Sucroferric Oxyhydroxide Velphoro for Hyperphosphatemia ...p 73p 76 Glycerol Phenylbutyrate Ravicti for Urea Cycle Disorders ...p 77 A Transcutaneous Electrical Nerve Stimulation Device
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on Drugs and Therapeutics
Objective Drug Reviews Since 1959
IN THIS ISSUE
ISSUE
1433
Volume 56
Published by The Medical Letter, Inc • A Nonprofi t Organization
ISSUE No
1449 Two New Drugs for Skin and Skin Structure Infections Sucroferric Oxyhydroxide (Velphoro) for Hyperphosphatemia p 73p 76
Glycerol Phenylbutyrate (Ravicti) for Urea Cycle Disorders p 77
A Transcutaneous Electrical Nerve Stimulation Device (Cefaly) for Migraine Prevention p 78
Trang 273
ALSO IN THIS ISSUE
ISSUE
1433
Volume 56
ISSUE No
1449
on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Take CME exams
Sucroferric Oxyhydroxide (Velphoro) for Hyperphosphatemia p 76
Glycerol Phenylbutyrate (Ravicti) for Urea Cycle Disorders p 77
A Transcutaneous Electrical Nerve Stimulation Device (Cefaly) for Migraine Prevention p 78
Two New Drugs for Skin and Skin
Structure Infections
▶
The FDA has approved two new drugs for treatment
of adults with acute bacterial skin and skin structure
infections caused by susceptible gram-positive
bacteria Dalbavancin (Dalvance – Durata) is a
long-acting intravenous (IV) lipoglycopeptide antibiotic
similar to telavancin (Vibativ).1 Tedizolid phosphate
(Sivextro – Cubist) is an IV and oral oxazolidinone
antibacterial drug similar to linezolid (Zyvox).2 A
third IV antibiotic, oritavancin (Orba ctiv), recently
approved by the FDA for the same indication, will be
reviewed in a future issue
STANDARD TREATMENT — Patients hospitalized for non-purulent skin and soft-tissue infections, which are often caused by streptococci, can usually
be treated empirically with IV penicillin, cefazolin, ceftriaxone, or clindamycin.3 Purulent skin infections are now caused predominantly by methicillin-resistant
Staphylococcus aureus (MRSA) in many parts of the US
Patients hospitalized for complicated MRSA skin and soft-tissue infections are usually treated with IV van-comycin Alternatives include linezolid, daptomycin, clindamycin, telavancin, and ceftaroline fosamil For less serious MRSA infections, incision and drainage alone or with oral trimethoprim/sulfamethoxazole (TMP/SMX) or doxycycline is usually effective.4
Table 1 Some IV Drugs for MRSA Skin and Skin Structure Infections
Ceftaroline fosamil 3 – 400, 600 mg vials 600 mg q12h 5-14 days
Dalbavancin 3 – 500 mg vials 1000 mg x 1, then 14 days (2 doses
Dalvance (Durata) 500 mg 1 wk later 1 week apart) 1490.00 4
Daptomycin 3 – 500 mg vials 4 mg/kg q24h 7-14 days
Linezolid – 200, 400, 600 mg infusion bags 5 600 mg q12h 6 10-14 days
Tedizolid 3 – 200 mg single-use vials 7 200 mg once/d 6 days
Telavancin 3 – 250, 750 mg vials 10 mg/kg q24h 7-14 days
Vancomycin – 500, 750 mg, 1, 5, 10 g vials 15 mg/kg (max 2 g) –
1 Dosage adjustment may be needed for renal or hepatic impairment.
2 Approximate wholesale acquisition cost (WAC) for 1 day’s treatment of a 70-kg patient with the lowest usual dosage Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) August 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher.
3 Not FDA-approved for use in children.
4 Cost for one 500-mg vial.
5 Also available for oral administration in 600-mg tabs and a 100 mg/5 mL oral suspension.
6 Dosage for children <12 years old is 10 mg/kg q8h.
7 Also available for oral administration in 200-mg tabs.
8 Dose may be too low to achieve adequate trough concentions in many patients with normal renal function Some experts recommend 15-20 mg/kg q8-12 hours (M Rybak et al Am J Health Syst Pharm 2009; 66:82) Initial pediatric dosage is 10-15 mg/kg q6h.
For further information call: 800-211-2769
Trang 3The Medical Letter Vol 56 (1449) August 18, 2014
related reactions (red-man syndrome) Serious hypersensitivity reactions, including anaphylaxis, have been reported with dalbavancin; the long half-life of the drug can further complicate these reactions Patients with a history of a hypersensitivity reaction
to another glycopeptide (vancomycin or telavancin) may be at increased risk
Unlike telavancin, dalbavancin does not prolong the QT interval Use of telavancin has been limited by its adverse effects, which include taste disturbances, nausea, vomiting, and nephrotoxicity
Pregnancy – Dalbavancin is classified as category C (some fetal toxicity in animals; no adequate human studies) for use during pregnancy
DOSAGE — The recommended dosage of dalbavancin
is 1000 mg infused over 30 minutes, followed one week later by 500 mg Patients with creatinine clear-ance <30 mL/min should receive 750 mg for the fi rst dose and 375 mg for the second
TEDIZOLID
ACTIVITY — Tedizolid, the active moiety of the prodrug tedizolid phosphate, inhibits bacterial protein synthesis.7
In vitro and in clinical studies, it has shown activity against S aureus (including MRSA), S pyogenes, S agalactiae, S anginosus group, and E faecalis Tedizolid
is active in vitro against other gram-positive pathogens, including coagulase-negative staphylococci and E faecium It also appears to have activity in vitro against
some staphylococcal and enterococcal strains that are non-susceptible to vancomycin and against some strains of gram-positive cocci that are non-susceptible
to linezolid.8,9 Tedizolid is also active in vitro against Mycobacterium tuberculosis strains resistant to
isoniazid, rifampin, or both.10
PHARMACOLOGY — The pharmacokinetics of tedizolid are similar after IV or oral administration Steady-state concentrations are achieved within 3 days
DALBAVANCIN
ACTIVITY — Dalbavancin inhibits cell wall synthesis
in gram-positive bacteria In vitro, it is bactericidal
against Streptococcus pyogenes and S aureus,
including MRSA, in concentrations readily achieved
in blood with recommended doses of the drug It has
been shown to be active clinically and in vitro against S
aureus (including MRSA), S pyogenes, Streptococcus
agalactiae and Streptococcus anginosus group It is
also active in vitro against vancomycin-susceptible
Enterococcus faecium and Enterococcus faecalis, and
against vancomycin-intermediate S aureus.5
PHARMACOLOGY — After IV injection of a single
1000-mg dose, serum concentrations of dalbavancin remain
above the minimum inhibitory concentration for MRSA
for about 8 days The terminal half-life of dalbavancin
is about 14 days, but when given once a week for 8
weeks to healthy adults with normal renal function, the
drug did not accumulate
Table 3 Dalbavancin Clinical Trials
DISCOVER 1 Dalbavancin 83% (240/288) 90% (259/288) (n=573) Vancomycin/ 82% (233/285) 91% (259/285)
linezolid DISCOVER 2 Dalbavancin 77% (285/371) 88% (325/371) (n=739) Vancomycin/ 78% (288/368) 86% (316/368)
linezolid)
1 No increase from baseline in lesion surface area and temperature <37.6°C 48-72 hrs after the fi rst dose.
2 Reduction from baseline of >20% in lesion surface area 48-72 hrs after the
fi rst dose.
Table 2 Pharmacology of Dalbavancin
Class Lipoglycopeptide antibiotic
Route IV
Formulation 500 mg single-use vials
Distribution 93% protein bound
Metabolism Minimal; not a substrate, inhibitor, or inducer
of CYP450 enzymes Excretion Very slow; urine (33% unchanged, 12%
me-tabolite) in 42 days; feces (20%) in 70 days Half-life (terminal) ~14 days
CLINICAL STUDIES — FDA approval of dalbavancin was
based on the results of 2 double-blind non-inferiority
trials (DISCOVER 1 and DISCOVER 2) comparing it to IV
vancomycin followed by oral linezolid in a total of 1312
adult patients with acute bacterial skin and skin
struc-ture infections Patients treated with dalbavancin
re-ceived 1000 mg once on day 1 and 500 mg on day 8;
those randomized to vancomycin received 1 g or 15 mg/
kg every 12 hours for at least 3 days, after which they
could be switched to oral linezolid to complete a 10- to
14-day course.The primary endpoint in both studies was
no increase from baseline in the size of the infected area
48-72 hours after starting treatment and a temperature
≤37.6°C.6 The results are summarized in Table 3 Clinical
success rates were maintained at follow-up (day 26-30)
ADVERSE EFFECTS — In phase 2 and 3 clinical trials
that included a total of 1778 patients treated with
dalbavancin, the most common adverse effects
of the drug were nausea, diarrhea, and headache,
each of which occurred in about 5% of patients
Rapid IV infusion of the drug could cause
Trang 4infusion-CLINICAL STUDIES — FDA approval of tedizolid
was based on 2 double-blind non-inferiority trials
(ESTABLISH-1 and ESTABLISH-2) comparing tedizolid
200 mg once daily for 6 days with linezolid 600 mg
twice daily for 10 days Patients in the fi rst trial received
oral therapy and those in the second trial started with IV
treatment for at least 1 day before being given the option
to switch to the oral formulation The primary endpoint
in both trials was clinical response 48-72 hours after
the fi rst dose, which was defi ned as no increase from
baseline in lesion size and an oral temperature of
し37.6°C in ESTABLISH-1 and as a じ20% reduction from
baseline in lesion size in ESTABLISH-2.11,12 The results
are summarized in Table 5 Clinical response rates were
maintained 7-14 days after the end of therapy
DRUG INTERACTIONS — In vitro, tedizolid is a weak,
reversible inhibitor of monoamine oxidase (MAO), but
it may be less likely than linezolid to interact with sero-tonergic drugs or adrenergic agents such as tyramine and pseudoephedrine.13
DOSAGE — The recommended oral or IV dosage of te-dizolid for skin and skin structure infections is 200 mg once daily for 6 days
CONCLUSION
Dalbavancin (Dalvance) and tedizolid phosphate (Sivextro) are effective for treatment of acute bacterial
skin and skin structure infections, including those caused by MRSA Use of dalbavancin in 2 doses one week apart may permit outpatient treatment of some infections that previously required hospitalization Once-daily tedizolid may be more convenient
than twice-daily linezolid (Zyvox) The effi cacy of
these drugs for more invasive infections, including pneumonia and bacteremia, is unknown and their long-term safety has not been established Older, less expensive antibiotics are generally preferred ■
1 Telavancin (Vibativ) for gram-positive skin infections Med Lett Drugs Ther 2010; 52:1.
2 Linezolid (Zyvox) Med Lett Drugs Ther 2000; 42:45.
3 DL Stevens et al Executive summary: practice guidelines for the diagnosis and management of skin and soft tissue infections:
2014 update by the Infectious Diseases Society of America Clin Infec Dis 2014; 59:147.
4 Drugs for MRSA skin and soft-tissue infections Med Lett Drugs Ther 2014; 56:39.
5 HF Chambers Pharmacology and the treatment of complicated skin and skin-structure infections N Engl J Med 2014; 370:2238.
6 HW Boucher et al Once-weekly dalbavancin versus daily con-ventional therapy for skin infection N Engl J Med 2014; 370:2169.
7 O Urbina et al Potential role of tedizolid phosphate in the treat-ment of acute bacterial skin infections Drug Des Devel Ther 2013; 7:243.
8 RN Jones et al TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens J Anti-microb Chemother 2009; 63:716
9 SD Brown and MM Traczewski Comparative in vitro antimicro-bial activities of torezolid (TR-700), the active moiety of a new oxazolidinone, torezolid phosphate (TR-701), determination of tentative disk diffusion interpretive criteria, and quality control ranges Antimicrob Agents Chemother 2010; 54:2063.
10 L Vera-Cabrera et al In vitro activities of DA-7157 and DA-7218 against Mycobacterium tuberculosis and Nocardia brasiliensis Antimicrob Agents Chemother 2006; 50:3170.
11 P Prokocimer et al Tedizolid phosphate vs linezolid for treat-ment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial JAMA 2013; 309:559.
12 GJ Moran et al Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTAB-LISH-2): a randomised, double-blind, phase 3, non-inferiority trial Lancet Infect Dis 2014; 14:696.
13 S Flanagan et al In vitro, in vivo, and clinical studies of tedizolid
to assess the potential for peripheral or central monoamine oxi-dase interactions Antimicrob Agents Chemother 2013; 57:3060.
Table 4 Pharmacology of Tedizolid
Class Oxazolidinone antibiotic
Route Oral and IV
Formulations 200 mg tabs and single-use vials
Tmax (single-dose) 2.5 hrs (oral); 1.1 hrs (IV)
Distribution 70-90% protein bound
Metabolism The prodrug tedizolid phosphate is rapidly
converted to tedizolid by endogenous phos-phatases; it is not a substrate, inhibitor, or inducer of CYP450 enzymes
Excretion 82% (feces), 18% (urine) as inactive metabolite
Half-life (terminal) 12 hrs
Table 5 Tedizolid Clinical Trials
ESTABLISH-1 Tedizolid 79% (256/323) 78% (252/323)
(n=649) Linezolid 79% (258/326) 76% (246/326)
ESTABLISH-2 Tedizolid 86% (286/332) 85% (283/332)
(n=666) Linezolid 84% (281/334) 83% (276/334)
1 No increase from baseline in lesion surface area and temperature <37.6°C
48-72 hrs after the fi rst dose.
2 Reduction from baseline of >20% in lesion surface area 48-72 hrs after the
fi rst dose.
ADVERSE EFFECTS — The most common adverse
effects of tedizolid reported in clinical trials were nausea
(8%), headache (6%), diarrhea (4%), vomiting (3%),
and dizziness (2%); similar reactions have occurred in
patients taking linezolid Potentially clinically signifi cant
decreases in platelet counts occurred in 2.3% of
patients taking tedizolid in clinical trials, compared to
4.9% of those who received linezolid Higher doses and/
or longer treatment durations might increase the risk
of hematologic abnormalities with tedizolid Peripheral
and optic neuropathy have been reported with both
tedizolid and linezolid
Pregnancy – Tedizolid is classifi ed as category C (fetal
toxicity in animals; no adequate human studies) for use
during pregnancy
Trang 5The Medical Letter Vol 56 (1449) August 18, 2014
Sucroferric Oxyhydroxide (Velphoro)
for Hyperphosphatemia
▶
Most patients with end-stage renal disease develop
hyperphosphatemia, which can lead to secondary
hyper-parathyroidism, vascular calcifi cation, and cardiovascular
mortality The FDA has approved sucroferric oxyhydroxide
(Velphoro – Fresenius Medical Care), a chewable
phosphate binder, for treatment of hyperphosphatemia in
patients with chronic kidney disease (CKD) on dialysis It
is the fi rst iron-based phosphate binder to be approved for
this indication
STANDARD TREATMENT — Dietary restriction of
phosphate and dialysis treatment are somewhat
effective in lowering serum phosphorus levels, but
addition of an oral phosphate binder is often needed
Whether phosphate-binding drugs can improve clinical
outcomes has not been established
The anion-exchange resin sevelamer carbonate (Renvela)1
and the calcium-based phosphate binder calcium acetate
(PhosLo, and others) are similarly effective in decreasing
serum phosphorus levels, but they can cause adverse
gastrointestinal effects and hypercalcemia Lanthanum
carbonate (Fosrenol)2 may be preferred for patients with
concomitant hypercalcemia, but it also causes adverse
gastrointestinal effects and the long-term effects of
possible accumulation of the metal in human bone and
other tissues are unknown Use of magnesium-based
phosphate binders has been limited by hypermagnesemia
with respiratory arrest.3 Aluminum-based agents can
cause systemic aluminum toxicity and are rarely used
MECHANISM OF ACTION — The active moiety of
sucroferric oxyhydroxide is polynuclear
iron(III)-oxyhydroxide, which is almost completely insoluble
and is not absorbed It reduces dietary phosphate
absorption by exchanging hydroxyl groups and/or
water for phosphate in the gut The bound phosphate
is then eliminated in feces
Table 1 Some Drugs for Hyperphosphatemia
Calcium acetate – PhosLo Gelcaps 667 mg caps (169 mg Ca) 2001-2668 mg (507-676 mg Ca) $189.50
Phoslyra (Fresenius Medical Care) 667 mg/5 mL oral solution 228.30
Sevelamer carbonate – Renvela (Genzyme) 800 mg tabs; 0.8, 2.4 g packet 1600-3200 mg PO tid with meals 347.70
Lanthanum carbonate – Fosrenol (Shire) 500, 750 mg, 1 g chewable tabs 2 500 mg-1 g PO tid with meals 3 778.90
Sucroferric oxyhydroxide – Velphoro 500 mg chewable tabs 500 mg PO tid with meals 3 855.00 (Fresenius Medical Care)
1 Approximate wholesale acquisition cost (WAC) for 30 days' treatment with the lowest usual dosage Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) August 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher.
2 Tablet strength based on elemental lanthanum content
3 Tablet must be chewed completely before swallowing.
A CLINICAL STUDY — In an open-label, randomized
trial in 1059 patients with CKD and hyperphosphatemia
on peritoneal dialysis or hemodialysis, sucroferric oxyhydroxide 1-3Ｘg/day (2-6 tablets/day; mean of
3 tablets) was non-inferior to sevelamer carbonate 4.8-14.4Ｘg/day (6-18 tablets/day; mean of 8 tablets)
in reducing serum phosphorus levels at week 12 (-2.2 mg/dL with sucroferric oxyhydroxide vs -2.4 mg/dL with sevelamer carbonate).4 These results were maintained at 52 weeks
ADVERSE EFFECTS — In the controlled trial, about 15%
of patients taking sucroferric oxyhydroxide and 21% of those taking sevelamer carbonate were non-adherent
to the treatment regimen, but more patients taking sucroferric oxyhydroxide withdrew because of adverse effects (15.7% vs 6.6%).4 Diarrhea was more common with sucroferric oxyhydroxide, while nausea and consti-pation were more common with sevelamer carbonate
As with other iron-containing products, fecal discolor-ation was common with sucroferric oxyhydroxide
Pregnancy – Sucroferric oxyhydroxide is classifi ed
as category B (no evidence of harm in animals; no adequate human studies) for use during pregnancy
DRUG INTERACTIONS — Iron-containing products
such as sucroferric oxyhydroxide can interfere with the absorption of other drugs taken concurrently
Alendronate (Fosamax, and others) and doxycycline (Vibramycin, and others) should be taken at least one hour before taking Velphoro Patients who are taking
oral levothyroxine or vitamin D analogs should not
take Velphoro.
DOSAGE AND ADMINISTRATION — The recommended
starting dosage of Velphoro is 500 mg three times
daily with meals The dose can be titrated at weekly intervals in decrements or increments of 500 mg/day
as needed until serum phosphorus levels are <5.5 mg/
dL (normal range 3.5-5 mg/dL) The tablets should not
be swallowed whole; they can be chewed or crushed
Trang 6CONCLUSION — Sucroferric oxyhydroxide (Velphoro)
appears to be as effective as sevelamer carbonate
(Renvela) in reducing serum phosphorus levels in
patients with chronic kidney disease on dialysis The
daily pill burden to control phosphorus levels with
sucroferric oxyhydroxide is generally less than that
with sevelamer carbonate ■
1 In brief: Sevelamer-based phosphate binders Med Lett Drugs
Ther 2008; 50:13.
2 Phosphate binders Med Lett Drugs Ther 2006; 48:15.
3 M Tonelli et al Oral phosphate binders in patients with kidney
failure N Engl J Med 2010; 362:1312.
4 J Floege et al A phase III study of the effi cacy and safety of a
novel iron-based phosphate binder in dialysis patients Kidney
Int 2014 March 19 (epub)
Glycerol Phenylbutyrate (Ravicti) for
Urea Cycle Disorders
▶
The FDA has approved an oral liquid formulation of glycerol
phenylbutyrate (Ravicti – Hyperion) for chronic
manage-ment of patients >2 years old with urea cycle disorders that
cannot be adequately managed by a protein- restricted
diet Sodium phenylbutyrate (Buphenyl, and generics),
another oral drug approved by the FDA for this indication,
has a bitter taste The new product, which contains no
so-dium, has little or no taste Either drug must be used in
addition to a protein-restricted diet and, if needed, dietary
supplementation with amino acids and other nutrients
UREA CYCLE DISORDERS — Defi ciencies in the enzymes
that convert nitrogen from ammonia into urea are the
cause of urea cycle disorders, which can present at birth
Accumulation of ammonia can lead to neurologic toxicity
ranging from mild cognitive impairment to cerebral
ede-ma, seizures, coede-ma, and death.1 Long-term management
of the disorder typically includes a protein-restricted diet,
dietary supplements to aid in the formation or activation
of the defi cient enzymes, and sodium phenylbutyrate
that is converted by beta-oxidation to phenyl acetate Phenylacetate combines with glutamine to form phenylacetylglutamine, which contains 2 moles of nitrogen, is water soluble, and is excreted in urine
CLINICAL STUDIES — Several short-term randomized controlled trials in adults and children with urea cycle disorders have found less daily ammonia exposure with glycerol phenylbutyrate than with sodium phenylbuty rate Two open-label uncontrolled extension trials in adults and children with urea cycle disorders receiving glycerol phen-ylbutyrate found that mean ammonia values remained below the upper limit of normal (ULN) of 35 micromol/L at each monthly visit over a 12-month period.2-4
ADVERSE EFFECTS — The most common adverse effects of glycerol phenylbutyrate have been diarrhea, flatulence, and headache Phenylacetate, the major
metabolite of Ravicti, has been associated with
neu-rotoxicity.5 The dosage of the drug should be reduced
if the patient experiences nausea, vomiting, headache, somnolence, or confusion in the absence of increased ammonia levels or other possible causes
DRUG INTERACTIONS — Corticosteroids, valproic
acid (Depakene, and others), and haloperidol (Haldol,
and generics) can increase plasma concentrations of ammonia Concomitant use of probenecid may decrease excretion of phenylacetate and phenylacetylglutamine
DOSAGE, ADMINISTRATION, AND COST — The initial
dosage of Ravicti ranges from 4.5 to 11.2 mL/m2/day, which is divided into three equal doses (rounded up to the nearest 0.5 mL) and taken with meals The lower end of the range is recommended for patients with residual enzyme activity or hepatic impairment Patients switching from sodium phenylbutyrate should multiply the current total daily dosage (in grams) by 0.86 to derive their total daily dosage of glycerol phenylbutyrate (in mL) Glycerol phenylbutyrate is contraindicated in infants <2 months old who may have immature pancreatic systems that may not be able to metabolize the drug This is not a concern with sodium phenylbutyrate
The cost of a 25-mL (1.1 g/mL) bottle of Ravicti is
$2484.40, which is about fi ve times the cost per gram
of generic sodium phenylbutyrate.6
CONCLUSION — Used in addition to a protein-restricted
diet, glycerol phenylbutyrate (Ravicti) can help control
ammonia levels in adults and children with urea cycle disorders Glycerol phenylbutyrate does not have the
bitter taste of sodium phenylbutyrate (Buphenyl, and
generics), but it costs much more and it has not been approved by the FDA for use in children <2 years old ■
Table 1 Pharmacology
Drug class Nitrogen-binding agent
Formulation 1.1 g/mL oral liquid in 25-mL bottle
Route Oral
Metabolism Hydrolyzed by pancreatic lipases to
phenyl-butyric acid, then converted by beta-oxidation
to phenylacetate Excretion As phenylacetylglutamine in urine
MECHANISM OF ACTION — Use of glycerol
phenyl-butyrate permits excretion of nitrogen independent
of the urea cycle The drug is hydrolyzed by
pancreatic lipases to phenylbutyric acid, a prodrug
Trang 7The Medical Letter Vol 56 (1449) August 18, 2014
1 J Häberle et al Suggested guidelines for the diagnosis and
management of urea cycle disorders Orphanet J Rare Dis
2012; 7:32.
2 GA Diaz et al Ammonia control and neurocognitive outcome
among urea cycle disorder patients treated with glycerol
phenylbutyrate Hepatology 2013; 57:2171
3 U Lichter-Konecki et al Ammonia control in children with
urea cycle disorders (UCDs); phase 2 comparison of sodium
phenylbutyrate and glycerol phenylbutyrate Mol Genet Metab
2011; 103:323.
4 W Smith et al Ammonia control in children ages 2 months
through 5 years with urea cycle disorders: comparison of
sodi-um phenylbutyrate and glycerol phenylbutyrate J Pediatr 2013;
162:1228.
5 M Mokhtarani et al Elevated phenylacetic acid levels do not
correlate with adverse events in patients with urea cycle
dis-orders or hepatic encephalopathy and can be predicted based
on the plasma PAA to PAGN ratio Mol Genet Metab 2013;
110:446.
6 Approximate wholesale acquisition cost (WAC) Source:
Analy$ource® Monthly (Selected from FDB MedKnowledge™)
August 5, 2014 Reprinted with permission by FDB, Inc All
rights reserved ©2014
www.fdbhealth.com/policies/drug-pricing-policy Actual retail price may be higher.
A Transcutaneous Electrical Nerve
Stimulation Device (Cefaly) for
Migraine Prevention
▶
The FDA has approved the use of a transcutaneous
electrical nerve stimulation device (Cefaly – Cefaly
Technology) for prevention of episodic migraine in
patients >18 years old The fi rst device to be approved
in the US for migraine prevention, it is available in
Canada and Europe for treatment and prevention of
migraines A Ｙtranscranial magnetic stimulation device
(SpringTMS - eNeura Therapeutics) recently approved
by the FDA for treatment of migraine preceded by aura
will be reviewed in a future issue
THE DEVICE — The Cefaly device consists of a
battery-operated electrical pulse generator and a
self-adhesive electrode The patient applies the electrode
to the middle of the forehead and lowers a headband
containing the electrical pulse generator over the
forehead to engage a pin located on the electrode
Pressing a button on the band generates a pulsed
electric current that stimulates the upper branches of
the trigeminal nerve, producing a tingling or massaging
sensation During the treatment, which has a fi xed
duration of 20 minutes, the intensity of the electric
current gradually increases; if the current becomes
uncomfortable, the patient can press the button again
to reduce the intensity The device should not be used
in patients who have a cardiac pacemaker, a wearable
or implanted defi brillator, or an implanted metallic or
electrical device in their head
1 Approximate cost according to the manufacturer.
2 J Schoenen et al Migraine prevention with a supraorbital trans-cutaneous stimulatorＹ: a randomized controlled trial Neurology 2013; 80:697.
3 D Magis et al Safety and patients’ satisfaction of transcutane-ous supraorbital neurostimulation (tSNS) with the Cefaly device
in headache treatment: a survey of 2,313 headache sufferers in the general population J Headache Pain 2013; 14:95.
The Cefaly band is available only by prescription and
costs $299 A pack of 3 electrodes, each of which can
be used up to 20 times, costs $25.1
CLINICAL STUDIES — Approval of the device was based on the results of a double-blind trial (PREMICE)
in 67 patients 18-65 years old who had >2 migraine attacks with or without aura during a one-month
run-in period Patients were randomized to 3 months of
daily treatment for 20 minutes with the Cefaly device
or a sham stimulator device emitting a very small
electric current Patients using the Cefaly device had
a greater decrease from baseline in monthly migraine days at 3 months than those receiving sham treatment (-2.06 days vs -0.32 days), but the difference was not statistically signifi cant The number of patients meeting the co-primary endpoint of a >50% reduction
in migraine days per month was 13 (38.2%) with active treatment compared to 4 (12.1%) with sham treatment,
a statistically signifi cant difference Improvement in monthly migraine frequency was greater for patients who had >6 migraine headaches per month at baseline, compared to those who had <6 migraine headaches per month.2
Use of the Cefaly device resulted in a signifi cant
decrease in the use of acute anti-migraine drugs, but the severity of migraine attacks was not signifi cantly decreased in device users
In a patient satisfaction survey, about half of the 2313
headache sufferers who tested the Cefaly device for
an average of 58 days said they were satisfi ed with the treatment enough to buy the device; the other half returned it.3
ADVERSE EFFECTS — In the patient satisfaction survey, the most commonly reported adverse effect
of the device was local discomfort from the electrical stimulation Some patients reported forehead skin irritation, sleepiness, fatigue, insomnia, and headache after stimulation
CONCLUSION — In one small 3-month study, the
Cefaly device appeared to be modestly effective in
reducing the number of migraine days per month Its long-term safety is unknown ■
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1 Review the effi cacy and safety of dalbavancin (Dalvance) and tedizolid phosphate (Sivextro) for treatment of acute bacterial skin and skin structure infections.
2 Review the effi cacy and safety of sucroferric oxyhydroxide (Velphoro) for treatment of hyperphosphatemia in patients with chronic kidney disease.
3 Review the effi cacy and safety of glycerol phenylbutyrate (Ravicti) for treatment of urea cycle disorders.
4 Review the effi cacy and safety of Cefaly, a transcutaneous electrical nerve stimulation device, for prevention of episodic migraine.
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medicalletter.org/CMEstatus Issue 1449 Questions
(Correspond to questions #31-40 in Comprehensive Exam #71, available January 2015)
6 Adverse effects of sucroferric oxyhydroxide include:
Glycerol Phenylbutyrate (Ravicti) for Urea Cycle Disorders
7 Compared to sodium phenylbutyrate, glycerol phenylbutyrate:
c is less effective
d all of the above
8 Adverse effects of glycerol phenylbutyrate include:
d all of the above
A Transcutaneous Electrical Nerve Stimulation Device (Cefaly) for Migraine Prevention
9 Cefaly:
a is FDA-approved for treatment and prevention of migraine
b is less effective in patients with 6 or more migraines per month
occurred
d was superior to sham stimulation in producing a 50% or greater reduction in migraine days per month
10 A 32-year-old woman with frequent migraines asks you about
Cefaly, the new migraine headband she saw in a magazine She
currently takes propranolol for migraine prevention and sumatriptan for acute migraine You could tell her that:
b She can buy Cefaly without a prescription at her local
pharmacy.
c It is recommended that Cefaly be used for 20 minutes each day.
d all of the above
Two New Drugs for Skin and Skin Structure Infections
1 An otherwise healthy 28-year-old woman presents to a walk-in clinic
with a cutaneous abscess on her forearm The most common organism
responsible for this type of infection in many parts of the US is:
2 The patient from question 1 is afebrile and has no signs of
progressing cellulitis The most appropriate thing to do is:
a incision and drainage of the abscess
b give her a prescription for oral cephalexin
c admit her to the hospital for treatment with IV dalbavancin
d admit her to the hospital for treatment with IV tedizolid
3 Which of the following statements about dalbavancin is true?
a it is not active against MRSA
b it is dosed once daily
c it was found to be more effective than telavancin for treatment
of MRSA skin infections
d none of the above
4 Which of the following statements about tedizolid is true?
a it is available only in a parenteral formulation
b it is administered once daily
c it is more likely to interact with pseudoephedrine than linezolid
due to inhibition of monoamine oxidase
d all of the above
Sucroferric Oxyhydroxide (Velphoro) for Hyperphosphatemia
5 A 69-year-old woman with chronic kidney disease has
hyperphospha-temia despite dietary phosphate restriction and dialysis treatment She
also has hypercalcemia You are considering giving her a prescription
for a phosphate binder Which of the following statements about the
use of phosphate binders in this patient is true?
a Sucroferric oxyhydroxide is the only phosphate binder that has
been shown to improve clinical outcomes in such a patient.
b Sucroferric oxyhydroxide can increase calcium levels, so
sevelamer carbonate would be a better choice for her.
c Sevelamer carbonate and sucroferric oxyhydroxide are similarly
effective, but she would need to take more pills on a daily basis
with sevelamer carbonate than with sucroferric oxyhydroxide.
d Lanthanum carbonate is not a good choice because she also
has hypercalcemia.
ACPE UPN: Per Issue Exam: 0379-0000-14-449-H01-P; Release: August 18, 2014, Expire: August 18, 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.,
Weill Medical College of Cornell University
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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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