1515 on Drugs and Therapeutics Auvi-Q Epinephrine Auto-Injector Returns ...p 33 Crisaborole Eucrisa for Atopic Dermatitis ...p 34 Anticoagulation of Elderly Patients at High Risk for Fal
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ISSUE
1433
Volume 56
Published by The Medical Letter, Inc • A Nonprofi t Organization
ISSUE No
1515
on Drugs and Therapeutics
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
ALSO IN THIS ISSUE
Trang 233
on Drugs and Therapeutics
Take CME Exams
ISSUE
1433
Volume 56
ISSUE No
1515 Crisaborole (Eucrisa) for Atopic DermatitisAnticoagulation of Elderly Patients at High Risk for Falls with Atrial Fibrillation p 34p 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
ALSO IN THIS ISSUE
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of anaphylaxis and voluntarily withdrawn in 2015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
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 ■
Auvi-Q Epinephrine Auto-Injector
Returns
▶
Table 1 Epinephrine Auto-Injectors
Epinephrine injection, USP –
generic (Mylan)3 0.15 mg/0.3 mL, $300.00
EpiPen Jr (Mylan) 0.15 mg/0.3 mL 608.60
EpiPen 0.3 mg/0.3 mL 608.60
Epinephrine injection, USP 4 –
generic (Impax) 0.15 mg/0.15 mL, 395.20 5,6
Adrenaclick (Impax)7 0.3 mg/0.3 mL 460.90 5
Epinephrine injection, USP – 0.15 mg/0.15 mL, 4500.00 9
Auvi-Q (Kaléo)8 0.3 mg/0.3 mL 4500.00 9
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
whole-salers; 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 benefi t
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-of-pocket 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
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 Feb
-ru ary 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.
Pronunciation Key
Epinephrine: ep" i nef' rin Auvi-Q: aw vee' cue
Trang 3Crisaborole (Eucrisa) for Atopic
Dermatitis
▶
Pronunciation Key
Crisaborole: kris” a bor’ ole Eucrisa: you kris’ a
The FDA has approved crisaborole 2% ointment
(Eucrisa – Pfi zer) for topical treatment of mild to
moderate atopic dermatitis in patients ≥2 years old It
is the fi rst phosphodiesterase type-4 (PDE4) inhibitor
to be approved in the US for this indication
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
in-fants, 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
high-potency 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
effi cacy 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
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 signifi cantly 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 fi rst 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 effi cacy to topical corticosteroids or calcineurin inhibitors remains to be established, and its long-term effi cacy and safety are unknown ■
Table 1 Some Topical Nonsteroidal Drugs for Atopic Dermatitis
Calcineurin Inhibitors
Pimecrolimus 1% cream – Elidel (Valeant) $517.70 Tacrolimus 0.03%, 0.1% ointment – generic 416.70 2
Protopic (Astellas) 486.20 2
PDE4 Inhibitor
Crisaborole 2% ointment – Eucrisa (Pfi zer) 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 pub-lished catalogue or list price and may not represent an actual transac-tional 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.
Trang 41 LF Eichenfi eld 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
nonsteroi-dal, 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 Effi cacy 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 fi brillation.2,3 Atrial fi brillation
has, however, been associated with an increased
risk of falls, and older patients starting warfarin for
atrial fi brillation 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),
rivarox-aban (Xarelto), apixrivarox-aban (Eliquis), and edoxrivarox-aban
(Savaysa) have been shown to be at least as effective
as warfarin in preventing ischemic stroke or systemic
embolism in patients with nonvalvular atrial fi brillation
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 specifi cally
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 fi bril lation
(mean age 83.0) and 18,261 other patients hospitalized
with atrial fi brillation (mean age 79.3) examined the
risk of subsequent intracranial hemorrhage About
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 patient-years), 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 fi brillation, warfarin (target INR 2-3) was compared to aspirin 75 mg/day After a mean
follow-up 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
fi brillation In a trial (ARISTOTLE) comparing apixaban with warfarin in patients with atrial fi brillation, 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
Trang 5CONCLUSION — No prospective randomized trial has
evaluated the risks and benefi ts of anticoagulation
in elderly patients at high risk for falls with atrial
fi brillation Available data suggest that the benefi ts
may outweigh the risks ■
1 Treatment of atrial fi brillation Med Lett Drugs Ther 2014;
56:53.
2 CT January et al 2014 AHA/ACC/HRS guideline for the
man-agement of patients with atrial fi brillation: 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 fi brillation 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 fi brillation
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
in-tracranial bleeding among older veterans receiving warfarin for
atrial fi brillation JAMA Cardiol 2016; 1:65.
6 Which oral anticoagulant for atrial fi brillation? Med Lett Drugs
Ther 2016; 58:45.
7 M Sharma et al Effi cacy and harms of direct oral
anticoagu-lants in the elderly for stroke prevention in atrial fi brillation and
secondary prevention of venous thromboembolism:
system-atic review and meta-analysis Circulation 2015; 132:194.
8 BF Gage et al Incidence of intracranial hemorrhage in patients
with atrial fi brillation 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 fi brillation (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 benefi t of warfarin in patients with
atrial fi brillation: a report from the Swedish atrial fi brillation
co-hort study Circulation 2012; 125:2298.
11 CB Granger et al Apixaban versus warfarin in patients with
atrial fi brillation 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
hyper-parathyroidism is a common complication of CKD;
it develops in response to declining renal function,
impaired phosphate excretion, and the inability
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, double-blind trials in a total of 429 patients with stage 3 or
4 CKD who had SHPT and vitamin D insuffi ciency.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 signifi cantly 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
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
Trang 61 J Cunningham et al Secondary hyperparathyroidism: patho-genesis, 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 hyperparathyroid-ism: how and why? Clin Exp Nephrol 2017 Jan 2 (epub).
5 M Petkovich et al Modifi ed-release oral calcifediol corrects vitamin D insuffi ciency 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 kid-ney 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.
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
hyper-calcemia 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
Table 2 Some Vitamin D Analogs for SHPT
Drug Some Available Formulations Initial Adult Oral Dosage Cost 1
Inactive
Cholecalciferol (vitamin D3) – generic 1000 IU tabs 1000 IU/d $0.50 Ergocalciferol (vitamin D2) – generic 50,000 IU caps 50,000 IU/wk 2.40
Active
Calcifediol ER − Rayaldee (Opko) 30 mcg ER caps 30 mcg once/d at bedtime 2 928.00 Calcitriol − generic 0.25, 0.5 mcg caps; 0.25 mcg once/d 3 30.70
Paricalcitol − generic 1, 2 mcg caps; 2, 5 mcg/mL Baseline iPTH: 152.40 6
Zemplar (Abbvie) IV soln ≤500 pg/mL: 1 mcg once/d or 2 mcg 3x/wk 4,5 390.30 6
>500 pg/mL: 2 mcg once/d or 4 mcg 3x/wk 4,5
Doxercalciferol − generic 0.5, 1, 2.5 mcg caps; 2 mcg/mL, 1 mcg once/d 7 736.50
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.
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 insuffi ciency 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 ■
Trang 7Kyleena – Another Hormonal IUD
▶
Pronunciation Key Levonorgestrel: lee" voe nor jes' trel Kyleena: kye lee’ nah
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.
IUDs — IUDs provide convenient, long-term
contra-ception 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;
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 ef-fects that interfere with conception include thicken ing
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 woman-years) 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 of Use 1 Rate 2 Content Some Advantages Some Disadvantages Cost 3
Copper-Containing IUD
ParaGard T380A 10 years 0.8 4 None ▶ Nonhormonal ▶ Irregular/heavy bleeding $739.00
▶ Lack of protection against STIs
Levonorgestrel-Releasing IUDs
(Allergan/Actavis)
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.
▶ 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
Trang 81 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.
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 fi rst 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 fi rst-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
levonorgestrel-releasing intrauterine device (IUD), provides effective
contraception for at least 5 years It is smaller in size
and contains less levonorgestrel than the Mirena IUD ■
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
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 fi rst 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
bicarbon-ate (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.
Trang 9POSSIBLE 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 fi xed-dose combination of omeprazole
and clopidogrel used in the trial was specifi cally
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
clinically signifi cant 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 specifi cally warns against their concomitant use, it would be reasonable
to use another PPI such as pantoprazole in patients taking clopidogrel ■
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 inhibi-tors 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 profi les of proton pump inhibitors: an update Drug Saf 2014; 37:201.
design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state 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 pan-toprazole 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 clopidogrel-proton pump inhibitors interaction World J Gastrointest Pharmacol Ther 2015; 6:17.
11 DN Juurlink et al A population-based study of the drug interac-tion between proton pump inhibitors and clopidogrel CMAJ 2009; 180:713.
12 PM Ho et al Risk of adverse outcomes associated with con-comitant 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 omepra-zole in coronary artery disease N Engl J Med 2011; 364:681.
17 SP Dunn et al Impact of proton pump inhibitor therapy on the
ef-fi cacy 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 Circula-tion 2012; 125:978.
Online Only Article
Atezolizumab (Tecentriq) for Bladder Cancer and NSCLC
www.medicalletter.org/TML-article-1515g
Trang 10e40
The Medical Letter
on Drugs and Therapeutics
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
fi rst 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
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 superfi cial 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 superfi cial 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 platinum-based 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 sup-presses 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 objec-tive response rate (ORR), the primary endpoint, was 15% (compared to a historical control ORR of 10% for second-line 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
Atezolizumab (Tecentriq) for
Bladder Cancer and NSCLC
▶
Pronunciation Key Atezolizumab: a” te zoe liz’ ue mab Tecentriq: te sen' trik
Table 1 Immune Checkpoint Inhibitors for Bladder Cancer and NSCLC
Drug Usual Adult Dosage Cost 1
PD-1 Inhibitors
Nivolumab – Bladder Cancer 2 :
Opdivo (BMS) 240 mg IV q2 wks $12,036.20
NSCLC 3,4 : 240 mg IV q2 wks 12,036.20
Pembrolizumab – NSCLC 4,5 : 200 mg IV q3 wks 8893.00
Keytruda (Merck)
PD-L1 Inhibitor
Atezolizumab – Bladder Cancer 2 :
Tecentriq (Genentech) 1200 mg IV q 3wks 8620.00
NSCLC 3,4 : 1200 mg IV q3wks 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
transac-tional 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
chemo-therapy
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 specifi c for these aberrations before receiving a
PD-1 or PD-L1 inhibitor.
5 FDA-approved for fi rst-line treatment of metastatic NSCLC with
PD-L1 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.