1493 on Drugs and Therapeutics In Brief: New Recommendations for Use of Metformin in Renal Impairment ...p 51 Cariprazine Vraylar for Schizophrenia and Bipolar I Disorder ...p 51 Maestr
Trang 1FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS
The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited.
Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited.
By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc.
or call customer service at: 800-211-2769
Important Copyright Message
IN THIS ISSUE
ISSUE
1433
Volume 56
Published by The Medical Letter, Inc • A Nonprofi t Organization
ISSUE No
1493
on Drugs and Therapeutics
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
Trang 2
51
on Drugs and Therapeutics
Take CME Exams
ISSUE
1433
Volume 56
ISSUE No
1493 Maestro Rechargeable System for Weight Loss Mifepristone (Mifeprex) Label Changes p 54p 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
ALSO IN THIS ISSUE
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
fi ltration 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 fi rst 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 m 2 , and starting treatment with
the drug in patients with an eGFR between 30 and 45 mL/
min/1.73 m 2 is not recommended If the eGFR falls below
45 mL/min/1.73 m 2 in a patient already taking metformin,
the benefi ts 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 m 2 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
regard-ing 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 treat-ment of schizophrenia and for acute treattreat-ment 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 fi rst-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
second-generation antipsychotics generally have similar effi cacy, but individual patients may have greater improvement with one or another, and adverse effects may vary widely
Table 1 Pharmacology
Class Second-generation antipsychotic Mechanism Dopamine (D 2 ) and serotonin (5-HT 1A ) partial
of action agonist; 5-HT 2A antagonist Formulation 1.5, 3, 4.5, 6 mg capsules
Metabolism Hepatic, primarily by CYP3A4 and (for
caripra-zine and DCAR 1 ) to a lesser extent by CYP2D6 Elimination Urine (21%)
Half-life Cariprazine: 2-4 days
1 DCAR and DDCAR are active metabolites equipotent to cariprazine.
Trang 3Table 3 Some Relative Adverse Effects of Second-Generation Antipsychotics
* Limited experience
Table 2 Results of Some Cariprazine Clinical Trials
Mean
Acute Exacerbation of Schizophrenia
n=732 4 Cariprazine 1.5 mg/d -19.4 -1.0
Cariprazine 3 mg/d -20.7 -1.1 Cariprazine 4.5 mg/d -22.3 -1.3 Risperidone 4 mg/d 5 -26.9 -1.5
n=604 6 Cariprazine 3 mg/d -20.2 -1.4
Cariprazine 6 mg/d -23.0 -1.5 Aripiprazole 10 mg/d 5 -21.2 -1.4
n=439 7 Cariprazine 3-6 mg/d -22.8 -1.4
Cariprazine 6-9 mg/d -25.9 -1.6
Acute Manic/Mixed Bipolar Episodes
n=492 8 Cariprazine 3-6 mg/d -18.6 -1.9
Cariprazine 6-12 mg/d -18.5 -1.9
n=235 9 Cariprazine 3-12 mg/d -15.0 -1.6
n=310 10 Cariprazine 3-12 mg/d -19.6 -1.9
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 signifi cantly 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 signifi cantly 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 effi cacy of cariprazine and is not recommended Unlike aripiprazole and brexpiprazole, cariprazine pharmacokinetics are not signifi cantly affected by inhibitors of CYP2D6.9
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
recep-tors and serotonin 5-HT1A receptors, and antagonists at
5-HT2A receptors Uniquely among second-generation
antipsychotics, cariprazine has about 10-fold greater
affi nity 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
schizo-phrenia 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 signifi cantly
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
Trang 4DOSAGE 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 effi cacy and
safety and is now available generically, may be a
better choice ■
Table 4 Some Oral Second-Generation Antipsychotics
Usual Adult Dosage
Aripiprazole 2 – generic 2, 5, 10, 15, 20, 30 mg tabs 10-30 mg once/d 15-30 mg once/d $598.30
Asenapine – Saphris (Forest) 2.5, 5, 10 mg sublingual tabs 5-10 mg bid 5-10 mg bid 915.50
Brexpiprazole – Rexulti (Otsuka/Lundbeck) 0.25, 0.5, 1, 2, 3, 4 mg tabs 2-4 mg once/d N/A 934.70
Cariprazine – Vraylar (Actavis) 1.5, 3, 4.5, 6 mg caps 1.5-6 mg once/d 3-6 mg once/d 1006.10
Iloperidone – Fanapt (Novartis) 1, 2, 4, 6, 8, 10, 12 mg tabs 6-12 mg bid N/A 1139.20
Lurasidone – Latuda (Sunovion) 20, 40, 60, 80, 120 mg tabs 40-160 mg once/d N/A 921.90 Olanzapine 2 – generic 2.5, 5, 7.5, 10, 15, 20 mg tabs 10-20 mg once/d 10-20 mg once/d 15.60
Quetiapine – generic 25, 50, 100, 200, 300, 150-750 mg/d divided 400-800 mg/d divided 44.40
extended-release – Seroquel XR 50, 150, 200, 300, 400 mg ER tabs 400-800 mg once/d 400-800 mg once/d 750.30 Risperidone 2 – generic 0.25, 0.5, 1, 2, 3, 4, mg tabs; 4-8 mg/d divided 1-6 mg/d divided 29.70
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
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 effi cacy of cariprazine in patients with acute exacerbation of schizophre-nia: a phase II, randomized clinical trial Schizophr Res 2014; 152:450.
4 S Durgam et al Cariprazine in acute exacerbation of schizo-phrenia: a fi xed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial J Clin Psychiatry 2015; 76:e1574.
5 JM Kane et al Effi cacy 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 Effi cacy 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 Psy-chiatry 2015; 76:284.
7 S Durgam et al The effi cacy 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.
Trang 5Table 1 Procedures for Weight Loss 1
Excess
Adjustable gastric An adjustable band squeezes the stomach 47% 3 Band slippage and erosion, excess vomiting,
Biliopancreatic Combines a restrictive procedure with a ≥70% 1 Higher risk of complications and death, diversion with procedure that bypasses about three quarters protein and nutrient defi ciencies
duodenal switch of the small intestine
Gastric balloon device Silicone balloon(s) placed in stomach endoscopic- 27-28% 4,5 Gastric ulceration, abdominal pain,
ally and inflated with a sterile solution nausea, vomiting, abdominal distention Roux-En-Y gastric Proximal 20-30 mL pouch of stomach is anasto- 66% 6 Perioperative mortality rate of 0.2-2.1%, bypass mosed to a limb of the jejunum, bypassing most nutrient defi ciencies, dumping syndrome
of the stomach, all of the duodenum, and the fi rst (nausea, bloating, colic, diarrhea), hyper-
Sleeve gastrectomy Most of the greater curvature of the stomach is 59% 7 Dumping syndrome, aggravation of
Vagus nerve blockade Device delivers intermittent electrical pulses to 24% 9 Pain at neuroregulator site, heartburn,
block vagus nerve signals between the stomach nausea, belching, abdominal pain and the brain
1 Med Lett Drugs Ther 2015; 57:21.
2 Defi ned as the weight in kilograms above the weight at a BMI of 25.
3 ≥10 years follow-up PE O'Brien et al Ann Surg 2013; 257:87.
4 At 24 weeks J Ponce et al Surg Obes Relat Dis 2015; 11:874.
5 At 9 months Results of an unpublished trial summarized in the Orbera package insert Excess weight loss was defi ned as weight above ideal body weight lost
6 ≥2 years follow up N Puzziferri et al JAMA 2014; 312:934.
7 ≥5 years follow up T Diamantis et al Surg Obes Relat Dis 2014; 10:177.
8 R Peterli et al Ann Surg 2013; 258:690.
9 At 12 months S Ikramuddin et al JAMA 2014; 312:915
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
high-frequency 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
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 signifi cant 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
Trang 6In another double-blind trial (ReCharge), 239 patients with
a BMI of 40 to 45 or a BMI ≥35 and at least one
obesity-related 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 signifi cant, the primary effi cacy
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 defi brillator
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 ■
Mifepristone (Mifeprex) Label
Changes
▶
The FDA has approved several signifi cant 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 fi rst 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, effi cacy 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-offi ce administration of misoprostol is no longer required; women can now self-administer misoprostol at home.4 Follow-up with the provider to confi rm
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, prospec-tive, 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-ab-dominal 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 Re-Charge Study Obes Surg 2016 April 5 (epub).
6 SA Shikora et al Sustained weight loss with vagal nerve block-ade 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 improve-ments 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).
Trang 7Table 1 Mifeprex Label Changes
▶ Can be used later in pregnancy, up to 70 days from fi rst 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-offi ce), reducing the number of total offi ce
visits from 3 to 2
▶ Follow-up visit 7-14 days after mifepristone administration
(vs 14 days)
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 fi rst trimester Obstet
Gynecol 2015; 126:22.
4 K Iyengar et al Home use of misoprostol for early medical
abor-tion in a low resource setting: secondary analysis of a
random-ized controlled trial Acta Obstet Gynecol Scand 2016; 95:173.
5 T Middleton et al Randomized trial of mifepristone and
buc-cal or vaginal misoprostol for abortion through 56 days of last
menstrual period Contraception 2005; 72:328.
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 offi ce 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 certifi ed
prescribers who meet specifi ed qualifi cations 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 offi ce, or hospital by or under the
supervision of a certifi ed 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 fi rst
trimester, self-administration of misoprostol (Cytotec,
and generics) at a higher dose and by the more
effective buccal route, and fewer offi ce visits ■
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 fat-soluble 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 fi rst 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 man-ufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an ac-tual 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
6 B Winikoff et al Two distinct oral routes of misoprostol in mife-pristone medical abortion: a randomized controlled trial Obstet Gynecol 2008; 112:1303.
7 R Kulier et al Medical methods for fi rst trimester abortion Co-chrane Database Syst Rev 2011; 11:CD002855.
Follow us on Twitter Like us on Facebook
Online Only Article
In Brief: Jadenu – A New Formulation of Deferasirox for
Iron Overload www.medicalletter.org/TML-article-1493f
Trang 8
e56
on Drugs and Therapeutics
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
once-daily 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
Available Usual
(Novartis) for oral suspension PO once/d 3-5
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 diffi culty 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.
Follow us on Twitter Like us on Facebook
Trang 9Questions start on next page
ACCREDITATION INFORMATION:
ACCME: The Medical Letter is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians The Medical
Letter designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™ Physicians should claim only the credit commensurate with the extent of their
participation in the activity This CME activity was planned and produced in accordance with the ACCME Essentials and Policies.
ABIM MOC: Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 2 MOC points in the
American Board of Internal Medicine's (ABIM) Maintenance of Certifi cation (MOC) program Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
AAFP : This enduring material activity, The Medical Letter Continuing Medical Education Program, has been reviewed and is acceptable for up to 52 Prescribed credits by the
American Academy of Family Physicians Term of approval begins January 1, 2016 Term of approval is for one year from this date Each issue is approved for 2 Prescribed credits Credit may be claimed for one year from the date of each issue Physicians should claim only the credit commensurate with the extent of their participation in the activity
ACPE: The Medical Letter is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education This exam is acceptable
for 2.0 hour(s) of knowledge-based continuing education credit (0.2 CEU)
This activity, being ACCME (AMA) approved, is acceptable for Category 2-B credit by the American Osteopathic Association (AOA)
The National Commission on Certifi cation of Physician Assistants (NCCPA) accepts AMA PRA Category 1 Credit™ from organizations accredited by ACCME NCCPA also
accepts AAFP Prescribed credits for recertifi cation The Medical Letter is accredited by both ACCME and AAFP.
The American Nurses Credentialing Center (ANCC) and the American Academy of Nurse Practitioners (AANP) accept AMA PRA Category 1 Credit™ from organizations
accredited by the ACCME
Physicians in Canada: Members of The College of Family Physicians of Canada are eligible to receive Mainpro-M1 credits (equivalent to AAFP Prescribed credits) as per our
reciprocal agreement with the American Academy of Family Physicians
MISSION:
The mission of The Medical Letter’s Continuing Medical Education Program is to support the professional development of healthcare providers including physicians, nurse practitioners, pharmacists, and physician assistants by providing independent, unbiased drug information and prescribing recommendations that are free of industry influence The program content includes current information and unbiased reviews of FDA-approved and off-label uses of drugs, their mechanisms of action, clinical trials, dosage and administration, adverse effects, and drug interactions The Medical Letter delivers educational content in the form of self-study material.
The expected outcome of the CME program is to increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in
materials contained in The Medical Letter.
The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical Letter aims to be a leader in supporting the professional development of healthcare providers through Core Competencies by providing continuing medical education that is unbiased and free of industry influence The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations.
GOAL:
Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and timely educational content that they will use to make independent and informed therapeutic choices in their practice.
LEARNING OBJECTIVES:
Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities Activity participants will be
able to select and prescribe, or confi rm the appropriateness of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with
specifi c attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient management Activity participants will make independent and informed therapeutic choices in their practice.
Upon completion of this program, the participant will be able to:
1 Discuss the new recommendations for use of metformin (Glucophage, and others) in patients with renal impairment.
2 Review the effi cacy and safety of cariprazine (Vraylar) for treatment of schizophrenia and bipolar I disorder.
3 Review the effi cacy and safety of the Maestro Rechargeable System for weight loss
4 Discuss the new recommendations for use of mifepristone (Mifeprex) for termination of pregnancy.
Privacy and Confi dentiality: The Medical Letter guarantees our fi rm commitment to your privacy We do not sell any of your information Secure server software (SSL) is used
for commerce transactions through VeriSign, Inc No credit card information is stored.
IT Requirements: Windows 7/8/10, Mac OS X+; current versions of Microsoft IE/Edge, Mozilla Firefox, Google Chrome, Safari, or any other compatible Web browser
High-speed connection.
Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org
The Medical Letter ®
Continuing Medical Education Program
medicalletter.org/cme-program
Earn Up To 52 Credits Per Year
Choose CME from The Medical Letter in the format that’s right for you!
▶ Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 130 question exam enables you to earn 26 credits immediately
upon successful completion of the test A score of 70% or greater is required to pass the exam Our comprehensive exams allow you to test at your own pace in the comfort of your home or offi ce Comprehensive exams are offered every January and July enabling you to earn up to 52 credits per year $49/exam.
▶ Free Individual Exams– Free to active subscribers of The Medical Letter Answer 10 questions per issue and submit answers online Earn 2 credits/exam
A score of 70% or greater is required to pass the exam.
▶ Paid Individual Exams – Available to non-subscribers Answer 10 questions per issue and submit answers online Earn 2 credits/exam $12/exam
A score of 70% or greater is required to pass the exam.
Trang 10DO NOT FAX OR MAIL THIS EXAM
To take CME exams and earn credit, go to:
medicalletter.org/CMEstatus
Issue 1493 Questions
(Correspond to questions #81-90 in Comprehensive Exam #74, available July 2016)
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 fi rst 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
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 m 2 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 m 2
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 fi rst-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 effi cacy
b a longer record of safety
c generic availability
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,
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;
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; David N Juurlink, BPhm, M.D., Ph.D.,
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
University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT AND SYSTEMS MANAGER: Cristine Romatowski; EXECUTIVE DIRECTOR OF MARKETING AND COMMUNICATIONS:
Joanne F Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
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.
Subscription Services
The Medical Letter, Inc Call: 800-211-2769 or 914-235-0500 To reproduce any portion of this issue, 1 year - $129; 2 years - $232; E-mail: info@medicalletter.org
145 Huguenot St Ste 312 Fax: 914-632-1733 please e-mail your request to: 3 years - $345 $65 per year Call: 800-211-2769 ext 315 New Rochelle, NY 10801-7537 E-mail: custserv@medicalletter.org permissions@medicalletter.org for students, interns, residents, and Special rates available for bulk www.medicalletter.org fellows in the US and Canada subscriptions.
Reprints - $12 each