The medical letter on drugs and therapeutics july 20 2015

Prestalia – Another Combination for Hypertension ...p 101p 103 Namzaric – A Combination of 2 Old Drugs for Alzheimer’s Disease ...p 105 on Drugs and Therapeutics Objective Drug Reviews S

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IN THIS ISSUE

ISSUE

1433

Volume 56

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

ISSUE No

1473 Aptensio XR – A Long-Acting Methylphenidate for ADHD Prestalia – Another Combination for Hypertension p 101p 103

Namzaric – A Combination of 2 Old Drugs for Alzheimer’s Disease p 105

on Drugs and Therapeutics Objective Drug Reviews Since 1959

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on Drugs and Therapeutics Objective Drug Reviews Since 1959

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ISSUE

1433

Volume 56

ISSUE No

1473 Prestalia – Another Combination for Hypertension Namzaric – A Combination of 2 Old Drugs for Alzheimer’s Disease p 103p 105

ALSO IN THIS ISSUE

The FDA has approved Aptensio XR (Rhodes), an

extended-release formulation of methylphenidate

hydrochloride, for treatment of attention-defi cit/

hyper activity disorder (ADHD) The Aptensio XR

capsules contain multilayer beads designed to provide

both a rapid onset and a long duration of action This

formulation of methylphenidate has been available in

Canada as Biphentin since 2006.

have been found to release the drug at a slower rate after

7 hours and may have a shorter duration of action.3-5

Immediate-release tablets are sometimes given in addition to long-acting formulations to provide a boost early in the morning or to smooth withdrawal later in the day

CLINICAL STUDIES — In a randomized, double-blind,

placebo-controlled trial, 26 children 6-12 years old with

ADHD were titrated to an optimal dose of Aptensio XR

for 2-4 weeks, followed by crossover treatment for 1 week each with placebo and the new methylphenidate formulation After each 1-week treatment period, the children were evaluated using the SKAMP-Total score, which measures ADHD symptoms in a laboratory school setting, at 9 time points between 1 and 12 hours post-dose SKAMP-Total scores were signifi cantly better (lower) with the active drug than with placebo at each of the 9 time points.6

In a double-blind trial, 230 children 6-17 years old with

ADHD were randomized to receive Aptensio XR 10, 15,

20, or 40 mg or placebo for 1 week ADHD symptoms,

Aptensio XR – Another

Long-Acting Methylphenidate for ADHD

▶

Table 1 Pharmacology of Some Oral Long-Acting Methylphenidate Products

Aptensio XR Concerta Ritalin LA Metadate CD Quillivant XR

Formulation ER capsules ER tablets ER capsules ER capsules ER oral suspension

Mechanism of Multilayer beads Osmotic-release Beads Beads Powder

drug delivery 40% IR, 60% CR delivery system 50% IR, 50% DR 30% IR, 70% ER 20% IR, 80% DR

20% IR, 80% CR

Tmax 2 h and 8 h 1 h and 6-10 h 2 h and 5.5-6.6 h 1.5 h and 4.5 h 5 h

ER = extended-release; IR = immediate-release; CR = controlled-release; DR = delayed-release

1 Concerta, Ritalin LA, and Metadate CD have generic equivalents, which could have a different mechanism of drug delivery and somewhat different

pharmacokinetic parameters.

2 The generic formulations manufactured by Mallinckrodt and UCB are not considered therapeutically equivalent to Concerta The only generic formulation currently

considered therapeutically equivalent (AB-rated) is an authorized generic manufactured by Janssen and marketed by Actavis (http://www.fda.gov/drugs/drug safety/ucm422568.htm).

Pronunciation Key Methylphenidate: meth” il fen’ i date Aptensio: app ten’ see oh

METHYLPHENIDATE — Methylphenidate is effective in

reducing the symptoms of ADHD in both children and

adults.1,2 The effects of immediate-release

methyl-phenidate products on behavior begin within 30 minutes

and last for 3-5 hours; repeat dosing at mid-day is

usually required Long-acting methylphenidate products

are dosed once daily Some generic formulations of

Concerta, which has a duration of action of 10-12 hours,

as measured by the ADHD-RS-IV questionnaire,

decreased from baseline with all doses of the active

drug, but only the 20- and 40-mg doses resulted in

signifi cantly lower symptom scores compared to

placebo.7 Patients who completed the double-blind

trial and enrolled in an 11-week open-label phase were

titrated to their optimal dose of Aptensio XR

ADHD-RS-IV scores continued to decline throughout the

open-label phase

No studies are available comparing Aptensio XR

directly with other long-acting methylphenidate

form-ulations

ADVERSE EFFECTS — The most common adverse

effects reported with Aptensio XR (occurring in ˃5%

of patients and at a higher rate than with placebo)

were headache, insomnia, abdominal pain, and

decreased appetite

Adverse effects of stimulants generally include

suppression of appetite, failure to gain weight,

slow-ing of growth, tachycardia, irritability, insomnia, tics,

and rarely priapism and peripheral vasculopathy

Stimulants can induce or exacerbate symptoms

in patients with psychiatric disorders; these drugs

should be used with caution in patients with a history

of mania, psychosis, drug dependence, or alcoholism

Several large studies have found no evidence that stimulants used to treat ADHD increase the risk of seri-ous cardiovascular events in children or adults Patients with no history or clinical signs of heart disease do not need to undergo an electrocardiogram or consult with a cardiologist before starting treatment with a stimulant.8

Use of stimulants should be avoided in patients with structural cardiac abnormalities, cardiomyopathy, seri-ous arrhythmias, or coronary artery disease

PREGNANCY AND LACTATION — Methylphenidate did

not cause any teratogenic effects in rats and rabbits when administer ed at 2 and 11 times, respectively, the maximum recommended human dose Spina bifi da occurred in rabbits and decreased body weight occurred in rats given methylphenidate at doses that were, respectively, 40 and 4 times the maximum recommended human dose Small amounts of methylphenidate are present in breast milk; no adverse effects on infants have been reported, but long-term studies are lacking

DRUG INTERACTIONS — Methylphenidate should

not be administered concurrently with a monoamine oxidase inhibitor (MAOI), or within 14 days after stopping one Alcohol consumption can increase the rate of release of methylphenidate from the

Aptensio XR capsule and should be avoided.

Table 2 Some Long-Acting Methylphenidate Products for ADHD

Some Available Pediatric Dosage 1 Adult Dosage

Aptensio XR3 (Rhodes) 10, 15, 20, 30, 40, 50, 60 mg ER caps 4 10 mg qAM/30 mg qAM No data $195.00

Concerta (Janssen) 18, 27, 36, 54 mg ER tabs 5 18 mg qAM/36 mg qAM 18 or 36 mg qAM/72 mg qAM 265.20

Daytrana7 (Noven) 10 mg/9 hrs, 15 mg/9 hrs, 20 mg/9 hrs, 10 mg patch on 9 hrs, 30 mg patch on 9 hrs, off 275.80

30 mg/9 hrs transdermal patches 8 off 15 hrs/30 mg patch 15 hrs/60 mg patch on

on 9 hrs, off 15 hrs 9 9 hrs, off 15 hrs 9

Metadate CD3 (UCB) 10, 20, 30, 40, 50, 60 mg ER caps 4 20 mg qAM/30 mg qAM 20 mg qAM/80 mg qAM 206.70

Ritalin LA3,10 (Novartis) 10, 20, 30, 40, 60 mg ER caps 4 10-20 mg qAM/30 mg qAM 10-20 mg qAM/80 mg qAM 212.70

Quillivant XR (Pfi zer) 25 mg/5 mL ER susp 11 20 mg qAM/30-40 mg qAM No data 204.50

ER = extended-release

1 Dosage for children ≥6 years old.

2 Approximate WAC for 30 days' treatment with the lowest usual pediatric 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 July 5,

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

3 Alcohol consumption may increase the rate of release of methylphenidate and should be avoided.

4 The contents of the capsule may be sprinkled on a small amount of applesauce or ice cream and taken immediately Pharmacokinetics are identical whether the beads are swallowed whole inside a capsule or sprinkled on food.

5 Tablets must be swallowed whole, and should not be crushed or chewed.

6 The generic formulations manufactured by Mallinckrodt and UCB are not considered therapeutically equivalent to Concerta The only generic formulation

currently considered therapeutically equivalent (AB-rated) is an authorized generic manufactured by Janssen and marketed by Actavis (http://www.fda.gov/ drugs/drug safety/ucm422568.htm).

7 FDA-approved only for use in children 6-17 years old

8 Daytrana is supplied in sealed trays containing 10 or 30 patches in individual pouches.

9 The patch should be applied 2 hours before an effect is needed and removed 9 hours after application The patch can be removed before 9 hours if a shorter duration of action is desired.

10 Should not be taken with antacids or other drugs that decrease gastric acidity.

11 Available in bottles containing 60, 120, 150, or 180 mL Must be reconstituted before administration and is stable for up to 4 months Each bottle is packaged with an adapter and dosing syringe

1 L Greenhill et al Effi cacy and safety of immediate-release

methylphenidate treatment for preschoolers with ADHD J Am

Acad Child Adolesc Psychiatry 2006; 45:1284.

2 T Epstein et al Immediate-release methylphenidate for

atten-tion defi cit hyperactivity disorder (ADHD) in adults Cochrane

Database Syst Rev 2014 Sept 18; 9:CD005041.

3 WE Pelham et al Once-a-day Concerta methylphenidate versus

three-times-daily methylphenidate in laboratory and natural

settings Pediatrics 2001; 107:E105.

4 FDA Methylphenidate hydrochloride extended release tablets

(generic Concerta) made by Mallinckrodt and Kudco Available

at: http://www.fda.gov/drugs/drugsafety/ucm422568.htm

Ac-cessed July 9, 2015.

5 R Maldonado Comparison of the pharmacokinetics and clinical

effi cacy of new extended-release formulations of

methylpheni-date Expert Opin Drug Metab Toxicol 2013; 9:1001

6 SB Wigal et al A randomized placebo-controlled double-blind

study evaluating the time course of response to

methylpheni-date hydrochloride extended-release capsules in children with

attention-defi cit/hyperactivity disorder J Child Adolesc

Psy-chopharmacol 2014; 24:562

7 SB Wigal et al Effi cacy of methylphenidate hydrochloride

ex-tended-release capsules (Aptensio XR™) in children and

ado-lescents with attention-defi cit/hyperactivity disorder: a phase

III, randomized, double-blind study CNS Drugs 2015; 29:331.

8 Drugs for ADHD Med Lett Drugs Ther 2015; 57:37.

Prestalia — Another Combination

for Hypertension

The FDA has approved Prestalia (Symplmed), an

oral fi xed-dose combination of the dihydropyridine

calcium channel blocker amlodipine (Norvasc, and

generics) and a new salt form of the

angiotensin-converting enzyme (ACE) inhibitor perindopril, for

treatment of hypertension in patients not adequately

controlled on monotherapy or already taking both

drugs, and in those just starting therapy who are

likely to need multiple drugs to control their blood

pressure The new salt form (perindopril arginine) is

more stable and has a longer shelf-life than

perindo-pril erbumine (Aceon, and generics).1 Two other ACE

inhibitor/calcium channel blocker combinations,

benazepril/amlodipine (Lotrel, and generics) and

trandolapril/verapamil ER (Tarka, and generics), have

been available in the US for many years

Pronunciation Key Perindopril: per in’ doe pril Prestalia: pres ta li a

Amlodipine: am loe’ di peen

STANDARD TREATMENT — Nearly all recent guidelines

recommend a thiazide-type diuretic (chlorthalidone

is preferred), a calcium channel blocker, an ACE inhibitor, or an angiotensin receptor blocker (ARB)

as initial therapy for hypertension in most non-black patients For black patients, a thiazide-type diuretic or calcium channel blocker is preferred for initial therapy, except for those with chronic kidney disease or heart failure, who should receive an ACE inhibitor or an ARB Beta blockers generally are no longer recommended

as initial therapy except for patients with another indication, such as coronary heart disease or left ventricular dysfunction Most guidelines recommend

an ACE inhibitor or an ARB over other classes for initial treatment of hypertension in non-black patients with diabetes

Table 1 Initial Monotherapy for Hypertension

General Population

Non-black THZD, ACE inhibitor, ARB, or CCB Black THZD or CCB

Chronic Kidney Disease (CKD)

Non-black ACE inhibitor or ARB Black ACE inhibitor or ARB

Diabetes

Non-black ACE inhibitor or ARB Black THZD or CCB 1 THZD = thiazide-type diuretic; ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker

1 Black patients with both diabetes and CKD should receive an ACE inhibitor

or an ARB.

▶

Many patients with hypertension need more than one drug to control their blood pressure If monotherapy does not achieve blood pressure goals, adding a second drug with a different mechanism of action is generally more effective than increasing the dose of the fi rst drug and often allows for use of lower, better tolerated doses of both drugs If an ACE inhibitor or an ARB was used initially, it would be reasonable to add

a thiazide-type diuretic or a calcium channel blocker When baseline blood pressure is >20/10 mm Hg above goal, many experts would begin therapy with two drugs.2

CLINICAL STUDIES — Approval of Prestalia was

based on a prospective, active-controlled trial (PATH) in 837 patients with a mean seated blood pressure of 158/101 mm Hg who were randomized

to Prestalia 14/10 mg, perindopril erbumine 16 mg, or

amlodipine 10 mg once daily for 6 weeks The mean reduction in blood pressure with the combination was 10.1/6.3 mm Hg more than with perindopril and

DOSAGE AND ADMINISTRATION — The recommended

starting dosage of Aptensio XR in patients ≥6 years

old is 10 mg once daily in the morning with or

without food The dose can be increased in weekly

increments of 10 mg up to a maximum of 60 mg

once daily The capsules may be swallowed whole or,

alternatively, opened, sprinkled on applesauce, and

taken immediately

CONCLUSION — In the absence of comparative

trials, Aptensio XR appears to offer no clinical

advantage over older long-acting methylphenidate

preparations ■

3.9/2.5 mm Hg more than with amlodipine In black

patients and in those with diabetes, reductions in

blood pressure with the combination were similar to

those with amlodipine alone.3

Another trial in 1581 patients with mild to moderate

uncomplicated hypertension found that the mean

reduction in blood pressure after 8 weeks was

7.2/4.1 mm Hg more with Prestalia 3.5/2.5 mg than

with placebo; the combination was noninferior to the

individual components alone in decreasing blood

pressure.4

ADVERSE EFFECTS — Common adverse effects

of Prestalia include edema, cough, headache, and

dizziness Angioedema and hyperkalemia can occur

with ACE inhibitors The combination is

contra-indicated in patients with hereditary or idiopathic

angioedema

PREGNANCY — Prestalia is classifi ed as category D

(positive evidence of risk) for use during pregnancy

Use of ACE inhibitors during the second and third

trimester reduces fetal renal function and increases

fetal and neonatal morbidity and death

1 E Telejko Perindopril arginine: benefi ts of a new salt of the ACE inhibitor perindopril Curr Med Res Opin 2007; 23:953.

2 Drugs for hypertension Treat Guidel Med Lett 2014; 12:31.

3 WJ Elliott et al Effi cacy and safety of perindopril arginine + amlodipine in hypertension J Am Soc Hypertens 2015; 9:266.

4 S Laurent et al Randomized evaluation of a novel, fi xed-dose combination of perindopril 3.5 mg/amlodipine 2.5 mg as a fi rst-step treatment in hypertension J Hypertens 2015; 33:653.

Table 2 Prestalia and Some Other Combinations for Hypertension

Some Available Usual Adult

Prestalia and Its Components

Perindopril erbumine –

Amlodipine –

Perindopril arginine/amlodipine –

Prestalia (Symplmed) 3.5/2.5, 7/5, 14/10 mg tabs 3.5/2.5 mg-14/10 mg once/d 146.70 3

Other ACE Inhibitor/Calcium Channel Blocker Combinations

Benazepril/amlodipine –

generic 10/2.5, 10/5, 20/5, 20/10, 10/2.5-40/10 mg once/d 23.30

Trandolapril/verapamil ER –

generic 1/240, 2/180, 2/240, 2/180-4/240 mg once/d 126.90

ARB/Calcium Channel Blocker Combinations

Olmesartan/amlodipine – 20/5, 20/10, 40/5, 20/5-40/10 mg once/d

Telmisartan/amlodipine –

generic 40/5, 40/10, 80/5, 40/5-80/10 mg once/d 126.30

Valsartan/amlodipine –

generic 160/5, 160/10, 320/5, 160/5-320/10 mg once/d 51.20

1 Dosage adjustments may be needed for renal or hepatic impairment

2 Approximate WAC for 30 days’ treatment at the lowest usual adult maintenance 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 July 5,

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

3 WAC according to the manufacturer Prestalia is also available through a membership program sponsored by Symplmed (bpcareconnect.com) for $9.95/month or

$19.95/3 months.

DOSAGE AND ADMINISTRATION – The recommended

starting dosage of Prestalia is 3.5/2.5 mg once daily The

dose can be increased every 7-14 days up to a maximum

of 14/10 mg daily Prestalia is not recommended

for patients ≥65 years old, or for those with hepatic impairment or a creatinine clearance <60 mL/min

CONCLUSION – Prestalia, a combination of

the ACE inhibitor perindopril arginine and the dihydropyridine calcium channel blocker amlodipine,

is more convenient and (for patients who enroll in

a manufacturer-sponsored program) may cost less than perindopril and amlodipine taken separately

The strengths of perindopril in the Prestalia

combination are not the same as those in

single-ingredient perindopril erbumine tablets (Aceon, and

generics) ■

Table 1 FDA-Approved Drugs for Alzheimer’s Disease

Drugs Formulations Usual Dosage Starting Dose/Titration Cost 1

Acetylcholinesterase Inhibitors

Donepezil – generic 5, 10, 23 mg tabs 5-10 mg once/d 5 mg once/d; after 4-6 wks $9.60

Aricept (Eisai) in the evening increase to 10 mg once/d; 460.50 orally disintegrating – generic 5, 10 mg orally after an additional 3 months, 32.00

Aricept ODT (Eisai) disintegrating tabs can consider increasing to 460.50

23 mg once/d Galantamine – generic 4, 8, 12 mg tabs; 8-12 mg bid preferably 4 mg bid; after 4 wks increase 144.00

Razadyne2 (Janssen) 4 mg/mL soln with meals 3 to 8 mg bid; after an additional 291.30

4 wks can increase to 12 mg bid extended-release – generic 8, 16, 24 mg ER caps 16-24 mg once/d 8 mg once/d; after 4 wks increase 140.00

Razadyne ER (Janssen) preferably with to 16 mg once/d; after an additional 291.30

the AM meal 4 wks can increase to 24 mg once/d Rivastigmine – generic 1.5, 3, 4.5, 6 mg caps 4.5-6 mg bid with 1.5 mg bid; increase in 145.30

Exelon (Novartis) 1.5, 3, 4.5, 6 mg caps; meals increments of 1.5 mg bid 343.90

2 mg/mL soln every 2 wks 4 to 6 mg bid transdermal

Exelon Patch (Novartis) 4.6 mg/24 hrs, 9.5 mg or 13.3 mg 4.6 mg once/d; after 4 wks 450.60

9.5 mg/24 hrs, once/d increase to 9.5 mg once/d;

13.3 mg/24 hrs after an additional 4 wks can patches increase to 13.3 mg once/d

NMDA-Receptor Antagonist

Memantine – generic 5, 10 mg tabs; 10 mg bid 5 5 mg once/d; increase in increments N.A 6

Namenda (Forest) 2 mg/mL soln of 5 mg/wk to 10 mg bid 339.10 extended-release

Namenda XR (Forest) 7, 14, 21, 28 mg ER caps 28 mg once/d 5 7 mg once/d; increase in increments 322.10

of 7 mg/wk to 28 mg once/d

NMDA-Receptor Antagonist/Acetylcholinesterase Inhibitor

Memantine/donepezil 14/10 mg, 28/10 mg 28/10 mg once/d Approved for patients previously 322.10

Namzaric (Forest) ER caps in the evening 7 stabilized on memantine 10 mg bid

or 28 mg once/d and donepezil 10 mg once/d 7

ER = extended-release; N.A = not yet available

1 Approximate WAC for 30 days’ treatment at the lowest usual 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 July 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy

2 Formerly Reminyl.

3 In patients with CrCl 9-59 mL/min or moderate hepatic impairment, dosage should not exceed 16 mg/day Patients with CrCl <9 mL/min or severe hepatic impairment should not take galantamine.

4 Every 4 weeks for dementia associated with Parkinson’s disease.

5 In patients with severe renal impairment (CrCl 5-29 mL/min) the target dose of memantine is 5 mg bid and of extended-release memantine is 14 mg once/day.

6 Generic formulations of memantine 5- and 10-mg tablets have been approved by the FDA, but are not yet available.

7 The recommended dosage of Namzaric is 14/10 mg once/day for patients with severe renal impairment (CrCl 5-29 mL/min) previously stabilized on memantine

5 mg bid or 14 mg once/day and donepezil 10 mg once/day.

Namzaric – A Combination of 2

Old Drugs for Alzheimer’s Disease

▶

The FDA has approved Namzaric (Forest), a fi

xed-dose combination of extended-release (ER)

memantine (Namenda XR), an NMDA-receptor

antagonist, and donepezil (Aricept, and generics),

an acetylcholinesterase inhibitor, for treatment of

moderate to severe Alzheimer’s type dementia in

patients previously stabilized on both drugs The

patent for Namenda has recently expired and generic

formulations of memantine 5- and 10-mg tablets have

been approved

STANDARD TREATMENT — Acetylcholinesterase

inhibitors and memantine are the only drugs currently

available for treatment of Alzheimer’s disease (AD)

They have produced modest but apparently persistent improvements in cognition, activities of daily living, and behavior None of these agents have been shown

to stop or reverse the underlying neurodegenerative process.1

Many patients with moderate to severe AD are treated with a combination of an acetylcholinesterase inhibitor and memantine Some randomized, placebo-controlled clinical trials have found that combination therapy produces more improvement in measures of cognition and function compared to treatment with an acetylcholinesterase inhibitor alone,2,3 but others have

Pronunciation Key Memantine: mem' an teen Namzaric: nam zair' ick

Donepezil: doe nep' e zil

not.4 A pooled area-under-the-curve analysis of

six-month data from four randomized, placebo-controlled

trials in a total of ˃1400 patients with moderate to

severe AD found that adding memantine to donepezil

signifi cantly improved a composite index of cognition,

function, behavior, and global status compared to

treatment with donepezil or memantine alone; these

clinical benefi ts continued to accumulate over six

months of treatment.5

CLINICAL STUDIES — No new effi cacy data were

required for approval of the combination Two

single-dose, randomized, open-label, crossover studies

in a total of 74 healthy volunteers 18-45 years old

evaluated the combination capsule formulation for

bioequivalence with coadministered ER memantine

and donepezil The capsule containing 28 mg of ER

memantine and 10 mg of donepezil was bioequivalent

to the same doses of the coadministered drugs in

both studies The second study also found that the

bioavailability of the combination capsule was not

affected by taking it after a high-fat meal or sprinkling

its contents on applesauce.6

ADVERSE EFFECTS — Memantine is usually well

tolerated Adverse effects include dizziness,

headache, and diarrhea Agitation and confusion can

occur, particularly with higher doses in older patients

Insomnia, hallucinations, and delusions have also

been reported

The most common adverse effects of donepezil have

been nausea, vomiting, diarrhea, and anorexia Urinary

incontinence, vivid dreams, bradycardia, and syncope

have also occurred Insomnia, fatigue, and muscle

cramps have been reported

DRUG INTERACTIONS — Concurrent use of memantine

and other NMDA-receptor antagonists such as

dextromethorphan or amantadine, which is used to

treat Parkinson’s disease, could theoretically increase

the risk of adverse effects Concomitant use of drugs

that raise urine pH such as carbonic anhydrase

inhibitors or sodium bicarbonate could decrease renal

excretion of memantine According to the labeling

for memantine, clearance was reduced by about 80%

under alkaline urine conditions (pH 8) Memantine

does not appear to interact with drugs metabolized by

CYP enzymes

Use of donepezil with another cholinergic drug such

as bethanechol could result in additive cholinergic

adverse effects The activity of donepezil could be

decreased if it is administered with drugs that have

1 Drugs for cognitive loss and dementia Treat Guidel Med Lett 2013; 11:95.

2 PN Tariot et al Memantine treatment in patients with moder-ate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial JAMA 2004; 291:317.

3 GT Grossberg et al The safety, tolerability, and effi cacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors CNS Drugs 2013; 27:469.

4 R Howard et al Donepezil and memantine for moderate-to-severe Alzheimer’s disease N Engl J Med 2012; 366:893.

5 A Atri et al Cumulative, additive benefi ts of memantine-done-pezil combination over component monotherapies in moderate

to severe Alzheimer’s dementia: a pooled area under the curve analysis Alzheimers Res Ther 2015; 7:28.

6 R Boinpally et al A novel once-daily fi xed-dose combination of memantine extended release and donepezil for the treatment of moderate to severe Alzheimer’s disease: two phase I studies in healthy volunteers Clin Drug Investig 2015 May 28 (epub).

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

anticholinergic effects such as fi rst-generation antihistamines, drugs for overactive bladder, or tricyclic antidepressants Donepezil is metabolized by CYP3A4 and 2D6 Inhibitors of CYP3A4 or 2D6 could increase serum concentrations of donepezil, and 3A4 inducers could reduce them.7 Concomitant use of donepezil with an NSAID could increase the risk of GI bleeding and use with a beta blocker could increase the risk of bradycardia

DOSAGE AND ADMINISTRATION — Namzaric is

available in capsules containing 14 or 28 mg of ER memantine and 10 mg of donepezil Patients currently taking either memantine 10 mg twice daily or ER memantine 28 mg once daily with donepezil 10 mg can

be switched to Namzaric 28 mg/10 mg once daily in the

evening Patients with severe renal impairment taking either memantine 5 mg twice daily or ER memantine 14

mg once daily with donepezil 10 mg can be switched

to Namzaric 14 mg/10 mg Namzaric capsules can be

taken with or without food and should be swallowed whole or opened and sprinkled on applesauce

CONCLUSION — Namzaric is a new once-daily fi

xed-dose combination of two old drugs, extended-release

memantine (Namenda XR) and donepezil (Aricept, and

generics), for treatment of Alzheimer’s disease Taking memantine and an acetylcholinesterase inhibitor together may be superior to taking either drug alone in patients with moderate to severe Alzheimer’s disease, but for many patients the ease of administration associated with use of a fi xed-dose combination may not outweigh the flexibility, safety, and likely lower cost

of taking the drugs separately at individually optimized doses None of these drugs have been shown to delay progression of the disease ■

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3 Review the effi cacy and safety of the combination of extended-release memantine and donepezil (Namzaric) for treatment of moderate to severe Alzheimer’s type

dementia.

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Issue 1473 Questions

(Correspond to questions #11-20 in Comprehensive Exam #73, available January 2016)

6 A 67-year-old black man with hepatic impairment recently saw

an advertisement on television for Prestalia and asks you if he should switch from amlodipine to Prestalia You could tell him

that:

b the new combination should not be used in patients with hepatic impairment

c reductions in blood pressure with Prestalia in one clinical

trial were similar to those with amlodipine alone in black patients

d all of the above

7 Adverse effects of Prestalia include:

d all of the above

Namzaric – A Combination of 2 Old Drugs for Alzheimer’s Disease

8 Acetylcholinesterase inhibitors and memantine:

a are the only drugs for Alzheimer’s disease that have been shown to stop the underlying neurodegenerative process

b are available together in fi xed-dose combinations under a number of brand names

c are the only drugs approved by the FDA for treatment of Alzheimer’s disease

d all of the above

9 Namzaric has been compared to which of the following in clinical

effi cacy trials?

c memantine and donepezil given separately

d none of the above

10 The most common adverse effects of donepezil have been:

Aptensio XR – Another Long-Acting Methylphenidate for ADHD

1 Aptensio XR:

a is identical to Concerta

b was removed from the market in Europe because of

concerns about teratogenicity

c has been available for years under a different brand name in

Canada

d all of the above

2 Which long-acting methylphenidate products have a duration of

action that can extend to 12 hours?

d Aptensio XR, Concerta, and Quillivant XR

3 In clinical trials, Aptensio XR has been compared to:

b Ritalin LA

c Concerta and Quillivant XR

d all of the above

4 A woman brings her 8-year-old son to see you because the school

nurse said he has ADHD and should take methylphenidate She is

concerned because she has heard that the drug can damage the

heart The boy has no history or clinical signs of heart disease You

could tell her that:

a he should have an electrocardiogram before taking the drug

b he should have a cardiology consultation before taking the

drug

c he does not need to have an ECG or see a cardiologist

d he could take the drug, but stimulants used to treat

ADHD have been shown to increase the risk of serious

cardiovascular events in children

Prestalia – Another Combination for Hypertension

5 Which of the following antihypertensive drugs is not

recommended as initial monotherapy in healthy black patients?

b calcium channel blocker

d all of the above

ACPE UPN: Per Issue Exam: 0379-0000-15-473-H01-P; Release: July 20, 2015, Expire: July 20, 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; 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; 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 University

MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown

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Founded in 1959 by Arthur Kallet and Harold Aaron, M.D.

Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofi t organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial

process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors do not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission.

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