MANAGING EDITOR: Molly Walbrown, Pharm.D., BCPS, CACP, CDE
VOLUME 51, NUMBER 12
DECEMBER 2015
REVIEW OF IDARUCIZUMAB (PRAXBIND®) FOR
THE REVERSAL OF DABIGATRAN
Lauren Chambers, Pharm.D.
Warfarin used to be the mainstay of therapy for the treatment of venous thromboembolism and for the prevention
of stroke in atrial fibrillation. Over the past several years, numerous new oral anticoagulants have received
approval from the United States Food and Drug Administration (FDA) for those same indications. The new
agents include the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, and the direct thrombin inhibitor
dabigatran. These newer agents offer the advantage of more predictable absorption, shorter half-lives,
standardized dosing regimens, and no need for routine monitoring for efficacy. However, physicians may be
reluctant to prescribe them secondary to the lack of reversal agents if patients develop bleeding.1,2
In October 2015, the first reversal agent for a novel anticoagulant was brought to market. Idarucizumab
(Praxbind®) is a humanized monoclonal antibody fragment that binds and neutralizes both free and bound
dabigatran. Idarucizumab has an affinity for dabigatran that is 350 times higher than the binding affinity of
dabigatran for thrombin. Idarucizumab was granted both Orphan Drug and Breakthrough Therapy designation
from the FDA and was subsequently approved for dabigatran reversal during emergency surgery, urgent
procedures, or life-threatening or uncontrolled bleeding.3 In a randomized study in healthy volunteers
idarucizumab reached peak plasma exposure in less than five minutes and was rapidly eliminated. The half-life
was approximately 45 minutes, and after 4 hours, plasma concentrations were less than 5%. The study also
found that idarucizumab had no effect on coagulation parameters when administered in the absence of an
anticoagulant.4 Another study of healthy male volunteers found that idarucizumab immediately and completely
normalized dabigatran-induced coagulation parameters in a dose-dependent manner with no serious or severe
adverse events reported.5
Idarucizumab was reviewed in November 2015 by the Pharmacy and Therapeutics committees at WellSpan
York, Gettysburg, and Good Samaritan Hospital, and was approved by all institutions. With the addition of this
agent to formulary, a subsequent update to the PowerPlan for anticoagulation reversal will take place. The
“Dabigatran bleeding management” subphase of the Anticoagulation Reversal PowerPlan currently guides
management of bleeding secondary to dabigatran with recommendations for the use of prothrombin complex
concentrate (PCC) 50units/kg (max of 5000 units). Until the PowerPlan can be updated, the medical and surgical
intensivists will call the pharmacy directly to order idarucizumab for dabigatran reversal. If idarucizumab is given
for the reversal of dabigatran, the patient should not concomitantly receive PCC for reversal. The recommended
dose of idarucizumab for dabigatran reversal is 5 grams provided as 2 vials, each containing 2.5gm. The dose
can be administered by hanging 2 consecutive vials. In an effort to provide prompt administration of
idarucizumab, the order will default to a P1 priority. Similar to the ordering of PCC, idarucizumab will be restricted
to the medical and surgical intensivists. To allow for the use of idarucizumab in non-bleeding patients who
require immediate surgery, an additional phase will be added to the PowerPlan entitled “Dabigatran-Procedure”
which will include the same dosing recommendations for idarucizumab.
References:
1. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke
and major bleeding in atrial fibrillation patients: the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol
2014;63:321-8.
2. Van Ryn, J, Stangier J, Haertter S, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation
assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116-27.
3. FDA grants priority review to Boehringer Ingelheim’s biologics license application for idarucizumab. Boehringer Ingelheim. http://us.boehringeringelheim.com/news_events/press_releases/press_release_archive/2015/4-23-2015-fda-grants-priority-review-boehringer-ingelheims-biologicslicense-application-idarucizumab.html. April 2015. Accessed September 1, 2015.
4. Glund S, Moschetti V, Norris S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of
idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015;113:943-51.
5. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised,
placebo-controlled, double-blind phase 1 trial. Lancet 2015; Epub ahead of print.
6. Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20
UMECLIDINIUM/VILANTEROL (ANORO ELLIPTA®) ADDED TO FORMULARY
Alisha Mutch, Pharm.D., BCPS
Anoro Ellipta® (umeclidinium/ vilanterol) is a dry powder inhaler that was added to formulary at the
November 2015 Pharmacy and Therapeutics (P&T) committee meeting. It is the first inhaler to combine
a long-acting anticholinergic (umeclidinium) with a long-acting beta-agonist (vilanterol).
Umeclidinium/vilanterol was approved by the U.S. Food and Drug Administration (FDA) in 2013 as
maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). One of the
limitations of umeclidinium/vilanterol is that its safety and efficacy has not been evaluated in patients
with asthma; hence, it is not indicated for the relief of acute bronchospasm or for the treatment of
asthma.
The FDA approval of umeclidinium/vilanterol is based on a 24-week, multicenter, randomized, doubleblind, placebo controlled, parallel-group study. The study evaluated the safety and efficacy of
umeclidinium/vilanterol 62.5/25mcg, both agents as a singular medication, and placebo when
administered once-daily via a novel dry powder inhaler in subjects with COPD. The trial found that all
treatment arms produced statistically significant improvements in trough forced expiratory volume in
one second (FEV1) compared with placebo. Umeclidinium/vilanterol 62.5/25mcg was well tolerated and
provided clinically significant improvements in lung function and symptoms in patients with COPD.
The most common adverse effects seen with umeclidinium/vilanterol were pharyngitis, sinusitis, lower
respiratory tract infections, constipation, diarrhea, pain in extremities, muscle spasms, and neck and
chest pain. Additional reports included increased risk for asthma-related deaths, hypersensitivity
reactions, increased risk of QT prolongation, and possible drug interactions with strong cytochrome
P450 3A4 inhibitors.
While umeclidinium/vilanterol was initially not added to formulary at the February 2015 P&T Committee
meeting, a six-month drug use evaluation found increasing inpatient use of this as a non-formulary
product. Based upon increased out-patient usage and the proposed benefits with patient compliance
through use of combination products, pharmacy recommended that umeclidinium/vilanterol be added
to York, Gettysburg, Good Samaritan, and WSRH formulary. This addition to formulary will go into effect
on December 15, 2015, pending approval from the Medical Executive Committee.
References:
1. Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and Safety of once-daily Umeclidinium/Vilanterol
62.5/25mcg in COPD. Respiratory Medicine 2013; 107: 1538-1546
2. Anoro Ellipta [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014
HUMALOG® KWIKPEN U-200
Brittany Thomas, Pharm.D., Candidate
®
Humalog U-200 KwikPen (insulin lispro) is a concentrated, rapid-acting, insulin analog that was approved in
May 2015 for the treatment of Type 1 and Type 2 diabetes mellitus. Insulin lispro U-200 is bioequivalent to insulin
lispro U-100. As a result, no dosage conversion is needed when switching from insulin lispro U-100 to lispro U200. Additionally, both agents have an onset of 15 to 30 minutes, peak of 30 to 90 minutes, and duration of 3 to
5 hours. However lispro U-200 is only available in a pen formulation.
Concentrated insulin lispro U-200 has a different pharmacokinetic profile compared to other concentrated insulin
preparations, such as Humulin® U-500 and Toujeo® (insulin glargine) U-300. As a result, concentrated insulins
are not interchangeable.
The role and availability of the new concentrated insulin products were discussed at the June 2015 WellSpan
Diabetes Clinical Effectiveness Team (CET) Meeting. Given the safety risk and costs, the CET does not support
the addition of these new concentrated insulin products to the inpatient WellSpan formulary. At the November
Pharmacy and Therapeutics Committee meeting, insulin lispro U-200 was not added to the formulary and the
following therapeutic substitution to the current rapid-acting insulin analog on formulary is insulin aspart
(Novolog®) 100 units/ml was approved. The Ephrata Diabetes Advisory Board and WellSpan Endocrinology at
York and Gettysburg are also in support of this recommendation.
Orders for insulin lispro U-200 will be substituted as follows:
Substituted Medication
Ordered Medication
1 unit
insulin aspart
(Novolog)
1 unit
inuslin lispro U-200
(Humalog)
For
Reference:
1. Insulin lispro injection (Humalog) prescribing information. Indianapolis, IN: Lilly USA, LLC; 2015
INSULIN ADMINISTRATION: SAME OR SEPARATE SYRINGE?
Molly Walbrown, Pharm.D., BCPS, CACP, CDE
Changes to insulin delivery and formulary products throughout WellSpan inpatient facilities has raised
several questions regarding insulin administration via syringes. Insulin glargine (Lantus®) is a widely
used long acting insulin analog that is utilized both in the inpatient and in the outpatient setting. It is
currently the preferred basal insulin at York, Gettysburg, and WellSpan Rehabilitation and Surgical
Hospitals. Questions and concerns have surfaced regarding mixing glargine insulin in the same syringe
as other insulin products that a patient may be concurrently ordered. Manufacturer recommendations
and published literature were reviewed.
Per Manufacturer recommendations:
“Do NOT dilute or mix Lantus® with any other insulin or solution. If Lantus® is diluted or mixed, the
solution may become cloudy, and the pharmacokinetic or pharmacodynamic profile (e.g., onset of
action, time to peak effect) of Lantus® and the mixed insulin may be altered in an unpredictable
manner”.1
In animal studies, when insulin glargine was mixed in the same syringe with regular insulin, a delayed
onset of action and time to maximum effect for regular human insulin was observed. The relevance of
these observations in canines to humans is unknown. In the published literature, there are limited
studies addressing mixing glargine with other insulins in the same syringe.
The impact on
pharmacokinetics as well as the impact on clinical outcome and glucose management is still
unclear. The existing studies were limited to healthy patients with Type 1 Diabetes and the duration
of the studies were limited to 10-30 days.5 It has not been clearly demonstrated or widely studied in
the inpatient setting. Based upon the above warnings and limited data supporting mixing of insulin
glargine, it is not recommended to mix glargine in the same syringe with other insulins.2,3,4
Manufactured pre-mixed insulin products Novolog 70/30®, Humalog 75/25®, and Humalog 50/50® are
frequently used in the outpatient setting. The manufacturers of marketed pre-mixed insulin products
listed above also advise against further diluting or mixing in the same syringe with any other insulin
product.5 A study compared patients and healthcare professionals mixing and drawing up insulin
compared to manufactured pre-mixed formulations. The study found that the risk of errors increased
with lowest doses and errors were mostly associated with ratios of insulin instead of total volume.
According to manufacturer recommendations and available data, mixing of glargine or pre-mixed insulin
in the same syringe with another insulin should be avoided. Separate syringes for insulin administration
is best.
References:
1. Lantus (glargine) package insert. Bridgewater, NJ. Sanofi Aventis 2015.
2. Levlen T et al. Insulin glargine: new basal insulin. Annal Pharmacother. 2002; 36: 1019-21.
3. Goylehoran S et al. Insulin Glargine: a review 8 years after its introduction. Expert Opinion Pharmacotherap 2009; 10 (4): 70518.
4. Kaplan W et al. Effects of Mixing Glargine and Short-Acting Insulin Analogs on Glucose Control. Diabetes Care 2004; 27 (11):
2739-40.
5. Fiallo-Scharer et al. Mixing rapid-acting insulin analogues with insulin glargine in children with type 1 diabetes mellitus. J Ped.
2006; 148 (4): 481-4.
6. Bell D et al. Dosage Accuracy of Self-mixed vs Premixed Insulin. Arch Intern Med 1991; 151(11): 2265-9.
PHARMACY & THERAPEUTICS COMMITTEE APPROVES UPDATES
TO INHALER THERAPEUTIC SUBSTITUTIONS
Molly Walbrown, Pharm.D., BCPS, CACP, CDE
Fluticasone/Salmeterol (Advair®)
Fluticasone/Salmeterol is the preferred long acting corticosteroid/beta agonist combination product
across the health-system. Fluticasone/Salmeterol is widely used for the treatment and management
of asthma and chronic obstructive pulmonary disease. Fluticasone/Salmeterol is commercially
available in both the dry powder inhaler (DPI) known as Advair Diskus ® and meter dose inhaler (MDI)
known as Advair HFA®
York Hospital (YH), Gettysburg Hospital (GH), and WellSpan Surgical and Rehabilitation Hospital
(WSRH) are routinely stocking both formulations. However, due to manufacturer backorder and drug
shortage of select Advair HFA® products, the WellSpan Pharmacy & Therapeutics (P&T) Committee
approved a temporary therapeutic substitution at YH, GH, and WSRH, for the low (45/21 mcg) and
medium (115/21 mcg) HFA products in the spring of 2013.
Temporary Substitution:
Substituted Medication
Fluticasone/Salmeterol
(Advair Diskus®)
100/50 mcg 1 puff BID
Fluticasone/Salmeterol
(Advair Diskus®)
250/50 mcg 1 puff BID
FOR
Ordered Medication
Fluticasone/Salmeterol
(Advair HFA®)
45/21 mcg 2 puffs BID
Fluticasone/Salmeterol
(Advair HFA®)
115/21 mcg 2 puffs BID
In response to the 2013 shortage, WellSpan Ephrata Hospital approved a permanent substitution for
Fluticasone/Salmeterol HFA to Fluticasone/Salmeterol Diskus. The Diskus formulation is also the
preferred product at Good Samaritan Hospital.
The availability, cost and utilization of Fluticasone/Salmeterol products across WellSpan inpatient
facilities was discussed with WellSpan Pulmonology. At the November 2015 WellSpan P&T Meeting,
a permanent substitution to Diskus products was approved. Effective December 15, 2015 pending
approval from the Medical Executive Committee, the Diskus formulation will be the preferred
Fluticasone/Salmeterol product and the following therapeutic substitution will be implemented:
For non-ventilated or non-tracheostomy patients*
Substituted Medication
Fluticasone/Salmeterol
(Advair Diskus®)
100/50 mcg 1 inhalation BID
Fluticasone/Salmeterol
(Advair Diskus®)
250/50 mcg 1 inhalation BID
Fluticasone/Salmeterol
(Advair Diskus®)
500/50 mcg 1 inhalation BID
FOR
Ordered Medication
Fluticasone/Salmeterol
(Advair HFA®)
45/21 mcg 2 puffs BID
Fluticasone/Salmeterol
(Advair HFA®)
115/21 mcg 2 puffs BID
Fluticasone/Salmeterol
(Advair HFA®)
230/21 mcg 2 puffs BID
For patients on an HFA product while ventilated, no substitution will be made when they are
extubated.
Ipratropium/Albuterol (Combivent®)
Another opportunity was identified to standardize the current therapeutic substitution for
ipratropium/albuterol (Combivent Respimat®) across the health-system. Since the removal of
ipratropium/albuterol MDI (Combivent®) in 2013, WellSpan Ephrata Community and Good Samaritan
Hospitals, have been successful with their current substitution to nebulized ipratropium/albuterol for
Combivent® products.
In an effort to standardize the process for substitution of Combivent ® across WellSpan inpatient
facilities, address concerns with the existing substitution to tiotropium (Spiriva®) and albuterol
(Ventolin®) at YH, GH, WSRH, and minimize expenditures, the WellSpan P&T Committee approved a
revised therapeutic substitution. The following updated substitution was approved by Pulmonary and
Respiratory Therapy at YH, GH, and WSRH:
Substituted Medication
FOR
Ordered Medication
Non-ventilated patients:
Combivent Respimat®
Ipratropium/albuterol
nebs
same frequency per
bronchodilator protocol
Ventilated patients:
Combivent Respimat®
Ipratropium HFA 6 puffs at
prescribed frequency AND
Albuterol HFA 6 puffs at
prescribed frequency
The anticipated go-live date is January 6, 2016, pending Medical Executive Committee approval.
THERAPEUTIC SUBSTITUTION FOR TIOTROPIUM/OLODATEROL (STIOLTO RESPIMAT®)
By Alisha Mutch, Pharm.D., BCPS
Stiolto Respimat® is a new combination inhaler recently approved by the FDA to treat chronic
obstructive pulmonary disease (COPD). The product is a combination long-acting anticholinergic
(LAMA) and long-acting beta2-adrenergic agonist (LABA). It was recently reviewed at the October 2015
Pharmacy and Therapeutics (P&T) meeting and was not included into formulary based upon higher
cost and the availability of other LABA/LAMA formulations. As providers anticipated that patients may
be admitted to WellSpan facilities with this as a home medication, a therapeutic substitution was
requested. At the November 2015 P&T meeting, the following substitution was approved for
Gettysburg, York, and WSRH Hospitals:
Substituted Medication
Umeclidinium/vilanterol
(Anoro Ellipta®)
62.5/25 mcg 1 inhalation Qday
For
Ordered Medication
Tiotropium/olodaterol
(Stiolto Respimat®)
2.5/2.5 mcg 2 inhalations Qday
Reversible
Yes
As with any therapeutic substitution, providers may write for the non-formulary product and denote that
the patient will be providing the medication from home. If the patient cannot bring in the home
medication, the substitution will ensure the patient is not without an appropriate alternative.
INHALED CORTICOSTEROID SUBSTITUTION UPDATE
Theresa Langeheine, PharmD, BCPS
Christine Kahley, PharmD
Mometasone (Asmanex®) 220 mcg inhaler is the current formulary medication for Beclomethasone
(Asmanex®) 40 mcg and 80 mcg inhalers. Due to inconsistency with the Therapeutic Substitution
recommendations, new recommendations were presented to the Pharmacy and Therapeutics
Committee for therapeutic substitution approval. The current recommendations are as follows:
INHALED STEROIDS
* * * NO Change if Pediatric Patient * * *
Mometasone (Asmanex®) 220 mcg 1 puff qday
Fluticasone (Flovent®) 44 mcg 1 puff BID
for Beclomethasone (Qvar®) 40 mcg 1 – 2 puffs BID
Budesonide (Pulmicort Flexhaler) 90 – 180 mcg 1 puff
BID
Flunisolide (Aerospan®) 80 mcg 2 puffs BID
Fluticasone (Flovent®) 110 mcg 1 puff BID
Mometasone (Asmanex®) 220 mcg 1 puff BID
for Beclomethasone (Qvar®) 80 mcg 1 – 2 puffs BID
Budesonide (Pulmicort Flexhaler®) 180 mcg 2 puffs BID
Flunisolide (Aerospan®) 80 mcg 3 – 4 puffs BID
Fluticasone (Flovent®) 220 mcg 1 puff BID
Mometasone (Asmanex®) 220 mcg 2 puffs BID
for Fluticasone (Flovent®) 220 mcg 2 puffs BID
The Beclomethasone 40 mcg 2 puffs BID is equivalent in mcg/day to the Beclomethasone 80 mcg 1
puff BID however the substitution scheme recommends mometasone daily for the beclomethasone 40
mcg 2 puffs BID and mometasone BID for the beclomethasone 80 mcg 1 puff BID. The total daily
beclomethasone doses were equivalent in both of these situations, but the recommended total daily
mometasone doses were different.
Six months of beclomethasone data were reviewed from York Hospital, from 1/1/15 to 6/30/15. From
the data, it was determined that there was an inconsistency in practice which correlated to confusion
when using the formulary recommendations. There were 38 therapeutic substitutions evaluated during
this time frame which illustrated inconsistent substitution selections.
Based upon the above review, the WellSpan Pharmacy and Therapeutics Committee approved the
updated therapeutic substitution of beclomethasone to mometasone based on total daily mcg dose. At
the current time this recommendation only pertains to York Hospital. Examples of the recommended
changes can be found below.
 If the total daily dose of beclomethasone is < 80 mcg/day (40 mcg 1 puff qday, 40 mcg 1 puff
BID or 80 mcg 1 puff qday), the therapeutic substitution will be to mometasone 220 mcg 1 puff
qday
 If the total daily dose of beclomethasone is > 160 mcg/day (80 mcg 1 puff BID or 80 mcg 2
puffs bid), the therapeutic substitution will be to mometasone 220 mcg 1 puff bid.
These changes will take effect December 15th 2015, pending approval from the Medical Executive
Committee.