The medical letter on drugs and therapeutics july 18 2016

1499 The Medical Letter on Drugs and Therapeutics SGLT2 Inhibitors and Renal Function ...p 91 Onzetra Xsail — Sumatriptan Nasal Powder ...p 92 Buprenorphine Implants Probuphine for Opioi

Trang 1

FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS

The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited.

Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited.

By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc.

or call customer service at: 800-211-2769

Important Copyright Message

IN THIS ISSUE

ISSUE

1433

Volume 56

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

ISSUE No

1499

The Medical Letter

on Drugs and Therapeutics

SGLT2 Inhibitors and Renal Function .p 91

Onzetra Xsail — Sumatriptan Nasal Powder p 92

Buprenorphine Implants (Probuphine) for Opioid Dependence p 94

Brivaracetam (Briviact) for Epilepsy p 95

Asfotase Alfa (Strensiq) for Hypophosphatasia online only

In Brief: Cabozantinib (Cabometyx) for Advanced Renal Cell Carcinoma online only

Trang 2

91

Take CME Exams

ISSUE

1433

Volume 56

ISSUE No

1499 Onzetra Xsail — Sumatriptan Nasal Powder Buprenorphine Implants (Probuphine) for Opioid Dependence p 92p 94

Brivaracetam (Briviact) for Epilepsy p 95

Asfotase Alfa (Strensiq) for Hypophosphatasia online only

In Brief: Cabozantinib (Cabometyx) for Advanced Renal Cell Carcinoma online only

ALSO IN THIS ISSUE

At the same time that the FDA announced it was

strengthening existing warnings about the risk of acute

kidney injury in patients with type 2 diabetes treated with

the sodium-glucose co-transporter 2 (SGLT2) inhibitors

canagliflozin (Invokana, and others) and dapagliflozin

(Farxiga, and others),1 a study was published showing

that the third SGLT2 inhibitor, empagliflozin (Jardiance,

and others), slowed the progression of renal dysfunction

in patients with type 2 diabetes.2

SGLT2 INHIBITION — SGLT2, a membrane protein

expressed mainly in the kidney, transports fi ltered

glucose from the proximal renal tubule into tubular

epithelial cells SGLT2 inhibitors decrease renal

glucose and sodium reabsorption and increase urinary

glucose excretion, resulting in lower blood glucose

levels and a modest reduction in HbA1c These drugs

also increase urinary sodium excretion, cause weight

loss, and lower blood pressure

View our detailed online table: SGLT-2 Inhibitors

ADVERSE EFFECTS — SGLT2 inhibitors can cause

genital mycotic infections, increases in LDL cholesterol,

and ketoacidosis,3,4 and recently the FDA updated the

canagliflozin label to warn about an increased risk of

fracture.5 Warnings about increases in serum creatinine

and decreases in eGFR have been included in the labels

of all three SGLT2 inhibitors since their initial approval;

elderly patients with hypovolemia or pre-existing renal

dysfunction are at increased risk

ACUTE KIDNEY INJURY — SGLT2 inhibitors have diuretic

effects, and drugs that have diuretic effects could increase

the risk of acute kidney injury From March 2013 to October

2015, 101 cases of acute kidney injury in patients taking

canagliflozin (73 patients) or dapagliflozin (28 patients)

SGLT2 Inhibitors and Renal

Function

▶

were reported to the FDA Most of the patients required hospitalization and some received dialysis In more than half the cases, acute kidney injury occurred within one month of starting the drug Among the 101 patients,

51 reported concomitant ACE inhibitor use, 26 reported concomitant diuretic use, and 6 reported concomitant nonsteroidal anti-inflammatory drug (NSAID) use Some patients had a prior history of chronic kidney disease or were dehydrated or hypotensive at the time of the acute kidney injury In most cases, renal function improved after the drug was stopped

EMPAGLIFLOZIN — The EMPA-REG OUTCOME trial,

which found that empagliflozin reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes and established cardiovascular disease,6 also evaluated the long-term effects of the drug on renal function, a pre-specifi ed component

of the secondary microvascular outcome of that trial Over a median follow-up of 3.1 years, incident

or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group, compared

to 388 of 2061 patients (18.8%) in the placebo group, a statistically signifi cant difference Patients randomized

FDA Recommendations to Reduce the Risk of Acute Kidney Injury with SGLT2 Inhibitors

▶ Before starting therapy, consider factors that may predispose patients to acute kidney injury, such as hypovolemia, chronic renal insuffi ciency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs).

▶ Evaluate renal function before starting treatment and periodically thereafter; adjustments should be made based

on eGFR.

▶ If acute kidney injury occurs, discontinue the SGLT2 inhibitor promptly and institute treatment.

▶ Consider temporarily discontinuing the SGLT2 inhibitor

in cases of reduced oral intake (such as acute illness or fasting) or fluid loss (such as gastrointestinal illness or excessive heat exposure).

The Medical Letter publications are protected by US and international copyright laws.

Forwarding, copying or any other distribution of this material is strictly prohibited.

For further information call: 800-211-2769

Trang 3

to empagliflozin were also less likely to have progression

to macroalbuminuria (11.2% vs 16.2% with placebo),

doubling of serum creatinine levels (1.5% vs 2.6% with

placebo), or initiation of renal-replacement therapy

(0.3% vs 0.6% with placebo) The exact mechanism of

these protective effects is unknown, but improved serum

glucose control, reduced glomerular pressure, and

reduced arterial stiffness could play a role.2

co-transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance,

and others) has been shown to slow progression of

renal disease in patients with type 2 diabetes and

established cardiovascular disease Whether the other

two SGLT2 inhibitors, canagliflozin (Invokana, and

others) and dapagliflozin (Farxiga, and others), have

cardiovascular or renal benefi ts is unknown All three

of these drugs could increase serum creatinine and

decrease eGFR, particularly in elderly patients with

hypovolemia and other risk factors ■

Onzetra Xsail – Sumatriptan

Nasal Powder

▶

The FDA has approved Onzetra Xsail (Avanir), a nasal

powder formulation of sumatriptan, for acute treatment

of migraine in adults Nasal spray formulations of

sumatriptan (Imitrex) and zolmitriptan (Zomig) have

been available for many years

Table 1 Pharmacology

Route Intranasal Cmax 21 ng/mL (22-mg dose) Tmax 45 minutes (range 10 mins - 2 hrs) Bioavailability 19% (relative to SC injection) Metabolism Monoamine oxidase (MAO),

predominantly A isoenzyme Half-life 3 hours

Elimination Urine (42% as the major metabolite indole (nasal spray) acetic acid; 3% unchanged)

1 FDA FDA Drug Safety Communication (6/14/2016): FDA

strength-ens kidney warnings for diabetes medicines canagliflozin

(Invo-kana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR) Available

at: www.fda.gov/Drugs/DrugSafety/ucm505860.htm Accessed

July 7, 2016.

2 C Wanner et al Empagliflozin and progression of kidney

dis-ease in type 2 diabetes N Engl J Med 2016 June 14 (epub).

3 In brief: Ketoacidosis with SGLT2 inhibitors Med Lett Drugs

Ther 2015; 57:94.

4 AL Peters et al Euglycemic diabetic ketoacidosis: a potential

complication of treatment with sodium-glucose cotransporter

2 inhibition Diabetes Care 2015; 38:1687.

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

57:139.

6 B Zinman et al Empagliflozin, cardiovascular outcomes, and

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

PHARMACOKINETICS — A single-dose, crossover

study in 20 healthy subjects compared sumatriptan 22-mg nasal powder, 20-mg liquid nasal spray,

100-mg oral tablets, and 6-100-mg SC injection Compared with the nasal spray, use of the nasal powder resulted in

a faster rise in plasma concentrations of sumatriptan and a 27% higher peak serum concentration (Cmax) The Cmax and systemic exposure (AUC) with the nasal powder were signifi cantly lower than with the oral tablet or SC injection.4

CLINICAL STUDIES — FDA approval of sumatriptan

nasal powder was based on the results of a randomized, double-blind, placebo-controlled trial in 212 patients treated for a single acute migraine headache Pain

Table 1 Dosage and Cost of SGLT2 Inhibitors

Drug Formulations Dosage Cost 1

Canagliflozin – 100, 300 mg 100-300 mg $391.70

Invokana (Janssen) tabs once/d 2

Dapagliflozin – 5, 10 mg 5-10 mg 391.70

Farxiga (AstraZeneca) tabs once/d 3

Empagliflozin – 10, 25 mg 10-25 mg 391.70

Jardiance (Boehringer tabs once/d 4

Ingelheim/Lilly)

1 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®

Month-ly July 5, 2016 Reprinted with permission by First Databank, Inc All rights

2 Dosage adjustment and more frequent renal function monitoring are

recom-mended in patients with an eGFR <60 mL/min/1.73 m 2 Dosage is limited to

100 mg once daily in patients with an eGFR of 45 to <60 mL/min/1.73 m 2

Use is not recommended when eGFR is persistently <45 mL/min/1.73 m 2

and is contraindicated in patients with an eGFR <30 mL/min/1.73 m 2

3 Should not be started in patients with an eGFR <60 mL/min/1.73 m 2 Use is

not recommended when eGFR is persistently between 30 and <60 mL/min/

1.73 m 2 and is contraindicated in patients with an eGFR <30 mL/min/1.73 m 2

4 Should not be started in patients with an eGFR <45 mL/min/1.73 m 2 The

drug should be discontinued if eGFR is persistently <45 mL/min/1.73 m 2

Pronunciation Key Sumatriptan: soo" ma trip' tan

SUMATRIPTAN FORMULATIONS — Subcutaneously

administered sumatriptan relieves pain faster (in about 10 minutes) and more effectively than other triptan formulations, but it causes more adverse effects.1,2 With oral sumatriptan, onset of pain relief generally occurs 45-60 minutes after administration, but patients with migraine who have nausea, vomiting,

or gastroparesis may not be able to take or absorb an oral triptan.3 Sumatriptan nasal spray formulations have a more rapid onset of action than oral tablets, but their effi cacy also depends on GI absorption (of the signifi cant portion of the dose that is swallowed), and they can have an unpleasant taste The new breath-powered delivery device used with sumatriptan nasal powder is designed to increase intranasal absorption and reduce the amount of the drug that is swallowed

Trang 4

The Medical Letter ® Vol 58 (1499) July 18, 2016

monoamine oxidase (MAO) inhibitors and sumatriptan increases serum concentrations of sumatriptan; they should not be used within 2 weeks of each other Serotonin syndrome has occurred when triptans were used concomitantly with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants,

or MAO inhibitors

DOSAGE AND ADMINISTRATION — The recommended

dosage of Onzetra Xsail is 22 mg The drug is

supplied in capsules in disposable nosepieces, each containing 11 mg of nasal powder After attaching the nosepiece to the breath-powered delivery device, the patient presses a button to pierce the capsule, inserts the nosepiece deep into one nostril, places the mouthpiece in the mouth, and blows forcefully to deliver the medication These steps are then repeated

in the other nostril One additional 22-mg dose can be administered in a 24-hour period; it should be given at least 2 hours after the fi rst dose

CONCLUSION — Whether sumatriptan nasal powder

(Onzetra Xsail), the fi rst triptan intranasal powder

to be marketed for acute treatment of migraine, offers any advantages in effi cacy or tolerability over sumatriptan or zolmitriptan liquid nasal spray remains

to be established ■

Table 2 Intranasal Triptans for Acute Treatment of Migraine

Drug Formulations Usual Dosage Cost 1

Sumatriptan – Imitrex (GSK) 5, 20 mg/0.1 mL nasal spray 5, 10, or 20 mg intranasally; can be $69.20

repeated once after 2 hrs (max 40 mg/d)

Onzetra Xsail (Avanir) 11 mg nasal powder capsules 22 mg intranasally, can be repeated 61.00

Zolmitriptan – Zomig 2.5, 5 mg/0.1 mL nasal spray 2.5 or 5 mg intranasally; can be repeated 56.90

1 Approximate WAC for one dose at the lowest usual 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 July 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.

relief at 30 minutes post-dose occurred signifi cantly

more often in patients taking sumatriptan (42% vs

27% with placebo) The median time to meaningful

pain relief was 48 minutes in the sumatriptan group

versus >120 minutes with placebo Signifi cantly more

patients achieved the primary endpoint (reduction in

pain intensity from moderate or severe to mild or none

at 2 hours) with sumatriptan nasal powder than with

placebo (68% vs 45%).5

In a randomized, double-blind, crossover trial, 185

patients were treated for multiple migraine attacks

with either sumatriptan nasal powder or 100 mg of

oral sumatriptan Rates of pain relief and pain freedom

were signifi cantly higher with the nasal powder than

with the oral tablets from 15 to 90 minutes post-dose,

but were similar in the two groups from 2 to 48 hours.6

ADVERSE EFFECTS — The most common adverse

effects reported in clinical trials at a higher rate

with sumatriptan nasal powder than with placebo

were abnormal taste (20%), nasal discomfort (11%),

rhinorrhea (5%), and rhinitis (2%)

Angina, myocardial infarction, cardiac arrhythmias,

stroke, seizures, and death have occurred rarely with

triptans Like other triptan formulations, sumatriptan

nasal powder is contraindicated for use in patients

who have had a stroke or transient ischemic attack and

in those with ischemic or vasospastic coronary artery

disease, Wolff-Parkinson-White syndrome, peripheral

vascular disease, ischemic bowel disease, uncontrolled

hypertension, or severe hepatic impairment

PREGNANCY AND LACTATION — Sumatriptan is

classifi ed as category C (fetal harm in animals, no

adequate studies in pregnant women) for use during

pregnancy It has been found in human breast milk

following SC administration; breastfeeding should be

avoided for at least 12 hours after taking the drug

DRUG INTERACTIONS — Administration of sumatriptan

is contraindicated within 24 hours after use of

another triptan or an ergot-containing drug because

vasoconstriction could be additive Concurrent use of

1 Drugs for migraine Treat Guidel Med Lett 2013; 11:107.

2 CJ Derry et al Sumatriptan (all routes of administration) for acute migraine attacks in adults – overview of Cochrane re-views Cochrane Database Syst Rev 2014; 5:CD009108.

3 SD Silberstein and DA Marcus Sumatriptan: treatment across

the full spectrum of migraine Expert Opin Pharmacother 2013; 14:1659.

4 M Obaidi et al Improved pharmacokinetics of sumatriptan with breath powered nasal delivery of sumatriptan powder Head-ache 2013; 53:1323.

5 RK Cady et al A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study) Headache 2015; 55:88.

6 SJ Tepper et al AVP-825 breath-powered intranasal delivery system containing 22 mg sumatriptan powder vs 100 mg oral sumatriptan in the acute treatment of migraines (the COMPASS study): a comparative randomized clinical trial across multiple attacks Headache 2015; 55:621

Trang 5

Buprenorphine Implants (Probuphine)

for Opioid Dependence

▶

Table 1 Some Buprenorphine Products for Opioid Dependence

Buprenorphine

generic 2, 8 mg sublingual tabs 16 mg once/day $1671.80

Probuphine (Titan) 74.2 mg subdermal implant 4 implants for 6 months 4950.00

Buprenorphine/Naloxone

generic 2/0.5 mg, 8/2 mg sublingual tabs 16/4 mg once/day 2813.90

Bunavail (BioDelivery Sciences) 2.1/0.3 mg, 4.2/0.7 mg, 6.3/1 mg buccal fi lms 8.4/1.4 mg once/day 2660.40

Suboxone (Reckitt Benckiser) 2/0.5 mg, 4/1 mg, 8/2 mg, 12/3 mg sublingual fi lms 16/4 mg once/day 2660.40

Zubsolv (Orexo) 1.4/0.36 mg, 5.7/1.4 mg sublingual tabs 11.4/2.8 mg once/day 2660.40

1 Approximate WAC for 6 months’ treatment at the target maintenance dosage WAC = wholesaler acquisition cost, or manufacturer’s published price to wholesalers; WAC represents published catalogue or list prices and may not represent an actual transactional price Source: AnalySource® Monthly July 5,

The FDA has approved subdermal implants of the partial

opioid agonist buprenorphine (Probuphine – Titan) for

maintenance treatment of opioid dependence in patients

stabilized on low to moderate doses of transmucosal

buprenorphine Probuphine was designed to provide

continuous low levels of buprenorphine for 6 months

and to safeguard against illicit use of the drug

are comparable to those achieved with 8 mg/day

of sub lingual buprenorphine In one unpublished pharmacokinetic study, summarized in the package insert, subjects were given sublingual buprenorphine

16 mg daily for a minimum of 5 consecutive days, followed by insertion of 4 buprenorphine implants Peak plasma concentrations of buprenorphine were much lower after insertion of the implants than with daily sublingual tablets

CLINICAL STUDIES — One unpublished trial found

that buprenorphine implants were noninferior to sublingual buprenorphine/naloxone in maintaining clinical stability in opioid-dependent patients A total

of 177 patients treated with ≤8 mg/day of sublingual buprenorphine who met criteria for clinical stability (e.g., no reports of illicit opioid use, signifi cant withdrawal symptoms, or hospitalization) were randomized to receive buprenorphine implants and placebo tablets or sublingual buprenorphine/naloxone tablets and placebo implants During the 6-month study period, 63% of patients in the buprenorphine implant group and 54% of those in the buprenorphine/ naloxone group had no evidence of illicit opioid use.4

ADVERSE EFFECTS — Probuphine is only available

through a restricted-access (REMS) program The most common implant-site adverse effects have been pain, pruritus, and erythema, but insertion and removal of the implants are associated with serious risks such as implant migration, extrusion, and nerve injury Healthcare providers must complete a live training session and become certifi ed before they can prescribe, insert, or remove buprenorphine implants

DRUG INTERACTIONS — Buprenorphine in any form

may interfere with the analgesic effi cacy of full opioid agonists It is metabolized primarily by CYP3A4; plasma levels of buprenorphine should be monitored in

Pronunciation Key Buprenorphine: bue" pre nor' feen Probuphine: pro bue' feen

DRUGS FOR OPIOID DEPENDENCE — Methadone was

the fi rst successful treatment for opioid addiction; it

can diminish the craving for opioids without causing

euphoria or sedation, but it is itself a Schedule II

controlled substance and can be dangerous in

overdosage Naltrexone is a long-acting opioid

antagonist; it is effective in diminishing the euphoric

effects of opioids, but it is much less effective than

methadone in treating addiction because it does not

abolish the craving for opioids

Buprenorphine, which is both a weak opioid agonist and a

strong antagonist, is available alone and in combination

with the opioid antagonist naloxone as an alternative

to methadone (and alone for management of chronic

pain).1-3 Taken orally, naloxone is poorly absorbed

and generally has no clinical effects; its presence in

sublingual or buccal formulations with buprenorphine

is intended to discourage intravenous or intranasal

abuse of buprenorphine Buprenorphine is a Schedule

III controlled substance and has fewer prescribing

restrictions than Schedule II drugs such as methadone

PHARMACOKINETICS — Buprenorphine levels after

insertion of 4 Probuphine implants (0.5-1 ng/mL)

Trang 6

The Medical Letter ® Vol 58 (1499) July 18, 2016

patients who are taking a CYP3A4 inducer or inhibitor5

when switching to Probuphine or who begin taking one

while on Probuphine treatment As with any opioid,

concomitant use of buprenorphine with selective

serotonin reuptake inhibitors (SSRIs), serotonin and

norepinephrine reuptake inhibitors (SNRIs), tricyclic

antidepressants, or other serotonergic drugs can

result in serotonin syndrome

DOSAGE AND ADMINISTRATION — Patients who are

eligible for treatment with buprenorphine implants

should be clinically stable and maintained on a stable

transmucosal buprenorphine dose, such as ≤8 mg/

day of sublingual buprenorphine or Suboxone, for ≥3

months Each buprenorphine implant, measuring 26

mm in length and 2.5 mm in diameter, contains 74.2 mg

of buprenorphine A total of 4 buprenorphine implants

are inserted subdermally in the inner upper arm They

should be removed after 6 months Four new implants

could then be placed in the opposite arm

1 RP Mattick et al Buprenorphine maintenance versus placebo

or methadone maintenance for opioid dependence Cochrane Database Syst Rev 2014; 2:CD002207.

2 Bunavail: another buprenorphine/naloxone formulation for opi-oid dependence Med Lett Drugs Ther 2015; 57:19.

3 Buprenorphine buccal fi lm (Belbuca) for chronic pain Med Lett Drugs Ther 2016; 58:47.

4 R Rosenthal et al Sensitivity analysis of a comparative trial of

6 month buprenorphine implants (Probuphine) and sublingual buprenorphine in stable opioid-dependent patients (abstract) Presented at College on Problems of Drug Dependence 78 th an-nual meeting, Palm Springs, California, June 11-16, 2016

5 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2016; 58:e46.

Brivaracetam (Briviact) for Epilepsy

▶

Brivaracetam (Briviact – UCB), an analog of

levetiracetam (Keppra, and others), has been approved

by the FDA for adjunctive treatment of partial-onset

seizures in patients ≥16 years old New drugs for

epilepsy are often approved initially only as adjunctive

treatment for partial seizures.1

Pronunciation Key Brivaracetam: briv" a ra' se tam Briviact: briv' ee akt

MECHANISM OF ACTION — Brivaracetam binds

selectively to synaptic vesicle protein 2A (SV2A)

in the brain, modulating neurotransmitter release

into the synapse Brivaracetam has a 10- to 30-fold

higher affi nity for SV2A than levetiracetam It is also a

partial antagonist on neuronal voltage-gated sodium

channels In animal models, brivaracetam had higher

brain permeability and a more rapid onset of action

than levetiracetam.2

CONCLUSION — Buprenorphine implants (Probuphine)

may provide more consistent dosing for opioid-dependent patients stabilized on low to moderate doses of transmucosal buprenorphine The implants also provide an additional safeguard against illicit use

of buprenorphine, but they are much more expensive than oral transmucosal buprenorphine, which is similarly effective ■

Class Antiepileptic

Tmax 1 hour (fasting); delayed by 3 hours with

a high-fat meal Metabolism Primarily hydrolysis; secondarily hydroxlation,

mainly by CYP2C19 Elimination Urine (>95%; <10% unchanged)

Half-life (terminal) 9 hours

CLINICAL STUDIES — Approval was based on the

re-sults of three randomized, double-blind, placebo-con-trolled 12-week trials of adjunctive brivaracetam in

patients ≥16 years old with uncontrolled partial-onset

seizures Most of these patients were already taking

one or two other antiepileptic drugs.3-5 Results for the primary endpoint of mean reduction in seizure

frequen-cy are summarized in Table 2 Adding brivaracetam was not benefi cial for the 20% of patients in studies 1 and

2 receiving concomitant levetiracetam treatment, but adjunctive brivaracetam signifi cantly reduced seizure frequency among the patients in study 3 who had previ-ously tried and discontinued levetiracetam

Table 2 Clinical Trials with Brivaracetam

Reduction in Seizure Frequency 1

50 mg 100 mg 200 mg

Study 1 (n=299) 9.5% 17.0% — Study 2 (n=197) 16.9%* — — Study 3 (n=760) — 25.2%* 25.7%*

* statistically signifi cant

1 Mean reduction over placebo from baseline per week (studies 1 and 2) or per 28 days (study 3) at doses of 50, 100, or 200 mg/day Data from the manufacturer’s package insert The FDA required some revisions to the data from the published trials.

A randomized, double-blind trial that included 49

patients with uncontrolled generalized seizures

(tonic-clonic, absence, or myoclonic) found that adjunctive brivaracetam 20-150 mg/day reduced seizure frequency in these patients compared to placebo.6 In two small placebo-controlled studies in patients with

Trang 7

Table 3 Brivaracetam and Levetiracetam

Brivaracetam – Briviact (UCB) 10, 25, 50, 75, 100 mg tabs; 50-200 mg/day PO or IV $910.00

10 mg/mL PO soln; 50 mg/5 mL IV soln in 2 divided doses 2

Levetiracetam – Keppra (UCB) 250, 500, 750, 1000 mg tabs; 100 mg/mL PO 1000-3000 mg/day PO or IV 436.40 generic soln; 500 mg/5 mL IV soln in 2 divided doses 3 33.10 4

Spritam (Aprecia) 250, 500, 750, 1000 mg tabs for oral susp 433.40

extended-release – Keppra XR 500, 750 mg ER tabs 1000-3000 mg PO once/d 3 395.60

soln = solution; susp = suspension; ER = extended-release

1 Approximate WAC for 30 days’ treatment with tablets at the lowest usual adult dosage WAC = wholesaler acquisition cost, or manufacturer’s published price

to wholesalers; WAC represents published catalogue or list prices and may not represent an actual transactional price Source: AnalySource® Monthly July 5,

2 The recommended dosage for patients with hepatic impairment is 50-150 mg/day

3 Dosage may need to be adjusted for renal impairment.

4 The cost for 300 mL of generic oral solution is $130.00

1 Drugs for epilepsy Treat Guidel Med Lett 2013; 11:9.

2 L Mumoli et al Brivaracetam: review of its pharmacology and potential use as adjunctive therapy in patients with partial on-set seizures Drug Des Devel Ther 2015; 9:5719.

3 P Ryvlin et al Adjunctive brivaracetam in adults with uncon-trolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial Epilepsia 2014; 55:47.

4 V Biton et al Brivaracetam as adjunctive treatment for uncon-trolled partial epilepsy in adults: a phase III randomized, dou-ble-blind, placebo-controlled trial Epilepsia 2014; 55:57.

5 P Klein et al A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the effi cacy and safety of adjunctive brivaracetam in adult patients with uncon-trolled partial-onset seizures Epilepsia 2015; 56:1890.

6 P Kwan et al Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial Epilepsia 2014; 55:38.

7 R Kälviäinen et al Brivaracetam in Unverricht-Lundborg dis-ease (EPM1): results from two randomized, double-blind, pla-cebo-controlled studies Epilepsia 2016; 57:210

progressive myoclonic epilepsy (Unverricht-Lundborg

disease), addition of brivaracetam 5-150 mg/day did

not result in a signifi cant improvement in myoclonus.7

ADVERSE EFFECTS — The adverse effect profi le of

brivaracetam is similar to that of other antiepileptic

drugs Common adverse effects in patients taking

doses ≥50 mg/day in clinical trials were somnolence

and sedation (16%), dizziness (12%), fatigue (9%),

and nausea and vomiting (5%) Psychiatric adverse

reactions, mainly consisting of anxiety and depression,

but also including some cases of aggression and

psychosis, were reported in 13% of patients receiving

brivaracetam compared to 8% of those taking placebo

Chronic interstitial nephritis occurred in one patient

taking brivaracetam; a cause-and-effect relationship

could not be established Hypersensitivity reactions

(bronchospasm and angioedema) have occurred

Brivaracetam is classifi ed as a Schedule V controlled

substance

PREGNANCY — Brivaracetam is classifi ed as category

C for use during pregnancy Developmental toxicity

occurred in rabbits and rats at exposures >4 times and

>7 times, respectively, those achieved in humans at the

maximum recommended dose; there are no adequate

studies in pregnant women

DRUG INTERACTIONS — Coadministration with rifampin

decreased plasma concentrations of brivaracetam by

45%; the dosage of brivaracetam should be increased

by up to 100% in patients also taking rifampin

Concurrent administration of carbamazepine and

brivaracetam increased concentrations of an active

metabolite of carbamazepine; a reduction in the dose of

carbamazepine may be necessary if the two drugs are

used together Brivaracetam increased concentrations

of phenytoin by up to 20%; phenytoin levels should be

monitored when brivaracetam is added or discontinued

Serum concentrations of brivaracetam are increased

by 22% in patients who are heterozygous for the

CYP2C19 loss-of-function genetic polymorphism and

by 42% in those who are homozygous; CYP2C19 poor metabolizers and patients also taking inhibitors of CYP2C19 may require dose reductions.8

DOSAGE AND ADMINISTRATION — The recommended

starting dosage of brivaracetam is 50 mg twice daily, which can be decreased to 25 mg twice daily

or increased to 100 mg twice daily In patients with hepatic impairment, the recommended starting dosage is 25 mg twice daily and the maximum dosage

is 75 mg twice daily

CONCLUSION — Brivaracetam (Briviact), an analog

of levetiracetam (Keppra, and others), appears to be

modestly effective as add-on treatment in adults with refractory partial-onset seizures, including some who previously failed to respond to levetiracetam Like levetiracetam, it may also be effective in myoclonic and primarily generalized seizures, but more studies are needed Generic levetiracetam costs much less ■

Trang 8

e96

among historical controls At 504 weeks (~9.6 years), survival was 91% among treated patients and 27% among controls Treated patients also had improvements in growth, skeletal mineralization, and general health.4,5

In a study comparing 8 patients with juvenile-onset hypophosphatasia treated with asfotase alfa to 6 untreated historical controls, patients treated with the drug had improvements in growth, rickets se-verity, and gait.5

ADVERSE EFFECTS — The most common adverse

ef-fects of asfotase alfa have been injection-site reactions (63%) Other common adverse effects have included lipodystrophy at the injection site (28%), ectopic calcifi -cations (14%), and hypersensitivity reactions (12%)

DOSAGE, ADMINISTRATION, AND COST – The

recom-mended dosage of asfotase alfa is 2 mg/kg SC 3 times weekly or 1 mg/kg SC 6 times weekly The dosage can be increased to 3 mg/kg SC 3 times weekly in patients with perinatal- or infantile-onset hypophosphatasia The drug should be injected into the thigh, deltoid, or abdomen; in-jection sites should be rotated, and reddened, inflamed,

or swollen sites should not be used A 4-week supply of

Strensiq for a child weighing 20 kg costs $33,600.6

CONCLUSION — Asfotase alfa (Strensiq) injections

can reverse skeletal mineralization defects and im-prove survival in infants and young children with hy-pophosphatasia ■

1 National Organization for Rare Disorders Hypophosphatasia Available at: www.rarediseases.org/rarediseases/hypophospha-tasia Accessed July 7, 2016.

2 H Orimo Pathophysiology of hypophosphatasia and the potential role of asfotase alfa Ther Clin Risk Manag 2016; 12:777.

3 MP Whyte et al Enzyme replacement therapy in life-threatening hypophosphatasia N Engl J Med 2012; 366:904.

4 MP Whyte et al Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia J Clin Endocrinol Metab 2016; 101:334.

5 FDA Asfotase alfa medical review Available at: www.accessda-ta.fda.gov/drugsatfda_docs/nda/2015/125513Orig1s000MedR pdf Accessed July 7, 2016.

6 Approximate WAC WAC = wholesaler acquisition cost or manufac-turer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transac-tional price Source: AnalySource® Monthly July 5, 2016 Re-printed with permission by First Databank, Inc All rights reserved

Pronunciation Key Asfotase alfa: as foe’ tase al’ fa Strensiq: stren’ sik

The FDA has approved asfotase alfa (Strensiq – Alexion),

a recombinant form of tissue-nonspecifi c alkaline

phosphatase, for subcutaneous treatment of

perina-tal-, infantile-, and juvenile-onset hypophosphatasia

Asfotase alfa is the fi rst treatment to be approved in

the US for this rare genetic metabolic disorder

Route Subcutaneous

Formulation 18 mg/0.45 mL, 28 mg/0.7 mL, 40 mg/1 mL,

80 mg/0.8 mL 1 single-use vials Tmax 14.9 hours (≤5 years old);

20.8 hours (>5-12 yeas old) Half-life ~5 days

1 The 80 mg/0.8 mL formulation should not be used in patients weighing <40 kg.

CLINICAL STUDIES — Effi cacy of asfotase alfa

in patients with perinatal- or infantile-onset

hypophosphatasia was demonstrated in two

open-label trials in a total of 68 children with perinatal-

or infantile-onset hypophosphatasia treated with

subcutaneous asfotase alfa compared to 48 similar

untreated historical controls Estimated survival at

age 1 year was 97% with treatment, compared to 42%

Asfotase Alfa (Strensiq) for

Hypophosphatasia

▶

HYPOPHOSPHATASIA — Tissue-nonspecifi c alkaline

phosphatase is essential for mineralization of bones

and teeth Hypophosphatasia is caused by mutations

in the alkaline phosphatase gene It can present

at any time (in utero to adulthood) and is highly

variable in severity Perinatal- and infantile-onset

hypophosphatasia can cause deformities of the chest

and underdevelopment of lungs, and is often fatal

Juvenile-onset hypophosphatasia is somewhat less

severe, but growth failure, skeletal deformities, and

fractures can occur Spontaneous remission seems to

occur in some young adults, but bone symptoms can

recur later in adulthood.1,2

MECHANISM OF ACTION — Asfotase alfa reduces

ex-tracellular levels of inorganic pyrophosphate and other

substrates of tissue-nonspecifi c alkaline phosphatase.3

The Medical Letter publications are protected by US and international copyright laws.

Forwarding, copying or any other distribution of this material is strictly prohibited.

Trang 9

e97

IN BRIEF

Cabozantinib (Cabometyx) for

Advanced Renal Cell Carcinoma

The FDA has approved the oral tyrosine kinase inhibitor

cabozantinib (Cabometyx – Exelixis) for treatment of

patients with advanced renal cell carcinoma previously

treated with antiangiogenic therapy Cabozantinib was

fi rst approved in 2012 as Cometriq for treatment of

progressive, metastatic medullary thyroid cancer

Anti-VEGF antibodies, tyrosine kinase inhibitors, and mTOR

kinase inhibitors have become the standard of care for

treatment of unresectable or metastatic renal cell cancer 1

FDA approval was based on the results of a randomized

open-label trial (METEOR) comparing cabozantinib to

everolimus in 658 patients with advanced or metastatic

renal cell carcinoma that had progressed on antivascular

endothelial growth factor receptor (VEGFR) therapy In

patients treated with cabozantinib, median

progression-free survival was signifi cantly longer (7.4 vs 3.8 months

with everolimus) and the objective response rate was

signifi cantly higher (21% vs 5% with everolimus) 2 Median

overall survival was 21.4 months with cabozantinib and

16.5 months with everolimus 3

Table 1 Some Drugs for Advanced Renal Cell Carcinoma

Dosage

Tyrosine Kinase Inhibitors

Axitinib – Inlyta (Pfi zer) 5 mg PO bid $12,527.70

Cabozantinib – Cabometyx 60 mg PO once/d 13,750.00

(Exelixis)

Pazopanib – Votrient (GSK) 800 mg PO once/d 10,026.90

Sorafenib – Nexavar (Bayer) 400 mg PO bid 14,398.80

Sunitinib – Sutent (Pfi zer) 50 mg PO once/d 2 14,843.20

mTOR Kinase Inhibitors

Everolimus – Afi nitor (Novartis) 10 mg PO once/d 12,901.80

Temsirolimus – Torisel (Pfi zer) 25 mg IV once/wk 6509.30

Anti-VEGF Antibody

Bevacizumab – Avastin 10 mg/kg IV q2 wks 9933.80 3

(Genentech) with interferon alfa

1 Approximate WAC for 30 days’ treatment WAC = wholesaler acquisition

cost or manufacturer’s published price to wholesalers; WAC represents a

published catalogue or list price and may not represent an actual

trans-actional price Source: AnalySource® Monthly July 5, 2016 Reprinted

fdbhealth.com/policies/drug-pricing-policy.

2 Each 4-week treatment period is followed by 2 weeks off.

3 Cost for one month’s treatment of a 70-kg patient with Avastin only.

Common adverse effects of cabozantinib include diarrhea, fatigue, nausea, vomiting, weight loss, palmar-plantar erythrodysesthesia, and hypertension Serious adverse effects, including GI perforation, hemorrhage, and arterial thromboembolic events, occurred in >60% of patients treated with cabozantinib in the clinical trial.

The recommended dosage of cabozantinib is 60 mg taken once daily without food Dosage adjustments are required for patients taking strong CYP3A4 inhibitors

or inducers concomitantly 4 In patients who experience severe or intolerable adverse effects, reducing the dosage

or withholding the drug until improvement occurs is recommended

1 Axitinib (Inlyta) for advanced renal cell carcinoma Med Lett Drugs Ther 2012; 54:47.

2 TK Choueiri et al Cabozantinib versus everolimus in advanced renal-cell carcinoma N Engl J Med 2015; 373:1814.

3 TK Choueiri et al Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): fi nal results from a randomised, open-label, phase 3 trial Lancet Oncol 2016 June 3 (epub).

Trang 10

Questions start on next page

ACCREDITATION INFORMATION:

ACCME: The Medical Letter is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians The Medical

Letter designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits ™ Physicians should claim only the credit commensurate with the extent of their participation in the activity This CME activity was planned and produced in accordance with the ACCME Essentials and Policies.

ABIM MOC: Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 2 MOC points in the

American Board of Internal Medicine's (ABIM) Maintenance of Certifi cation (MOC) program Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

AAFP : This enduring material activity, The Medical Letter Continuing Medical Education Program, has been reviewed and is acceptable for up to 52 Prescribed credits by the

American Academy of Family Physicians Term of approval begins January 1, 2016 Term of approval is for one year from this date Each issue is approved for 2 Prescribed credits Credit may be claimed for one year from the date of each issue Physicians should claim only the credit commensurate with the extent of their participation in the activity

ACPE: The Medical Letter is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education This exam is acceptable

for 2.0 hour(s) of knowledge-based continuing education credit (0.2 CEU)

This activity, being ACCME (AMA) approved, is acceptable for Category 2-B credit by the American Osteopathic Association (AOA)

The National Commission on Certifi cation of Physician Assistants (NCCPA) accepts AMA PRA Category 1 Credit™ from organizations accredited by ACCME NCCPA also

accepts AAFP Prescribed credits for recertifi cation The Medical Letter is accredited by both ACCME and AAFP.

The American Nurses Credentialing Center (ANCC) and the American Academy of Nurse Practitioners (AANP) accept AMA PRA Category 1 Credit™ from organizations

accredited by the ACCME

Physicians in Canada: Members of The College of Family Physicians of Canada are eligible to receive Mainpro-M1 credits (equivalent to AAFP Prescribed credits) as per our

reciprocal agreement with the American Academy of Family Physicians

MISSION:

The mission of The Medical Letter’s Continuing Medical Education Program is to support the professional development of healthcare providers including physicians, nurse practitioners, pharmacists, and physician assistants by providing independent, unbiased drug information and prescribing recommendations that are free of industry influence The program content includes current information and unbiased reviews of FDA-approved and off-label uses of drugs, their mechanisms of action, clinical trials, dosage and administration, adverse effects, and drug interactions The Medical Letter delivers educational content in the form of self-study material.

The expected outcome of the CME program is to increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in

materials contained in The Medical Letter.

The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical Letter aims to be a leader in supporting the professional development of healthcare providers through Core Competencies by providing continuing medical education that is unbiased and free of industry influence The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations.

GOAL:

Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and timely educational content that they will use to make independent and informed therapeutic choices in their practice.

LEARNING OBJECTIVES:

Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities Activity participants will be

able to select and prescribe, or confi rm the appropriateness of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with

specifi c attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient management Activity participants will make independent and informed therapeutic choices in their practice.

Upon completion of this program, the participant will be able to:

1 Discuss the adverse effects of SGLT2 inhibitors and explain their effects on renal function

2 Discuss the differences between sumatriptan nasal powder (Onzetra Xsail) and other sumatriptan formulations for treatment of acute migraine.

3 Review the effi cacy and safety of buprenorphine subdermal implants (Probuphine) for maintenance treatment of opioid dependence.

4 Review the effi cacy and safety of brivaracetam (Briviact) for adjunctive treatment of partial-onset seizures.

Privacy and Confi dentiality: The Medical Letter guarantees our fi rm commitment to your privacy We do not sell any of your information Secure server software (SSL) is used

for commerce transactions through VeriSign, Inc No credit card information is stored.

IT Requirements: Windows 7/8/10, Mac OS X+; current versions of Microsoft IE/Edge, Mozilla Firefox, Google Chrome, Safari, or any other compatible Web browser

High-speed connection.

Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org

The Medical Letter ®

Continuing Medical Education Program

medicalletter.org/cme-program

Earn Up To 52 Credits Per Year

Choose CME from The Medical Letter in the format that’s right for you!

upon successful completion of the test A score of 70% or greater is required to pass the exam Our comprehensive exams allow you to test at your own pace in the comfort of your home or offi ce Comprehensive exams are offered every January and July enabling you to earn up to 52 credits per year $49/exam.

A score of 70% or greater is required to pass the exam.

Định dạng
Số trang	11
Dung lượng	235,18 KB