The medical letter on drugs and therapeutics december 8 2014

The Medical Letter

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on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 56

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ISSUE
No.

1433
1457
Volume 56

December 8, 2014

IN THIS ISSUE

Antiviral Drugs for Seasonal Influenza 2014-2015 ..................................................... p 121
Two New Drugs for Idiopathic Pulmonary Fibrosis ..................................................... p 123
Invokamet and Xigduo XR − Two New Combinations for Type 2 Diabetes ....................... p 124
Secondary Prevention of Stroke ................................................................................. p 125
In Brief: Adding Ezetimibe to a Statin Improves Clinical Outcomes ............................ p 126
In Brief: Topiramate Extended-Release Capsules (Qudexy XR) ........................... online only

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Revised 1/7/15: Since publication of the Antiviral Drugs for Seasonal Influenza article, peramivir has been approved. We have updated the table to reflect this.
Revised 2/23/15: See p. 126

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 56

ISSUE

ISSUE No.

1433
1457
Volume 56

▶

December 8, 2014
Take CME Exams
ALSO IN THIS ISSUE

Two New Drugs for Idiopathic Pulmonary Fibrosis ..................................................... p 123
Invokamet and Xigduo XR – Two New Combinations for Type 2 Diabetes .................. p 124
Secondary Prevention of Stroke ................................................................................ p 125
In Brief: Adding Ezetimibe to a Statin Improves Clinical Outcomes ............................ p 126
In Brief: Topiramate Extended-Release Capsules (Qudexy XR) ........................... online only

Antiviral Drugs for Seasonal
Influenza 2014-2015

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.
NEURAMINIDASE INHIBITORS — Oseltamivir (Tamiflu),
which is taken orally, and zanamivir (Relenza), which is
inhaled, can be used for chemoprophylaxis and treatment
of influenza. When used for prophylaxis after exposure to

susceptible strains of seasonal influenza A or B viruses,
they have generally been about 70-90% effective.2

In patients with mild illness caused by a susceptible strain
of influenza, starting treatment with a neuraminidase
inhibitor within 48 hours after the onset of illness can
decrease the duration of fever and symptoms and
may also reduce the risk of complications such as
pneumonia.3 In hospitalized and critically ill patients,
observational studies indicate that these drugs can
decrease the risk of death when started soon after
symptom onset; the results of some studies suggest
that treatment within 4-5 days after symptoms appear
may still have some benefit.4-6 The usual duration of
treatment with a neuraminidase inhibitor is 5 days, but
a prolonged treatment course (e.g., 10 days) is often
used for critically ill or immunocompromised patients,
in whom viral replication may be protracted.

Table 1. Antiviral Drugs for Seasonal Influenza
Drug

Formulations

Adult Dosage

Pediatric Dosage

Cost1

Oseltamivir –
Tamiflu
(Genentech)
Peramivir –
Rapivab (BioCryst)
Zanamivir –
Relenza10 (GSK)

30, 45, 75 mg caps;
6 mg/mL oral
suspension
200 mg/20 mL
single-use vials
5 mg/blister
for inhalation11

Prophylaxis2: 75 mg PO once/d3
Treatment5: 75 mg PO bid x 5d6,7

Prophylaxis2: 30-75 mg PO once/d4
Treatment5: 30-75 mg PO bid x 5d4

$120.60

Prophylaxis:
Treatment:
Prophylaxis2:
Treatment5:

Prophylaxis:

Treatment:
Prophylaxis2:
Treatment5:

Not approved
600 mg IV once8
2 inhalations once/d
2 inhalations bid x 5d

Not approved
Not approved
$950.009
≥5 yrs: 2 inhalations once/d
≥7 yrs: 2 inhalations bid x 5d
59.00

1.

Approximate WAC for 5 days’ treatment at 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. November 5, 2014. Reprinted with
permission by First Databank, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy.
2. 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 daily; 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, the ACIP and CDC recommend that children 3-11
months old receive 3 mg/kg once/day.

5. Hospitalized, critically ill, or immunocompromised patients are sometimes treated longer.
6. Dosage for patients with CrCl >30-60 mL/min: 30 mg bid; CrCl >10-30 mL/min: 30 mg once daily; end-stage renal disease on hemodialysis (HD): 30 mg after
every HD; continuous ambulatory peritoneal dialysis (CAPD): 30 mg immediately following exchange.
7. In adults with pneumonia or severe lower respiratory tract disease, some expert clinicians recommend 150 mg bid x 10 days for treatment (off-label).
8. 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.
9. Approximate WAC for 3 single-use vials.
10. Not recommended for use in patients with underlying respiratory disease such as asthma or COPD.
11. 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.

121

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Resistance to oseltamivir can occur,7 especially in
immunocompromised patients with prolonged viral
shedding, but recently almost all of the circulating
influenza A and B viruses tested by the CDC and the
World Health Organization have been susceptible to both
oseltamivir and zanamivir. The rare oseltamivir-resistant
isolates have remained susceptible to zanamivir.
In critically ill patients, oseltamivir capsules can be
opened and dissolved in water and given by nasogastric
tube.8 An IV formulation of zanamivir is available for

hospitalized patients with severe influenza under an
emergency investigational new drug request to the
manufacturer (GSK: 1-877-626-8019); it has been
used successfully to treat some severely ill patients
with proven or suspected oseltamivir resistance.9
Peramivir (BioCryst), an investigational IV neuraminidase inhibitor that was available under an
emergency use authorization during the 2009-2010
influenza season, has been approved by the FDA
for treatment of influenza. A review of peramivir will
appear in our February 2, 2015 issue.
Adverse Effects – Nausea, vomiting, and headache are
the most common adverse effects of oseltamivir; taking
the drug with food may improve its gastrointestinal
tolerability. Neuropsychiatric events including selfinjury and delirium have occurred in some patients
taking neuraminidase inhibitors, particularly children
treated with oseltamivir.10 Bronchospasm can occur
with inhaled zanamivir; the drug should not be used in
patients with underlying airway disease.
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 efficacy.
Inactivated influenza vaccine can be given at any time
relative to use of a neuraminidase inhibitor.
ADAMANTANES — Amantadine and rimantadine
(Flumadine, and generics) have activity against
some influenza A viruses, but not against influenza
B viruses. They have not been active against most
circulating influenza A viruses in recent years and
are currently not recommended for treatment or

chemoprophylaxis of influenza.
INDICATIONS FOR TREATMENT — Antiviral treatment
is recommended as soon as possible for patients
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 patients (BMI ≥40),
122

Vol. 56 (1457)

December 8, 2014

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.
Treatment is also recommended for patients with
suspected or confirmed influenza who show signs
of clinical deterioration, develop symptoms of lower
respiratory tract infection, or require hospitalization.
Antiviral treatment could be considered for previously
healthy persons with uncomplicated influenza if it can
be started within 48 hours of symptom onset.11
INDICATIONS FOR PROPHYLAXIS — Chemoprophylaxis with antiviral drugs is not recommended
for healthy persons exposed to influenza. It can be
considered after exposure for persons at high risk
of complications who are unvaccinated or unlikely
to respond to vaccination or who have received

the 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.
PREGNANCY — Pregnant women are at high risk
for complications of influenza, including death.12
Even though oseltamivir and zanamivir are both
classified as category C (some fetal toxicity in
animals; no adequate studies in pregnant women)
for use during pregnancy, prompt treatment with
one of these antiviral medications is recommended.
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. Oseltamivir appears to be
safe for use during pregnancy.13
CONCLUSION — Chemoprophylaxis with antiviral drugs
is not recommended for healthy persons exposed to
influenza. A neuraminidase inhibitor, either oseltamivir
(Tamiflu) or zanamivir (Relenza), remains the drug
of choice for treatment of patients with influenza.
Oseltamivir is preferred for use in pregnant women
and in patients with underlying airway disease. ■
1. Influenza vaccine for 2014-2015. Med Lett Drugs Ther 2014;
56:97.
2. AE Fiore et al. Antiviral agents for the treatment and
chemoprophylaxis of influenza – recommendations of the
Advisory Committee on Immunization Practices (ACIP). MMWR
Recomm Rep 2011; 60:1.

3. SA Harper et al. Seasonal influenza in adults and children – diagnosis, treatment, chemoprophylaxis, and institutional outbreak
management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:1003.


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4. JK Louie et al. Neuraminidase inhibitors for critically ill children
with influenza. Pediatrics 2013; 132:e1539.
5. SG Muthuri et al. Effectiveness of neuraminidase inhibitors in
reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual
participant data. Lancet Respir Med 2014; 2:395.
6. JK Louie et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis
2012; 55:1198.
7. RE Ariano et al. Enteric absorption and pharmacokinetics of
oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ 2010; 182:357.
8. QM Le et al. A community cluster of oseltamivir-resistant cases
of 2009 H1N1 influenza. N Engl J Med 2010; 362:86.
9. AH Gaur et al. Intravenous zanamivir for oseltamivir-resistant
2009 H1N1 influenza. N Engl J Med 2010; 362:88.
10. 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.
11. CDC. Influenza antiviral medications: summary for clinicians.
Available at www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed November 21, 2014.
12. MH Yudin. Risk management of seasonal influenza during pregnancy: current perspectives. Int J Womens Health 2014; 6:681.
13. M Wollenhaupt et al. The safety of oseltamivir in pregnancy: an
updated review of post-marketing data. Pharmacoepidemiol
Drug Saf 2014; 23:1035.

▶

Two New Drugs for Idiopathic
Pulmonary Fibrosis

The FDA has approved 2 oral drugs for treatment
of idiopathic pulmonary fibrosis (IPF). Pirfenidone
(Esbriet) has been available in Europe since 2011 and
in Canada since 2012. Nintedanib (Ofev) is available
only in the US.
Pronunciation Key
Pirfenidone: per fen” i done’
Esbriet: es' bree et
Nintedanib: nin teh” duh nib’
Ofev: oh' fev

THE DISEASE — IPF is a chronic, progressive disease
with a median survival of 3 years that primarily occurs
in adults ≥50 years old. It is characterized by abnormal
fibroproliferation that leads to scarring and destruction
of the lungs. The only treatment shown to prolong survival in patients with advanced IPF is lung transplant;
the post-transplant 5-year survival rate is about 44%.1
MECHANISM OF ACTION — The exact mechanism
of action of pirfenidone is unknown, but the drug is
thought to downregulate profibrotic growth factors,
particularly transforming growth factor (TGF) -1.
Nintedanib is a tyrosine kinase inhibitor that reduces
fibroblast activity by binding to receptors for various
growth factors, including vascular endothelial growth

factor (VEGF), platelet-derived growth factor (PDGF),
and fibroblast growth factor (FGF).

Vol. 56 (1457)

December 8, 2014

Table 1. Pharmacology
Class

Pirfenidone

Nintedanib

Synthetic pyridone
derivative

Tyrosine kinase inhibitor

Formulation 267 mg capsules

100, 150 mg capsules

Route

Oral

Oral

Tmax

3 hours with food

4 hours with food

Metabolism

Hepatic via CYP1A2,
Hydrolysis via esterases,
lesser extent via CYP2C9, then glucuronidation via
2C19, 2D6, and 2E1
UGT1A1, 1A7, 1A8, and
1A10; minor extent via
CYP3A4

Elimination

Renal as 5-carboxy
metabolite (80%)

Feces (93.4%)

Half-life
(terminal)

~3 hours

~9.5 hours

CLINICAL STUDIES — Pirfenidone – Following 2 earlier

trials that the FDA found inconclusive, the ASCEND trial
randomized 555 patients with well-documented, mild to
moderate IPF (mean forced vital capacity [FVC] 68% of
predicted value) to pirfenidone or placebo for 52 weeks.
The decline from baseline in FVC, the primary endpoint,
was significantly greater among patients who received
placebo (428 mL) compared to those who received
pirfenidone (235 mL); patients taking pirfenidone were
less likely to die or lose ≥10% of the predicted value of
FVC. There was no significant difference in all-cause
mortality (4% with pirfenidone vs. 7.2% with placebo).2
Nintedanib – Two 52-week trials (INPULSIS-1 and
INPULSIS-2) randomized a total of 1066 patients
with mild to moderate IPF (mean FVC 79% and 80% of
predicted value) in a 3:2 ratio to nintedanib or placebo.
In the 2 trials, the annual rate of decline in FVC, the
primary endpoint, was 114.7 and 113.6 mL with
nintedanib versus 239.9 and 207.3 mL with placebo,
both statistically significant differences. The time to
a first acute exacerbation, a secondary endpoint, was
significantly longer with nintedanib in the second trial,
but not in the first. There was no significant difference
in pooled all-cause mortality (5.5% with nintedanib vs.
7.8% with placebo).3
ADVERSE EFFECTS — The most common adverse effects of pirfenidone in the ASCEND trial were nausea,
which occurred in 36% of patients and was sometimes
accompanied by vomiting and weight loss, and rash,
which occurred in 28% of patients. Both were usually
mild to moderate in severity. Pirfenidone also caused
phototoxicity. The drug is classified as category C (not

teratogenic in animals; no adequate human studies)
for use during pregnancy.
The most frequent adverse effect of nintedanib was
diarrhea, which occurred in more than 60% of patients.
123


The Medical Letter

Vol. 56 (1457)

®

Table 2. Drugs for Idiopathic Pulmonary Fibrosis
Drug

Maintenance Dosage

Cost1

Pirfenidone – Esbriet
(Intermune)
Nintedanib – Ofev
(Boehringer Ingelheim)

3 caps (801 mg)
tid2 with food
1 cap (150 mg)
bid with food

$7800.00
8000.00

1. Approximate WAC for 30 days’ maintenance treatment. WAC = wholesaler
acquisition cost, or manufacturer’s published price to wholesalers; WAC
represents a published catalogue or list price and may not represent actual
transactional prices. Source: AnalySource® Monthly. November 5, 2014.
Reprinted with permission by First Databank, Inc. All rights reserved.
©2014. www.fdbhealth.com/policies/drug-pricing-policy.
2. Initial dosage is 1 cap tid x 7 days, then 2 caps tid x 7 days, then 3 caps tid.

It was usually mild to moderate in severity, but led to
discontinuation of the drug in about 5% of patients.
Nausea occurred in about 25% of patients and vomiting
in about 10%. Nintedanib is classified as category D
(embryofetal deaths and teratogenicity in animals) for
use during pregnancy.
Both pirfenidone and nintedanib can increase hepatic
enzyme levels; dosage adjustment or treatment interruption may be required.

DRUG INTERACTIONS — Pirfenidone is primarily
metabolized by CYP1A2; concurrent use with strong
CYP1A2 inhibitors, such as fluvoxamine (Luvox, and
generics), or CYP1A2 inducers, such as carbamazepine (Tegretol, and others), should be avoided.4
Nintedanib is a substrate of P-glycoprotein (P-gp)
and is metabolized to a minor extent by CYP3A4.
Coadministration of nintedanib with dual inducers of
P-gp and CYP3A4, such as carbamazepine, should be
avoided; nintedanib dosage adjustments or treatment
interruption may be needed if a dual P-gp and CYP3A4

inhibitor, such as ketoconazole, is administered
concomitantly.4
Smoking can decrease exposure to both drugs and
should be avoided.
CONCLUSION — Both pirfenidone (Esbriet) and nintedanib
(Ofev) can slow the rate of decline in lung function in
patients with mild to moderate idiopathic pulmonary
fibrosis. It is not clear which is more effective. Whether
either of these drugs, which cost about $100,000 per year,
offers any significant benefit for patients with advanced
disease remains to be determined. ■
1. TE King Jr et al. Idiopathic pulmonary fibrosis. Lancet 2011;
378:1949.
2. TE King Jr et al. A phase 3 trial of pirfenidone in patients with
idiopathic pulmonary fibrosis. N Engl J Med 2014; 370:2083.
3. L Richeldi et al. Efficacy and safety of nintedanib in idiopathic
pulmonary fibrosis. N Engl J Med 2014; 370:2071.
4. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.

124

▶

December 8, 2014

Invokamet and Xigduo XR – Two New
Combinations for Type 2 Diabetes

The FDA has approved fixed-dose combinations of

metformin with either canagliflozin (Invokamet) or
dapagliflozin (Xigduo XR) for treatment of patients
with type 2 diabetes not adequately controlled
with any one of these drugs, or in those already
being treated with both metformin and either
canagliflozin or dapagliflozin.
Pronunciation Key
Canagliflozin: kan" a gli floe' zin Invokamet: in voe' ka met
Dapagliflozin: dap" a gli floe' zin Xigduo: zig doo oh

MECHANISMS OF ACTION — Metformin decreases
hepatic glucose production and, to a lesser extent,
increases peripheral glucose uptake. Canagliflozin
and dapagliflozin inhibit SGLT2 (sodium-glucose cotransporter 2); they decrease renal glucose reabsorption,
thereby increasing urinary glucose excretion.
STANDARD TREATMENT — Metformin is generally the
preferred first-line treatment for type 2 diabetes, but
most patients eventually require multi-drug therapy,
which may include insulin, to achieve glycemic
control. There is no consensus agreement on which
drug should be added to metformin, which is already
available in fixed-dose combinations with many other
antihyperglycemic drugs.1
CLINICAL STUDIES — No new clinical trials were
required for approval of the combination products,
but both have been shown to be bioequivalent to the
individual tablets of metformin and either canagliflozin
or dapagliflozin taken together. In randomized, doubleblind trials with the individual drugs in patients who
had not achieved glycemic goals with metformin
alone, addition of either canagliflozin or dapagliflozin

lowered A1C by 0.4-0.9%. Direct comparisons are
lacking, but A1C reductions with either canagliflozin or
dapagliflozin appear to be similar. Both canagliflozin
and dapagliflozin reduce body weight by 2-3 kg and
lower systolic blood pressure by 3-5 mm Hg.2,3
ADVERSE EFFECTS — Metformin commonly causes
gastrointestinal adverse effects (metallic taste,
nausea, diarrhea, abdominal pain), which can be
minimized by starting with a low dose, titrating slowly,
dividing doses, and taking the drug with food. Lactic
acidosis is a rare, but potentially fatal, complication
that can occur with accumulation of metformin.
Decreases in vitamin B12 serum concentrations have
occurred in patients taking metformin long-term and
have rarely been associated with anemia.


The Medical Letter

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December 8, 2014

Table 1. Canagliflozin, Dapagliflozin and Combinations with Metformin
Drug

Some Available Formulations

Usual Daily Dosage

Cost1

Canagliflozin – Invokana (Janssen)
Canagliflozin/metformin – Invokamet (Janssen)

100, 300 mg tabs
50/500, 50/1000, 150/500,
150/1000 mg tabs

100-300 mg PO once/d
50/500-150/500 mg PO bid3-5

Dapagliflozin – Farxiga (AstraZeneca)
Dapagliflozin/metformin – Xigduo XR (AstraZeneca)

5, 10 mg tabs
5/500, 5/1000, 10/500,
10/1000 mg ER tabs

5-10 mg PO once/d6,7
5/500-10/1000 mg PO once/d6,7

2,3

$312.00
312.00
312.10
312.10

ER = extended-release
1. Approximate WAC for 30 days’ treatment at the lowest usual daily 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. November 5,
2014. Reprinted with permission by First Databank, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy.
2. Once-daily dose should be taken with breakfast or first meal of the day.
3. Maximum dose of canagliflozin is 100 mg in patients with moderate renal impairment (eGFR 45-59 mL/min/1.73m2). It should not be given to patients with an
eGFR <45 mL/min/1.73m2.
4. Should be taken with meals.
5. Maximum daily dose is 300 mg/2000 mg in patients with an eGFR ≥60 mL/min/1.73m2.
6. Taken in the morning with or without food.
7. Should not be used in patients with an eGFR <60 mL/min/1.73m2 or in those with active bladder cancer.

Canagliflozin and dapagliflozin can cause genital
mycotic infections and urinary tract infections in
both men and women. Both drugs have a diuretic
effect, which can lead to dehydration, hypovolemia,
and hypotension, particularly in elderly patients with
renal dysfunction and in those taking loop diuretics.
Increased serum creatinine levels, decreased estimated
glomerular filtration rate (eGFR), hyperkalemia,
hypermagnesemia, hyperphosphatemia, and increased
LDL-cholesterol can occur. An increased incidence of
fracture has been reported with both drugs; the risk
may be greater in patients with renal impairment.
In clinical trials, patients treated with dapagliflozin
had a higher incidence of bladder cancer (10/6045;
0.17%) than those taking placebo (1/3512; 0.03%).
When patients treated for less than one year before
diagnosis were excluded, there were 4 cases of
bladder cancer with dapagliflozin and none with

▶

Secondary Prevention of Stroke

Recent guidelines from the American Heart Association
and American Stroke Association reviewed antithrombotic therapy options for secondary prevention of
stroke in patients who have had a stroke or transient
ischemic attack (TIA).1
ASPIRIN — Aspirin monotherapy has been shown to
reduce the risk of secondary stroke by about 15%. In
doses ≤325 mg/day, the annual risk of serious gastrointestinal hemorrhage is about 0.4%, which is 2.5
times the risk without aspirin.2
DIPYRIDAMOLE PLUS ASPIRIN — The antiplatelet drug
dipyridamole (Persantine, and generics) is available in
combination with aspirin (Aggrenox, and generics). A
randomized, controlled trial (ESPRIT) in 2739 patients
who had a TIA or minor stroke in the previous 6
months found that a combination of extended-release

placebo. Canagliflozin has not been associated with
an increase in the incidence of bladder cancer.
View our detailed online table: SGLT-2 Inhibitors
CONCLUSION — The fixed-dose combinations
of metformin and canagliflozin (Invokamet) and
metformin plus dapagliflozin (Xigduo XR) should be
more convenient than taking the drugs separately.
Neither canagliflozin nor dapagliflozin offers any
advantage in glycemic efficacy over other secondline drugs for type 2 diabetes, but both cause weight
loss rather than weight gain and do not cause

hypoglycemia. ■
1. Drugs for type 2 diabetes. Treat Guidel Med Lett 2014; 12:17.
2. Canagliflozin (Invokana) for type 2 diabetes. Med Lett Drugs
Ther 2013; 55:37.
3. Dapagliflozin (Farxiga) for type 2 diabetes. Med Lett Drugs Ther
2014; 56:13.

dipyridamole (200 mg bid) and low-dose aspirin (30325 mg per day) was more effective than aspirin alone
in preventing a composite of vascular death, stroke,
MI, or major bleeding (173 vs. 216 events; HR 0.80).
More patients discontinued the combination (470 vs.
184), mainly because of headache.3 Dipyridamole can
cause severe headache and diarrhea, which tend to
resolve with continued use.
CLOPIDOGREL — A randomized, double-blind trial
(PRoFESS) compared a combination of aspirin
25 mg and extended-release dipyridamole 200 mg
twice daily with the thienopyridine clopidogrel (Plavix,
and generics) 75 mg daily for secondary prevention
of stroke in more than 20,000 patients followed
for a mean of 2.5 years. The incidence of recurrent
stroke was 9.0% with the combination and 8.8% with
clopidogrel. The incidence of major hemorrhagic
events was 4.1% (419 events) with the combination
compared to 3.6% (365 events) with clopidogrel. The
125


Revised 2/23/15: In the Clopidogrel Plus Aspirin section, the last sentence has been revised. In the Conclusion, "90 days" has been
changed to "21 days"

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®

net risk of a recurrent stroke or major hemorrhagic
event was similar in the 2 groups, but the incidence
of intracranial hemorrhage was significantly greater
with the combination (147 vs. 103 events), as was the
incidence of permanent discontinuation of treatment
(16.4% vs. 10.6%), mainly due to headache.4
CLOPIDOGREL PLUS ASPIRIN — In 7599 patients
with a recent ischemic stroke or TIA and at least one
additional vascular risk factor who were already taking
clopidogrel 75 mg daily, a randomized, double-blind trial
(MATCH) compared the addition of aspirin or placebo.
The combination showed no significant benefit over
clopidogrel alone in preventing a composite of stroke,
vascular death, MI, or rehospitalization for acute
ischemia, and it doubled the incidence of life-threatening
bleeding (2.6% vs. 1.3%).5 Studies comparing clopidogrel
plus aspirin with aspirin alone in patients who have had
a stroke generally also found no significant benefit with
the combination and a higher risk of bleeding, but one
90-day, randomized controlled trial in China (CHANCE)
that enrolled 5170 patients within 24 hours after a minor
ischemic stroke or TIA and limited the treatment duration
of clopidogrel plus aspirin to 21 days found significantly
fewer recurrences with the combination compared to
aspirin alone (212 vs. 303 recurrences).6

ORAL ANTICOAGULANTS — Randomized trials comparing warfarin with antiplatelet drugs for prevention of
recurrent stroke have found no evidence of benefit with
warfarin and a higher incidence of major bleeding.7 No
data are available on the use of other oral anticoagulants
for this indication.
CONCLUSION — For prevention of stroke recurrence
in patients who have had an ischemic stroke or
a TIA, American Heart Association and American
Stroke Association guidelines recommend aspirin
monotherapy (50-325 mg/day) or a combination of
aspirin 25 mg and extended-release dipyridamole
200 mg (Aggrenox, and generics) twice daily as initial
therapy, with clopidogrel (Plavix, and generics) 75 mg
once-daily monotherapy as an option. The guidelines
also recommend considering use of clopidogrel plus
aspirin if that combination is started within 24 hours
after a minor ischemic stroke or TIA and discontinued
after 21 days; this combination is not recommended
for routine long-term secondary prevention because
of an increased risk of hemorrhage compared with
either aspirin or clopidogrel alone. ■
1. WN Kernan et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for
healthcare professionals from the American Heart Association/
American Stroke Association. Stroke 2014; 45:2160.

126

Vol. 56 (1457)

December 8, 2014

2. SM Weisman and DY Graham. Evaluation of the benefits and
risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med 2002;
162:2197.
3. ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin
alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367:1665.
4. RL Sacco et al. Aspirin and extended-release dipyridamole versus
clopidogrel for recurrent stroke. N Engl J Med 2008; 359:1238.
5. HC Diener et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic
attack in high-risk patients (MATCH): randomised, doubleblind, placebo-controlled trial. Lancet 2004; 364:331.
6. Y Wang et al. Clopidogrel with aspirin in acute minor stroke or
transient ischemic attack. N Engl J Med 2013; 369:11.
7. EL De Schryver et al. Vitamin K antagonists versus antiplatelet therapy after transient ischaemic attack or minor ischaemic
stroke of presumed arterial origin. Cochrane Database Syst Rev
2012; 9:CD001342.

IN BRIEF

Adding Ezetimibe to a Statin Improves
Clinical Outcomes
Combining a statin with another drug that lowers
low-density lipoprotein cholesterol (LDL-C), such as
colesevelam (Welchol), niacin (Niaspan, and others), or
ezetimibe (Zetia), can reduce LDL-C levels more than
a statin alone, but studies convincingly demonstrating
that such combinations improve clinical outcomes
have been lacking. The results of a long-term
randomized, double-blind clinical trial (IMPROVE-IT)
recently presented at the American Heart Association's
Scientific Sessions 2014 indicate that addition of

ezetimibe to simvastatin in high-risk patients reduces
cardiovascular events.1
IMPROVE-IT compared the efficacy of simvastatin
40 mg plus placebo with that of simvastatin 40 mg
plus ezetimibe 10 mg (Vytorin) in preventing the
primary endpoint, a composite of cardiovascular
events (cardiovascular death, MI, hospital admission
for unstable angina, coronary revascularization, or
stroke) in patients with acute coronary syndrome
and normal LDL-C levels (≤125 mg/dL; mean 95
mg/dL). After one year, mean LDL-C was reduced
further with the addition of ezetimibe (to 53.2 vs.
69.9 mg/dL with simvastatin alone). After 7 years,
2742 events had occurred among the 9077 patients
taking simvastatin plus placebo and 2572 among the
9067 taking simvastatin plus ezetimibe (event rate:
34.7% vs. 32.7%; p = 0.016). There was no significant
difference between the 2 groups in noncardiovascular
adverse events, including gallbladder-related events,
myopathy, or cancer. ■
1. C Cannon et al. IMProved Reduction of Outcomes: Vytorin
Efficacy International Trial. Available at www.timi.org/index.
php?page=improve-it-timi-40. Accessed November 21, 2014.

Online Only Article
In Brief: Topiramate Extended-Release Capsules (Qudexy XR)
www.medicalletter.org/TML-article-1457f


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The Medical Letter

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on Drugs and Therapeutics
Objective Drug Reviews Since 1959

Volume 56

ISSUE

ISSUE No.

1433
1457

December 8, 2014
IN THIS ISSUE

In Brief: Topiramate Extended-Release Capsules (Qudexy XR)..............................online only

Volume 56

IN BRIEF

Pronunciation Key :

Topiramate Extended-Release Capsules
(Qudexy XR)
The FDA has approved a new extended-release
capsule formulation of topiramate (Qudexy XR –
Upsher Smith), which can be opened and sprinkled
on food for patients who have difficulty swallowing
tablets or capsules, for treatment of epilepsy. Qudexy
XR was marketed as a branded drug in March 2014
and as a generic drug four months later. An earlier
extended-release formulation (Trokendi XR) must be
swallowed whole.
Table 1. Oral Formulations of Topiramate for Epilepsy
Drug

Formulations

Immediate-release –
generic
25, 50, 100,
200 mg tabs;
15, 25 mg
sprinkle caps
Topamax
25, 50, 100,
(Janssen)
200 mg tabs
Topamax Sprinkle
15, 25 mg caps
(Janssen)
Extended-release –

Trokendi XR
(Supernus)
Qudexy XR
(Upsher Smith)
generic

Usual
Adult Dosage1 Cost2
100-200 mg/ $10.10
day in 2
divided doses

25, 50, 100,
100-200 mg
200 mg caps
once/d
25, 50, 100, 150,
200 mg caps

Topiramate: toe pir' a mate

Qudexy: cue deks' ee

Trokendi  XR is approved for initial monotherapy in
patients ≥10 years old with partial-onset seizures
or primary generalized tonic-clonic seizures and
for adjunctive therapy in patients ≥6 years old with
partial-onset seizures, primary generalized tonicclonic seizures, or seizures associated with LennoxGastaut syndrome. Qudexy XR has been approved for
the same indications, but the indication for adjunctive
therapy has been extended to children ≥2 years old.

Topiramate has been available for many years in
immediate-release formulations (Topamax, and
others) for the same indications for patients ≥2 years
old. Trokendi XR and Qudexy XR both appear to be
bioequivalent to immediate-release formulations of
topiramate; whether they are bioequivalent to one
another has not been established. ■

475.70
545.00

445.20
365.00
186.80

1. For monotherapy. Higher doses (up to a maximum of 400 mg/day) may
be needed for adjunctive use.
2. Approximate WAC for 30 days’ treatment at the lowest usual adult
dosage. WAC = wholesaler acquisition cost or manufacturer’s published
price to wholesalers; WAC represents a published catalogue or list price
and may not represent an actual transactional price. Source: AnalySource® Monthly. November 5, 2014. Reprinted with permission by First
Databank, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/
drug-pricing-policy.

e126

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Issue 1457 Questions

(Correspond to questions #111-120 in Comprehensive Exam #71, available January 2015)
Antiviral Drugs for Seasonal Influenza 2014-2015
1. How effective have neuraminidase inhibitors been for
prophylaxis after exposure to susceptible strains of seasonal
influenza?
a. 90-100%
b. 70-90%
c. 50-70%
d. <50%
2. Antiviral treatment of influenza is recommended for which of the
following patients with suspected influenza?

a. a 15-month-old boy
b. a 78-year-old woman
c. a 25-year-old woman who gave birth 1 week ago
d. all of the above
3. Pregnant women with influenza:
a. should be treated with oseltamivir
b. should not be treated with an antiviral drug
c. have a low risk of complications
d. should not be treated with an antiviral drug during the first
trimester
Two New Drugs for Idiopathic Pulmonary Fibrosis
4. The only treatment that has been shown to prolong survival in
patients with advanced IPF is:
a. prednisone
b. pirfenidone
c. nintedanib
d. lung transplant
5. Clinical trials demonstrating the efficacy of pirfenidone and
nintedanib for treatment of IPF were in patients with:
a. asymptomatic disease
b. mild to moderate disease
c. moderate to severe disease
d. all of the above
6. Both pirfenidone and nintedanib:
a. should be taken with food
b. have adverse gastrointestinal effects
c. may be less effective in smokers
d. all of the above

Invokamet and Xigduo XR – Two New Combinations for Type 2

Diabetes
7. A 54-year-old woman with type 2 diabetes, mild hypertension,
and a BMI of 31.2 has not achieved her glycemic targets with
metformin and, based on favorable comments she has seen on
the Internet, would like to switch to Invokamet. You could tell
her that:
a. this combination drug would probably cause weight gain
b. this combination drug would probably increase her blood
pressure
c. one of the drugs in the combination could cause genital
mycotic infections
d. all of the above
8. In randomized, double-blind trials in patients who had not
achieved glycemic goals with metformin, addition of either
canagliflozin or dapagliflozin lowered A1C by:
a. 0.0-0.4%
b. 0.4-0.9%
c. 1.0-1.5%
d. 1.4-1.9%
9. Which of the following has been associated with an increased
incidence of bladder cancer?
a. canagliflozin
b. dapagliflozin
c. both
d. neither
Secondary Prevention of Stroke
10. For prevention of stroke recurrence in patients who had an
ischemic stroke or TIA more than 24 hours before starting
treatment, AHA/ASA guidelines recommend:
a. aspirin plus clopidogrel

b. warfarin
c. aspirin monotherapy or aspirin plus extended-release
dipyridamole
d. none of the above

ACPE UPN: Per Issue Exam: 0379-0000-14-457-H01-P; Release: December 8, 2014, Expire: December 8, 2015
Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016
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; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; 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.,
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