forst Lixisenatide as add-on to insulin glargine for the treat-ment of type 2 diabetes mellitus Expert Opin Pharmacother 2016; 17:1703.

4 J Rosenstock et al Effi cacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately con-trolled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X) Diabetes Care 2013; 36:2945.

5 M Nauck et al Once-daily liraglutide versus lixisenatide as

add-on to metformin in type 2 diabetes: a 26-week randomized cadd-on- con-trolled clinical trial Diabetes Care 2016; 39:1501.

6 MA Pfeffer et al Lixisenatide in patients with type 2 diabetes and acute coronary syndrome N Engl J Med 2015; 373:2247.

7 VR Aroda et al Effi cacy and safety of LixiLan, a titratable fi xed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately controlled on basal insulin and metformin: the LixiLan-L randomized trial Diabetes Care 2016; 39:1972.

8 J Rosenstock et al Benefi ts of LixiLan, a titratable fi xed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan-O random-ized trial Diabetes Care 2016; 39:2026.

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Pembrolizumab (Keytruda) for

First-Line Treatment of Metastatic NSCLC

▶

The FDA has approved the immune checkpoint

inhibi-tor pembrolizumab (Keytruda – Merck), a programmed

death receptor-1 (PD-1) inhibitor, for fi rst-line treatment

of patients with metastatic non-small cell lung cancer

(NSCLC) that highly expresses programmed

death-ligand 1 (PD-L1) and has no epidermal growth factor

receptor (EGFR) mutations or anaplastic lymphoma

kinase (ALK) translocations About 25% of patients with

advanced NSCLC have tumors with high levels of PD-L1

expression (PD-L1 expressed on ≥50% of tumor cells)

Pembrolizumab was approved earlier for treatment of

metastatic NSCLC with PD-L1 expression ≥1% that

Pembrolizumab: pem” broe liz’ ue mab Keytruda: key true' duh

MECHANISM OF ACTION — PD-1 is an inhibitory

receptor expressed by T-cells during long-term antigen exposure Activation of PD-1 by its ligands (PD-L1 and PD-L2) inhibits T-cell proliferation and cytokine production Upregulation of these ligands occurs

in some tumors Pembrolizumab is a humanized monoclonal antibody that binds to the PD-1 receptor, blocking the interaction of PD-1 with its ligands and promoting antitumor immune responses

OTHER IMMUNE CHECKPOINT INHIBITORS —

Nivolumab (Opdivo), the only other FDA-approved

PD-1 inhibitor, is approved for second-line treatment of metastatic NSCLC In previously untreated patients, it

Table 1 Some Drugs for Metastatic NSCLC

Drug FDA-Approved Indication Usual Adult Dosage 1 Cost 2

ALK/ROS1 Tyrosine Kinase Inhibitor

Crizotinib – Xalkori ALK-positive metastatic NSCLC 250 mg PO bid $14,845.90 (Pfi zer) ROS1-positive metastatic NSCLC

ALK Tyrosine Kinase Inhibitors

Alectinib – Alecensa ALK-positive metastatic NSCLC in patients with disease 600 mg PO bid 3 13,313.60 (Genentech) progression on or who are intolerant to crizotinib

Ceritinib – Zykadia ALK-positive metastatic NSCLC in patients with disease 750 mg PO once/d 4 15,079.50 (Novartis) progression on or who are intolerant to crizotinib

EGFR Tyrosine Kinase Inhibitors

Afatinib – Gilotrif First-line treatment of metastatic NSCLC with EGFR 40 mg PO once/d 5 7550.70 (Boehringer Ingelheim) exon 19 deletions or exon 21 (L858R) substitutions

Metastatic squamous NSCLC with disease progression after platinum-based chemotherapy

Erlotinib – Tarceva Metastatic NSCLC with EGFR exon 19 deletions or exon 21 150 mg PO once/d 6 7825.40 (Genentech) (L858R) substitutions with disease progression after

at least one chemotherapy regimen

Gefi tinib – Iressa First-line treatment of metastatic NSCLC with EGFR exon 250 mg PO once/d 7597.80 (AstraZeneca) 19 deletions or exon 21 (L858R) substitutions

Necitumumab – Portrazza First-line treatment of metastatic squamous NSCLC in 800 mg IV on days 1 8160.00 7 (Lilly) combination with gemcitabine and cisplatin and 8 of a 3-week cycle

Osimertinib – Tagrisso EGFR T790M mutation-positive metastatic NSCLC with 80 mg PO once/d 14,190.80 (AstraZeneca) disease progression on or after EGFR tyrosine kinase

inhibitor therapy

PD-1 Inhibitors

Nivolumab – Opdivo Metastatic NSCLC with disease progression on or after 240 mg IV q2 wks 12,036.20 (BMS) platinum-based chemotherapy 8

Pembrolizumab – Keytruda First-line treatment of metastatic NSCLC with high PD-L1 200 mg IV q3 wks 8893.00 (Merck) expression (on ≥50% of tumor cells)

Metastatic NSCLC with PD-L1 expression (≥1%) and disease progression on or after platinum-based chemotherapy 8

PD-L1 Inhibitor

Atezolizumab – Tecentriq Metastatic NSCLC with disease progression on or after 1200 mg IV q3 wks 8620.00 (Genentech) platinum-based chemotherapy 8

ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; PD-1 = programmed death receptor-1; PD-L1 = programmed death-ligand 1;

ROS1 = c-ros oncogene 1

1 Dosage adjustment may be needed for hepatic or renal impairment.

2 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 January 5, 2017 Reprinted with permission by First Databank, Inc All rights reserved ©2017 www.fdbhealth.com/policies/drug-pricing-policy.

3 Taken with food.

4 Should not be taken within 2 hours of a meal.

5 Taken at least 1 hour before or 2 hours after a meal.

6 Taken on an empty stomach.

7 Cost of gemcitabine and cisplatin not included.

8 Patients with EGFR or ALK genomic tumor aberrations should receive treatment with drugs specifi c for these aberrations before receiving a PD-1 or PD-L1 inhibitor.

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failed to improve progression-free survival in a clinical

trial that was not limited to patients with NSCLC that

Atezolizumab (Tecentriq), a PD-L1 inhibitor, is also

approved for second-line treatment of metastatic NSCLC

In one clinical trial, increased PD-L1 expression was

as-sociated with improvement in overall survival in patients

effi cacy in previously untreated patients are in progress

CLINICAL STUDIES — FDA approval of pembrolizumab

for fi rst-line treatment of metastatic NSCLC was based

on the results of an open-label trial in 305 patients with

previously untreated metastatic NSCLC with high levels

of PD-L1 expression who were randomized to receive

either pembrolizumab 200 mg every 3 weeks or

platinum-based chemotherapy Patients with EGFR mutations

or ALK translocations were excluded from the trial

Median progression-free survival, the primary endpoint,

was signifi cantly longer with pembrolizumab than with

chemotherapy (10.3 vs 6.0 months) The estimated rate

of overall survival at 6 months, a secondary endpoint,

was signifi cantly higher with pembrolizumab than with

ADVERSE EFFECTS — Diarrhea, fatigue, and fever were

the most common adverse effects of pembrolizumab

in the clinical trial Severe (grade 3 or higher)

treatment-related adverse effects occurred in 26.6%

of patients who received pembrolizumab and in

53.3% of those who received chemotherapy

Immune-mediated adverse effects including pneumonitis,

colitis, nephritis, hepatitis, and hypothyroidism have

occurred rarely with pembrolizumab in other studies

Type 1 diabetes has been reported

CONCLUSION — Pembrolizumab (Keytruda) is more

effective and better tolerated than platinum-based

chemotherapy for fi rst-line treatment of patients with

1 RS Herbst et al Pembrolizumab versus docetaxel for previously

treated, PD-L1-positive, advanced non-small-cell lung cancer

(KEYNOTE-010): a randomised controlled trial Lancet 2016;

387:1540

2 M Socinski et al NSCLC, metastatic CheckMate 026: a phase

3 trial of nivolumab vs investigator's choice (IC) of

platinum-based doublet chemotherapy (PT-DC) as fi rst-line therapy for

stage IV/recurrent programmed death ligand 1

(PD-L1)−posi-tive NSCLC Ann Oncol 2016; 27(Suppl 6):LBA7_PR.

3 L Fehrenbacher et al Atezolizumab versus docetaxel for

pa-tients with previously treated non-small-cell lung cancer

(POP-LAR): a multicentre, open-label, phase 2 randomised controlled

trial Lancet 2016; 387:1837.

4 M Reck et al Pembrolizumab versus chemotherapy for

PD-L1-positive non-small-cell lung cancer N Engl J Med 2016;

375:1823.

Inflectra – An Infliximab

Biosimilar

▶

The FDA has approved infliximab-dyyb (Inflectra – Pfi zer; marketed as Remsima in some countries), as a biosimilar of the TNF inhibitor infliximab (Remicade)

Infliximab-dyyb was approved in the European Union (EU) in 2013 and in Canada in 2014 It is the second biosimilar to be approved by the FDA Filgastrim-sndz

(Zarxio), a recombinant human granulocyte

colony-stimulating factor, was the fi rst.1

Infliximab: in flix' i mab Inflectra: in flek' tra

BIOSIMILARS — US law defi nes a biosimilar as a

biologic product that is highly similar to an approved biologic product (reference product) with no clinically meaningful differences in safety, purity, or potency; minor differences in clinically inactive components are allowed An approved biosimilar product must have the same mechanism of action, route of administration, dosage form, and strength as the reference product Bioanalytical and functional assays have found that the structural and functional characteristics of infliximab-dyyb are highly similar to those of

US-licensed Remicade Inflectra is approved for most of the same indications as US-licensed Remicade (see

Table 2), but was not reviewed for “interchangeability”

with Remicade A biosimilar that is approved as an

interchangeable product may be substituted by a pharmacist for the reference product in states that

The FDA recently issued a draft of new guidance on the criteria for biosimilars to meet the standard for interchangeability To demonstrate interchangeability, the data and information submitted to the FDA must show that a proposed interchangeable product is biosimilar to the reference product and that it can

be expected to produce the same clinical results as the reference product in any given patient Also, for

Table 1 Remicade and Inflectra

Drug Available Formulations Cost 1

Infliximab – 100 mg/20 mL vials $20,038.90

Remicade (Janssen)

Infliximab-dyyb – 100 mg/20 mL vials 17,033.00

Inflectra (Pfi zer)

1 Approximate WAC for 54 weeks’ treatment of rheumatoid arthritis in a pa-tient weighing 65 kg (3 mg/kg IV at 0, 2, and 6 weeks, then every 8 weeks) 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 January 5, 2017 Reprinted with permission by First Databank, Inc All rights reserved ©2017 www.fdbhealth.com/policies/drug-pricing-policy.

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Assessment of Spondyloarthritis International Society [ASAS] 20 and ASAS40 criteria) at week 30 were 70.5%

and 51.8%, respectively, with Inflectra compared to

response rates were 67.0% and 54.7% with Inflectra

no statistically signifi cant differences between the groups In an open-label extension, patients receiving

Inflectra remained on it and those receiving Remicade

switched to Inflectra At week 102, ASAS response

A randomized, double-blind trial comparing Inflectra

with Remicade in patients with active Crohn’s disease

patients with Crohn’s disease or ulcerative colitis

In an unpublished, double-blind, 52-week trial (NOR-SWITCH), available only as an abstract, 481 Norwegian adults with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, ulcerative colitis, Crohn’s disease,

or chronic plaque psoriasis who had been on stable

infliximab treatment for at least 6 months were

randomized to either switch to infliximab-dyyb or

continue their current treatment Overall, the biosimilar

product was found to be noninferior to infliximab; disease worsening (the primary endpoint) occurred in 61 (29.6%) patients who switched to the biosimilar compared to 53

(26.2%) of those who continued to take infliximab In the

subgroup of patients with Crohn’s disease, however, the rate of disease worsening was higher among patients

ADVERSE EFFECTS — In patients treated for up to 54

weeks in the clinical trials, there were no signifi cant

differences in adverse effects between Inflectra and

Remicade Serious infections, including bacterial

infections, invasive or disseminated fungal infections, and reactivation of tuberculosis and hepatitis B virus, have occurred with infliximab Transaminase elevations and hepatotoxicity, including autoimmune hepatitis, and cases of new-onset or worsening heart failure have been reported Hypersensitivity reactions, mainly related to the infusion, can occur Malignancies have been reported in patients receiving infliximab, but a cause-and-effect relationship has not been established

Inflectra should not be offered to patients with a

previous anaphylactic or infusion-related reaction to infliximab, or to those with antibodies to infliximab

IMMUNOGENICITY — Use of infliximab has been

associated with the development of antibodies that reduced the effi cacy of the drug In clinical trials

Table 2 Summary of FDA-Approved Indications for

Remicade and Inflectra1

▶ Induction and maintenance treatment of moderately to severely

active Crohn’s disease or ulcerative colitis in adults who have

had an inadequate response to conventional therapy

▶ Induction and maintenance treatment of moderately to severely

active Crohn’s disease in children ≥6 years old who have had an

inadequate response to conventional therapy

▶ Treatment of moderately to severely active rheumatoid arthritis

(in combination with methotrexate)

▶ Treatment of active ankylosing spondylitis and psoriatic arthritis

▶ Treatment of adults with chronic severe plaque psoriasis

1 Remicade is also approved for induction and maintenance treatment of

moderately to severely active ulcerative colitis in children ≥6 years old

who have had an inadequate response to conventional therapy This

indi-cation is protected by orphan drug exclusivity until September 23, 2018.

products that will be administered more than once,

the data and information must show that switching a

patient back and forth between the reference product

and the proposed interchangeable product is not less

safe or effective than treating them with the reference

PHARMACOKINETICS — In a randomized,

double-blind, single-dose, pharmacokinetic study in 213

healthy volunteers, Inflectra was compared with

both US-licensed and EU-approved Remicade

The pharmacokinetic profi les of all three products

were highly similar; all comparisons fell within the

CLINICAL STUDIES — The clinical development

program for infliximab-dyyb was conducted outside

the US using EU-approved Remicade as a comparator

In a randomized, double-blind trial (PLANETRA) in 606

adults with moderately to severely active rheumatoid

arthritis and an inadequate response to methotrexate,

Inflectra 3 mg/kg IV at weeks 0, 2, and 6, and then

every 8 weeks was compared to the same dosage of

Remicade, both given in combination with methotrexate

12.5-25 mg/week The ACR20 response rates (≥20%

improvement on the American College of Rheumatology

scale) in the per-protocol population at weeks 30 and

54 were 73.4% and 74.7% with Inflectra, compared to

69.7% and 71.3% with Remicade; these differences were

not statistically signifi cant At 54 weeks, radiographic

open-label extension, patients who were receiving

Inflectra remained on the drug and those receiving

Remicade switched to Inflectra At week 102, ACR

A randomized, double-blind trial in 250 adults with

active ankylosing spondylitis (PLANETAS) compared

Inflectra with Remicade, both given as 5 mg/kg IV at

weeks 0, 2, and 6, and then every 8 weeks ASAS20 and

ASAS40 response rates (clinical response according to

Trang 8

in patients with rheumatoid arthritis or ankylosing

spondylitis, the percentage of patients who developed

antidrug antibodies was similar with Inflectra and

Remicade after up to 102 weeks of treatment

Preliminary results from the ongoing trial in patients

with Crohn’s disease found that the incidence of

antidrug antibodies was similar with Inflectra and

Remicade after 14 weeks of treatment.10

CONCLUSION — Infliximab-dyyb (Inflectra) has been

approved by the FDA as a biosimilar of infliximab

(Remicade) In clinical trials in patients with

rheumatoid arthritis or ankylosing spondylitis, it was

similar to Remicade in effi cacy and safety Inflectra

could be a less expensive alternative to Remicade

in such patients The effi cacy and adverse effects of

Inflectra are also expected to be generally similar to

those of Remicade in patients with other conditions for

which infliximab is approved, but in one unpublished

study, the rate of disease worsening in patients with

Crohn’s disease was higher in those who switched

from Remicade to Inflectra than in those who remained

1 Zarxio – a fi lgrastim biosimilar Med Lett Drugs Ther 2016;

58:34.

2 FDA Biosimilars Guidances Available at: www.fda.gov/Drugs/

GuidanceComplianceRegulatoryInformation/Guidances/

ucm290967.htm Accessed January 19, 2016.

3 W Park et al Comparison of the pharmacokinetics and safety

of three formulations of infliximab (CT-P13, EU-approved

ref-erence infliximab and the US-licensed refref-erence infliximab) in

healthy subjects: a randomized, double-blind, three-arm,

paral-lel-group, single-dose, phase I study Expert Rev Clin Immunol

2015; 11 Suppl 1:S25.

4 DH Yoo et al A randomised, double-blind, parallel-group study

to demonstrate equivalence in effi cacy and safety of CT-P13

compared with innovator infliximab when coadministered with

methotrexate in patients with active rheumatoid arthritis: the

PLANETRA study Ann Rheum Dis 2013; 72:1613.

5 DH Yoo et al A phase III randomized study to evaluate the

ef-fi cacy and safety of CT-P13 compared with reference infliximab

in patients with active rheumatoid arthritis: 54-week results

from the PLANETRA study Arthritis Res Ther 2016; 18:82.

6 DH Yoo et al Effi cacy and safety of CT-P13 (biosimilar

inflix-imab) in patients with rheumatoid arthritis: comparison

be-tween switching from reference infliximab to CT-P13 and

con-tinuing CT-P13 in the PLANETRA extension study Ann Rheum

Dis 2017; 76:355.

7 W Park et al A randomised, double-blind, multicenter,

parallel-group, prospective study comparing the pharmacokinetics,

safety, and effi cacy of CT-P13 and innovator infliximab in

pa-tients with ankylosing spondylitis: the PLANETAS study Ann

Rheum Dis 2013; 72:1605.

8 W Park et al Comparable long-term effi cacy, as assessed by

patient-reported outcomes, safety and pharmacokinetics, of

CT-P13 and reference infliximab in patients with ankylosing

spondylitis: 54-week results from the randomized,

parallel-group PLANETAS study Arthritis Res Ther 2016; 18:25.

9 W Park et al Effi cacy and safety of switching from reference

infliximab to CT-P13 compared with maintenance of CT-P13 in

ankylosing spondylitis: 102-week data from the PLANETAS

ex-tension study Ann Rheum Dis 2016; Apr 26 (epub).

10 FDA Medical Review Inflectra (infliximab-dyyb) for injec-tion Available at: www.accessdata.fda.gov/drugsatfda_docs/ nda/2016/125544Orig1s000TOC.cfm Accessed January 19, 2017.

11 J Jahnsen Clinical experience with infliximab biosimilar Rem-sima (CT-P13) in inflammatory bowel disease patients Therap Adv Gastroenterol 2016; 9:322.

12 KK Jorgensen et al Biosimilar infliximab (CT-P13) is not in-ferior to originator infliximab: results from the 52-week ran-domized NOR-SWITCH trial UEG Journal 2016; 4(6):805 Ab-stract LB15 Available at: http://journals.sagepub.com/doi/ pdf/10.1177/2050640616678364 Accessed January 19, 2017.

Yosprala – A Combination of

Aspirin and Omeprazole

▶

The FDA has approved Yosprala (Aralez), a fi

xed-dose combination of delayed-release aspirin and immediate-release omeprazole, for secondary prevention of cardiovascular and cerebrovascular events in patients who are at risk of developing aspirin-associated gastric ulcers (≥55 years old or history of

gastric ulcers) Yosprala is the fi rst product to become

available in the US that combines aspirin and a proton pump inhibitor (PPI)

Yosprala: yo spra' lah

SECONDARY PREVENTION — Aspirin irreversibly

acetylates cyclooxygenase-1, blocking thromboxane synthesis and inhibiting platelet activation and aggregation for the life of the platelet (up to 10 days) It reduces the incidence of myocardial infarction by 30%, stroke by 20%, and all-cause mortality by 18% when used for secondary prevention of thromboembolic events The annual risk of serious GI bleeding with aspirin doses ≤325 mg/day is about 0.4%, which is 2.5 times

reduce the risk of recurrent gastric ulcers and bleeding

in patients who continue to take aspirin for secondary prevention of thromboembolic events despite a history

of aspirin-induced GI toxicity.2

CLINICAL STUDIES — Approval of Yosprala was based

on the results of two 6-month trials in a total of 1049 patients at risk for developing aspirin-associated gastric ulcers (≥55 years old or 18 to 54 years old with

a history of gastric or duodenal ulceration within 5 years) who had been taking aspirin 325 mg/day for ≥3 months for secondary prevention of cardiovascular or cerebrovascular events and were expected to continue taking it for ≥6 months In both trials, patients were

randomized to receive either Yosprala 325/40 mg or

enteric-coated aspirin 325 mg once daily for 6 months Signifi cantly fewer patients taking the combination

Trang 9

developed endoscopic gastric ulcers compared to those

taking enteric-coated aspirin alone (3.8% vs 8.7% in trial

1 and 2.7% vs 8.5% in trial 2) Treatment discontinuation

due to upper GI adverse effects was signifi cantly lower

with the combination than with enteric-coated aspirin

DOSAGE AND COST — Yosprala tablets consist of a

core of either 81 or 325 mg of enteric-coated aspirin

surrounded by an outer layer of 40 mg of

immediate-release omeprazole The combination should be taken

once daily at least 60 minutes before a meal The

tablets must be swallowed whole; they should not be

split, crushed, dissolved, or chewed A 30-day supply

supply of enteric-coated aspirin (30 81-mg or 325-mg

tablets) and delayed-release omeprazole (60 20-mg

tablets), which are both available generically over the

CONCLUSION — Use of the fi xed-dose combination

of delayed-release aspirin and immediate-release

omeprazole (Yosprala) can decrease the incidence

of endoscopically-detected gastric ulcers in

patients taking aspirin for secondary prevention of

thromboembolic events who are at increased risk of

aspirin-associated gastric ulcers How it compares

with taking a delayed-release proton pump inhibitor

and enteric-coated aspirin separately, which costs

1 SM Weisman and DY Graham Evaluation of the benefi ts and risks

of low-dose aspirin in the secondary prevention of cardiovascular

and cerebrovascular events Arch Intern Med 2002; 162:2197

2 Primary prevention of ulcers in patients taking aspirin or

NSAIDs Med Lett Drugs Ther 2010; 52:17.

3 DJ Whellan et al PA32540 (a coordinated-delivery tablet of

enteric-coated aspirin 325 mg and immediate-release

omepra-zole 40 mg) versus enteric-coated aspirin 325 mg alone in

sub-jects at risk for aspirin-associated gastric ulcers: results of two

6-month, phase 3 studies Am Heart J 2014; 168:495.

4 Approximate WAC WAC = wholesaler acquisition cost or

manufac-turer's published price to wholesalers; WAC represents a published

catalogue or list price and may not represent an actual

transac-tional price Source: AnalySource® Monthly January 5, 2017

5 Cost at CVS.com Accessed January 19, 2017.

Comparison Chart of SGLT2 Inhibitors (online only)

www.medicalletter.org/downloads/SGLT-2_inhibitors_LS.pdf

Corrections

Drugs for Diabetes (Med Lett Drugs Ther 2017; 59:9)

In the 4th paragraph of the GLP-1 receptor agonists section,

we mistakenly stated that Xultophy 100/3.6 is a combination

of insulin degludec and albiglutide; Xultophy 100/3.6 is a

combination of insulin degludec and liraglutide.

Another Insulin Glargine (Basaglar) for Diabetes (Med Lett Drugs

Ther 2017; 59:3)

In the Dosage and Administration section, we removed the word

“syringe” to describe Basaglar’s KwikPen device Basaglar is not

available as a prefi lled syringe; it is only available as a KwikPen

Drug Interaction: Dabigatran (Pradaxa) and Statins

The results of a recently published study suggest that taking the oral direct thrombin inhibitor dabigatran

etexilate (Pradaxa) with either simvastatin (Zocor, and others) or lovastatin (Altoprev, and others) increases the

risk of major hemorrhage.1

POSSIBLE MECHANISMS — The mechanism for this

potential interaction has not been established Dabigatran etexilate is a substrate of the transporter P-glycoprotein (P-gp); drugs that inhibit P-gp could increase dabigatran serum concentrations and the risk of bleeding.2 In in vitro

studies, simvastatin and lovastatin have been shown to inhibit P-gp3; however, limited data from in vivo studies

suggest simvastatin and lovastatin have little to no effect on serum concentrations of P-gp substrates such

as digoxin.4-6 Some studies have suggested that statins may have antiplatelet effects.7

THE STUDY — The risk of major hemorrhage was

evaluated in a population-based, case-control study in patients ≥66 years old with nonvalvular atrial fi brillation who were taking dabigatran etexilate and had received a prescription for a statin Patients prescribed simvastatin

or lovastatin were more likely to have a major hemorrhage than those prescribed other statins (adjusted OR 1.46; 95% CI 1.17-1.82) The number of patients prescribed simvastatin or lovastatin in this study was small compared to the number prescribed other statins such

as atorvastatin (Lipitor, and others).

CONCLUSION — The results of one case-control study

suggest that older patients taking dabigatran etexilate

(Pradaxa) with either simvastatin (Zocor, and others) or

lovastatin (Altoprev, and others) are at increased risk of

major hemorrhage, compared to those taking the drug with another statin Although the study had several limitations and a mechanism has not been fi rmly estab-lished, it may be reasonable to use another statin such as

atorvastatin (Lipitor, and others) in older patients taking

dabigatran until more data become available ■

1 T Antoniou et al Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial

fi brillation CMAJ 2016 Nov 21 (epub).

2 Which oral anticoagulant for atrial fi brillation? Med Lett Drugs Ther 2016; 58:45.

3 C Chen et al Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1 Drug Metab Dispos 2005; 33:537.

4 FDA Center for Drug Evaluation and Research Juvisync (sitagliptin + simvastatin tablets) Clinical Pharmacology and Biopharmaceutics Review(s) Available at: www.accessdata.fda.gov/drugsatfda_docs/ nda/2011/202343orig1s000ClinPharmR.pdf Accessed January 19, 2017.

5 A Bernsdorf et al Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms Br J Clin Pharmacol 2006; 61:440.

6 W Dieterle et al Pharmacokinetic interactions of the oral renin in-hibitor aliskiren with lovastatin, atenolol, celecoxib and cimetidine Int J Clin Pharmacol Ther 2005; 43:527.

7 F Violi et al Statins as antithrombotic drugs Circulation 2013; 127:251.

Trang 10

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4 Review the effi cacy and safety of the fi xed-dose combination of aspirin and omeprazole (Yosprala) for secondary prevention of thromboembolic events in patients who

are at risk of developing aspirin-associated gastric ulcers.

5 Discuss the possible mechanism for the interaction between dabigatran etexilate (Pradaxa) and simvastatin (Zocor, and others) or lovastatin (Altoprev, and others), and

the risks of taking these drugs concurrently.

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