The medical letter on drugs and therapeutics february 27 2017

The Medical Letter

®

on Drugs and Therapeutics
Volume 59

ISSUE
ISSUE
No.

1433
1515
Volume 56

February 27, 2017

ALSO IN THIS ISSUE

Auvi-Q Epinephrine Auto-Injector Returns ................................................................................. p 33
Crisaborole (Eucrisa) for Atopic Dermatitis ................................................................................ p 34
Anticoagulation of Elderly Patients at High Risk for Falls with Atrial Fibrillation .......................... p 35
Extended-Release Calcifediol (Rayaldee) for Secondary Hyperparathyroidism ............................ p 36
Kyleena – Another Hormonal IUD .............................................................................................. p 38
Drug Interaction: Clopidogrel and PPIs ...................................................................................... p 39
Atezolizumab (Tecentriq) for Bladder Cancer and NSCLC ...................................................online only

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The Medical Letter

®

on Drugs and Therapeutics
Volume 59

February 27, 2017
Take CME Exams

ISSUE

ISSUE No.

1433
1515
Volume 56

▶

ALSO IN THIS ISSUE

Crisaborole (Eucrisa) for Atopic Dermatitis ................................................................................ p 34
Anticoagulation of Elderly Patients at High Risk for Falls with Atrial Fibrillation .......................... p 35
Extended-Release Calcifediol (Rayaldee) for Secondary Hyperparathyroidism ............................ p 36
Kyleena – Another Hormonal IUD .............................................................................................. p 38
Drug Interaction: Clopidogrel and PPIs ...................................................................................... p 39
Atezolizumab (Tecentriq) for Bladder Cancer and NSCLC ...................................................online only

Auvi-Q Epinephrine Auto-Injector
Returns

Auvi-Q (Kaléo; previously manufactured and
marketed by Sanofi), the epinephrine auto-injector
approved by the FDA in 2012 for emergency treatment
of anaphylaxis and voluntarily withdrawn in 2015
due to potential inaccurate dosage delivery,1 has
become available once more. According to Kaléo,
improvements in the manufacturing process have
addressed the concerns that led to its recall.
Table 1. Epinephrine Auto-Injectors
Drug
Epinephrine injection, USP –
generic (Mylan)3

EpiPen Jr (Mylan)
EpiPen
Epinephrine injection, USP4 –
generic (Impax)
Adrenaclick (Impax)7
Epinephrine injection, USP –
Auvi-Q (Kaléo)8

Formulations1

Cost2

0.15 mg/0.3 mL,
0.3 mg/0.3 mL
0.15 mg/0.3 mL
0.3 mg/0.3 mL

$300.00
300.00
608.60
608.60

0.15 mg/0.15 mL,
0.3 mg/0.3 mL
0.15 mg/0.15 mL,
0.3 mg/0.3 mL

395.205,6
460.905
4500.009

4500.009

1. The dose of epinephrine is 0.15 mg for patients who weigh 15-30 kg and
0.3 mg for those who weigh ≥30 kg.
2. Approximate WAC for one package containing two auto-injectors. 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.
February 5, 2017. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.
3. Interchangeable with EpiPen and EpiPen Jr.
4. Adrenaclick and its generic equivalent are similar to EpiPen and EpiPen Jr
in size and functionality, but they are not considered interchangeable due to
differences in device design and instructions for use.
5. Both strengths cost the same.
6. Both strengths are available at CVS for a cash price of $110.00 for two
auto-injectors.
7. Adrenaclick is no longer being manufactured; its generic equivalent will
continue to be marketed after supplies of Adrenaclick are depleted.
8. Auvi-Q is not interchangeable with other currently available epinephrine
auto-injectors.
9. Manufacturer's list price for insurers. Insurers and pharmacy benefit
managers may negotiate with the manufacturer for a lower price or decide
not to pay for Auvi-Q at all. According to the manufacturer, the out-ofpocket cost is $0 for all commercially insured patients, whether or not their
insurer covers the device. The cash price for patients without government
or commercial insurance is $360 for those with a household income
≥$100,000/year and $0 for those with a household income <$100,000/year.

Pronunciation Key
Epinephrine: ep" i nef' rin
Auvi-Q: aw vee' cue

THE DEVICE — No changes were made to the device
itself, which is about the length and width of a credit
card and as thick as a smartphone. It has an automatic
needle retraction system and a red safety guard at the
needle-end of the device. Removal of the outer case
initiates visual signals and an audio recording that
provides step-by-step instructions and a 5-second
countdown during the injection process. The shelf-life
of the epinephrine in the auto-injector is 18 months;
the shelf-life of the battery is longer.
Auvi-Q’s needle length, gauge, and injection force are
similar to those of EpiPen. In a randomized, crossover,
bioavailability study, injection of epinephrine 0.3 mg
from Auvi-Q and EpiPen resulted in similar peak
epinephrine levels and total epinephrine exposure.2 In
one study, patients and caregivers found Auvi-Q easier
to use than other epinephrine auto-injectors.3,4
CONCLUSION — Auvi-Q, which is being reintroduced
after having been voluntarily withdrawn from the
market in 2015, is a smaller epinephrine auto-injector
that provides visual signals and audio instructions as
it is being used. It appears to be more convenient to
carry and easier to use than EpiPen. ■
1. FDA. Updated: Sanofi US issues voluntary nationwide recall of all
Auvi-Q due to potential inaccurate dosage delivery. Available at
www.fda.gov/Safety/Recalls/ucm469980.htm. Accessed February 6, 2017.
2. ES Edwards et al. Bioavailability of epinephrine from Auvi-Q
compared with EpiPen. Ann Allergy Asthma Immunol 2013;
111:132.

3. CA Camargo Jr. et al. Auvi-Q versus EpiPen: preferences of
adults, caregivers, and children. J Allergy Clin Immunol Pract
2013; 1:266.
4. T Umasunthar et al. Patients’ ability to treat anaphylaxis using
adrenaline autoinjectors: a randomized controlled trial. Allergy
2015; 70:855.

33

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The Medical Letter

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®

Crisaborole (Eucrisa) for Atopic
Dermatitis

The FDA has approved crisaborole 2% ointment
(Eucrisa – Pfizer) for topical treatment of mild to
moderate atopic dermatitis in patients ≥2 years old. It
is the first phosphodiesterase type-4 (PDE4) inhibitor
to be approved in the US for this indication.
Pronunciation Key
Crisaborole: kris” a bor’ ole
Eucrisa: you kris’ a

ATOPIC DERMATITIS — Atopic dermatitis (also known
as atopic eczema) is a chronic pruritic inflammatory
skin disease that commonly presents in infancy or early
childhood and is frequently associated with other atopic
disorders such as allergic rhinitis and asthma. It has a
relapsing course, often improving by adolescence. In infants, atopic dermatitis typically involves the face, scalp,
and extensor surfaces of the limbs. In older patients, it
characteristically involves the flexural areas.
STANDARD TREATMENT — Application of moisturizers,
emollients, and barrier creams can reduce the need
for pharmacologic therapy. Low-potency topical
corticosteroids are generally used for treatment of
mild atopic dermatitis when lesions fail to respond
to nonpharmacologic therapy, and medium- to highpotency topical corticosteroids are used for moderate
to severe disease. For maintenance treatment,
the lowest potency topical corticosteroid that is
effective should be used. Long-term use of topical
corticosteroids can cause skin atrophy, purpura,
telangiectasias, and permanent striae.1,2
The topical calcineurin inhibitors tacrolimus (Protopic,
and generics) and pimecrolimus (Elidel) can be used
for topical corticosteroid-resistant atopic dermatitis
and for cases involving the face or intertriginous
areas where corticosteroid adverse effects can be
troublesome. Calcineurin inhibitors are similar in
efficacy to low- to medium-potency corticosteroids,
and they do not cause skin atrophy or other
corticosteroid adverse effects. Skin malignancies
and lymphomas have been reported rarely in patients
treated with a topical calcineurin inhibitor; the labels of

tacrolimus and pimecrolimus include a boxed warning
about the risk of malignancy, but a causal relationship
has not been established.3
PHARMACOLOGY — Crisaborole inhibits PDE4,
resulting in increased levels of cyclic adenosine
monophosphate (cAMP). Its exact mechanism of
action for treatment of atopic dermatitis is unclear,
but increased cAMP levels suppress production of
34

Vol. 59 (1515)

February 27, 2017

Table 1. Some Topical Nonsteroidal Drugs for Atopic Dermatitis
Drug

Cost1

Calcineurin Inhibitors
Pimecrolimus 1% cream – Elidel (Valeant)
Tacrolimus 0.03%, 0.1% ointment – generic
Protopic (Astellas)

$517.70
416.702
486.202

PDE4 Inhibitor
Crisaborole 2% ointment – Eucrisa (Pfizer)

580.00

PDE4 = phosphodiesterase type-4
1. Approximate WAC for a 60-g tube. 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 February 5, 2017. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2017. www.
fdbhealth.com/policies/drug-pricing-policy.
2. Both strengths cost the same.

proinflammatory cytokines.4 Systemic absorption of
crisaborole is minimal after topical administration.5
CLINICAL STUDIES — In two identically-designed
randomized, double-blind trials in a total of 1522
patients ≥2 years old with mild (investigator’s static
global assessment [ISGA] score of 2) to moderate
(ISGA score of 3) atopic dermatitis, crisaborole 2%
ointment applied twice daily for 28 days was compared
to its vehicle alone. A significantly higher percentage
of patients using crisaborole achieved the primary
endpoint, an ISGA score at day 29 of 0 (clear) or 1
(almost clear) with a ≥2-grade improvement from
baseline, compared to those using the vehicle alone
(32.8% vs 25.4% in trial 1 and 31.4% vs 18.0% in trial 2).6
ADVERSE EFFECTS — The most common adverse
effect of crisaborole in the two clinical trials was
burning or stinging at the application site, mainly on
the first day of treatment. Contact urticaria occurred in
<1% of patients.
PREGNANCY AND LACTATION — There are no adequate

studies of crisaborole in pregnant or lactating women.
No adverse effects on embryofetal development were
observed in pregnant rabbits and rats administered
crisaborole orally at doses up to 3 and 5 times,
respectively, the maximum recommended human dose.
DOSAGE AND ADMINISTRATION — Eucrisa is available
in 60- and 100-g tubes. A thin layer of crisaborole 2%
ointment should be applied to the affected area twice
daily. Patients should be advised to wash their hands
immediately after applying the drug.
CONCLUSION — Crisaborole 2% ointment (Eucrisa)
appears to be modestly effective for short-term
treatment of mild to moderate atopic dermatitis. How
it compares in efficacy to topical corticosteroids or
calcineurin inhibitors remains to be established, and
its long-term efficacy and safety are unknown. ■


The Medical Letter

®

1. LF Eichenfield et al. Guidelines of care for the management of
atopic dermatitis: section 2. Management and treatment of
atopic dermatitis with topical therapies. J Am Acad Dermatol
2014; 71:116.
2. Drugs for allergic disorders. Treat Guidel Med Lett 2013; 11:43.
3. WW Carr. Topical calcineurin inhibitors for atopic dermatitis:
review and treatment recommendations. Paediatr Drugs 2013;
15:303.

4. K Jarnagin et al. Crisaborole topical ointment, 2%: a nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 inhibitor in
clinical development for the treatment of atopic dermatitis. J
Drugs Dermatol 2016; 15:390.
5. LT Zane et al. Crisaborole topical ointment, 2% in patients ages
2 to 17 years with atopic dermatitis: a phase 1b, open-label,
maximal-use systemic exposure study. Pediatr Dermatol 2016;
33:380.
6. AS Paller et al. Efficacy and safety of crisaborole ointment, a
novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for
the topical treatment of atopic dermatitis (AD) in children and
adults. J Am Acad Dermatol 2016; 75:494.

▶

Anticoagulation of Elderly
Patients at High Risk for Falls
with Atrial Fibrillation

With the widespread adoption of the CHA2DS2-VASc
scoring system,1 oral anticoagulation therapy is
now recommended for all patients ≥75 years old
with nonvalvular atrial fibrillation.2,3 Atrial fibrillation
has, however, been associated with an increased
risk of falls, and older patients starting warfarin for
atrial fibrillation have a high rate of hospitalization
for intracranial bleeding.4,5 Many practitioners are
reluctant, therefore, to prescribe an oral anticoagulant
for elderly patients who are at high risk for falls.
Most data on this subject come from patients who
were treated with warfarin. The newer direct oral

anticoagulants dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban
(Savaysa) have been shown to be at least as effective
as warfarin in preventing ischemic stroke or systemic
embolism in patients with nonvalvular atrial fibrillation
and less likely to cause intracranial bleeding.6,7
CLINICAL STUDIES — Warfarin – Three large studies
of warfarin anticoagulation offer some useful
information, but only one was conducted specifically
in elderly patients at high risk for falls, and only one
was randomized.
A chart review of 1245 elderly Medicare patients at high
risk for falls who were hospitalized with atrial fibrillation
(mean age 83.0) and 18,261 other patients hospitalized
with atrial fibrillation (mean age 79.3) examined the
risk of subsequent intracranial hemorrhage. About

Vol. 59 (1515)

February 27, 2017

33% of the patients at high risk for falls and 49% of the
other patients were treated with warfarin at the time of
hospital discharge. Patients at high risk for falls were
older and had more comorbidities. They had a higher
rate of intracranial hemorrhage than the other patients
(2.8 vs 1.1 per 100 patient-years), especially traumatic
intracranial hemorrhage (2.0 vs 0.34 per 100 patientyears), and they also had a higher rate of ischemic stroke
(13.7 vs 6.9 per 100 patient-years). The patients at high
risk for falls who were treated with warfarin and had risk
factors other than age had a lower risk of a composite

endpoint of out-of-hospital death or hospitalization
for stroke, myocardial infarction, or any hemorrhage
compared to those at high risk for falls who were not
treated with warfarin (HR 0.75; 95% CI 0.61-0.91).8
In a randomized trial in 973 patients ≥75 years old
with atrial fibrillation, warfarin (target INR 2-3) was
compared to aspirin 75 mg/day. After a mean followup of 2.7 years, there were 21 fatal or disabling strokes
(ischemic or hemorrhagic), two other intracranial
hemorrhages, and one systemic embolus in patients
taking warfarin, and 44 strokes, one other intracranial
hemorrhage, and three systemic emboli in those taking
aspirin. The annual risk of a primary event was 1.8%
with warfarin and 3.8% with aspirin.9
In the Swedish Atrial Fibrillation Cohort study, 90,706
patients who never took warfarin were compared to
68,306 patients who took the drug. The patients who
were not anticoagulated with warfarin were generally
older and more likely to have a history of previous
bleeding, dementia, or frequent falls. With the exception
of patients with a CHA2DS2-VASc score of 0 (low stroke
risk; no therapy preferred), the risk of ischemic stroke
without anticoagulant treatment was greater than the
risk of intracranial bleeding with anticoagulation.10
Low-Dose Apixaban – No randomized trial has
compared a direct oral anticoagulant with placebo
in elderly patients at high risk for falls with atrial
fibrillation. In a trial (ARISTOTLE) comparing apixaban
with warfarin in patients with atrial fibrillation, a
subgroup of 831 patients received a low dose of
apixaban (2.5 mg bid) approved by the FDA for use in

patients with at least two of the following risk factors:
≥80 years old; weight ≤60 kg; serum creatinine ≥1.5
mg/dL. In this subgroup, patients taking apixaban,
compared to those taking warfarin, had lower
incidences of stroke or systemic embolism (1.7% vs
3.3%) and major bleeding (3.3% vs 6.7%).11 None of the
other direct oral anticoagulants has an FDA-approved
lower dose for elderly patients.
35


The Medical Letter

®

CONCLUSION — No prospective randomized trial has
evaluated the risks and benefits of anticoagulation
in elderly patients at high risk for falls with atrial
fibrillation. Available data suggest that the benefits
may outweigh the risks. ■
1. Treatment of atrial fibrillation. Med Lett Drugs Ther 2014;
56:53.
2. CT January et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary:
a report of the American College of Cardiology/American Heart
Association Task Force on practice guidelines and the Heart
Rhythm Society. Circulation 2014; 130:2071.
3. P Kirchhof et al. 2016 ESC guidelines for the management of
atrial fibrillation developed in collaboration with EACTS. Rev
Esp Cardiol (Engl Ed) 2017; 70:50.
4. WT O’Neal et al. Effect of falls on frequency of atrial fibrillation

and mortality risk (from the REasons for Geographic and Racial
Differences in Stroke [REGARDS] Study). Am J Cardiol 2015;
116:1213.
5. JA Dodson et al. Incidence and determinants of traumatic intracranial bleeding among older veterans receiving warfarin for
atrial fibrillation. JAMA Cardiol 2016; 1:65.
6. Which oral anticoagulant for atrial fibrillation? Med Lett Drugs
Ther 2016; 58:45.
7. M Sharma et al. Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and
secondary prevention of venous thromboembolism: systematic review and meta-analysis. Circulation 2015; 132:194.
8. BF Gage et al. Incidence of intracranial hemorrhage in patients
with atrial fibrillation who are prone to fall. Am J Med 2005;
118:612.
9. J Mant et al. Warfarin versus aspirin for stroke prevention in
an elderly community population with atrial fibrillation (the
Birmingham Atrial Fibrillation Treatment of the Aged Study,
BAFTA): a randomised controlled trial. Lancet 2007; 370:493.
10. L Friberg et al. Net clinical benefit of warfarin in patients with
atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation 2012; 125:2298.
11. CB Granger et al. Apixaban versus warfarin in patients with
atrial fibrillation. N Engl J Med 2011; 365:981.

▶

Extended-Release Calcifediol
(Rayaldee) for Secondary
Hyperparathyroidism

The FDA has approved extended-release (ER)
calcifediol (25-hydroxyvitamin D3; Rayaldee –
Opko), a prohormone of calcitriol, the active form of

vitamin D3. It is indicated for treatment of secondary
hyperparathyroidism (SHPT) in adults with stage 3 or
4 chronic kidney disease (CKD) who have serum total
25-hydroxyvitamin D levels <30 ng/mL.
Pronunciation Key
Calcifediol: kal” sif e dye’ ol
Rayaldee: ray al’ dee

TREATMENT OF SHPT
— Secondary hyperparathyroidism is a common complication of CKD;
it develops in response to declining renal function,
impaired phosphate excretion, and the inability
36

February 27, 2017

Vol. 59 (1515)

Table 1. Pharmacology of ER Calcifediol
Class

Vitamin D3 analog

Mechanism of action

Conversion to calcitriol, which binds to
vitamin D receptors

Route

Oral

Formulation

30 mcg ER capsules

Metabolism

CYP27B1 to calcitriol; CYP24A1 to inactive
metabolites

Elimination half-life

~25 days in patients with stage 3 or 4 CKD

Excretion

Primarily biliary fecal route

of the kidneys to convert vitamin D to calcitriol
(1,25-dihydroxyvitamin D3). Reduced synthesis of
calcitriol leads to low levels of serum calcium and
elevated levels of serum phosphorus, which results in
increased parathyroid hormone (PTH) secretion.1
Nutritional (inactive) vitamin D is effective in repleting
vitamin D stores, but it is inferior to calcitriol and other
active vitamin D analogs (see Table 2) in reducing PTH
levels. Calcimimetic agents increase sensitivity of
calcium-sensing receptors on the parathyroid gland
to extracellular calcium, decreasing PTH and serum

calcium levels. Cinacalcet (Sensipar) is FDA-approved
for oral treatment of SHPT in patients with CKD on
dialysis.2 Etelcalcetide (Parsabiv), an IV calcimimetic
agent, was recently approved by the FDA for the same
indication; it will be reviewed in a future issue.
Whether reductions in PTH levels decrease
cardiovascular risk, bone fractures, and mortality in
patients with CKD remains to be established.3,4 When
SHPT fails to respond to pharmacologic therapy,
parathyroidectomy may be considered.
PHARMACOKINETICS — Even though calcifediol is a
prodrug of calcitriol, the ER formulation may be more
effective than calcitriol itself in lowering PTH levels
because the slower rise in calcitriol levels causes
less induction of the catabolic enzyme that degrades
calcitriol.5
CLINICAL STUDIES — Approval of ER calcifediol was
based on the results of two similarly designed, doubleblind trials in a total of 429 patients with stage 3 or
4 CKD who had SHPT and vitamin D insufficiency.6
Patients were randomized to take ER calcifediol or
placebo once daily for 26 weeks. The percentage
of patients who achieved a mean reduction of ≥30%
from baseline in plasma intact parathyroid hormone
(iPTH) during weeks 20-26, the primary endpoint,
was significantly higher with ER calcifediol than
with placebo in both trials (33% vs 8% in trial 1 and
34% vs 7% in trial 2). Serum total 25-hydroxyvitamin D


The Medical Letter

®

Vol. 59 (1515)

February 27, 2017

Table 2. Some Vitamin D Analogs for SHPT
Drug

Some Available Formulations

Initial Adult Oral Dosage

Cost1

Inactive
Cholecalciferol (vitamin D3) – generic
Ergocalciferol (vitamin D2) – generic

1000 IU tabs
50,000 IU caps

1000 IU/d
50,000 IU/wk

$0.50
2.40

Calcifediol ER − Rayaldee (Opko)

Calcitriol − generic
Rocaltrol (Validus)
Paricalcitol − generic
Zemplar (Abbvie)

30 mcg ER caps
0.25, 0.5 mcg caps;
1 mcg/mL PO soln
1, 2 mcg caps; 2, 5 mcg/mL
IV soln

30 mcg once/d at bedtime2
0.25 mcg once/d3

Doxercalciferol − generic
Hectorol (Genzyme)

0.5, 1, 2.5 mcg caps; 2 mcg/mL,
4 mcg/2 mL IV soln

Active

Baseline iPTH:
≤500 pg/mL: 1 mcg once/d or 2 mcg 3x/wk4,5
>500 pg/mL: 2 mcg once/d or 4 mcg 3x/wk4,5
1 mcg once/d7

928.00
30.70
42.70

152.406
390.306
736.50
872.10

ER = extended release; iPTH = intact parathyroid hormone; SHPT = secondary hyperparathyroidism; soln = solution
1. Approximate WAC cost for 30 days’ treatment at the lowest initial adult oral 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. February
5, 2017. Reprinted with permission by First Databank, Inc. All rights reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.
2. Serum calcium level should be <9.8 mg/dL before starting treatment with calcifediol. After 3 months, the dosage can be increased to 60 mcg once/d if iPTH is
above treatment goal and if serum calcium is <9.8 mg/dL, phosphorus is <5.5 mg/dL, and total 25-hydroxyvitamin D is <100 ng/mL. Monitor serum calcium,
phosphorus, total 25-hydroxyvitamin D, and iPTH levels 3 months after initiating therapy or changing dosage and every 6-12 months thereafter.
3. Dosage for predialysis patients. Can be increased to 0.5 mcg daily if necessary. Serum calcium levels should be checked twice weekly during the titration
period, then monthly once the optimal dosage has been determined.
4. Dosage for patients with stage 3 or 4 CKD. Thrice-weekly regimens should not be administered more frequently than every other day.
5. If iPTH levels relative to baseline remain unchanged or increase or decrease by <30%, the initial dosage should be increased by 1 mcg daily (or 2 mcg 3x/wk) at 2-4
week intervals. If iPTH levels relative to baseline decrease by >60% or if iPTH is <60 pg/mL, the initial dosage should be decreased by 1 mcg daily (or 2 mcg 3x/wk).
6. Cost based on dosage of 1 mcg once/d. A dosage of 2 mcg once/d costs $332.20 for the generic formulation and $780.60 for Zemplar.
7. Dosage for predialysis patients. The dose can be increased by 0.5 mcg every 2 weeks to reach target levels of iPTH, as summarized in the package insert.
Maximum dosage is 3.5 mcg once/d.

concentrations ≥30 ng/mL occurred in 80% and 83% of
patients taking ER calcifediol compared to 3% and 7%
of those taking placebo.
ADVERSE EFFECTS — Among patients taking ER
calcifediol in the clinical trials, 2% developed hypercalcemia and 0.4% developed hyperphosphatemia,
compared to none of those taking placebo. Adverse
reactions that occurred in at least 4% of patients treated
with ER calcifediol and more frequently than with
placebo were anemia (4.9% vs 3.5%), nasopharyngitis

(4.9% vs 2.8%), increased serum creatinine (4.9% vs
1.4%), and dyspnea (4.2% vs 2.8%).
DRUG INTERACTIONS — Coadministration of thiazide
diuretics, which reduce excretion of calcium in the
urine, and ER calcifediol may cause hypercalcemia.
Cholestyramine may reduce the absorption of ER
calcifediol. Phenobarbital and other anticonvulsants
can reduce plasma concentrations of ER calcifediol
by increasing its metabolism. Strong CYP3A
inhibitors may inhibit enzymes involved in vitamin
D metabolism, and may alter serum levels of ER
calcifediol.7 Patients taking ER calcifediol with
digoxin (Lanoxin, and others) should be monitored for
high serum calcium levels because hypercalcemia
increases the risk of digitalis toxicity.
PREGNANCY AND LACTATION — There are no adequate
studies of ER calcifediol in pregnant women. Teratogenic
effects were seen in rabbits given calcifediol at doses

equivalent to 8-16 times the human dose of 60 mcg/
day. The drug was not teratogenic in rabbits at a dose
of 5 mcg/kg/day or in rats at doses ≤60 mcg/kg/day.
Limited evidence suggests that calcifediol is poorly
excreted in breast milk.
CONCLUSION
—
Extended-release
calcifediol
(Rayaldee) can lower concentrations of parathyroid
hormone and correct vitamin D insufficiency in adults

with secondary hyperparathyroidism and stage 3
or 4 chronic kidney disease (CKD). It has not been
compared to other vitamin D analogs that cost much
less. Randomized, controlled trials showing that any of
these drugs improve morbidity or decrease mortality in
patients with CKD are lacking. ■
1. J Cunningham et al. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J
Am Soc Nephrol 2011; 6:913.
2. Cinacalcet (Sensipar). Med Lett Drugs Ther 2004; 46:80.
3. SN Salam et al. Pharmacological management of secondary
hyperparathyroidism in patients with chronic kidney diseases.
Drugs 2016; 76:841.
4. H Komaba et al. Management of secondary hyperparathyroidism: how and why? Clin Exp Nephrol 2017 Jan 2 (epub).
5. M Petkovich et al. Modified-release oral calcifediol corrects
vitamin D insufficiency with minimal CYP24A1 upregulation. J
Steroid Biochem Mol Biol 2015; 148:283.
6. SM Sprague et al. Use of extended-release calcifediol to treat
secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease. Am J Nephrol 2016; 44:316.
7. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2016 Aug 2 (epub). Available at: secure.
medicalletter.org/downloads/CYP_PGP_Tables.pdf. Accessed
February 16, 2017.

37


The Medical Letter

▶

Vol. 59 (1515)

®

Kyleena – Another Hormonal IUD

The FDA has approved Kyleena (Bayer), an intrauterine
device (IUD) that releases the synthetic progestin
levonorgestrel, for prevention of pregnancy. It is the
fourth levonorgestrel-releasing IUD to be approved in
the US. Like Mirena, which has been available since
2000, Kyleena is approved for up to 5 years of use.
Pronunciation Key
Levonorgestrel: lee" voe nor jes' trel Kyleena: kye lee’ nah

IUDs — IUDs provide convenient, long-term contraception and a rapid return to fertility after removal;
they are considered safe for use in most women,
including adolescents and nulliparous women.1 All
levonorgestrel-releasing IUDs, which are approved for
3 or 5 years of use, can reduce menstrual bleeding and
dysmenorrhea. Amenorrhea can occur, especially with
devices that contain more levonorgestrel.2 ParaGard
T380A, a copper-containing IUD, is FDA-approved for
up to 10 years of use.
THE NEW DEVICE — Kyleena has a 30x28-mm T-shaped
polyethylene frame with a drug reservoir containing 19.5
mg of levonorgestrel. It is the same size as Skyla3 and
smaller than Mirena and Liletta,4 which are both 32x32
mm. Kyleena is packaged with an inserter device that
is narrower than the Mirena inserter (3.8 vs 4.4 mm).

The release rate of levonorgestrel from Kyleena into
the uterine cavity is about 17.5 mcg/day after 24 days;

February 27, 2017

it gradually declines to 9 mcg/day after 1 year and 7.4
mcg/day after 5 years. Unlike Mirena, Kyleena and other
levonorgestrel-releasing IUDs do not have restrictions in
their labeling that limit use to women who have had at
least one child.
MECHANISM OF ACTION — The mechanism by which
levonorgestrel produces a contraceptive effect has not
been conclusively established. Local progestogenic effects that interfere with conception include thickening
of the cervical mucus, inhibition of sperm capacitation,
and changes in the endometrial lining. The device itself
causes inflammatory changes in the endometrium that
can affect sperm survival and impair implantation.
CLINICAL STUDY — In an unpublished, open-label
trial, 1452 women 18-35 years old (40% nulliparous)
received the Kyleena IUD. The results of the trial
are summarized in the package insert. The primary
endpoint was the pregnancy rate calculated as the
Pearl Index (number of pregnancies per 100 womanyears). A total of 870 women (60%) completed 3 years
of the trial. Among 707 patients (49%) who enrolled in
an extension phase, 550 (38%) completed 5 years of
use. The annual pregnancy rates for years 1-5 were
0.16, 0.38, 0.45, 0.15, and 0.37, respectively. The 5-year
estimated cumulative pregnancy rate was 1.45. About
71% of 163 women who desired to become pregnant
after stopping the trial conceived within 12 months of

removing the device.

Table 1. Comparison of Intrauterine Devices (IUDs)
IUD

Duration
of Use1

Pregnancy
Rate2

LNG
Content

10 years

0.84

None

▶ Nonhormonal

▶ Irregular/heavy bleeding $739.00
and dysmenorrhea
▶ Lack of protection against
STIs

▶ Decreased menstrual
bleeding and
dysmenorrhea

▶ Amenorrhea after one
year in 6% with Skyla,
in 12% with Kyleena,
in 19% with Liletta, and
in 20% with Mirena
▶ Smaller T-frame and
narrower insertion
tube with Kyleena and
Skyla

▶ Irregular bleeding in first
3-6 months
▶ Progestin-related
adverse effects such as
headache, nausea, and
acne
▶ Ovarian cysts
▶ Lack of protection
against STIs

Some Advantages

Some Disadvantages

Cost3

Copper-Containing IUD
ParaGard T380A
(Teva Women’s Health)

Levonorgestrel-Releasing IUDs
Kyleena (Bayer)

5 years

0.16

19.5 mg

Liletta
(Allergan/Actavis)

3 years

0.15

52 mg

Mirena (Bayer)5

5 years

0.2

52 mg

Skyla (Bayer)

3 years

0.4

13.5 mg

858.30

684.40

858.30

714.70

LNG = levonorgestrel; STIs = sexually transmitted infections
1. FDA-approved maximum duration of use.
2. Pearl Index (number of pregnancies per 100 woman-years) for the first year of use, according to results of clinical trials summarized in the package insert for
each IUD product.
3. Approximate WAC for one IUD. Cost of insertion not included. 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. February 5, 2017. Reprinted with
permission by First Databank, Inc. All rights reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.
4. Percent unintended pregnancy during first year of use. Source: J Trussel in RA Hatcher et al. Contraceptive Technology, 20th ed. revised, New York, NY: Ardent
Media, 2011.
5. According to the FDA-approved labeling, Mirena is recommended only for women who have had at least one child.

38


The Medical Letter

®

ADVERSE EFFECTS — The most common adverse
effects reported in Kyleena users were vulvovaginitis
(24%), ovarian cysts (22%), abdominal/pelvic pain
(21%), headache/migraine (15%), acne/seborrhea
(15%), dysmenorrhea/uterine spasm (10%), breast
pain or discomfort (10%), and increased bleeding (8%).
Women using Kyleena can experience altered bleeding
patterns, especially during the first 3-6 months after
insertion. Amenorrhea developed in 12%, 20%, and 23%
of patients by the end of years 1, 3, and 5, respectively.
Uterine perforation can occur during insertion of
Kyleena and may not be detected until a later date.
During clinical trials, the incidence of perforation
was <0.1%. A systematic review of IUD safety found
an increased risk of uterine perforation among
breastfeeding women.5 Severe infection or sepsis,
including Group A streptococcal sepsis, and pelvic
inflammatory disease have been reported rarely
following insertion of levonorgestrel-releasing IUDs.
Partial or complete expulsion of the device can occur;
in Kyleena clinical trials, the 5-year expulsion rate was
3.5%. The risk of expulsion is higher when the device is
placed immediately postpartum.
If an intrauterine pregnancy occurs with Kyleena in
place, the device should be removed; failure to remove
it could result in miscarriage, sepsis, or premature
labor and delivery. About 50% of pregnancies that
occur with Kyleena in place are likely to be ectopic.
In Kyleena clinical trials, the incidence of ectopic
pregnancy was 0.2% per year.

TIMING OF INSERTION — Pregnancy must be ruled
out before inserting an IUD. The manufacturer of
Kyleena recommends insertion of the IUD within 7
days of the start of the menstrual cycle or immediately
after a first-trimester abortion. Postpartum insertion
and insertion following a second-trimester abortion
should be postponed for a minimum of six weeks or
until the uterus is fully involuted to reduce the risk of
expulsion.
Practice guidelines generally recommend abstaining
from sexual intercourse or using backup contraception
for 7 days after insertion of a levonorgestrel-releasing
IUD unless the device is inserted within 7 days of the
start of menstrual bleeding.6
CONCLUSION — Kyleena, a new levonorgestrelreleasing intrauterine device (IUD), provides effective
contraception for at least 5 years. It is smaller in size
and contains less levonorgestrel than the Mirena IUD. ■

Vol. 59 (1515)

February 27, 2017

1. KM Curtis and JF Peipert. Long-acting reversible contraception.
N Engl J Med 2017; 376:461.
2. Choice of contraceptives. Med Lett Drugs Ther 2015; 57:127.
3. A new low-dose levonorgestrel-releasing IUD (Skyla). Med Lett
Drugs Ther 2013; 55:21.
4. Liletta – a third levonorgestrel-releasing IUD. Med Lett Drugs
Ther 2015; 57:99.
5. EN Berry-Bibee et al. The safety of intrauterine devices in

breastfeeding women: a systematic review. Contraception
2016; 94:725.
6. KM Curtis et al. U.S. selected practice recommendations for
contraceptive use, 2016. MMWR Recomm Rep 2016; 65:1.

Drug Interaction: Clopidogrel and PPIs
The antiplatelet drug clopidogrel (Plavix, and others)
reduces major cardiovascular events, but can cause
bleeding. Proton pump inhibitors (PPIs) are often
used with clopidogrel to prevent gastrointestinal
bleeding, however, some evidence suggests that PPIs
may interfere with the activation of clopidogrel and
diminish its antiplatelet effect.1 FDA-approved labeling
recommends avoiding concurrent use of the PPIs
omeprazole and esomeprazole with clopidogrel.
Table 1. Oral Proton Pump Inhibitors
Drug

Usual
Adult Dosage1,2

Cost3

Dexlansoprazole – Dexilant (Takeda)

30-60 mg once/d

$244.10

Esomeprazole magnesium – generic

Nexium (AstraZeneca)
Nexium 24HR (OTC) (Pfizer)

20-40 mg once/d

140.40
250.90
17.904

Lansoprazole – generic
Prevacid (Takeda)
Prevacid Solutab (Takeda)
Prevacid 24HR (OTC)5 (GSK)

15-30 mg once/d

29.10
415.10
415.10
18.504

Omeprazole – generic
Prilosec OTC 5 (AstraZeneca/P&G)

20-40 mg once/d

11.80
16.804

Omeprazole/sodium bicarbonate6 –

generic
Zegerid (Salix)
Zegerid OTC5 (Bayer)

20-40 mg once/d

Pantoprazole – generic
Protonix (Pfizer)

40 mg once/d

6.00
359.40

Rabeprazole – generic
Aciphex (Eisai)
Aciphex Sprinkle (Eisai)

20 mg once/d

48.60
524.70
450.007

2528.10
3033.80
16.104

OTC = over the counter
1. The lower end of the range is generally used for initial treatment of GERD.

Higher or more frequent doses may be needed for patients with erosive
esophagitis, peptic ulcer disease, hypersecretory conditions such as
Zollinger-Ellison syndrome, or for treatment of Helicobacter pylori infection.
2. PPIs are generally taken 30-60 minutes before the first meal of the day.
Taking one before the evening meal or taking the drug twice daily may be
more effective for nocturnal acid control. PPIs should generally be swallowed
whole and should not be crushed or chewed. Omeprazole/sodium bicarbonate (Zegerid) should be taken on an empty stomach at least 1 hour before a
meal. Dexlansoprazole (Dexilant) can be taken with or without food.
3. Approximate WAC for 30 days’ treatment with 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.
February 5, 2017. Reprinted with permission by First Databank, Inc. All rights
reserved. ©2017. www.fdbhealth.com/policies/drug-pricing-policy.
4. Approximate cost for 28 tablets or capsules.
5. Also available generically.
6. Immediate-release formulation that contains sodium bicarbonate as a
buffer; it should be used with caution in patients on a low-sodium diet.
7. Approximate cost for 5-mg sprinkle capsules.

39


The Medical Letter

®

POSSIBLE MECHANISM — Clopidogrel is a prodrug; the
CYP2C19 isozyme appears to be mainly responsible
for its bioactivation.2 Concurrent use of clopidogrel and

drugs that inhibit CYP2C19 could inhibit conversion
of clopidogrel to its active form. Among the PPIs,
omeprazole and esomeprazole appear to be the
strongest inhibitors of CYP2C19 and pantoprazole
appears to be the weakest.3,4
CLINICAL STUDIES — Some pharmacodynamic and
pharmacokinetic studies have reported reductions
in platelet inhibition and the AUC of the clopidogrel
active metabolite in patients taking clopidogrel with
omeprazole or esomeprazole. Similar effects were
not reported with pantoprazole, lansoprazole, or
dexlansoprazole.5-8
Whether concurrent use of clopidogrel and PPIs
results in clinically significant adverse cardiovascular
outcomes is not clear. The results of several (mostly
observational) studies have been inconsistent.9,10
In a case-control study in patients ≥66 years old
who were started on clopidogrel after an acute MI,
concurrent use of a PPI (other than pantoprazole)
was associated with an increased risk of recurrent
MI within 90 days.11 In a retrospective cohort study
in 8205 patients with acute coronary syndrome
(ACS), use of a PPI with clopidogrel after hospital
discharge was associated with a higher risk of death
or rehospitalization due to ACS.12
In a retrospective cohort study of patients who were
prescribed clopidogrel after hospitalization for acute
MI, coronary artery revascularization, or unstable
angina, concurrent use of a PPI was not associated
with a statistically significant increased risk of

serious cardiovascular disease.13
In a randomized, placebo-controlled trial (COGENT),
use of omeprazole in patients taking clopidogrel
and aspirin decreased the incidence of GI bleeding
without increasing the risk of a cardiovascular event.14
The FDA concluded, however, that because of study
design limitations and a low number of reported
cardiovascular events, the results do not prove that
concurrent use of clopidogrel and omeprazole is safe.15
In addition, the fixed-dose combination of omeprazole
and clopidogrel used in the trial was specifically
developed to delay absorption of omeprazole in order
to minimize an interaction.16
Some studies have suggested that PPI use is a
confounder associated with, rather than the cause of,
adverse cardiovascular outcomes in patients taking
clopidogrel.17,18
CONCLUSION — Concurrent use of clopidogrel and a
proton pump inhibitor (PPI) may result in decreased
levels of the clopidogrel active metabolite, and possibly
its antiplatelet activity, but whether it results in

40

Vol. 59 (1515)

February 27, 2017

clinically significant adverse cardiovascular outcomes
is not clear. Since omeprazole and esomeprazole

appear to be most likely to affect the antiplatelet
activity of clopidogrel and the FDA specifically warns
against their concomitant use, it would be reasonable
to use another PPI such as pantoprazole in patients
taking clopidogrel. ■
1. NS Abraham et al. ACCF/ACG/AHA 2010 expert consensus
document on the concomitant use of proton pump inhibitors and
thienopyridines: a focused update of the ACCF/ACG/AHA 2008
expert consensus document on reducing the gastrointestinal
risks of antiplatelet therapy and NSAID use. A Report of the
American College of Cardiology Foundation Task Force on Expert
Consensus Documents. J Am Coll Cardiol 2010; 56:2051.
2. JL Mega et al. Cytochrome P-450 polymorphisms and response
to clopidogrel. N Engl J Med 2009; 360:354.
3. T Zvyaga et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome
P450 2C19. Drug Metab Dispos 2012; 40:1698.
4. RS Wedemeyer and H Blume. Pharmacokinetic drug interaction
profiles of proton pump inhibitors: an update. Drug Saf 2014;
37:201.
5. AL Frelinger 3rd et al. A randomized, 2-period, crossover
design study to assess the effects of dexlansoprazole,
lansoprazole, esomeprazole, and omeprazole on the steadystate pharmacokinetics and pharmacodynamics of clopidogrel in
healthy volunteers. J Am Coll Cardiol 2012; 59:1304.
6. JM Siller-Matula et al. Effects of pantoprazole and esomeprazole on
platelet inhibition by clopidogrel. Am Heart J 2009;157:148.e1.
7. DJ Angiolillo et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of
clopidogrel in healthy subjects: randomized, placebo-controlled,
crossover comparison studies. Clin Pharmacol Ther 2011; 89:65.
8. N Simon et al. Omeprazole, pantoprazole, and CYP2C19 effects
on clopidogrel pharmacokinetic-pharmacodynamic relationships

in stable coronary artery disease patients. Eur J Clin Pharmacol
2015; 71:1059.
9. SA Scott et al. Antiplatelet drug interactions with proton pump
inhibitors. Expert Opin Drug Metab Toxicol 2014; 10:175.
10. SD Bouziana and K Tziomalos. Clinical relevance of clopidogrelproton pump inhibitors interaction. World J Gastrointest
Pharmacol Ther 2015; 6:17.
11. DN Juurlink et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;
180:713.
12. PM Ho et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following
acute coronary syndrome. JAMA 2009; 301:937.
13. WA Ray et al. Outcomes with concurrent use of clopidogrel and
proton pump inhibitors: a cohort study. Ann Intern Med 2010;
152:337.
14. DL Bhatt et al. Clopidogrel with or without omeprazole in coronary
artery disease. N Engl J Med 2010; 363:1909.
15. MR Southworth and R Temple. Interaction of clopidogrel and
omeprazole. N Engl J Med 2010; 363:1977.
16. DN Juurlink. Comment on: Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2011; 364:681.
17. SP Dunn et al. Impact of proton pump inhibitor therapy on the efficacy of clopidogrel in the CAPRIE and CREDO trials. J Am Heart
Assoc 2013; 2:e004564.
18. SG Goodman et al. Association of proton pump inhibitor use on
cardiovascular outcomes with clopidogrel and ticagrelor. Circulation 2012; 125:978.

Online Only Article
Atezolizumab (Tecentriq) for Bladder Cancer and NSCLC
www.medicalletter.org/TML-article-1515g


The Medical Letter

®

on Drugs and Therapeutics

Volume 59 (Issue 1515)

▶

February 27, 2017

Atezolizumab (Tecentriq) for
Bladder Cancer and NSCLC

The FDA has approved the immune checkpoint
inhibitor atezolizumab (Tecentriq – Genentech) for
treatment of locally advanced or metastatic urothelial
carcinoma and metastatic non-small cell lung cancer
(NSCLC) that have progressed during or following
platinum-based chemotherapy. Atezolizumab is the
first programmed death-ligand 1 (PD-L1) blocking
antibody to become available in the US. Two other
immune checkpoint inhibitors, the programmed death
receptor-1 (PD-1) inhibitors nivolumab (Opdivo) and
pembrolizumab (Keytruda), are also approved for
treatment of metastatic NSCLC, and nivolumab is
also approved for second-line treatment of locally
advanced or metastatic urothelial carcinoma.
Pronunciation Key
Atezolizumab: a” te zoe liz’ ue mab Tecentriq: te sen' trik
Table 1. Immune Checkpoint Inhibitors for Bladder Cancer and NSCLC

Drug
PD-1 Inhibitors
Nivolumab –
Opdivo (BMS)
Pembrolizumab –
Keytruda (Merck)

Usual Adult Dosage

Cost1

Bladder Cancer2:
240 mg IV q2 wks
NSCLC3,4: 240 mg IV q2 wks

$12,036.20
12,036.20

NSCLC4,5: 200 mg IV q3 wks

8893.00

PD-L1 Inhibitor
Atezolizumab –
Bladder Cancer2:
Tecentriq (Genentech) 1200 mg IV q 3wks
NSCLC3,4: 1200 mg IV q3wks

8620.00
8620.00

NSCLC = non-small cell lung cancer
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. February 5, 2017. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2017. www.
fdbhealth.com/policies/drug-pricing-policy.
2. FDA-approved for locally advanced or metastatic urothelial carcinoma
that has progressed during or following platinum-based chemotherapy
or within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy.
3. FDA-approved for metastatic NSCLC with disease progression on or after
platinum-based chemotherapy.
4. Patients with EGFR or ALK genomic tumor aberrations should receive
treatment with drugs specific for these aberrations before receiving a
PD-1 or PD-L1 inhibitor.
5. FDA-approved for first-line treatment of metastatic NSCLC with PDL1 expression on ≥50% of tumor cells and no EGFR or ALK genomic
tumor aberrations, and metastatic NSCLC with PD-L1 expression on
≥1% of tumor cells and disease progression on or after platinum-based
chemotherapy.

UROTHELIAL CARCINOMA — Urothelial carcinoma
(also known as transitional cell carcinoma) is the
most common type of bladder cancer in the US.
Most urothelial cancers of the bladder are superficial
and involve only the mucosa or submucosa with no
muscular invasion. Standard initial treatment for these
cancers is transurethral resection with or without
intravesical therapy (chemotherapy or BCG). About
10-15% of patients with superficial urothelial cancer
will develop muscle-invasive or metastatic disease.

The standard treatment for these invasive cancers is
radical cystectomy and platinum-based chemotherapy.1
Few options are available for treatment of metastatic
urothelial cancer that has progressed after platinumbased chemotherapy, and none have improved survival.2
NSCLC — Standard initial treatment for patients with
metastatic NSCLC with no epidermal growth factor
receptor (EGFR) mutations or anaplastic lymphoma
kinase (ALK) translocations is generally platinum
doublet therapy (a two-drug regimen that includes a
platinum derivative such as carboplatin or cisplatin).3
If the disease progresses after platinum doublet
therapy, nivolumab or pembrolizumab can be used.
MECHANISM OF ACTION — Binding of PD-L1 to its
receptors on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and
cytokine production. Atezolizumab is a humanized IgG1
monoclonal antibody that binds to PD-L1 on tumor cells,
preventing the ligand from interacting with its receptors
and permitting the antitumor immune response.
CLINICAL STUDIES — Urothelial Carcinoma – FDA
approval of atezolizumab for urothelial carcinoma
was based on the results of a single-arm trial in 310
patients with inoperable locally advanced or metastatic
urothelial cancer who had disease progression after a
platinum-based regimen. All patients were treated with
atezolizumab 1200 mg IV once every 3 weeks. The objective response rate (ORR), the primary endpoint, was 15%
(compared to a historical control ORR of 10% for secondline therapy). Increased PD-L1 expression on immune
cells was associated with an increased response.4
In a single-arm trial in 119 cisplatin-ineligible patients
with locally advanced or metastatic urothelial cancer
e40

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


The Medical Letter

®

treated with atezolizumab first line, the ORR was
23% and the complete response rate was 9%. Median
progression-free survival was 2.7 months and median
overall survival was 15.9 months. Responses occurred
across all subgroups of PD-L1 expression.5
NSCLC — Approval of atezolizumab for NSCLC was
based on the results of two open-label trials (OAK and
POPLAR) in a total of 1137 patients with metastatic
NSCLC that had progressed after platinum-based
chemotherapy. In both trials, patients were randomized
to receive either docetaxel 75 mg/m2 or atezolizumab
1200 mg IV once every 3 weeks. Median overall survival
was significantly longer with atezolizumab than with
docetaxel (13.8 months vs 9.6 months in the OAK trial
and 12.6 months vs 9.7 months in the POPLAR trial). In
the POPLAR trial, improvement correlated with PD-L1
expression; in the OAK trial, it did not.6,7
ADVERSE EFFECTS — As with the other immune
checkpoint inhibitors, the complication rates with
atezolizumab have been relatively low, compared
to chemotherapy. Immune-related adverse effects
including pneumonitis, hepatitis, colitis, thyroid

disorders, type 1 diabetes, pancreatitis, and
myocarditis have occurred rarely with these drugs.
Life-threatening infection can occur. More common
adverse effects of atezolizumab have included fatigue,
decreased appetite, nausea, urinary tract infection,
pyrexia, constipation, dyspnea, and musculoskeletal
pain. Infusion-related reactions have occurred in
about 1-2% of patients.
PREGNANCY AND LACTATION — Atezolizumab has
not been studied in pregnant women. Animal studies
have found that inhibition of the PD-L1/PD-1 pathway
increases the risk of immune-related rejection of the
fetus, resulting in fetal death. Women of childbearing
age should use contraception during treatment and for
at least 5 months after the last dose.
No information is available on the effects of
atezolizumab on lactating mothers or breastfed
infants. Since human IgG is excreted in breast milk,
patients are advised not to breastfeed during treatment
and for at least 5 months after the last dose.
DOSAGE AND ADMINISTRATION — Tecentriq is
available in 1200 mg/20 mL single-use vials. The
recommended dosage for treatment of locally
advanced or metastatic urothelial carcinoma or
metastatic NSCLC is 1200 mg infused IV over 60
minutes every 3 weeks until disease progression or
unacceptable toxicity occurs. Subsequent infusions
e41

Vol. 59 (1515)

February 27, 2017

can be administered over 30 minutes. In patients
who experience severe adverse effects, atezolizumab
should be withheld until improvement occurs; dosage
reductions are not recommended. It should be
discontinued permanently in patients who have severe
(grade 3-4) infusion-related reactions.
CONCLUSION — Atezolizumab (Tecentriq), an immune
checkpoint inhibitor and the first programmed deathligand 1 (PD-L1) blocking antibody to be approved
in the US, has produced responses in patients with
locally advanced or metastatic urothelial carcinoma
previously treated with platinum-based chemotherapy,
but whether it improves survival in these patients
remains to be determined. It has improved overall
survival, compared to docetaxel, in patients with
metastatic non-small cell lung cancer (NSCLC)
whose disease progressed following platinum-based
chemotherapy. Serious adverse effects can occur with
atezolizumab, but the rate of these complications,
compared to chemotherapy, has been relatively low.
How atezolizumab compares to nivolumab (Opdivo)
and pembrolizumab (Keytruda) in efficacy and safety
remains to be established. ■
1. M Hurwitz et al. Urothelial and kidney cancers. Oncology
2016 June 1. Available at www.cancernetwork.com/cancermanagement/urothelial-and-kidney-cancers. Accessed February 16, 2017.
2. PJ Cheetham and DP Petrylak. New agents for the treatment
of advanced bladder cancer. Oncology (Williston Park) 2016;
30:571.

3. GA Masters et al. Systemic therapy for stage IV non-small-cell
lung cancer: American Society of Clinical Oncology Clinical
Practice Guideline Update. J Clin Oncol 2015: 33:3488.
4. JE Rosenberg et al. Atezolizumab in patients with locally
advanced and metastatic urothelial carcinoma who have
progressed following treatment with platinum-based
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet
2016; 387:1909.
5. AV Balar et al. Atezolizumab as first-line treatment in cisplatinineligible patients with locally advanced and metastatic
urothelial carcinoma: a single-arm, multicentre, phase 2 trial.
Lancet 2017; 389:67.
6. A Rittmeyer et al. Atezolizumab versus docetaxel in patients
with previously treated non-small-cell lung cancer (OAK): a
phase 3, open-label, multicentre randomised controlled trial.
Lancet 2017; 389:255.
7. L Fehrenbacher et al. Atezolizumab versus docetaxel for
patients with previously treated non-small-cell lung cancer
(POPLAR): a multicentre, open-label, phase 2 randomised
controlled trial. Lancet 2016; 387:1837.


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Discuss the return of Auvi-Q to the market and describe how it compares to other available epinephrine auto-injectors in terms of ease of use and cost.
Review the efficacy and safety of crisaborole (Eucrisa) for topical treatment of atopic dermatitis.
Discuss the benefits and risks of oral anticoagulant therapy in elderly patients at high risk for falls with atrial fibrillation.
Review the efficacy and safety of extended-release calcifediol (Rayaldee) for treatment of secondary hyperparathyroidism.
Review the efficacy and safety of Kyleena, a new 5-year levonorgestrel-releasing IUD, for prevention of pregnancy and describe how it compares to other available IUDs.
Describe the evidence supporting a potential interaction between clopidogrel (Plavix, and others) and PPIs.

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Questions start on next page


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Online Continuing Medical Education
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Issue 1515 Questions
(Correspond to questions #41-50 in Comprehensive Exam #76, available July 2017)
6. The low dose of apixaban that is recommended for use in some elderly
patients:
a. is more effective than placebo in preventing ischemic stroke in
elderly patients with atrial fibrillation
b. is as effective as other direct oral anticoagulants in preventing
ischemic stroke in patients with atrial fibrillation
c. is more effective than warfarin in preventing stroke or systemic
embolism in elderly patients with atrial fibrillation
d. all of the above

Auvi-Q Epinephrine Auto-Injector Returns
1. The Auvi-Q auto-injector includes which of the following features?
a. an automatic needle retraction system
b. step-by-step audio instructions
c. a 5-second audio countdown during injection
d. all of the above
Crisaborole (Eucrisa) for Atopic Dermatitis
2. Crisaborole is:
a. a corticosteroid
b. a calcineurin inhibitor
c. a phosphodiesterase type-4 inhibitor
d. an emollient

Extended-Release Calcifediol (Rayaldee) for Secondary Hyperparathyroidism

3. A 22-year-old woman with mild to moderate atopic dermatitis affecting
her cheeks, chin, and the intertriginous areas of her arms and legs seeks
your advice about the best treatment. She is very concerned about
developing skin atrophy on her face, which she has heard is a side effect
of topical corticosteroids. You could tell her that:
a. crisaborole has been shown to be more effective than topical
corticosteroids
b. tacrolimus and pimecrolimus are similar in efficacy to low- to
medium-potency topical corticosteroids and do not cause skin
atrophy
c. crisaborole has been shown to be safe for long-term use
d. tacrolimus and pimecrolimus have been shown to be safe for longterm use
Anticoagulation of Elderly Patients at High Risk for Falls with Atrial Fibrillation
4. Which of the following is true?

a. oral anticoagulation is recommended for all patients ≥75 years old
with nonvalvular atrial fibrillation
b. atrial fibrillation has been associated with an increased risk of falls
c. older patients starting warfarin for atrial fibrillation have a high rate
of hospitalization for intracranial bleeding
d. all of the above
5. An 82-year-old man with diabetes, atrial fibrillation, and a history of
several falls in the past year is wondering whether he should take an
anticoagulant. You could tell him that:
a. everyone with nonvalvular atrial fibrillation should take an
anticoagulant
b. the latest guidelines recommend not anticoagulating patients >80
years old
c. he should not take an anticoagulant because he is at risk for falls
d. a study in Medicare patients with atrial fibrillation and a high risk for
falls found that those with risk factors other than age who took
warfarin had a lower risk of death, stroke, MI, or any hemorrhage

7. Calcifediol is:
a. a prohormone of calcitriol
b. a calcimimetic agent
c. an inactive form of vitamin D
d. all of the above
8. In clinical trials in patients with stage 3 or 4 chronic kidney disease,
secondary hyperparathyroidism, and vitamin D insufficiency, ER calcifediol:
a. reduced parathyroid hormone levels, but did not correct vitamin D
insufficiency
b. corrected vitamin D insufficiency, but did not reduce parathyroid
hormone levels
c. reduced parathyroid hormone levels and corrected vitamin D

insufficiency
d. did not reduce parathyroid hormone levels or correct vitamin D
insufficiency
Kyleena – Another Hormonal IUD
9. A 25-year-old nulliparous woman with heavy menstrual bleeding and
dysmenorrhea asks you whether the Kyleena IUD would be a good
choice for her because she has trouble remembering to take her oral
contraceptive every day. She plans to have children someday, but
probably not for 4-5 years. You could tell her that:
a. Kyleena is convenient and effective and can reduce her menstrual
symptoms
b. Kyleena is not recommended for women who have not had any
children
c. Kyleena will make her dysmenorrhea worse
d. she won’t be able to have children after Kyleena is removed
Drug Interaction: Clopidogrel and PPIs
10. Which of the following best describes the mechanism by which PPIs such
as omeprazole may reduce the antiplatelet activity of clopidogrel?
a. omeprazole reduces the absorption of clopidogrel by increasing
gastric pH
b. omeprazole is thrombogenic
c. omeprazole induces CYP2C19, lowering serum concentrations of
clopidogrel
d. omeprazole inhibits CYP2C19, limiting the conversion of clopidogrel
to its active form

ACPE UPN: Per Issue Exam: 0379-0000-17-515-H01-P; Release: February 27, 2017, Expire: February 27, 2018
Comprehensive Exam 76: 0379-0000-17-076-H01-P; Release: July 2017, Expire: July 2018

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