The medical letter on drugs and therapeutics december 21 2015

1484 Antiviral Drugs for Seasonal Influenza 2015-2016 ...Intravenous Diclofenac Dyloject ...p 169p 171 Empagliflozin/Metformin Synjardy for Type 2 Diabetes ...p 172 In Brief: Oral Phenyl

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IN THIS ISSUE

ISSUE

1433

Volume 56

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

ISSUE No

1484 Antiviral Drugs for Seasonal Influenza 2015-2016 Intravenous Diclofenac (Dyloject) p 169p 171

Empagliflozin/Metformin (Synjardy) for Type 2 Diabetes p 172

In Brief: Oral Phenylephrine for Nasal Congestion p 174

on Drugs and Therapeutics

169

on Drugs and Therapeutics

Take CME Exams

ISSUE

1433

Volume 56

ISSUE No

1484 Intravenous Diclofenac (Dyloject) Empagliflozin/Metformin (Synjardy) for Type 2 Diabetes p 171p 172

In Brief: Oral Phenylephrine for Nasal Congestion p 174

ALSO IN THIS ISSUE

Antiviral Drugs for Seasonal

Influenza 2015-2016

▶

Antiviral drugs can be used for treatment of influenza

and as an adjunct to influenza vaccination1 for

prophylaxis Frequently updated information on

influenza activity and antiviral resistance is available

from the CDC at www.cdc.gov/flu

INDICATIONS FOR TREATMENT — The CDC

recommends antiviral treatment as soon as possible

for all persons with suspected influenza who are at

high risk for complications, including children <2 years

old, persons <19 years old receiving long-term aspirin

therapy, adults ≥65 years old, morbidly obese persons

(BMI ≥40), women who are pregnant or ≤2 weeks

postpartum, persons of American Indian/Alaska Native

heritage, residents of nursing homes and other chronic

care facilities, and persons of any age who have certain

chronic medical conditions or are immunosuppressed Antiviral treatment is also recommended for patients with suspected or confi rmed influenza who show signs

of clinical deterioration, develop symptoms of lower respiratory tract infection, or require hospitalization, and it can be considered for previously healthy persons with uncomplicated influenza if it can be started within

48 hours of symptom onset.2

INDICATIONS FOR PROPHYLAXIS — Chemoprophylaxis

with antiviral drugs is not recommended for healthy persons exposed to influenza It can be considered for persons at high risk for complications who are unvaccinated or unlikely to respond to vaccination or have received influenza vaccine within the last 2 weeks, for unvaccinated healthcare workers who are exposed

to influenza, and to help control outbreaks in nursing homes When indicated, chemoprophylaxis should be started within 48 hours after exposure to the virus

Table 1 Antiviral Drugs for Seasonal Influenza 2015-2016

Oseltamivir – 30, 45, 75 mg caps; Prophylaxis: 75 mg PO once/d 2,3 Prophylaxis: 30-75 mg 4 PO once/d 2

Tamiflu (Genentech) 6 mg/mL oral susp Treatment: 75 mg PO bid x 5d 5,6 Treatment: 30-75 mg 4 PO bid x 5d 5 $131.50 Peramivir – 200 mg/20 mL Prophylaxis: Not approved Prophylaxis: Not approved

Rapivab (Seqirus) single-use vials Treatment: 600 mg IV once 5,7 Treatment: Not approved 950.00 8

Zanamivir – 5 mg/blister Prophylaxis: 2 inh once/d 2 Prophylaxis: ≥5 yrs: 2 inh once/d 2

Relenza9 (GSK) for inhalation 10 Treatment: 2 inh bid x 5d Treatment: ≥7 yrs: 2 inh bid x 5d 59.00

1 Approximate WAC for 5 days’ treatment at the adult dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC rep-resents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly December 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy

2 When indicated for post-exposure prophylaxis in households, a 10-day course is recommended For prophylaxis of exposures in institutions, the drug should

be taken for at least 2 weeks and continued for 1 week after the end of the outbreak For prophylaxis during community outbreaks, oseltamivir has been shown to be effective and safe when taken for up to 42 days, and zanamivir for up to 28 days Some expert clinicians would use twice-daily therapeutic doses for post-exposure prophylaxis in highly immunocompromised persons.

3 Dosage for patients with CrCl >30-60 mL/min: 30 mg once/d; CrCl >10-30 mL/min: 30 mg every other day; end-stage renal disease on hemodialysis (HD):

30 mg after every other HD; continuous ambulatory peritoneal dialysis (CAPD): 30 mg once/wk immediately following exchange.

4 Dose for children 1-12 yrs old: ≤15 kg: 30 mg; 15.1-23 kg: 45 mg; 23.1-40 kg: 60 mg; ≥40.1 kg: 75 mg The FDA-approved dose for treatment of infants

≥2 weeks to less than 1 year old is 3 mg/kg bid Although not FDA-approved for prophylaxis for children <1 year old, the ACIP and CDC recommend that children 3-11 months old receive 3 mg/kg once/d

5 Hospitalized, critically ill, or immunocompromised patients may be treated longer

6 Dosage for patients with CrCl >30-60 mL/min: 30 mg bid; CrCl >10-30 mL/min: 30 mg once/d; end-stage renal disease on hemodialysis (HD): 30 mg after every HD; continuous ambulatory peritoneal dialysis (CAPD): 30 mg immediately following exchange Oseltamivir is not recommended for patients with end-stage renal disease not on dialysis.

7 Dosage for patients with CrCl 30-49 mL/min: 200 mg IV once; CrCl 10-29 mL/min: 100 mg IV once; chronic renal impairment on hemodialysis: administer dose (based on renal function) after dialysis.

8 Approximate WAC for 3 single-use vials.

9 Not recommended for use in patients with underlying respiratory disease such as asthma or COPD or in patients with severe influenza.

10 Available in a carton containing 5 rotadisks (each rotadisk contains four 5-mg blisters of the active drug in a lactose carrier) and a Diskhaler inhalation device

Zanamivir should not be used in a nebulizer IV zanamivir is available under an emergency investigational new drug request to the manufacturer for hospital-ized patients with severe influenza (GSK 877-626-8019).

The Medical Letter ® Vol 57 (1484) December 21, 2015

NEURAMINIDASE INHIBITORS — Neuraminidase

in-hibitors are currently the drugs of choice for treatment

of influenza; most of the recently circulating influenza

viruses tested by the CDC have been susceptible to

these drugs When used for chemoprophylaxis against

susceptible strains of seasonal influenza A or B

viruses, oseltamivir (Tamiflu) and zanamivir (Relenza)

have generally been about 70-90% effective.3

Osel-tamivir, which is taken orally, and zanamivir, which

is inhaled, can be used for chemoprophylaxis or

treatment of influenza in children and adults Peramivir

(Rapivab), which is administered intravenously as

a single dose, is FDA-approved for treatment of

uncomplicated influenza in adults; it appears to be

similar in effi cacy to oseltamivir.4

Resistance – Resistance to oseltamivir or peramivir

can emerge during or after treatment, especially

in immunocompromised patients with prolonged

viral shedding.5 Resistant isolates have remained

susceptible to zanamivir.6,7

Treatment Recommendations – Neuraminidase

inhibitors can decrease the duration of fever and

symptoms.8 They are most effective when started

within 48 hours after symptom onset, but the results

of some observational studies in hospitalized and

critically ill patients suggest that starting treatment

up to 4-5 days after symptoms appear can reduce the

risk of complications such as pneumonia, respiratory

failure, and death.9-12 The usual duration of treatment

with oseltamivir or zanamivir is 5 days, but a longer

treatment course of oseltamivir (e.g., 10 days) is often

used for critically ill or immunocompromised patients,

in whom viral replication may be protracted Peramivir

is given as a single dose for treatment of acute

uncomplicated influenza

No neuraminidase inhibitor is FDA-approved for use in

hospitalized or critically ill patients For such patients,

the CDC recommends administering oseltamivir orally

or by nasogastric tube and considering use of IV

peramivir or investigational IV zanamivir (GSK:

877-626-8019) for those who cannot take oseltamivir.2

Adverse Effects – Nausea, vomiting, and headache

are the most common adverse effects of oseltamivir;

taking the drug with food may improve its

gastro-intestinal tolerability Bronchospasm can occur with

inhaled zanamivir; the drug should not be used in

patients with underlying airway disease Neutropenia

has occurred with peramivir Neuropsychiatric

events including self-injury and delirium, which can

be a complication of influenza illness, have been

1 Influenza vaccine for 2015-2016 Med Lett Drugs Ther 2015; 571:25.

2 CDC Influenza antiviral medications: summary for clinicians Available at: www.cdc.gov/flu Accessed December 10, 2015

3 AE Fiore et al Antiviral agents for the treatment and chemopro-phylaxis of influenza – recommendations of the Advisory Com-mittee on Immunization Practices (ACIP) MMWR Recomm Rep 2011; 60:1.

4 Peramivir (Rapivab): An IV neuraminidase inhibitor for treat-ment of influenza Med Lett Drugs Ther 2015; 57:17.

5 QM Le et al A community cluster of oseltamivir-resistant cases

of 2009 H1N1 influenza N Engl J Med 2010; 362:86

6 AH Gaur et al Intravenous zanamivir for oseltamivir-resistant

2009 H1N1 influenza N Engl J Med 2010; 362:88.

7 HT Nguyen et al Assessment of pandemic and seasonal influ-enza A (H1N1) virus susceptibility to neuraminidase inhibitors

in three enzyme activity inhibition assays Antimicrob Agents Chemother 2010; 54:3671.

8 J Dobson et al Oseltamivir treatment for influenza in adults:

a meta-analysis of randomised controlled trials Lancet 2015; 385:1729.

9 JK Louie et al Neuraminidase inhibitors for critically ill children with influenza Pediatrics 2013; 132:e1539

10 SG Muthuri et al Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with

influen-reported in patients taking neuraminidase inhibitors, particularly children treated with oseltamivir.13

Neuraminidase inhibitors administered within 48 hours before or <2 weeks after administration of the

intranasal live-attenuated influenza vaccine (FluMist Quadrivalent) may interfere with the vaccine’s effi cacy

Inactivated influenza vaccine can be given at any time relative to use of a neuraminidase inhibitor

PREGNANCY — Pregnant women are at high risk for

complications of influenza, including death.14 Even though all three neuraminidase inhibitors are classifi ed

as category C (some maternal and fetal toxicity in animals; no adequate studies in pregnant women) for use during pregnancy, prompt treatment with one

of these antiviral drugs is recommended Oseltamivir appears to be safe for use during pregnancy.15

Chemoprophylaxis can be considered for women who are pregnant or ≤2 weeks postpartum who have had close contact with someone likely to have been infected with influenza

CONCLUSION — Chemoprophylaxis with antiviral

drugs is not recommended for healthy persons exposed to influenza A neuraminidase inhibitor,

either oral oseltamivir (Tamiflu) or inhaled zanamivir (Relenza), is the drug of choice for treatment of

patients with uncomplicated influenza Oseltamivir

is preferred for use in pregnant women and in patients with underlying airway disease IV peramivir

(Rapivab) is an option for patients who are unable to

take oseltamivir or zanamivir ■

za A H1N1pdm09 virus infection: a meta-analysis of individual

participant data Lancet Respir Med 2014; 2:395

11 JK Louie et al Treatment with neuraminidase inhibitors for

criti-cally ill patients with influenza A (H1N1)pdm09 Clin Infect Dis

2012; 55:1198

12 IDSA Statement by the Infectious Disease Society of America

(IDSA) on the recent publication on "Neuraminidase inhibitors

for preventing and treating influenza in healthy adults and

chil-dren." April 2014 Available at: www.idsociety.org/influenza_

statement.aspx Accessed December 10, 2015.

13 S Toovey et al Post-marketing assessment of neuropsychiatric

adverse events in influenza patients treated with oseltamivir: an

updated review Adv Ther 2012; 29:826

14 MH Yudin Risk management of seasonal influenza during

preg-nancy: current perspectives Int J Womens Health 2014; 6:681

15 M Wollenhaupt et al The safety of oseltamivir in pregnancy: an

updated review of post-marketing data Pharmacoepidemiol

Drug Saf 2014; 23:1035.

The FDA has approved Dyloject (Hospira), an IV

formulation of the NSAID diclofenac sodium, for use

in adults It can be administered alone for treatment

of mild to moderate pain or in combination with opioid

analgesics for moderate to severe pain Dyloject is the

fi rst injectable formulation of diclofenac to become

available in the US

Intravenous Diclofenac (Dyloject)

▶

Pronunciation Key Diclofenac: dye kloe' fen ak Dyloject: dye' loe ject

NONOPIOIDS FOR PAIN — Use of an NSAID in

addition to an opioid analgesic for management of

postoperative pain has been shown to reduce opioid

use and the incidence of opioid-related adverse

effects.1 Administration of an oral drug may not

be possible during or immediately after surgery

Injectable formulations of ketorolac and ibuprofen

(Caldolor)2 are approved for treatment of pain; IV

ibuprofen must be infused over 30 minutes Use of

ketorolac is limited to 5 days because of an increased

risk of GI bleeding with longer use Acetaminophen is

available in an IV formulation (Ofi rmev) that is infused

over 15 minutes; it is generally less opioid-sparing

than NSAIDs, but it is not nephrotoxic and does not

increase the risk of bleeding.1,3

THE NEW FORMULATION — Diclofenac has poor

aqueous solubility IV formulations of diclofenac are

available outside the US, but they must be infused

slowly to minimize venous irritation Dyloject

was developed by complexing diclofenac sodium

with an inert solubility enhancer,

hydroxypropyl-ß-cyclodextrin (HPßCD), that releases diclofenac

immediately upon injection Following IV bolus

admi-nistration, peak serum concentrations of Dyloject are

achieved within 5 minutes, compared to about 1.5

hours with oral diclofenac potassium, and maximum concentrations are about 4.8-fold higher than those with the oral formulation.4

CLINICAL STUDIES — Approval of Dyloject was based on

the results of two randomized, double-blind, placebo- and active-controlled, short-term trials in >600 adults with moderate to severe postoperative pain

In one trial in patients who had undergone abdominal

or pelvic surgery, those who received an IV bolus

of diclofenac 37.5 mg or ketorolac 30 mg every

6 hours starting within 6 hours after surgery had similar reductions in pain intensity during the 48-hour interval following administration of the fi rst dose, the primary endpoint, and both active drugs were signifi cantly more effective than placebo A

≥30% reduction in pain intensity during the fi rst 6-hour dosing period occurred in 69.8% of patients receiving diclofenac 37.5 mg and in 76.8% of those receiving ketorolac 30 mg, compared to 55.3% with placebo Patients receiving the active treatments required signifi cantly less rescue IV morphine (total cumulative dose from 0-72 hours after surgery was 7.4 mg for diclofenac 37.5 mg and 8.5 mg for ketorolac 30 mg vs 15.9 mg for placebo).5

In the other trial, patients with pain following elective orthopedic surgery generally had similar mean pain intensity scores with IV diclofenac (18.75, 37.5, or

50 mg) or IV ketorolac (15 or 30 mg) given every 6

Table 1 Some Injectable Nonopioid Analgesics Drug Analgesic Dose Cost 1

Acetaminophen – 1000 mg IV q6h or $35.40

Ofi rmev (Mallinckrodt) 650 mg q4h 2

(max 4000 mg/d)

Dyloject (Hospira) (max 150 mg/d) Ibuprofen – 400-800 mg IV q6h 4 7.40

Caldolor (Cumberland) (max 3200 mg/d) Ketorolac – generic 30 mg IM or IV q6h 5 1.60 6

(max 120 mg/d x 5d)

1 Approximate WAC for one dose at the lowest recommended dosage or

1000 mg of Ofirmev 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 December 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/poli-cies/drug-pricing-policy

2 For patients 2-12 years old or <50 kg, the recommended dose is 15 mg/

kg (max 750 mg) q6h or 12.5 mg/kg q4h (max 75 mg/kg/d up to 3750 mg) Infusion time must be at least 15 minutes.

3 Administered as an IV bolus over 15 seconds

4 Dose for patients 6 months-11 years old: 10 mg/kg (max 400 mg) q4-6h (max 40 mg/kg/d or 2400 mg/d, whichever is less) and for those 12-17 years old: 400 mg q4-6h (max 2400 mg/d) The 400 mg/4 mL vials must

be diluted in 100 mL of fluid and the 800 mg/8 mL vials must be diluted in

200 mL of fluid Infusion time must be at least 30 minutes (10 minutes for patients 6 months-17 years old)

5 Can also be given as a single IM dose of 60 mg For patients ≥65 years old, renally impaired, or <50 kg, the dose is 15 mg q6h (max 60 mg/d x 5d) IV bolus must be given over at least 15 seconds

6 Approximate WAC for one 30-mg vial.

The Medical Letter ® Vol 57 (1484) December 21, 2015

The FDA has approved Synjardy (Boehringer Ingelheim/

Lilly), a fi xed-dose combination of the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin

(Jardiance) and metformin (Glucophage, and others),

for treatment of patients with type 2 diabetes not adequately controlled on either of these drugs alone

or already being treated with both empagliflozin and metformin It is the third SGLT2 inhibitor/metformin combination to be approved in the US.1

Empagliflozin/Metformin (Synjardy)

for Type 2 Diabetes

▶

Pronunciation Key Empagliflozin: em” pa gli floe’ zin Synjardy: sin jar’ dee

hours for up to 5 days; scores with both active drugs

were superior to those with placebo for all scheduled

assessments from 6 to 120 hours after treatment

initiation The onset of analgesia was faster with

diclofenac than with ketorolac (a mean of 10 vs 30

minutes) A ≥30% reduction in pain intensity occurred

in 81% of the patients receiving diclofenac and in 75%

of those receiving ketorolac, versus 43% of those

given placebo Patients receiving diclofenac used

signifi cantly less supplemental morphine over 5 days

of treatment than those receiving ketorolac (11.8 vs

18.1 mg) In patients ≥65 years old given low doses

of the active drugs, diclofenac was signifi cantly more

effective than ketorolac.6

ADVERSE EFFECTS — In clinical trials, infusion

site pain and extravasation were more common

with diclofenac than with placebo (10% and 3%,

respectively, vs 8% and 1%) GI adverse effects,

including ulceration, perforation, and bleeding, can

occur with any NSAID, but bleeding-related adverse

effects were not more common with diclofenac than

with placebo in the short-term trials An increased

risk of serious cardiovascular thrombotic events such

as myocardial infarction or stroke has been reported

with some NSAIDs; the risk appears to be highest with

diclofenac.7 There was no evidence of an increased

incidence of cardiovascular events in clinical trials,

but use of Dyloject is contraindicated in patients

undergoing coronary artery bypass graft surgery

All NSAIDs inhibit renal prostaglandins and decrease

renal blood flow In clinical trials, acute renal

decompensation occurred in 4% of patients with

renal impairment treated with Dyloject; it should

not be used in patients who are dehydrated or

have moderate to severe renal impairment NSAIDs

frequently cause small increases in aminotransferase

activity; serious hepatotoxicity is rare, but may occur

more frequently with diclofenac Dyloject is not

recommended for patients with moderate to severe

hepatic impairment

DRUG INTERACTIONS — Diclofenac is metabolized

primarily by CYP2C9; concomitant use with CYP2C9

inhibitors may increase its serum concentrations

and toxicity and use with CYP2C9 inducers may

decrease its effi cacy.8 Like other NSAIDs, diclofenac

may decrease the effectiveness of diuretics,

beta blockers, ACE inhibitors, and some other

antihypertensive drugs, may increase the toxicity

of lithium, methotrexate, and cyclosporine, and may

increase the risk of gastrointestinal bleeding in

patients taking anticoagulants

DOSAGE AND ADMINISTRATION — Dyloject is supplied

in single-dose vials containing 37.5 mg of diclofenac sodium per mL The recommended dosage is 37.5 mg administered by IV bolus injection over 15 seconds every 6 hours as needed The total daily dose should not exceed 150 mg

CONCLUSION — The new IV formulation of diclofenac

sodium (Dyloject) relieves postsurgical pain in adults,

has an opioid-sparing effect, and is generally well tolerated It acts more rapidly, but is otherwise similar

in effi cacy to IV ketorolac, which costs much less Acetaminophen is less opioid-sparing than an NSAID, but it is probably safer ■

1 E Maund et al Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a system-atic review Br J Anaesth 2011; 106:292.

2 Intravenous ibuprofen (Caldolor) Med Lett Drugs Ther 2010; 52:3.

3 Intravenous acetaminophen (Ofi rmev) Med Lett Drugs Ther 2011; 53:26.

4 F Mermelstein et al Single-dose and multiple-dose pharma-cokinetics and dose proportionality of intravenous and intra-muscular HPßCD-diclofenac (Dyloject) compared with other diclofenac formulations Pharmacotherapy 2013; 33:1012.

5 TJ Gan et al A novel injectable formulation of diclofenac com-pared with intravenous ketorolac or placebo for acute moder-ate-to-severe pain after abdominal or pelvic surgery: a multi-center, double-blind, randomized, multiple-dose study Anesth Analg 2012; 115:1212.

6 S Daniels et al Analgesic effi cacy and safety of a novel injectable formulation of diclofenac compared with intravenous ketorolac and placebo after orthopedic surgery: a multicenter, randomized, double-blinded, multiple-dose trial Clin J Pain 2013; 29:655.

7 Drugs for pain Treat Guidel Med Lett 2013; 11:31.

8 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44.

STANDARD TREATMENT — Used alone, oral

antihyper-glycemic drugs generally lower glycated hemoglobin (HbA1c) by 0.5-1.5% Metformin is the preferred fi rst-line treatment for type 2 diabetes, but most patients

eventually require multi-drug therapy or insulin to

achieve glycemic control.2 There is no consensus on

which drug(s) should be added to metformin, which is

available in fi xed-dose combinations with many other

antihyperglycemic drugs.3

View our detailed online table: SGLT-2 Inhibitors

MECHANISM OF ACTION — Metformin decreases

hepatic glucose production and, to a lesser extent,

increases peripheral glucose uptake Empagliflozin

decreases renal tubular reabsorption of glucose (and

sodium) and increases urinary glucose excretion

CLINICAL STUDIES — No new clinical studies were

required for approval of the combination, which has

been shown to be bioequivalent to the individual tablets

of metformin and empagliflozin taken together In

randomized, double-blind trials in patients who had not

achieved glycemic goals with metformin alone, addition

of empagliflozin lowered HbA1c by an additional

0.7-0.8%.Treatment with empagliflozin has also resulted

in reductions in systolic blood pressure and weight.4-6

An Empagliflozin Cardiovascular Study – A

random-ized, double-blind trial in 7020 patients with type 2

diabetes and established cardiovascular disease (prior

myocardial infarction or stroke or angiographically

demonstrated obstruction) found a signifi cant

reduction in cardiovascular mortality with use of

empagliflozin The mechanism of this reduction is

unclear and it is not known whether other SGLT2

inhibitors have a similar effect These results may

not apply to patients with type 2 diabetes and less

advanced cardiovascular disease.7,8

ADVERSE EFFECTS — Metformin commonly causes

gastrointestinal adverse effects (metallic taste, nausea, abdominal pain, diarrhea), which can be minimized by starting with a low dose, titrating slowly, dividing doses, and taking the drug with food Lactic acidosis can occur with accumulation of metformin; patients with renal impairment are at greatest risk Decreases in vitamin B12 serum concentrations have occurred in patients taking metformin long-term and have rarely been associated with anemia

Empagliflozin can cause genital mycotic infections

and urinary tract infections in both men and women, some of which have been serious (urosepsis and pyelonephritis).9 It has a diuretic effect, which can lead to dehydration, hypovolemia, and hypotension, particularly in elderly patients with renal dysfunction and in those taking loop diuretics Modest increases in serum creatinine and LDL cholesterol can occur Ketoacidosis has been reported with use of SGLT2 inhibitors.10 An increased risk of fractures has been reported with canagliflozin and dapagliflozin.7

PREGNANCY — Synjardy is classifi ed as category

C (developmental toxicity in animals; no adequate studies in women) for use during pregnancy

DRUG INTERACTIONS — Hypoglycemia can occur

if Synjardy is taken with insulin or a sulfonylurea; a

reduction in the dosage of the coadministered drug

may be needed Concurrent use of Synjardy and a

diuretic can increase the risk of volume depletion

Table 1 SGLT2 Inhibitors and Combinations with Metformin 1

Canagliflozin/metformin –

Invokamet (Janssen) 50/500, 50/1000, 150/500, 150/1000 mg tabs 50/500-150/500 mg bid 4-6 363.10

Dapagliflozin/metformin –

Xigduo XR (AstraZeneca) 5/500, 5/1000, 10/500, 10/1000 mg ER tabs 5/500-10/1000 mg once/d 6,8,9 363.10

Empagliflozin –

Empagliflozin/metformin –

Synjardy (Boehringer Ingelheim/Lilly) 5/500, 5/1000, 12.5/500, 12.5/1000 mg tabs 5/500-12.5/1000 mg bid 5,6,10 363.10

1 A one-month supply of generic metformin can be purchased for $4 at some pharmacies.

2 Approximate WAC for 30 days’ treatment WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published

catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly December 5, 2015 Reprinted with permission by

First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy

3 Should be taken before breakfast or the fi rst meal of the day

4 Maximum dosage of canagliflozin in patients with moderate renal impairment (eGFR 45-59 mL/min/1.73 m 2 ) is 100 mg once/d It should not be given to patients

with an eGFR <45 mL/min/1.73 m 2

5 Should be taken with meals

6 Metformin should not be used in men with serum creatinine levels ≥1.5 mg/dL or women with serum creatinine levels ≥1.4 mg/dL.

7 Taken in the morning with or without food.

8 Should not be used in patients with an eGFR <60 mL/min/1.73 m 2 or in those with active bladder cancer

9 Should be taken in the morning with food.

10 Empagliflozin should not be given to patients with an eGFR <45 mL/min/1.73 m 2

The Medical Letter ® Vol 57 (1484) December 21, 2015

DOSAGE AND ADMINISTRATION — Synjardy should

be taken twice daily with meals The recommended

dosage is based on the current dose of empagliflozin

and/or metformin In patients already taking

met-formin, the starting dose of Synjardy should be

empagliflozin 5 mg plus their current daily dose of

metformin In those already taking empagliflozin, the

initial Synjardy dose should be metformin 500 mg

with their current daily dose of empagliflozin The

maximum daily dose is 2000 mg of metformin and

25 mg of empagliflozin

The combination should not be used in men with

serum creatinine levels ≥1.5 mg/dL, women with

serum creatinine levels ≥1.4 mg/dL, or patients with

an eGFR <45 mL/min/1.73 m2

CONCLUSION — The fi xed-dose combination of

empagliflozin and metformin (Synjardy) would be

more convenient than taking the same drugs

sepa-rately, but adding empagliflozin to metformin has only

a modest effect on HbA1c A signifi cant decrease in

cardiovascular mortality has been reported with use

of empagliflozin (Jardiance) in patients with type

2 diabetes who have established cardiovascular

disease, but the long-term safety of SGLT2 inhibitors

is still unknown ■

1 Invokamet and Xigduo XR – two new combinations for type 2

diabetes Med Lett Drugs Ther 2014; 56:124.

2 American Diabetes Association Standards of medical care in

diabetes – 2015: summary of revisions Diabetes Care 2015; 38

(Suppl):S4.

3 Drugs for type 2 diabetes Treat Guidel Med Lett 2014; 12:17.

4 HU Häring et al Empagliflozin as add-on to metformin in

pa-tients with type 2 diabetes: a 24-week, randomized,

double-blind, placebo-controlled trial Diabetes Care 2014; 37:1650

5 HU Häring et al Empagliflozin as add-on to metformin plus

sulfonylurea in patients with type 2 diabetes: a 24-week,

ran-domized, double-blind, placebo-controlled trial Diabetes Care

2013; 36:3396

6 M Ridderstråle et al Comparison of empagliflozin and

glimepiride as add-on to metformin in patients with type 2

diabetes: a 104-week randomised, active-controlled,

double-blind, phase 3 trial Lancet Diabetes Endocrinol 2014; 2:691.

7 SGLT2 inhibitors: new reports Med Lett Drugs Ther 2015;

57:139.

8 B Zinman et al Empagliflozin, cardiovascular outcomes, and

mortality in type 2 diabetes N Engl J Med 2015; 373:2117.

9 SGLT2 inhibitors: drug safety communication – labels to include

warnings about too much acid in the blood and serious urinary

tract infections Available at www.fda.gov/Safety/MedWatch/

SafetyInformation/SafetyAlertsforHumanMedicalProducts/

ucm475553.htm Accessed December 10, 2015.

10 In brief: ketoacidosis with SGLT2 inhibitors Med Lett Drugs

Ther 2015; 57:94.

IN BRIEF

Oral Phenylephrine for Nasal Congestion

In 2007, an FDA advisory committee asked that placebo-controlled, dose-ranging trials be conducted to establish the effi cacy of the oral decongestant phenylephrine

(Sudafed PE, and others), which is sold over the counter

(OTC) as a single agent and in combination with other drugs for treatment of cold and allergy symptoms Phenylephrine

replaced pseudoephedrine (Sudafed, and others) in many

OTC formulations when access to pseudoephedrine-containing products was restricted in an effort to reduce their use in the synthesis of methamphetamine

CLINICAL STUDIES — In a randomized, open-label,

dose-ranging trial in 539 patients with seasonal allergic rhinitis, phenylephrine doses up to four times the recommended dose of 10 mg were no more effective than placebo in reducing symptomatic nasal congestion 1 Other recent studies have also found oral phenylephrine no more effective than placebo in reducing nasal congestion 2-4

ALTERNATIVES – Oral pseudoephedrine reduces nasal

congestion, but has no effect on other symptoms such as sneezing, itching, or rhinitis, and tolerance to its effects can occur with repeated use Potential adverse effects include insomnia, excitability, headache, nervousness, anorexia, palpitations, tachycardia, arrhythmias, hypertension, nausea, vomiting, and urinary retention Pseudoephedrine should be used cautiously in patients with cardiovascular disease, hypertension, diabetes, hyperthyroidism, narrow-angle glaucoma, or bladder neck obstruction

Intranasal decongestants such as oxymetazoline (Afrin,

and others) are effective and less likely than pseudo-ephedrine to cause systemic adverse effects, but they can cause stinging, burning, sneezing, dryness of the nose and throat, and, if used for more than 3-5 consecutive days,

rebound congestion (rhinitis medicamentosa) Intranasal corticosteroids are the most effective drugs available

for prevention and relief of nasal congestion and other seasonal allergic rhinitis symptoms 5

CONCLUSION — Oral phenylephrine is not effective for

treatment of nasal congestion ■

1 EO Meltzer et al Oral phenylephrine HCl for nasal congestion in sea-sonal allergic rhinitis: a randomized, open-label, placebo-controlled study J Allergy Clin Immunol Pract 2015; 3:702.

2 EO Meltzer at al Phenylephrine hydrochloride modifi ed-release tab-lets for nasal congestion: a randomized, placebo-controlled trial in allergic rhinitis patients Ann Allergy Asthma Immunol 2015 Novem-ber 7 (epub).

3 F Horak et al A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Chal-lenge Chamber Ann Allergy Asthma Immunol 2009; 102:116.

4 JH Day et al Effi cacy of loratadine-montelukast on nasal conges-tion in patients with seasonal allergic rhinitis in an environmental exposure unit Allergy Asthma Immunol 2009; 102:328.

5 Drugs for allergic disorders Treat Guidel Med Lett 2013; 11:43.

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1 Discuss the 2015-2016 recommendations for use of antiviral drugs for prophylaxis and treatment of seasonal influenza.

2 Review the effi cacy and safety of the new intravenous formulation of diclofenac (Dyloject) for management of pain in adults.

3 Review the effi cacy and safety of empagliflozin/metformin (Synjardy) for treatment of type 2 diabetes.

4 Discuss the effi cacy of the oral decongestant phenylephrine (Sudafed PE, and others) for treatment of cold and allergy symptoms.

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Issue 1484 Questions

(Correspond to questions #121-130 in Comprehensive Exam #73, available January 2016)

6 Diclofenac may decrease the effectiveness of:

a diuretics

b fluoroquinolone antibiotics

c glucocorticoids

d all of the above

Empagliflozin/Metformin (Synjardy) for Type 2 Diabetes

7 A 61-year-old man with type 2 diabetes well controlled on monotherapy with metformin has read about the reduction in cardiovascular mortality with empagliflozin and asks whether he could start taking the new combination You could tell him that:

a the reduced mortality with empagliflozin was only demonstrated in patients with established cardiovascular disease

b empagliflozin can cause genitourinary tract infections in men and women

c SGLT2 inhibitors like empagliflozin can cause ketoacidosis

d all of the above

8 In clinical trials in patients who had not achieved glycemic goals with metformin alone, addition of empagliflozin lowered HbA1c by about:

a 0.4-0.5%

b 0.7-0.8%

c 0.9-1.0%

d 1.2-1.3%

9 Metformin commonly causes:

a hepatotoxicity

b nephrotoxicity

c gastrointestinal adverse effects

d muscle cramps

Oral Phenylephrine for Nasal Congestion

10 The most effective drug for treatment of seasonal allergic rhinitis symptoms is:

a oral phenylephhrine

b an oral antihistamine

c an intranasal antihistamine

d an intranasal corticosteroid

Antiviral Drugs for Seasonal Influenza 2015-2016

1 Antiviral treatment is recommended for which of the following

with suspected influenza?

a adults ≥65 years old

b residents of nursing homes

c immunosuppressed patients

d all of the above

2 Neuraminidase inhibitors are most effective for treatment of

influenza when started how long after symptom onset?

a within 48 hours

b within 72 hours

c within 96 hours

d within 5 days

3 A 28-year-old woman in her fourth month of pregnancy was

exposed to family members with documented influenza and has

had influenza-like symptoms for one day When you suggest

treatment with an antiviral drug, she asks whether the drug

could hurt her baby You could tell her that:

a pregnant women are at high risk for complications of

influenza

b oseltamivir appears to be safe for use during pregnancy

c no adequate studies of oseltamivir have been done in

pregnant women

d all of the above

Intravenous Diclofenac (Dyloject)

4 IV diclofenac administered postoperatively has been shown to be:

a noninferior to morphine

b opioid-sparing

c less effective than IV acetaminophen

d safe in patients with renal impairment

5 Compared to IV ketorolac, IV diclofenac is:

a similar in effi cacy

b less likely to be prothrombotic

c less likely to cause nephrotoxicity

d all of the above

ACPE UPN: Per Issue Exam: 0379-0000-15-484-H01-P; Release: December 21, 2015, Expire: December 21, 2016 Comprehensive Exam 73: 0379-0000-16-073-H01-P; Release: January 2016, Expire: January 2017

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D.,

F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard

CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School;

Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Franco M Muggia, M.D., New York University Medical Center; Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle

R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell

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