The medical letter on drugs and therapeutics april 25 2016

The Medical Letter

®

on Drugs and Therapeutics
Volume 58

ISSUE
ISSUE
No.

1433
1493
Volume 56

April 25, 2016

IN THIS ISSUE

In Brief: New Recommendations for Use of Metformin in Renal Impairment .................. p 51
Cariprazine (Vraylar) for Schizophrenia and Bipolar I Disorder ........................................ p 51
Maestro Rechargeable System for Weight Loss ................................................................ p 54
Mifepristone (Mifeprex) Label Changes ............................................................................. p 55
In Brief: Cholic Acid (Cholbam) for Bile Acid Synthesis Disorders ................................... p 56
In Brief: Jadenu – A New Formulation of Deferasirox for Iron Overload .................. online only

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The Medical Letter

®

on Drugs and Therapeutics
Volume 58

April 25, 2016
Take CME Exams

ISSUE

ISSUE No.

1433

1493
Volume 56

ALSO IN THIS ISSUE

Maestro Rechargeable System for Weight Loss ................................................................ p 54
Mifepristone (Mifeprex) Label Changes ............................................................................. p 55
In Brief: Cholic Acid (Cholbam) for Bile Acid Synthesis Disorders ................................... p 56
In Brief: Jadenu – A New Formulation of Deferasirox for Iron Overload .................. online only

IN BRIEF

New Recommendations for Use of
Metformin in Renal Impairment
The FDA has required labeling changes that replace
serum creatinine (SCr) with estimated glomerular
filtration rate (eGFR) as the parameter used to determine
the appropriateness of treatment with the biguanide
metformin (Glucophage, and others) in patients with renal
impairment. These changes will allow more patients with
mild to moderate renal impairment to receive metformin,
which is generally the first drug prescribed for treatment
of type 2 diabetes.
Metformin was previously contraindicated in women with
a SCr level ≥1.4 mg/dL and in men with a SCr level ≥1.5
mg/dL, but use of SCr as a surrogate indicator tends to
underestimate renal function in certain populations (e.g.,
younger patients, men, black patients, patients with
greater muscle mass). The calculation of eGFR takes into
account age, race, and sex, as well as SCr level, providing a

more accurate assessment of kidney function. A literature
review summarized in an FDA Drug Safety Communication
concluded that, based on eGFR, metformin is safe to use in
patients with mild renal impairment and in some patients
with moderate renal impairment.1
The eGFR should be calculated before patients begin
treatment with metformin and at least annually thereafter.
Metformin is now contraindicated in patients with an
eGFR <30 mL/min/1.73 m2, and starting treatment with
the drug in patients with an eGFR between 30 and 45 mL/
min/1.73 m2 is not recommended. If the eGFR falls below
45 mL/min/1.73 m2 in a patient already taking metformin,
the benefits and risks of continuing treatment should be
assessed. Metformin should be not be administered for
48 hours after an iodinated contrast imaging procedure in
patients with an eGFR <60 mL/min/1.73 m2 or a history
of liver disease, alcoholism, or heart failure, or in those
receiving intra-arterial contrast, and the eGFR should be
re-evaluated before treatment is restarted. ■
1. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients
with reduced kidney function. Available at: www.fda.gov/Drugs/
DrugSafety/ucm493244.htm. Accessed April 14, 2016.

▶

Cariprazine (Vraylar) for
Schizophrenia and Bipolar I Disorder

The FDA has approved cariprazine (Vraylar – Actavis), an
oral, once-daily, second-generation antipsychotic, for treatment of schizophrenia and for acute treatment of manic or

mixed episodes associated with bipolar I disorder.
Pronunciation Key
Cariprazine : kar ip' ra zeen
Vraylar : vray' lar

STANDARD TREATMENT — With the exception of clozapine
(Clozaril, and others), second-generation antipsychotics
are not clearly more effective than first-generation
antipsychotics for treatment of schizophrenia, but in
usual doses they are much less likely to cause tardive
dyskinesia. Clozapine is usually reserved for refractory
disease because of its potential for serious toxicity,
including seizures and agranulocytosis. Olanzapine
(Zyprexa, and generics) may be the most effective of the
other second-generation antipsychotics, but it is also the
most likely to cause metabolic adverse effects. Patients
who do not respond to one antipsychotic may respond
to another. Long-acting injectable formulations may be
useful when adherence is a problem.
For treatment of manic or mixed episodes associated
with bipolar I disorder, lithium, valproate, and secondgeneration antipsychotics generally have similar efficacy,
but individual patients may have greater improvement
with one or another, and adverse effects may vary widely.
Table 1. Pharmacology
Class
Mechanism
of action
Formulation
Route
Metabolism

Elimination
Half-life

Second-generation antipsychotic
Dopamine (D2) and serotonin (5-HT1A) partial
agonist; 5-HT2A antagonist
1.5, 3, 4.5, 6 mg capsules
Oral
Hepatic, primarily by CYP3A4 and (for cariprazine and DCAR1) to a lesser extent by CYP2D6
Urine (21%)
Cariprazine: 2-4 days
DDCAR1: 1-3 weeks

1. DCAR and DDCAR are active metabolites equipotent to cariprazine.

51

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The Medical Letter

April 25, 2016

Vol. 58 (1493)

®

Both lithium and valproate can take days to weeks to
have a full therapeutic effect; patients with mania often

require adjunctive treatment with an antipsychotic drug
or temporary treatment with a benzodiazepine.1
PHARMACOLOGY — Cariprazine is metabolized by
CYP3A4 and, to a lesser extent, by CYP2D6 to its
equipotent active metabolites desmethylcariprazine
(DCAR) and didesmethylcariprazine (DDCAR). At
steady state, DDCAR serum concentrations are 300%
higher than those of cariprazine.
Like aripiprazole and brexpiprazole, cariprazine and its
metabolites are partial agonists at dopamine D2 receptors and serotonin 5-HT1A receptors, and antagonists at
5-HT2A receptors. Uniquely among second-generation
antipsychotics, cariprazine has about 10-fold greater
affinity for the D3 receptor than for the D2 receptor; the D3
receptor may play a role in mood modulation.2
CLINICAL STUDIES — Randomized, double-blind trials
comparing cariprazine to placebo for treatment of schizophrenia over 6 weeks or treatment of acute manic or mixed
episodes associated with bipolar I disorder over 3 weeks
are summarized in Table 2. Cariprazine was significantly
more effective than placebo for both indications.3-8
ADVERSE EFFECTS — Adverse effects occurring in
≥5% of patients taking cariprazine and more frequently
than in those taking placebo in at least one clinical trial
have included extrapyramidal symptoms, akathisia,
dyspepsia, vomiting, somnolence, and restlessness.
Mean weight gain over 6 weeks was 0.5-0.7 kg greater
with cariprazine than with placebo.
PREGNANCY — There are no adequate studies of
cariprazine in pregnant women. Administration of the
drug to pregnant rats at doses lower than the maximum
recommended human dose caused fetal malformations,

developmental delays, and decreased pup survival.

Table 2. Results of Some Cariprazine Clinical Trials
Trial

1

Arms

Acute Exacerbation of Schizophrenia
n=7324
Cariprazine 1.5 mg/d
Cariprazine 3 mg/d
Cariprazine 4.5 mg/d
Risperidone 4 mg/d5
Placebo
n=6046
Cariprazine 3 mg/d
Cariprazine 6 mg/d
Aripiprazole 10 mg/d5
Placebo
n=4397
Cariprazine 3-6 mg/d
Cariprazine 6-9 mg/d
Placebo
Acute Manic/Mixed Bipolar Episodes
n=4928
Cariprazine 3-6 mg/d
Cariprazine 6-12 mg/d
Placebo

n=2359
Cariprazine 3-12 mg/d
Placebo
n=31010
Cariprazine 3-12 mg/d
Placebo

Primary
Endpoint2

Mean
Change
in CGI-S3

-19.4
-20.7
-22.3
-26.9
-11.8
-20.2
-23.0
-21.2
-14.3
-22.8
-25.9
-16.0

-1.0
-1.1
-1.3

-1.5
-0.7
-1.4
-1.5
-1.4
-1.0
-1.4
-1.6
-1.0

-18.6
-18.5
-12.5
-15.0
-8.9
-19.6
-15.3

-1.9
-1.9
-1.3
-1.6
-0.9
-1.9
-1.5

1. All trials were randomized and double-blind. Schizophrenia trials were 6
weeks in duration. Bipolar I disorder trials were 3 weeks in duration.
2. The primary endpoint in the schizophrenia trials was mean change in the
181-point Positive and Negative Syndrome Scale (PANSS). The primary

endpoint in the bipolar I disorder trials was mean change in the 61-point
Young Mania Rating Scale (YMRS). Higher scores indicate more severe
disease. Each active treatment caused significantly more improvement
than placebo in each trial.
3. Clinical Global Impressions of Severity of Illness; a 7-point scale with
higher scores indicating more severe disease. Each active treatment
caused significantly more improvement than placebo in each trial.
4. S Durgam et al. Schizophr Res 2014; 152:450.
5. The trial was not designed to compare cariprazine to this active control,
which was included to ensure assay sensitivity.
6. S Durgam et al. J Clin Psychiatry 2015; 76:e1574.
7. JM Kane et al. J Clin Psychopharmacol 2015; 35:367.
8. JR Calabrese et al. J Clin Psychiatry 2015; 76:284.
9. S Durgam et al. Bipolar Disord 2015; 17:63.
10. GS Sachs et al. J Affect Disord 2015; 174:296.

DRUG INTERACTIONS — Cariprazine and its active
metabolites are substrates of CYP3A4. Concurrent
use of a CYP3A4 inducer such as carbamazepine
may reduce the efficacy of cariprazine and is not
recommended. Unlike aripiprazole and brexpiprazole,
cariprazine pharmacokinetics are not significantly
affected by inhibitors of CYP2D6.9

Table 3. Some Relative Adverse Effects of Second-Generation Antipsychotics
Drug

Diabetes

Weight Gain

Extrapyramidal
Symptoms

QTc Interval
Prolongation

Elevated
Prolactin

Aripiprazole
Asenapine
Brexpiprazole*
Cariprazine*
Clozapine
Iloperidone
Lurasidone
Olanzapine
Paliperidone
Quetiapine
Risperidone
Ziprasidone

+/–
+
+
+/–
++++
++
+/–

++++
++
++
++
+/–

+
++
++
+
++++
++
+/–
++++
+++
+++
+++
+/–

++
++
+
+++
+/–
+/–
++
+
+++
+/–
+++

–

+/–
+
–
–
+
++
+/–
+
+
+
+
++

–
++
+/–
–
+/–
+/–
+/–
+
+++
+/–
+++
+

*

Limited experience

52


The Medical Letter

Vol. 58 (1493)

®

April 25, 2016

Table 4. Some Oral Second-Generation Antipsychotics

Drug
Aripiprazole – generic
Abilify (BMS/Otsuka)
Asenapine – Saphris (Forest)
Brexpiprazole – Rexulti (Otsuka/Lundbeck)
Cariprazine – Vraylar (Actavis)
Clozapine – generic
Clozaril (Novartis)
orally disintegrating – generic
FazaClo (Jazz)
suspension – Versacloz (Jazz)
Iloperidone – Fanapt (Novartis)
Lurasidone – Latuda (Sunovion)
Olanzapine2 – generic
Zyprexa (Lilly)

orally disintegrating – generic
Zyprexa Zydis
Paliperidone2 – generic
Invega (Janssen)
Quetiapine – generic
Seroquel (AstraZeneca)
extended-release – Seroquel XR
Risperidone2 – generic
Risperdal (Janssen)
orally disintegrating – generic
Risperdal M-TAB
Ziprasidone – generic
Geodon2 (Pfizer)
2

Some Available
Oral Formulations

Usual Adult Dosage
Manic/Mixed
Schizophrenia
Bipolar I Disorder

2, 5, 10, 15, 20, 30 mg tabs

10-30 mg once/d

15-30 mg once/d

2.5, 5, 10 mg sublingual tabs

0.25, 0.5, 1, 2, 3, 4 mg tabs
1.5, 3, 4.5, 6 mg caps
25, 50, 100, 200 mg tabs
25, 100 mg tabs
12.5, 25, 100, 150, 200 mg ODT

5-10 mg bid
2-4 mg once/d
1.5-6 mg once/d
100-300 mg tid3

5-10 mg bid
N/A
3-6 mg once/d
N/A

50 mg/mL susp
1, 2, 4, 6, 8, 10, 12 mg tabs
20, 40, 60, 80, 120 mg tabs

6-12 mg bid
40-160 mg once/d

N/A
N/A

2.5, 5, 7.5, 10, 15, 20 mg tabs

10-20 mg once/d

10-20 mg once/d

1.5, 3, 6, 9 mg ER tabs

3-12 mg once/d

N/A

25, 50, 100, 200, 300,
400 mg tabs
50, 150, 200, 300, 400 mg ER tabs

150-750 mg/d divided
in 2 or 3 doses
400-800 mg once/d

743.70
934.00
400-800 mg/d divided 44.40
in 2 or 3 doses
600.00
400-800 mg once/d
750.30

0.25, 0.5, 1, 2, 3, 4, mg tabs;
1 mg/mL soln
0.25, 0.5, 1, 2, 3, 4 mg ODT
0.5, 1, 2, 3, 4 mg ODT
20, 40, 60, 80 mg caps

4-8 mg/d divided
in 1 or 2 doses

1-6 mg/d divided
in 1 or 2 doses

20-80 mg bid

40-80 mg bid

5, 10, 15, 20 mg ODT

Cost1
$598.30
892.00
915.50
934.70
1006.10
180.80
1125.80
588.60
1440.10
1387.50
1139.20
921.90
15.60
553.20
189.50
582.60

29.70
714.30
443.70
857.20
145.50
880.40

N/A = Not FDA-approved for this indication; ODT = orally disintegrating tablets; ER = extended-release
1. Approximate WAC for 30 days’ treatment at the lowest usual adult dosage in schizophrenia. 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.
April 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
2. Also available parenterally.
3. Clozapine can cause seizures and agranulocytosis and should be reserved for patients with schizophrenia who fail to respond to other drugs.

DOSAGE AND ADMINISTRATION — Cariprazine should
be taken once daily. Patients beginning treatment
should take 1.5 mg on day 1. Increasing the dose
to 3 mg on day 2 is recommended for patients with
bipolar I disorder and permitted for patients with
schizophrenia. The daily dose can then be adjusted in
1.5- or 3-mg increments up to a maximum of 6 mg. If a
strong CYP3A4 inhibitor must be coadministered with
cariprazine, dosage adjustments should be made as
described in the package insert.
CONCLUSION — In short-term trials, cariprazine
(Vraylar) was more effective than placebo in treating
acute exacerbations of schizophrenia and acute
manic or mixed episodes associated with bipolar I
disorder. It appears to have relatively mild metabolic
adverse effects and is long-acting, but extrapyramidal

symptoms can be a problem and its long-term safety
is unknown. Aripiprazole (Abilify, and generics), a
similar drug that has a longer record of efficacy and
safety and is now available generically, may be a
better choice. ■

1. Drugs for psychiatric disorders. Treat Guidel Med Lett 2013;
11:53.
2. JM Beaulieu et al. Regulation of Akt signaling by D2 and D3
dopamine receptors in vivo. J Neurosci 2007; 27:881.
3. S Durgam et al. An evaluation of the safety and efficacy of
cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res 2014;
152:450.
4. S Durgam et al. Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind,
placebo- and active-controlled trial. J Clin Psychiatry 2015;
76:e1574.
5. JM Kane et al. Efficacy and safety of cariprazine in acute
exacerbation of schizophrenia: results from an international,
phase III clinical trial. J Clin Psychopharmacol 2015; 35:367.
6. JR Calabrese et al. Efficacy and safety of low- and high-dose
cariprazine in acute and mixed mania associated with bipolar I
disorder: a double-blind, placebo-controlled study. J Clin Psychiatry 2015; 76:284.
7. S Durgam et al. The efficacy and tolerability of cariprazine in
acute mania associated with bipolar I disorder: a phase II trial.
Bipolar Disord 2015; 17:63.
8. GS Sachs et al. Cariprazine in the treatment of acute mania in
bipolar I disorder: a double-blind, placebo-controlled, phase III
trial. J Affect Disord 2015; 174:296.
9. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2016; 58:e46.

53


The Medical Letter

▶

®

Maestro Rechargeable System for
Weight Loss

The FDA has approved the Maestro Rechargeable
System (EnteroMedics), a subcutaneously implanted
device, for use in adults who have not been able to lose
weight with a weight loss program within the past 5 years
and who have a body mass index (BMI) of 40 to 45, or a
BMI ≥35 and at least one obesity-related comorbidity.
PROCEDURES FOR WEIGHT LOSS — Surgical treatment
for obesity is generally limited to patients with a BMI ≥40,
or a BMI ≥35 with an obesity-related comorbidity such
as diabetes, hypertension, or hypercholesterolemia.
Procedures that cause malabsorption (Roux-en-Y
gastric bypass and biliopancreatic diversion) result
in greater weight loss and more adverse effects than
purely restrictive procedures such as adjustable gastric
banding or sleeve gastrectomy.1 Gastric balloon devices
are inserted endoscopically and can be left in place for up
to 6 months; when they are removed, patients generally

regain a substantial fraction of the weight they had lost.2
THE NEW DEVICE — The Maestro Rechargeable System,
which consists of a rechargeable neuroregulator disc,
two wire leads, and two electrodes, utilizes highfrequency electrical pulses to block vagus nerve
signals between the stomach and the brain. According
to the manufacturer, vagal blocking therapy reduces
appetite by enhancing satiety and ultimately decreases
food intake. The 2.75 x 3.5 inch neuroregulator
is implanted subcutaneously in the thoracic side

Vol. 58 (1493)

April 25, 2016

wall; it delivers intermittent electrical pulses to the
electrodes, which are placed laparoscopically on the
anterior and posterior vagal nerve trunks above the
gastroesophageal junction.
The manufacturer recommends that the device
be programmed to deliver intermittent electrical
pulses over 13 hours while the patient is awake. The
neuroregulator is recharged by a mobile battery and
radiofrequency transmitter that is held or strapped
over the neuroregulator while charging. The battery
level should be checked daily and charged for about
30-60 minutes when low. The neuroregulator is
designed to operate for up to 8 years. According
to the manufacturer, the list price of the Maestro
Rechargeable System is $19,000.
CLINICAL STUDIES — In a double-blind trial (EMPOWER),

294 patients were randomized to active treatment with
the Maestro Rechargeable System for 9-16 hrs/day or
to a sham device (delivering a low frequency of electrical
impulses, but not enough to affect vagus nerve function)
in addition to weight loss counseling sessions. Patients
controlled the amount of time per day that the device
delivered impulses; more than half of the patients in
the active treatment group used the device ≤9 hrs/day.
After 12 months, there was no significant difference
between the 2 groups in the percent of excess weight
lost ("excess weight" is the weight in kilograms above
the weight at a BMI of 25).3 A subgroup analysis found
that the amount of weight lost was linearly related to
the time the device was used.

Table 1. Procedures for Weight Loss1
Procedure

Description

Adjustable gastric
banding
Biliopancreatic
diversion with
duodenal switch
Gastric balloon device

An adjustable band squeezes the stomach
and slows down food emptying
Combines a restrictive procedure with a

procedure that bypasses about three quarters
of the small intestine
Silicone balloon(s) placed in stomach endoscopically and inflated with a sterile solution
Proximal 20-30 mL pouch of stomach is anastomosed to a limb of the jejunum, bypassing most
of the stomach, all of the duodenum, and the first
15-20 cm of the jejunum
Most of the greater curvature of the stomach is
removed, leaving a tubular section
Device delivers intermittent electrical pulses to
block vagus nerve signals between the stomach
and the brain

Roux-En-Y gastric
bypass

Sleeve gastrectomy
Vagus nerve blockade
1.
2.
3.
4.
5.
6.
7.
8.
9.

54

Excess

Weight2 Loss
47%3
≥70%1

27-28%4,5
66%6

59%7
24%9

Some Adverse Effects
Band slippage and erosion, excess vomiting,
port site and tubing problems
Higher risk of complications and death,
protein and nutrient deficiencies
Gastric ulceration, abdominal pain,
nausea, vomiting, abdominal distention
Perioperative mortality rate of 0.2-2.1%,
nutrient deficiencies, dumping syndrome
(nausea, bloating, colic, diarrhea), hyperinsulinemic hypoglycemia
Dumping syndrome, aggravation of
gastroesophageal reflux disease (GERD)8
Pain at neuroregulator site, heartburn,
nausea, belching, abdominal pain

Med Lett Drugs Ther 2015; 57:21.
Defined as the weight in kilograms above the weight at a BMI of 25.
≥10 years follow-up. PE O'Brien et al. Ann Surg 2013; 257:87.
At 24 weeks. J Ponce et al. Surg Obes Relat Dis 2015; 11:874.
At 9 months. Results of an unpublished trial summarized in the Orbera package insert. Excess weight loss was defined as weight above ideal body weight lost.

≥2 years follow up. N Puzziferri et al. JAMA 2014; 312:934.
≥5 years follow up. T Diamantis et al. Surg Obes Relat Dis 2014; 10:177.
R Peterli et al. Ann Surg 2013; 258:690.
At 12 months. S Ikramuddin et al. JAMA 2014; 312:915.


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®

In another double-blind trial (ReCharge), 239 patients with
a BMI of 40 to 45 or a BMI ≥35 and at least one obesityrelated comorbidity were randomized to treatment with
the Maestro Rechargeable System or to a sham device in
addition to weight loss counseling sessions. The devices
were programmed to deliver a charge for ≥12 hours daily,
but the sham device had no leads. At 12 months, the
actively-treated group had a mean excess weight loss of
24.4% compared to 15.9% in the sham group; although the
difference was statistically significant, the primary efficacy
endpoint of a ≥10% superiority margin was not met. At 12
months, 52% of actively-treated patients achieved ≥20%
excess weight loss and 38% achieved ≥25% excess weight
loss, compared to 32% and 23%, respectively, with sham
therapy4; among the 84 patients who were moderately
obese (BMI 35-40), those receiving active treatment
achieved a 33% excess weight loss, compared to 19%
with sham therapy.5 Weight loss was sustained through
18 months in patients treated with the active device, while
those treated with the sham device regained >40% of the
weight lost between 12 and 18 months.6

An open-label study in 28 obese patients with type
2 diabetes found that mean excess weight loss was
9% at 1 week and 25% at 12 months with the Maestro
Rechargeable System. At 12 months, HbA1c levels
had decreased by 1% and, among 15 patients with
elevated blood pressure, mean arterial pressure
had decreased by 8 mm Hg.7 Reductions in weight,
HbA1c, and blood pressure were sustained through
24 months.8
ADVERSE EFFECTS — In the ReCharge trial, serious
adverse events related to vagal nerve blockade and
intra-abdominal surgery occurred in 8.6% of patients.4
Pain at the neuroregulator site occurred in about 40% of
patients, whether they received the active or sham device.
Heartburn/dyspepsia, nausea, dysphagia, eructation,
and abdominal pain occurred more frequently with the
active device.
Use of the Maestro device is contraindicated
in patients with cirrhosis, portal hypertension,
esophageal varices, or a hiatal hernia that cannot be
corrected by surgery, and in those who have another
implanted device such as a pacemaker or defibrillator.
Patients with the device should not undergo magnetic
resonance imaging (MRI) scans.
CONCLUSION — Vagal blocking therapy with the
Maestro Rechargeable System is less effective than
bariatric surgery for treatment of obesity. How it
compares to less invasive procedures such as gastric
balloon devices is not clear. ■

Vol. 58 (1493)

April 25, 2016

1. Diet, drugs, and surgery for weight loss. Med Lett Drugs Ther
2015; 57:21.
2. ReShape and Orbera – two gastric balloon devices for weight
loss. Med Lett Drugs Ther 2015; 57:122.
3. MG Sarr et al. The EMPOWER study: randomized, prospective, double-blind, multicenter trial of vagal blockade to induce
weight loss in morbid obesity. Obes Surg 2012; 22:1771.
4. S Ikramuddin et al. Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge
randomized clinical trial. JAMA 2014; 312:915.
5. JM Morton et al. Effect of vagal nerve blockade on moderate
obesity with an obesity-related comorbid condition: the ReCharge Study. Obes Surg 2016 April 5 (epub).
6. SA Shikora et al. Sustained weight loss with vagal nerve blockade but not with sham: 18-month results of the ReCharge trial.
J Obes 2015 July 12 (epub).
7. S Shikora et al. Vagal blocking improves glycemic control and
elevated blood pressure in obese subjects with type 2 diabetes
mellitus. J Obes 2013 July 30 (epub).
8. SA Shikora et al. Intermittent vagal nerve block for improvements in obesity, cardiovascular risk factors, and glycemic
control in patients with type 2 diabetes mellitus: 2-year results
of the VBLOC DM2 study. Obes Surg 2015 October 15 (epub).

▶

Mifepristone (Mifeprex) Label
Changes

The FDA has approved several significant changes in
the labeling of mifepristone (Mifeprex – Danco), an oral

antiprogestin that has been used in the US for more than
15 years for termination of intrauterine pregnancy.1 It
has generally been used with the prostaglandin analog
misoprostol (Cytotec, and generics).
TIMING OF USE — Under the new labeling, mifepristone
and misoprostol can now be used to terminate
pregnancy for up to 70 days, rather than 49 days, after
the first day of the last menstrual period. Multiple
studies have shown that the combination is >96.5%
effective through 63 days of gestation; data on its
effectiveness between 64 and 70 days are much more
limited.2 In a retrospective cohort study of data from
more than 30,000 women undergoing either medical
or surgical abortion before 64 days of gestation,
efficacy was >99.5% in both groups with no difference
in major adverse events.3
DOSAGE AND ADMINISTRATION — The new labeling
recommends a 200-mg oral dose of mifepristone
(rather than 600 mg) followed by 800 mcg of
misoprostol (rather than 400 mcg) administered
buccally (rather than orally) 24-48 hours later
(rather than 48 hours later). Additionally, in-office
administration of misoprostol is no longer required;
women can now self-administer misoprostol at
home.4 Follow-up with the provider to confirm
55


The Medical Letter

®

Table 1. Mifeprex Label Changes

▶ Can be used later in pregnancy, up to 70 days from first day
of last menstrual period (vs 49 days)

▶ Lower 200-mg PO dose of mifepristone (vs 600 mg)
▶ Higher 800-mcg buccal dose of misoprostol (vs 400 mcg PO)
▶ Misoprostol can be taken at home 24-48 hours later (vs 48

hours later in-office), reducing the number of total office
visits from 3 to 2
▶ Follow-up visit 7-14 days after mifepristone administration
(vs 14 days)

complete termination of pregnancy and evaluate the
degree of bleeding is recommended between 7 and
14 days after mifepristone administration (rather
than 14 days). The new regimen reduces the number
of office visits from 3 to 2.
Use of the lower dose of mifepristone has been
common practice for many years. Misoprostol tablets
have been administered orally, sublingually, buccally,
and intravaginally. The oral route has been less
effective and caused more adverse effects (nausea,
diarrhea) than intravaginal administration. Buccal
administration has been as effective as intravaginal
administration and more effective than oral
administration, with only a slightly higher incidence

of adverse effects than the intravaginal route.5-7
REMS PROGRAM — Mifepristone will continue to be
available only through a REMS program to certified
prescribers who meet specified qualifications and
agree to follow the guidelines for appropriate use
of the drug. Patients are also required to sign an
agreement form. The drug must be dispensed in
a clinic, medical office, or hospital by or under the
supervision of a certified prescriber, and ultrasound
must be available.
CONCLUSION — The FDA’s changes to the labeling
of mifepristone (Mifeprex) recommend use of a lower
dose of mifepristone, use of the drug later in the first
trimester, self-administration of misoprostol (Cytotec,
and generics) at a higher dose and by the more
effective buccal route, and fewer office visits. ■
1. Mifepristone (RU 486). Med Lett Drugs Ther 2000; 42:101.
2. MJ Chen and MD Creinin. Mifepristone with buccal misoprostol
for medical abortion: a systematic review. Obstet Gynecol 2015;
126:12.
3. LD Ireland et al. Medical compared with surgical abortion for
effective pregnancy termination in the first trimester. Obstet
Gynecol 2015; 126:22.
4. K Iyengar et al. Home use of misoprostol for early medical abortion in a low resource setting: secondary analysis of a randomized controlled trial. Acta Obstet Gynecol Scand 2016; 95:173.
5. T Middleton et al. Randomized trial of mifepristone and buccal or vaginal misoprostol for abortion through 56 days of last
menstrual period. Contraception 2005; 72:328.

56

Vol. 58 (1493)

April 25, 2016

6. B Winikoff et al. Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet
Gynecol 2008; 112:1303.
7. R Kulier et al. Medical methods for first trimester abortion. Cochrane Database Syst Rev 2011; 11:CD002855.

IN BRIEF

Cholic Acid (Cholbam) for Bile Acid
Synthesis Disorders
The FDA has approved oral cholic acid (Cholbam –
Retrophin) for treatment of children and adults with bile
acid synthesis disorders caused by single enzyme defects
and for adjunctive treatment of peroxisomal disorders
such as Zellweger spectrum disorders in patients who
have liver disease, steatorrhea, or complications from fatsoluble vitamin malabsorption. Patients with these rare
inborn errors of bile acid metabolism cannot synthesize
primary bile acids such as cholic acid, resulting in reduced
bile flow, decreased absorption of fat and fat-soluble
vitamins, and development of liver disease, which can be
fatal. Cholbam is the first drug to be approved in the US for
these indications.
FDA approval was based on a long-term, single-arm
clinical trial, an extension of that trial, and case reports in a
total of 77 patients with bile acid synthesis disorders and
34 patients with peroxisomal disorders. Administration
of cholic acid appeared to decrease hepatic injury and
increase height and weight; 67% of patients with bile acid
synthesis disorders and 42% of those with peroxisomal

disorders treated in the clinical trials survived for more
than 3 years.1 Some of these survivors have been treated
successfully for more than 20 years. Diarrhea has been
the most common adverse effect.
Cholbam is available in 50- and 250-mg capsules. The
usual dosage is 10-15 mg/kg taken once daily or in two
divided doses. The cost of 30 days’ treatment for a 50-kg
patient at a daily dose of 10 mg/kg is about $50,000.2 ■
1. FDA. Medical review: cholic acid (Cholbam). Available at:
www.accessdata.fda.gov/drugsatfda_docs/nda/2015/
205750Orig1s000MedR.pdf. Accessed April 14, 2016.
2. Approximate WAC. 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. April
5, 2016. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2016. www.fdbhealth.com/policies/drugpricing-policy.

Online Only Article
In Brief: Jadenu – A New Formulation of Deferasirox for
Iron Overload
www.medicalletter.org/TML-article-1493f

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on Drugs and Therapeutics
Volume 58 (Issue 1493)

April 25, 2016

IN BRIEF

Jadenu – A New Formulation of
Deferasirox for Iron Overload
The FDA has approved an oral tablet formulation of
deferasirox (Jadenu [ jade' new] – Novartis) for oncedaily treatment of chronic iron overload due to blood
transfusions (transfusional hemosiderosis) in patients ≥2
years old or chronic iron overload in patients ≥10 years old
with non-transfusion-dependent thalassemia syndromes.
A once-daily, oral tablet for suspension formulation of
deferasirox (Exjade) was approved in 2005 for the same
indications.1 Jadenu and Exjade are the only once-daily
oral formulations for iron chelation available in the US.
Table 1. Deferasirox Products
Drug

Available
Formulations

Usual
Dosage1

Exjade
(Novartis)

125, 250, 500 mg tabs 20-40 mg/kg $10,902.30
for oral suspension
PO once/d3-5

Jadenu
(Novartis)

90, 180, 360 mg tabs

Cost2

14-28 mg/kg 10,902.30
PO once/d3,4,6

1. Dosage for transfusional iron overload. Dosage adjustments are recommended
for hepatic or renal impairment.
2. Approximate WAC for 30 days' treatment at the lowest usual dosage 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. April 5, 2016. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
3. Jadenu dosages of 14, 21, and 28 mg/kg/day are equivalent to Exjade dosages
of 20, 30, and 40 mg/kg/day, respectively.
4. Recommended dosage for patients ≥2 years old.
5. Take on an empty stomach at least 30 minutes before food. Must be dispersed

in liquid before administration.
6. Can be taken on an empty stomach or with a low-fat meal. For patients who
have difficulty swallowing tablets, it can be crushed and sprinkled on soft food,
such as yogurt or applesauce.

No new clinical trials were required for approval of Jadenu,
which was based on earlier clinical trials with Exjade.
The most common adverse effects reported with use
of deferasirox in clinical trials were diarrhea, vomiting,
nausea, abdominal pain, rash, neutropenia, and increases
in serum creatinine. Severe skin reactions, including
Stevens-Johnson syndrome and erythema multiforme,
have been reported rarely. Hearing loss and ocular
disturbances, including cataracts, have been reported
with deferasirox; patients taking the drug should have
annual auditory and ophthalmic exams. Gastrointestinal
ulceration and hemorrhage and renal and hepatic toxicity
have also occurred.
1. Deferasirox (Exjade): a new iron chelator. Med Lett Drugs Ther
2006; 48:35.

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Discuss the new recommendations for use of metformin (Glucophage, and others) in patients with renal impairment.
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Review the efficacy and safety of cariprazine (Vraylar) for treatment of schizophrenia and bipolar I disorder.
3.

Review the efficacy and safety of the Maestro Rechargeable System for weight loss.
4.
Discuss the new recommendations for use of mifepristone (Mifeprex) for termination of pregnancy.
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Issue 1493 Questions
(Correspond to questions #81-90 in Comprehensive Exam #74, available July 2016)
New Recommendations for Use of Metformin in Renal Impairment
1. You are deciding on initial therapy for a 45-year-old black
man with type 2 diabetes. He weighs 225 lbs and has a serum
creatinine of 1.5 mg/dL and an eGFR of 57 mL/min/1.73 m2. Which
of the following is true about the use of metformin in this patient?
a. it is contraindicated because his serum creatinine is
≥1.5 mg/dL

b. it is contraindicated because his eGFR is <60 mL/min/1.73 m2
c. he can take metformin, but the dosage should be reduced
d. metformin is considered safe for use in this patient
2. The above patient is being scheduled for an iodinated contrast
imaging procedure. Which of the following should you
recommend?
a. continue metformin without interruption
b. do not administer metformin until 48 hours after the
procedure is completed and eGFR is reassessed
c. reduce the dose of metformin by 50% until 72 hours after
the procedure
d. none of the above
Cariprazine (Vraylar) for Schizophrenia and Bipolar I Disorder
3. The only second-generation antipsychotic that is clearly more
effective than first-generation antipsychotics for treatment of
schizophrenia is:
a. cariprazine
b. clozapine
c. olanzapine
d. aripiprazole
4. In clinical trials, cariprazine was more effective than:
a. placebo
b. aripiprazole
c. risperidone
d. all of the above
5. Compared to cariprazine, aripiprazole has:
a. a longer record of efficacy
b. a longer record of safety
c. generic availability
d. all of the above

6. Your colleague is considering using either cariprazine or
aripiprazole for treatment of acute mania in a 24-year-old
woman with bipolar l disorder. She is concerned about side
effects, especially weight gain. You could tell her that:
a. weight gain appears to be about the same with either
aripiprazole or cariprazine
b. cariprazine has been shown to be more effective than
aripiprazole
c. cariprazine is less likely than aripiprazole to cause diabetes
d. all of the above
Maestro Rechargeable System for Weight Loss
7. The Maestro Rechargeable System reduces excess weight by:
a. causing malabsorption
b. increasing GI transit time
c. reducing stomach capacity
d. blocking vagus nerve signals between the stomach and the
brain
8. In the ReCharge trial, the Maestro Rechargeable System reduced
excess weight at 12 months by about:
a. 25%
b. 35%
c. 55%
d. 65%
Mifepristone (Mifeprex) Label Changes
9. Under the new labeling, mifepristone and misoprostol can now
be used to terminate pregnancy for up to how many days after
the first day of the last menstrual period?
a. 49
b. 56

c. 63
d. 70
10. Which route of administration is now recommended for
misoprostol?
a. oral
b. buccal
c. vaginal
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-16-493-H01-P; Release: April 25, 2016, Expire: April 25, 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,
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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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