The medical letter on drugs and therapeutics may 23 2016

The Medical Letter

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on Drugs and Therapeutics
Volume 58

ISSUE
ISSUE
No.

1433
1495
Volume 56

May 23, 2016

IN THIS ISSUE

Antimicrobial Prophylaxis for Surgery ................................................................................ p 63
QuilliChew ER — Extended-Release Chewable Methylphenidate Tablets ........................ p 68
Ciprofloxacin (Otiprio) for Tympanostomy Tube Insertion ................................................ p 69
Three New Drugs for Multiple Myeloma ..................................................................... online only

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The Medical Letter

®

on Drugs and Therapeutics
Volume 58

ISSUE

ISSUE No.

1433
1495
Volume 56

▶

May 23, 2016
ALSO IN THIS ISSUE

QuilliChew ER — Extended-Release Chewable Methylphenidate Tablets ........................ p 68
Ciprofloxacin (Otiprio) for Tympanostomy Tube Insertion ................................................ p 69
Three New Drugs for Multiple Myeloma ..................................................................... online only

Antimicrobial Prophylaxis for Surgery

Antimicrobial prophylaxis can decrease the
incidence of postoperative surgical site infection
after some procedures. Since the last Medical Letter
article on this subject, consensus guidelines have
been published.1 Recommendations for prophylaxis
in specific surgical procedures are listed in the table
that begins on page 64.
CHOICE OF AGENT — Antimicrobial prophylaxis for
surgery should be directed against the most likely
infecting organisms, but it does not need to eradicate
every potential pathogen to be effective. Cefazolin
(Ancef, and others), a first-generation cephalosporin
active against many staphylococci and streptococci,
can be used for most procedures.
The second-generation cephalosporins cefoxitin
(Mefoxin, and others) and cefotetan (Cefotan, and
others) are recommended for procedures that involve
exposure to bowel flora, including Escherichia coli and
Bacteroides fragilis, but anaerobic resistance to these
drugs has increased.2 Ampicillin/sulbactam (Unasyn,
and generics), the broad-spectrum carbapenem

ertapenem (Invanz), or cefazolin plus metronidazole
(Flagyl, and others) may be considered, depending on
local susceptibility patterns.3
Most experts do not recommend routine use of broadspectrum antibiotics such as ertapenem or extendedspectrum cephalosporins such as cefotaxime
(Claforan, and generics), ceftriaxone (Rocephin, and
generics), ceftazidime (Fortaz, and others), cefepime
(Maxipime, and generics), or ceftaroline (Teflaro) for
surgical prophylaxis because they are expensive,
some are less active against staphylococci than
first- or second-generation cephalosporins, and their
spectrum of activity often includes organisms rarely
encountered in elective surgery.4

In patients who are colonized with methicillinresistant Staphylococcus aureus (MRSA) or in
institutions where surgical site infections are
frequently due to methicillin-resistant staphylococci,
vancomycin (Vancocin, and others) could be
considered for prophylaxis5; it should be given
in addition to the routine prophylactic regimen
recommended for the procedure. Vancomycin is less
effective than cefazolin for prevention of infections
due to methicillin-susceptible Staphylococcus
aureus (MSSA), it has a long infusion time, and
regular use possibly could lead to emergence of
vancomycin-resistant organisms.
Preoperative Screening and Decolonization –
Preoperative identification of patients who are nasal
carriers of MRSA or MSSA and decolonization using
intranasal mupirocin (Bactroban Nasal, and others)
and chlorhexidine (Peridex, and others) have been

shown to decrease surgical site infections following
some procedures (primarily cardiac and orthopedic),
but resistance to mupirocin could emerge if it is
used routinely.6-8
TIMING AND DURATION — Administration of the
prophylactic antibiotic should begin within 60
minutes before the initial surgical incision to ensure
adequate serum and tissue levels. If vancomycin or a
fluoroquinolone is used, the infusion should be started
within 60-120 minutes before the initial incision
because of the prolonged infusion times required for
these drugs.
A single prophylactic dose of an antimicrobial is
usually sufficient for most procedures; continuation
of prophylaxis for >24 hours after the procedure is
not recommended. There are no data to support
continuation of prophylaxis after wound closure, even
if all indwelling drains and intravascular catheters
have not yet been removed.
63

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The Medical Letter

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May 23, 2016

Table 1. Antimicrobial Prophylaxis for Surgery
Type of Surgical Procedure

Recommended
Antimicrobials

Common Pathogens

Usual Adult Dosage1

Cardiac
Coronary artery bypass grafting,
valve repairs, device implantation

Staphylococcus aureus,
Staphylococcus epidermidis

cefazolin2,3
OR cefuroxime2,3

Gastrointestinal
Esophageal, gastroduodenal
Entry into the GI lumen or
patients at high risk for infection6

Enteric gram-negative bacilli,
gram-positive cocci

cefazolin3,7

2 g IV4

Biliary tract
Open or high-risk laparoscopic8

Enteric gram-negative bacilli,
enterococci, clostridia

cefazolin3,7,9

2 g IV4

Colorectal10

Enteric gram-negative bacilli,
anaerobes, enterococci

cefazolin
+ metronidazole3,7
cefoxitin or cefotetan3,7
ampicillin/sulbactam3,7,11
ceftriaxone
+ metronidazole3,7,12
ertapenem3,7,13

2 g IV4
0.5 g IV
2 g IV

3 g IV
2 g IV
0.5 g IV
1 g IV

OR
OR
OR
OR
Appendectomy, non-perforated

Enteric gram-negative bacilli,
anaerobes, enterococci

Hernia

Gram-positive cocci

cefoxitin or cefotetan3,7
OR cefazolin
+ metronidazole3,7
cefazolin2,3

2 g IV4,5
1.5 g IV5

2 g IV
2 g IV4
0.5 g IV
2 g IV4

Genitourinary
Cystoscopy alone

Enteric gram-negative bacilli,
enterococci

High-risk14 only:
ciprofloxacin11
OR trimethoprim/
sulfamethoxazole11

Cystoscopy with manipulation or
upper tract instrumentation15

Enteric gram-negative bacilli,
enterococci

ciprofloxacin11
OR trimethoprim/
sulfamethoxazole11

Open or laparoscopic surgery16

Enteric gram-negative bacilli,
enterococci

cefazolin3,7

500 mg PO or 400 mg IV

160/800 mg (1 DS tab) PO
500 mg PO or 400 mg IV
160/800 mg (1 DS tab) PO
2 g IV4

1.

Parenteral prophylactic antimicrobials can be given as a single IV dose begun within 60 minutes before the initial incision. For procedures that exceed 2 halflives of the drug or those with major blood loss, or in patients with extensive burns, additional intraoperative doses should be given at intervals of about 2
times the half-life of the drug (ampicillin/sulbactam q2 hours, cefazolin q4 hours, cefuroxime q4 hours, cefoxitin q2 hours, clindamycin q6 hours, vancomycin
q12 hours) for the duration of the procedure in patients with normal renal function. If vancomycin or a fluoroquinolone is used, the infusion should be started
within 60-120 minutes before the initial incision to have adequate tissue levels at the time of incision and to minimize the possibility of an infusion reaction
close to the time of induction of anesthesia.
2. Vancomycin (15 mg/kg IV) or clindamycin (900 mg IV) is a reasonable alternative for patients who are allergic to beta-lactams. They only provide coverage
against gram-positive organisms; for procedures in which enteric gram-negative bacilli are common pathogens, many experts would add an aminoglycoside
(gentamicin, tobramycin or amikacin), aztreonam, or a fluoroquinolone.
3. A dose of vancomycin (15 mg/kg) can be given in addition to the recommended antimicrobial(s) in patients colonized with MRSA or in hospitals in which
methicillin-resistant S. aureus and S. epidermidis are a frequent cause of postoperative wound infection. Vancomycin is less effective than cefazolin in
preventing surgical site infections due to methicillin-susceptible Staphylococcus aureus (MSSA). Vancomycin has activity only against gram-positive
bacteria; for procedures in which enteric gram-negative bacilli are common pathogens, many experts would add another drug such as an aminoglycoside
(gentamicin, tobramycin or amikacin), aztreonam, or a fluoroquinolone. Rapid IV administration of vancomycin may cause hypotension, which could be
especially dangerous during induction of anesthesia. Even when the drug is given over 60 minutes, hypotension may occur; treatment with diphenhydramine
(Benadryl, and others) and further slowing of the infusion rate may be helpful. An infusion rate of 10-15 mg/minute (≥1 h/1000 mg) has been recommended
(T Crawford et al. Clin Infect Dis 2012; 54:1474).
4. Dose for patients who weigh <120 kg; the recommended dose is 3 g for those weighing ≥120 kg. Morbidly obese patients may need higher doses.
5. Some experts recommend an additional dose when patients are removed from bypass during open-heart surgery.
6. Morbid obesity, GI obstruction, decreased gastric acidity or GI motility, gastric bleeding, malignancy or perforation, or immunosuppression.
7. For patients who are allergic to beta-lactams, clindamycin (900 mg IV) or vancomycin (15 mg/kg IV) with either gentamicin, aztreonam, or a fluoroquinolone
is a reasonable alternative. Fluoroquinolones should not be used for prophylaxis in cesarean section.
8. Age >70 years, acute cholecystitis, non-functioning gallbladder, obstructive jaundice, common bile duct stones, duration >120 minutes, diabetes, pregnancy,
or immunosuppression.

9. Cefotetan, cefoxitin, and ampicillin/sulbactam are reasonable alternatives.
10. In addition to mechanical bowel preparation, 1 g of neomycin plus 1 g of erythromycin at 1 PM, 2 PM and 11 PM or 2 g of neomycin plus 2 g of metronidazole
at 7 PM and 11 PM the day before an 8 AM operation.

CARDIAC SURGERY — A preoperative dose of an
antibiotic can decrease the incidence of infection
after cardiac surgery; appropriate intraoperative
redosing should be continued for the duration of the
procedure. In a study in patients undergoing coronary
artery bypass grafting on cardiopulmonary bypass,
intraoperative continuous-infusion cefazolin was
superior to intermittent dosing every 2 hours.9
64

Antimicrobial prophylaxis is recommended before
placement of electrophysiologic devices, ventricular
assist devices, ventriculoatrial shunts, and arterial
patches to prevent device-related infections.
Administration of an antimicrobial prior to implantation
of permanent pacemakers and cardioverter-defibrillators
has been shown to significantly reduce the incidence of
wound infection, inflammation, and skin erosion.10


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May 23, 2016

Table 1. Antimicrobial Prophylaxis for Surgery (continued)
Type of Surgical Procedure

Recommended
Antimicrobials

Common Pathogens

Usual Adult Dosage1

Gynecologic and Obstetric
Vaginal, abdominal, or
laparoscopic hysterectomy

Enteric gram-negative bacilli,
anaerobes, Gp B strep,
enterococci

cefazolin3,7
OR cefoxitin or cefotetan3,7
OR ampicillin/sulbactam3,7,11

2 g IV4
2 g IV
3 g IV

Cesarean section

same as for hysterectomy

cefazolin3,7

2 g IV4

Abortion, surgical

same as for hysterectomy

doxycycline

300 mg PO17

Head and Neck Surgery
Incisions through oral or
pharyngeal mucosa

Anaerobes, enteric gramnegative bacilli, S. aureus

cefazolin
+ metronidazole3,18
OR ampicillin/sulbactam3,11,18

2 g IV4
0.5 g IV4
3 g IV

Neurosurgery
Craniotomy, spinal and CSF-shunting S. aureus, S. epidermidis,

procedures, intrathecal pump
Propionibacterium acnes
placement

cefazolin2,3

2 g IV4

S. epidermidis, S. aureus,
streptococci, enterococci,
P. acnes, Corynebacterium spp.,
enteric gram-negative bacilli,
Pseudomonas spp.

neomycin-gramicidinpolymyxin B, gatifloxacin, or
moxifloxacin
± cefazolin

1 drop q5-15 min
x 5 doses

S. aureus, S. epidermidis,
P. acnes (shoulder)

cefazolin2,3,20

2 g IV4

Ophthalmic19

100 mg subconjunctivally at the end
of the procedure

Orthopedic
Spinal, hip fracture, internal fixation,
total joint replacement
Thoracic (Non-Cardiac)
Lobectomy, pneumonectomy,
lung resection, thoracotomy

S. aureus, S. epidermidis,
streptococci, enteric gramnegative bacilli

cefazolin2.3
OR ampicillin/sulbactam2,3,11

2 g IV4
3 g IV

Vascular
Arterial involving a prosthesis,
the abdominal aorta, or a
groin incision

S. aureus, S. epidermidis,
enteric gram-negative bacilli

cefazolin2,3

2 g IV4

Lower extremity
amputation for ischemia

S. aureus, S. epidermidis,
enteric gram-negative bacilli,
clostridia

cefazolin2,3

2 g IV4

11.
12.
13.
14.
15.
16.
17.
18.
19.
20.

Due to increasing resistance of Escherchia coli, local sensitivity profiles should be reviewed prior to use.
Where there is increasing resistance of gram-negative isolates to first and second generation cephalosporins, a single dose of ceftriaxone plus metronidazole
may be preferred over routine use of carbapenems.
Ertapenem is FDA-approved for prophylaxis in colorectal surgery. It was more effective than cefotetan in one study, but it was associated with an increased
risk of Clostridium difficile infection and other adverse effects (KM Itani et al. N Engl J Med 2006; 355:2640). Routine use could promote carbapenem
resistance.
Urine culture positive or unavailable, preoperative catheter, transrectal prostatic biopsy, or placement of prosthetic material.

Shock wave lithotripsy, ureteroscopy.
Including percutaneous renal surgery, procedures with entry into the urinary tract, and those involving implantation of a prosthesis. If manipulation of bowel
is involved, prophylaxis is given according to colorectal guidelines.
Divided into 100 mg before the procedure and 200 mg after.
For patients who are allergic to beta-lactams, clindamycin (900 mg IV) is a reasonable alternative.
Preoperative application of povidone-iodine to the skin and conjunctiva is recommended.
If a tourniquet is to be used during the procedure, the entire dose of antibiotic must be infused prior to its inflation.

GASTROINTESTINAL SURGERY — Prophylaxis is
not recommended for routine gastroesophageal
endoscopy or colonoscopy.11 Antimicrobial prophylaxis
is recommended for patients undergoing esophageal
or gastroduodenal procedures that involve entry into
the GI lumen, such as resection for gastric carcinoma,
percutaneous endoscopic gastrostomy (PEG) insertion,
pancreatic duodenectomy, and perforated ulcer
procedures. For procedures that do not involve entry
into the GI tract, prophylaxis is recommended only for

patients at increased risk for infection, including those
with GI obstruction, increased gastric pH, decreased
GI motility, gastric bleeding, malignancy, or perforation,
morbid obesity, or immunosuppression.
Because the risk of postoperative infection is high
in patients undergoing bariatric surgeries, such
as adjustable gastric banding, vertical banded
gastroplasty, Roux-en-Y gastric bypass, and biliopancreatic diversion, antibiotic prophylaxis is used
65

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routinely for these procedures, but no controlled trials
are available. The appropriate antimicrobial regimen is
unclear, but higher doses of antibiotics may be needed
to achieve adequate serum and tissue concentrations
in morbidly obese patients.12
Antimicrobial prophylaxis is recommended before
biliary tract surgery for patients at high risk for
infection, including those >70 years old and those with
acute cholecystitis, a non-functioning gallbladder,
obstructive jaundice, or common bile duct stones.
Antibiotic prophylaxis for endoscopic retrograde
cholangiopancreatography (ERCP) is recommended
only if complete biliary drainage is unlikely to be
achieved.11 Prophylactic antibiotics are generally not
necessary for low-risk patients undergoing elective
laparoscopic cholecystectomy.13
Antibiotic prophylaxis can decrease the incidence of
infection after colorectal surgery. For most patients,
a combination of oral neomycin and either oral
erythromycin or oral metronidazole should be given
(after mechanical bowel preparation) in addition to IV
prophylaxis. Combined IV and oral prophylaxis is more
effective than IV prophylaxis alone in preventing surgical
site infection.14 Ertapenem has been approved by the
FDA for prevention of infection after elective colorectal
procedures, but many experts advise against using it

routinely for this purpose; it may be considered for use
in situations where a patient or an institution is known
to have organisms resistant to other antimicrobials.14,15
Antimicrobial prophylaxis can decrease the incidence
of infection after surgery for acute appendicitis.16,17 It
has been shown to reduce infection rates in patients
undergoing mesh hernioplasty or herniorrhaphy; the
risk is higher with hernioplasty.18,19
GENITOURINARY SURGERY — Most experts do not
recommend antimicrobial prophylaxis before cystoscopy without manipulation in patients with sterile urine.
When cystoscopy with manipulation (dilation, biopsy,
fulguration, resection, or ureteral instrumentation) is
planned, the urine culture is positive or unavailable, or an
indwelling urinary catheter is present, patients should
either be treated to sterilize the urine before surgery or
receive a single preoperative dose of an agent that is
usually active against the likely microorganisms.
Antimicrobial prophylaxis decreases the incidence
of postoperative bacteriuria and septicemia in
patients with sterile preoperative urine undergoing
transurethral prostatectomy and transrectal prostatic
biopsies.20-22 Prophylaxis is also recommended for
ureteroscopy, shock wave lithotripsy, percutaneous
66

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renal surgery, and open laparoscopic procedures,

and for placement of a urologic prosthesis (penile
implant, artificial sphincter, synthetic pubovaginal
sling, bone anchors for pelvic floor reconstruction).23
The efficacy of fluoroquinolones for prophylaxis in
urologic procedures is well established, but resistance
has emerged.24 Local resistance patterns, particularly
of E. coli, should guide appropriate selection of
antimicrobials for genitourinary procedures.
GYNECOLOGIC AND OBSTETRIC SURGERY —
Antimicrobial prophylaxis decreases the incidence of
infection after vaginal or abdominal hysterectomy.25
Prophylaxis is also recommended for laparoscopic
hysterectomy. Antimicrobials can prevent infection
after elective and non-elective cesarean section; giving
the dose prior to the initial skin incision appears to be
more effective than giving it after cord clamping.26
Antimicrobial prophylaxis can also prevent infection
following elective abortion.27
HEAD AND NECK SURGERY — Prophylaxis with
antimicrobials has decreased the incidence of surgical
site infection after clean-contaminated oncologic
head and neck operations that involve an incision
through the oral or pharyngeal mucosa.28 Prophylaxis
is not recommended for tonsillectomy or nasal
septoplasty.29,30
NEUROSURGERY — Antibiotic prophylaxis can
decrease the incidence of infection after craniotomy.31
It is also effective for spinal surgery. The infection
rate after conventional lumbar discectomy is low,
but the consequences of postoperative infection at

this site can be serious. Infection rates are higher
after prolonged spinal surgery or spinal procedures
involving fusion or insertion of foreign material.32
Studies have shown lower infection rates with use of
prophylactic antibiotics for implantation of permanent
cerebrospinal fluid shunts and for placement of
intrathecal pumps.33 The benefits of antimicrobial
prophylaxis for ventriculostomy placement remain
uncertain.34
OPHTHALMIC SURGERY — There is no consensus
supporting a particular choice, route, or duration of
antimicrobial prophylaxis for ophthalmic procedures,
but preoperative application of povidone-iodine to
the skin and conjunctiva has been shown to lower the
incidence of endophthalmitis.35 Other prophylactic
strategies include pre- and postoperative topical
antibiotic eye drops, addition of antibiotics to the
irrigating solution, and subconjunctival injections.
Use of intracameral injections is limited by lack


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of commercial availability and potential toxicity
if inaccurately dosed. There is no evidence that
prophylactic antibiotics are needed for procedures
that do not invade the globe.
ORTHOPEDIC SURGERY — Antistaphylococcal drugs

administered prophylactically can decrease the
incidence of both early and delayed infection after joint
replacement.36 They also decrease the rate of infection
when hip and other closed fractures are treated with
internal fixation by nails, plates, screws, or wires, and in
compound or open fractures.37-39 Whether prophylaxis
should be given as a single dose or as multiple doses
for up to 24 hours is unclear.38-40 Prophylaxis is also
recommended for orthopedic spinal procedures with
and without instrumentation.41 A retrospective review
of patients undergoing arthroscopic surgery concluded
that antibiotic prophylaxis is not indicated.42
THORACIC SURGERY — Antibiotic prophylaxis is
recommended for thoracic surgery, but supporting data
are sparse. In one study, a single preoperative dose of
cefazolin before pulmonary resection led to a decrease
in surgical site infection, but not in pneumonia or
empyema.43 Insertion of chest tubes for non-traumatic
indications, such as spontaneous pneumothorax, does
not require antimicrobial prophylaxis.
VASCULAR SURGERY — Preoperative prophylaxis
decreases the incidence of postoperative surgical
site infection after arterial reconstructive surgery
on the abdominal aorta, vascular operations on the
leg that include a groin incision, and amputation of
the lower extremity for ischemia.44,45 Many experts
also recommend prophylaxis for implantation of
any vascular prosthetic material, such as grafts for
vascular access in hemodialysis. Prophylaxis is not
indicated for carotid endarterectomy or brachial

artery repair without prosthetic material. Prophylactic
antibiotics are not routinely recommended for baremetal stenting, but risk factors that may justify their
use include repeat intervention within 7 days, prolonged
indwelling arterial sheath, prolonged procedure duration
(>2 hours), presence of other infected implants, and
immunosuppression. Although the incidence of infection after stent graft procedures is low (<1%), use of
prophylactic antibiotics is justified because the mortality
rate associated with graft infections is high (18-29%).46-48
OTHER PROCEDURES — Antimicrobial prophylaxis is
generally not indicated for cardiac catheterization,
varicose vein surgery, most dermatologic49 and
plastic surgeries, arterial puncture, thoracentesis,
paracentesis, repair of simple lacerations, or outpatient

Vol. 58 (1495)

May 23, 2016

treatment of burns because the incidence of surgical
site infections with all of these procedures is low.
Whether prophylaxis is needed in breast surgery
(other than for breast cancer50) and other “clean”
surgical procedures has been controversial. Most
experts generally do not recommend antibacterial
prophylaxis for these procedures because of the low
rate of infection and the potential for adverse effects
with prophylaxis. It may be considered for procedures
in which the consequences of infection can be serious,
such as those involving placement of prosthetic
material (e.g., saline implants, tissue expanders). ■

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prophylaxis in the surgical treatment of closed fractures: a
meta-analysis. J Orthop Trauma 2008; 22:264.

41. WO Shaffer et al. An evidence-based clinical guideline for antibiotic prophylaxis in spine surgery. Spine J 2013; 13:1387.
42. JM Bert et al. Antibiotic prophylaxis for arthroscopy of the knee:
is it necessary? Arthroscopy 2007; 23:4.
43. R Aznar et al. Antibiotic prophylaxis in non-cardiac thoracic surgery: cefazolin versus placebo. Eur J Cardiothorac Surg 1991;
5:515.
44. AH Stewart et al. Prevention of infection in peripheral arterial
reconstruction: a systematic review and meta-analysis. J Vasc
Surg 2007; 46:148.
45. S Homer-Vanniasinkam. Surgical site and vascular infections:
treatment and prophylaxis. Int J Infect Dis 2007; 11:S17.
46. JA Sutcliffe et al. Antibiotics in interventional radiology. Clin
Radiol 2015; 70:223.
47. WM Bosman et al. Infections of intravascular bare metal stents:

68

Vol. 58 (1495)

May 23, 2016

a case report and review of literature. Eur J Vasc Endovasc Surg
2014; 47:87.
48. AM Venkatesan et al. Practice guidelines for adult antibiotic
prophylaxis during vascular and interventional radiology procedures. Written by the Standards of Practice Committee for
the Society of Interventional Radiology and Endorsed by the
Cardiovascular Interventional Radiological Society of Europe
and Canadian Interventional Radiology Association [corrected].
J Vasc Interv Radiol 2010; 21:1611.
49. TI Wright et al. Antibiotic prophylaxis in dermatologic surgery:
advisory statement 2008. J Am Acad Dermatol 2008; 59:464.

50. DJ Jones et al. Prophylactic antibiotics to prevent surgical site
infection after breast cancer surgery. Cochrane Database Syst
Rev 2014; 3:CD005360.

▶

QuilliChew ER — Extended-Release
Chewable Methylphenidate Tablets

The FDA has approved a once-daily, extended-release
chewable tablet formulation of methylphenidate
(QuilliChew ER – Pfizer) for treatment of attentiondeficit/hyperactivity disorder (ADHD). It is the first
long-acting chewable formulation of the drug to be
marketed in the US. Immediate-release chewable
methylphenidate tablets (Methylin, and generics) have
been available since 2003.1
Pronunciation Key
Methylphenidate : meth" il fen' i date QuilliChew : quil" ih choo'

METHYLPHENIDATE — Short-acting methylphenidate
formulations are effective for treatment of ADHD,
but their 3-5 hour duration of action usually requires
mid-day dosing in school, which children may find
disruptive or stigmatizing. Long-acting methylphenidate
preparations have therefore become the mainstay
of clinical practice. Most long-acting formulations
are available only as tablets or capsules that many
children find difficult to swallow. Some capsules can
be opened and their contents sprinkled on applesauce.
All methylphenidate products are Schedule II controlled

substances.
THE NEW FORMULATION — QuilliChew ER is available
as tablets containing 15% methylphenidate HCl and
85% methylphenidate bound to sodium polystyrene
sulfonate particles; they contain a mixture of 30%
immediate-release and 70% extended-release
methylphenidate. In a pharmacokinetic study in
healthy adults comparing a single 40-mg dose of
QuilliChew ER with two 20-mg doses of immediaterelease chewable methylphenidate, the AUC of
methylphenidate with QuilliChew ER was within the
80% to 125% bioequivalence acceptance standard, but
the Cmax was 20% lower and the AUC was 11% lower
than those with immediate-release methylphenidate.2


The Medical Letter

Vol. 58 (1495)

®

Table 1. Some Long-Acting Methylphenidate Formulations
Drug

Some
Formulations

Pediatric Dosage
Initial/Usual1
Cost2

Dexmethylphenidate
5, 10, 15, 20, 25, 30,
5 mg qAM/
Focalin XR
(Novartis)
35, 40 mg ER caps3,4
10-20 mg qAM
generic
5, 10, 15, 20, 30, 40 mg
ER caps3,4
Methylphenidate
20 mg qAM/
Metadate CD 10, 20, 30, 40, 50,
(UCB)
60 mg ER caps3,5
30 mg qAM
generic
Ritalin LA
(Novartis)
generic

10, 20, 30, 40 mg
10-20 mg qAM/
ER caps3,4
30 mg qAM
20, 30, 40 mg ER caps3,4

Concerta
(Janssen)

generic6

18, 27, 36, 54 mg
ER tabs7

Daytrana
(Noven)

10, 15, 20, 30 mg
10 mg qAM/
transdermal patches8 30 mg qAM

18 mg qAM/
36 mg qAM

$289.70
218.30

227.00
134.40
242.80
121.20
291.30
208.40
303.10

Quillivant XR 25 mg/5 mL ER
(Pfizer)
oral suspension9

20 mg qAM/
30-40 mg qAM

216.80

Aptensio XR
(Rhodes)

10 mg qAM/
30 mg qAM

195.00

20 mg qAM/
30 mg qAM

270.00

10, 15, 20, 30, 40, 50,
60 mg ER caps3

QuilliChew ER 20, 30, 40 mg
(Pfizer)
chewable tabs

ER = extended-release
1. Dosage for children ≥6 years old.
2. Approximate WAC for 30 days’ treatment at 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. May

5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved.
©2016.www.fdbhealth.com/policies/drug-pricing-policy.
3. Capsules can be either swallowed whole or the contents sprinkled on
applesauce, but should not be crushed or chewed.
4. Should not be taken with antacids or other drugs that decrease gastric acidity.
5. Should be taken before breakfast.
6. Only the generic product distributed by Actavis is bioequivalent to the brand
name product.
7. Must be swallowed whole, and not be crushed or chewed.
8. The patch should be applied 2 hours before an effect is needed and removed
9 hours after application. It may be removed earlier than 9 hours if needed.
9. Quillivant XR must be reconstituted prior to administration and is stable for
up to 4 months. It is available in bottles containing 60, 120, 150 or 180 mL.
Each bottle is packaged with a bottle adapter and dosing syringe.

CLINICAL STUDIES — Approval of the new formulation
was based on the results of an unpublished,
randomized trial (summarized in the package insert)
in 90 children 6-12 years old with ADHD who were
titrated to an optimal dose (max 60 mg/day) of
QuilliChew ER over 6 weeks, followed by 1 week of
treatment with either the active drug or placebo.
After the 1-week treatment period, the children
were evaluated using the SKAMP-Combined score,
which measures ADHD symptoms in a laboratory
school setting, at 7 time points between 0.75 and
13 hours post-dose. SKAMP-Combined scores were
significantly better with the active drug than with
placebo at 0.75, 2, 4, and 8 hours post-dosing, but
not at 10, 12, or 13 hours. No head-to-head trials are

available comparing the new formulation to other
formulations of methylphenidate or other stimulants.

May 23, 2016

DOSAGE AND ADMINISTRATION — The recommended
starting dosage of QuilliChew ER in patients ≥6 years
old is 20 mg once daily in the morning with or without
food. The daily dose can be titrated at weekly intervals
by 10, 15, or 20 mg (20- and 30-mg tablets are scored)
to a maximum dose of 60 mg.
CONCLUSION — QuilliChew ER, a once-daily methylphenidate chewable tablet, provides another option for
children with ADHD who are unable to swallow tablets
or capsules. How it compares to other long-acting
methylphenidate products in efficacy and adverse
effects remains to be determined. ■
1. Drugs for ADHD. Med Lett Drugs Ther 2015; 57:37.
2. R Abbas et al. Single-dose pharmacokinetic properties and
relative bioavailability of a novel methylphenidate extendedrelease chewable tablet compared with immediate-release
methylphenidate chewable tablet. Clin Ther 2016 March 24
(epub).

▶

Ciprofloxacin (Otiprio) for
Tympanostomy Tube Insertion

The FDA has approved ciprofloxacin 6% otic
suspension (Otiprio – Otonomy) for single-dose
prophylaxis in children with bilateral otitis media

with effusion who are undergoing tympanostomy
tube placement. It is the first drug to be approved
for this indication in the US. Otic formulations
of the fluoroquinolone antibiotics ofloxacin
(Floxin Otic, and generics) and ciprofloxacin (plus
dexamethasone; Ciprodex) have been available for
years for treatment of acute otitis media in children
with tympanostomy tubes; an otic suspension
containing ciprofloxacin and fluocinolone acetonide
(Otovel) has recently been approved for the same
indication and will be reviewed in a future issue.
Otiprio : oh ti' pree oh

Pronunciation Key

TYMPANOSTOMY TUBE INSERTION — The primary
surgical intervention for recurrent acute otitis media
and otitis media with effusion in children 6 months
to 12 years old is tympanostomy tube insertion
(TTI).1 About 667,000 TTIs are performed annually in
the US in children <15 years old.2 TTI reduces middle
ear effusion and improves hearing in patients with
otitis media with effusion. Whether the procedure
prevents recurrences of acute otitis media is
less clear.3 Otorrhea, primarily due to a bacterial
infection, is the most common complication of
TTI. Tympanostomy tubes can be kept in place for
several months or years.
69

The Medical Letter

May 23, 2016

Vol. 58 (1495)

®

Table 1. Some Otic Fluoroquinolone Products
Drug

Formulation

Dosage

Cost1
$283.20

Ciprofloxacin 6% – Otiprio (Otonomy)

60 mg/1 mL single-use vial

0.1 mL in each ear once, intratympanically

Ciprofloxacin 0.3%/dexamethasone 0.1% –
Ciprodex4 (Alcon)

7.5 mL bottle

4 drops in affected ear bid x 7 days

Ciprofloxacin 0.3%/fluocinolone acetonide 0.025% –
Otovel4 (Arbor/Salvat)

0.25 mL single-dose vial5

0.25 mL in affected ear bid x 7 days

Ofloxacin 0.3%4 – generic

5, 10 mL bottles

5 drops in affected ear bid x 10 days

2

3

192.90

N.A.
16.80

N.A. = Product is not yet available.
1. Approximate WAC for the smallest-size bottle or vial. 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. May 5, 2016. Reprinted with permission
by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
2. FDA-approved for the treatment of children with bilateral otitis media with effusion who are undergoing tympanostomy tube placement.
3. Includes sufficient syringes and needles to treat both ears.

4. FDA-approved for treatment of acute otitis media in children with tympanostomy tubes.
5. Sold in cartons containing 14 single-dose vials.

PHARMACOKINETICS — Otiprio is a thermosensitive
suspension that is liquid at room temperature, but
gels at body temperature or when warmed. In animal
models, a single dose of Otiprio produced a higher
Cmax and AUC of ciprofloxacin than a pulsed course
of Ciprodex; release of ciprofloxacin in the middle ear
continued for as long as 2 weeks.4
CLINICAL STUDIES — Approval of Otiprio was based
on the results of 2 prospective, sham-controlled
trials in a total of 532 children (median age 1.5
years) with bilateral otitis media with effusion who
were randomized to TTI alone or TTI plus Otiprio.
The drug was administered as a single dose in each
ear intraoperatively. The primary endpoint was the
percentage of treatment failures, defined as otorrhea ≥3
days after surgery, need for antibiotics for any reason
at any time post-surgery, or a missed visit or failure
to follow-up. At day 15, the percentage of treatment
failures was 24.6% in the Otiprio group vs 44.8% with
TTI alone in the first study and 21.3% vs 45.5% in the
second study; in both studies the differences were
statistically significant. Otorrhea occurred in 7% of
patients treated with Otiprio in both trials compared to
11% and 27% of those treated with TTI alone.5
In a randomized, double-blind trial in 83 children with
bilateral middle ear effusion undergoing TTI, treatment
failures occurred in 14.3% and 15.8% of patients

treated with 4 mg and 12 mg of Otiprio, respectively,
and in 45.5% and 42.9% of those treated with placebo
or a sham procedure.6
ADVERSE EFFECTS — In the clinical trials, the only
adverse effects that occurred at a higher rate with
Otiprio than with sham treatment were nasopharyngitis
(5% vs 4%), irritability (5% vs 3%), and rhinorrhea (3% vs
2%). The effect of Otiprio administration on emergence
of bacterial resistance is unknown.
70

DOSAGE AND ADMINISTRATION — The recommended
dosage of Otiprio is 0.1 mL (6 mg) administered
intratympanically into each affected ear following
suctioning of the middle ear effusion.
CONCLUSION — Ciprofloxacin 6% otic suspension
(Otiprio), administered intratympanically once into
each ear during placement of tympanostomy tubes in
children with bilateral otitis media with effusion, can
reduce the incidence of postsurgical otorrhea, and it
appears to be safe. Its long-term safety and its effect
on bacterial resistance are unknown. Comparative
trials with systemic or other topical antimicrobials
are lacking. ■
1. AS Lieberthal et al. The diagnosis and management of acute
otitis media. Pediatrics 2013; 131:e964.
2. RM Rosenfeld et al. Clinical practice guideline: tympanostomy
tubes in children. Otolaryngol Head Neck Surg 2013; 149:S1.
3. IF Wallace et al. Surgical treatments for otitis media with effusion: a systematic review. Pediatrics 2014; 133:296.
4. X Wang et al. OTO-201: nonclinical assessment of a sustainedrelease ciprofloxacin hydrogel for the treatment of otitis media.

Otol Neurotol 2014; 35:459.
5. EA Mair et al. Safety and efficacy of intratympanic ciprofloxacin
otic suspension in children with middle ear effusion undergoing
tympanostomy tube placement: two randomized clinical trials.
JAMA Otolaryngol Head Neck Surg 2016 March 17 (epub).
6. EA Mair et al. Randomized clinical trial of a sustained-exposure
ciprofloxacin for intratympanic injection during tympanostomy
tube surgery. Ann Otol Rhinol Laryngol 2016; 125:105.

Online Only Article
Three New Drugs for Multiple Myeloma
www.medicalletter.org/TML-article-1495d

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The Medical Letter

®

on Drugs and Therapeutics

Volume 58 (Issue 1495)

▶

May 23, 2016

Three New Drugs for Multiple
Myeloma

The FDA recently approved ixazomib (Ninlaro –
Takeda), daratumumab (Darzalex – Janssen Biotech),
and elotuzumab (Empliciti – BMS) for treatment of
relapsed and/or refractory multiple myeloma.
Pronunciation Key
Ixazomib: ix az' oh mib
Ninlaro : nin lar' oh
Daratumumab: dar" a toom' ue mab
Darzalex : dar' zah lex
Elotuzumab: el" oh tooz' ue mab
Empliciti : em plis city

STANDARD TREATMENT — Use of drug regimens that
include the proteasome inhibitor bortezomib (Velcade)
plus either the immunomodulating drug thalidomide
(Thalomid) or lenalidomide (Revlimid), a thalidomide
analog, instead of chemotherapy has led to improved
response rates and survival in patients with multiple
myeloma.
Carfilzomib (Kyprolis), a second proteasome inhibitor,
is an alternative for treatment of refractory multiple
myeloma.1 Pomalidomide (Pomalyst), another
thalidomide analog, is an alternative for patients

with disease progression who have received at
least two prior therapies including lenalidomide
and bortezomib.2 Panobinostat (Farydak), an oral
histone deacetylase inhibitor, in combination with
bortezomib and dexamethasone is another option for
patients who have received at least two prior therapies
including bortezomib and an immunomodulatory
drug.3 Many patients discontinue these drugs due to
lack of response or toxicity; most who respond initially
subsequently relapse, and with each relapse the
disease becomes more resistant to treatment.4
IXAZOMIB (NINLARO) — Ixazomib, the only oral
proteasome inhibitor available in the US, is approved
by the FDA for use in combination with lenalidomide
and dexamethasone for treatment of patients with
multiple myeloma who were previously treated with at
least one other regimen.5
Clinical Studies – Approval of ixazomib was based
on the results of a randomized, double-blind
trial comparing ixazomib plus lenalidomide and

dexamethasone with lenalidomide, dexamethasone,
and placebo in 722 patients who had relapsed and/or
refractory multiple myeloma. The median duration of
progression-free survival, the primary endpoint, was
significantly longer with ixazomib (20.6 months vs
14.7 months). The overall response rate was 78% with
ixazomib and 72% with placebo.6
Adverse Effects – Diarrhea was the most common
non-hematologic adverse event; grade 3 diarrhea

occurred in 23 patients (6%) taking ixazomib and in
9 (3%) taking placebo. Hematologic events included
grade 3 and 4 thrombocytopenia (12% and 7%) and
neutropenia (18% and 5%), and grade 3 anemia (9%).
Drug Interactions – Coadministration of strong CYP3A
inducers with ixazomib should be avoided.7
DARATUMUMAB (DARZALEX) — Daratumumab, an
intravenous human monoclonal antibody that targets
the transmembrane glycoprotein CD-38, which is
overexpressed on myeloma cells, is approved for
use in patients with multiple myeloma who received
≥3 prior lines of therapy including a proteasome
inhibitor and an immunomodulatory drug or who are
double-refractory to a proteasome inhibitor and an
immunomodulatory drug.
Clinical Studies – Approval of daratumumab was based
on the results of 2 open-label monotherapy trials in 42
and 106 heavily pretreated patients; overall response
rates were 36% and 29%, respectively. The median
duration of progression-free survival was 5.6 and 3.7
months. In the smaller study, 65% of responders did
not have disease progression at one year.8,9
Adverse Effects – Serious adverse effects, which
occurred in 33% of patients, included infusion reactions,
pneumonia, hypertension, and grade 3-4 anemia,
lymphopenia, neutropenia, and thrombocytopenia.
ELOTUZUMAB (EMPLICITI) — Elotuzumab, the second
intravenous monoclonal antibody to receive approval
for use in patients with relapsed or refractory multiple
myeloma (1-3 prior therapies), targets signaling

lymphocytic activation molecule family member 7
(SLAMF7), which is expressed on myeloma cells

e70

Published by The Medical Letter, Inc. • A Nonprofit Organization


The Medical Letter

Vol. 58 (1495)

®

May 23, 2016

Table 1. New Drugs for Multiple Myeloma
Drug

Some Available
Formulations

Usual Adult
Maintenance Dosage1

Ixazomib – Ninlaro (Takeda)

2.3, 3, 4 mg caps

Daratumumab – Darzalex (Janssen Biotech)

100 mg/5 mL, 400 mg/20 mL
single-dose vials

Elotuzumab – Empliciti (BMS)

300, 400 mg single-dose vials
containing lyophilized powder for
reconstitution

4 mg PO on days 1, 8, and 15
of a 28-day cycle3
16 mg/kg IV q wk x 8 wks,
then q2 wks for wks 9-24,
then q4 wks
10 mg/kg IV on days 1, 8, 15, and
22 of a 28-day cycle x 2 cycles,
then on days 1 and 15 thereafter

Cost2
$8670.00
5400.00

8880.00

1. Dosage may need to be adjusted for hepatic or renal impairment.
2. Approximate WAC for 28 days’ maintenance treatment for a 70-kg patient. 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. May 5, 2016. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
3. Should be taken at least one hour before or at least two hours after food.

4. Should be administered in combination with lenalidomide and dexamethasone.

and natural killer cells, but not on healthy tissue.
Elotuzumab activates natural killer cells, which aid in
the killing of myeloma cells.
Clinical Studies – FDA approval of elotuzumab was
based on the results of an open-label, randomized,
24-month trial in 646 patients with relapsed
or refractory multiple myeloma that compared
elotuzumab in combination with lenalidomide and
dexamethasone with lenalidomide, dexamethasone,
and placebo. The elotuzumab group had a significantly
higher overall response rate (79% vs 66%) and a
significantly longer median duration of progressionfree survival (19.4 vs 14.9 months) than the control
group. Patients who received elotuzumab had a 30%
lower risk of disease progression or death than those
who received placebo.10
Adverse Effects – Adverse effects that occurred in
≥10% of patients and at least 5% more often with
elotuzumab than with placebo included fatigue,
diarrhea, constipation, fever, cough, peripheral
neuropathy, pneumonia, and lymphopenia. Infusion
reactions, opportunistic infections, and hepatotoxicity
can also occur.

e71

CONCLUSION — The new options for treatment
of relapsed/refractory multiple myeloma include
an oral proteasome inhibitor and 2 intravenous

monoclonal antibodies. All three offer some benefit
in progression-free survival. How they compare with
each other or the other drugs approved earlier for this
indication remains to be determined. ■
1. Carfilzomib (Kyprolis) for multiple myeloma. Med Lett Drugs
Ther 2012; 55:103.
2. Pomalidomide (Pomalyst) for multiple myeloma. Med Lett
Drugs Ther 2015; 57:e66.
3. Panobinostat (Farydak) for multiple myeloma. Med Lett Drugs
Ther 2015; 57:e118.
4. MA Dimopoulos et al. Current treatment landscape for relapsed
and/or refractory multiple myeloma. Nat Rev Clin Oncol 2015;
12:42.
5. M Gentile et al. Ixazomib for the treatment of multiple myeloma.
Expert Opin Investig Drugs 2015; 24:1287.
6. P Moreau et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016; 374:1621.
7. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2016; 58:e46.
8. HM Lokhorst et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 2015; 373:1207.
9. S Lonial et al. Daratumumab monotherapy in patients with
treatment-refractory multiple myeloma: (SIRIUS): an openlabel, randomised, phase 2 trial. Lancet 2016; 387:1551.
10. S Lonial et al. Elotuzumab therapy for relapsed or refractory
multiple myeloma. N Engl J Med 2015; 373:621.


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Online Continuing Medical Education
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Issue 1495 Questions
(Correspond to questions #101-110 in Comprehensive Exam #74, available July 2016)
Antimicrobial Prophylaxis for Surgery
1. To ensure adequate serum and tissue levels before surgery, the
first dose of cefazolin should be administered:
a. at induction of anesthesia
b. within 60 minutes before the initial incision
c. within 120 minutes of the initial incision
d. at wound closure
2. Intraoperative redosing of a prophylactic antibiotic is
recommended if:
a. the duration of the procedure exceeds 2 half-lives of the

antimicrobial agent
b. there is excessive blood loss
c. there are extensive burns
d. all of the above
3. For most procedures, antimicrobial prophylaxis should be given:
a. as a single dose
b. for 48 hours
c. for 72 hours
d. until all drains and catheters are removed
4. Compared to cefazolin, vancomycin:
a. is less effective in preventing surgical site infections due
to methicillin-susceptible Staphylococcus aureus (MSSA)
b. is more active against methicillin-resistant
Staphylococcus aureus (MRSA)
c. has a longer infusion time
d. all of the above
QuilliChew ER – Extended-Release Chewable Methylphenidate
Tablets
5. QuilliChew ER is the:
a. first chewable tablet formulation of methylphenidate
b. first extended-release tablet formulation of
methylphenidate
c. first chewable extended-release tablet formulation of
methylphenidate
d. all of the above

6. In the clinical trial that was the basis for FDA-approval of
QuilliChew ER, the drug was significantly more effective than
placebo at which time intervals post-dosing?
a. 8 hours

b. 10 hours
c. 12 hours
d. all of the above
Ciprofloxacin (Otiprio) for Tympanostomy Tube Insertion
7. Your sister-in law calls you in an agitated state because her
pediatrician has just recommended insertion of tympanostomy
tubes into the ears of her 4-year-old son, who has had several
episodes of otitis media in both ears, without explaining the
benefits and risks of the procedure. You could tell her that:
a. otorrhea, primarily due to a bacterial infection, is the main
complication of the procedure
b. if her son has an effusion in his middle ear, inserting
tympanostomy tubes could improve his hearing
c. it is not clear whether the procedure prevents recurrences
of acute otitis media
d. all of the above
8. In the pharmacokinetic study with Otiprio, ciprofloxacin
continued to be released in the middle ear for as long as:
a. 10 days
b. 2 weeks
c. 4 weeks
d. 2 months
9. Which of the following remains to be determined about Otiprio?
a. its long-term safety
b. its effect on bacterial resistance
c. how it compares with other topical antimicrobials
d. all of the above
10. In the clinical trials of Otiprio, the percentage of treatment
failures with the drug, compared to tympanostomy tube
insertion alone, was about:

a. the same
b. one tenth as high
c. half as high
d. twice as high

ACPE UPN: Per Issue Exam: 0379-0000-16-495-H01-P; Release: May 23, 2016, Expire: May 23, 2017
Comprehensive Exam 74: 0379-0000-16-074-H01-P; Release: July 2016, Expire: July 2017

PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm,
Pharm.D.; ASSOCIATE EDITORS: Susan M. Daron, Pharm.D., Amy Faucard, MLS, Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah,
Pharm.D., F. Peter Swanson, M.D.
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;
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Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Franco M. Muggia, M.D., New York University Medical Center; Sandip K. Mukherjee,
M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School; F. Estelle
R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell
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