The medical letter on drugs and therapeutics december 7 2015

The Medical Letter

®

on Drugs and Therapeutics
Volume 57 (Issue 1483)

ISSUE
ISSUE
No.

1433
1483
Volume 56

December 7, 2015

IN THIS ISSUE

Insulin Degludec (Tresiba) – A New Long-Acting Insulin for Diabetes ......................... p 163
Drugs Past Their Expiration Date .................................................................................... p 164
Deoxycholic Acid (Kybella) for Double Chin .................................................................... p 165
Ferric Citrate (Auryxia) for Hyperphosphatemia ............................................................. p 166
Nivolumab (Opdivo) plus Ipilimumab (Yervoy) for Metastatic Melanoma .................... p 168
Corrections ........................................................................................................................ p 168

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The Medical Letter

®

on Drugs and Therapeutics

Volume 57 (Issue 1483)

December 7, 2015
Take CME Exams

ISSUE

ISSUE No.

1433
1483
Volume 56

▶

ALSO IN THIS ISSUE

Drugs Past Their Expiration Date .......................................................................................p 164
Deoxycholic Acid (Kybella) for Double Chin ......................................................................p 165
Ferric Citrate (Auryxia) for Hyperphosphatemia ...............................................................p 166
Nivolumab (Opdivo) plus Ipilimumab (Yervoy) for Metastatic Melanoma ......................p 168
Corrections ..........................................................................................................................p 168

Insulin Degludec (Tresiba) – A New
Long-Acting Insulin for Diabetes
Revised 12/7/16: See page 164

The FDA has approved insulin degludec (Tresiba –
Novo Nordisk) for treatment of adults with type 1 or
type 2 diabetes. Insulin degludec is the third longacting human insulin analog to be approved by the
FDA; insulin detemir (Levemir) and insulin glargine
(Lantus, Toujeo) were approved earlier.1,2
Pronunciation Key
Degludec: de glu’ dek

Tresiba: tre si’ bah

Like other long-acting human insulin analogs, insulin
degludec is synthesized using recombinant DNA

technology. It forms multihexamers in subcutaneous
tissue, which delays its absorption, and binds to
circulating albumin, which delays its elimination and
results in a prolonged duration of action (>42 hours).3
Table 1. Pharmacology
Class

Long-acting human insulin analog

Formulation

3 mL prefilled pen (100, 200 units/mL)

Route

Subcutaneous

Tmax

9 hours

Half-life

~25 hours

CLINICAL STUDIES — Approval of insulin degludec
was based on the results of nine open-label, activecontrolled trials, which are summarized in the package
insert. In eight of the trials, insulin degludec was
noninferior to insulin glargine or detemir in lowering
HbA1c, with similar rates of hypoglycemia; in some

of these studies, the rate of nocturnal hypoglycemia
was significantly lower with insulin degludec. In the
ninth trial, insulin degludec was significantly more
effective than sitagliptin 100 mg in lowering HbA1c,
but it caused more episodes of hypoglycemia. Four
representative trials are summarized in Table 2.4-7
ADVERSE EFFECTS — Allergic reactions, injection-site
reactions, lipodystrophy, pruritus, rash, and edema

Table 2. Some Tresiba Clinical Trials
Study
Design

HbA1c
Change (%)1

HG2

Type 1 Diabetes
BEGIN Basal-Bolus Type 1 (52 weeks; n=629)3
Mealtime insulin aspart
+ degludec U-100
-0.40†
42.54
+ glargine U-100
-0.39
40.18
Type 2 Diabetes

Nocturnal

HG2

4.41*
5.86

BEGIN Once Long (52 weeks; n=1030)4
Oral antidiabetic drugs
+ degludec U-100
-1.06†
+ glargine U-100
-1.19

1.52
1.85

0.25*
0.39

BEGIN FLEX (26 weeks; n=458)5
Oral antidiabetic drugs
+ degludec U-100
-1.07†
+ glargine U-100
-1.26

3.6
3.5

0.6
0.8

A Philis-Tsimikas et al. (26 weeks; n=458)6
Oral antidiabetic drugs
+ degludec U-100
-1.52*
+ sitagliptin 100 mg/d
-1.09

3.07*
1.26

0.52
0.30

HG = hypoglycemia
†
Noninferior to insulin glargine; *Statistically significant difference
1. Mean change from baseline.
2. Rate of confirmed episodes per patient-year of exposure. Confirmed
hypoglycemic episodes were defined as episodes of self-measured blood
glucose of <3.1 mmol/L (<56 mg/dL) or severe episodes necessitating
assistance. Nocturnal hypoglycemic episodes were defined as hypoglycemic episodes that occurred from 0001 to 0559 hours (inclusive).
3. S Heller et al. Lancet 2012; 379:1489.
4. B Zinman et al. Diabetes Care 2012; 35:2464.
5. L Meneghini et al. Diabetes Care 2013; 36:858.
6. A Philis-Tsimikas et al. Diabetes Obes Metab 2013; 15:760.

have been reported with insulin degludec. All insulins
can cause hypoglycemia and weight gain.
PREGNANCY — Insulin degludec is classified as

category C (visceral and skeletal abnormalities in rats
and rabbits; no adequate studies in women) for use
during pregnancy.
DOSAGE AND ADMINISTRATION — Insulin degludec
should be injected subcutaneously once daily; the
injection site should be rotated with each injection.
Because of its delayed absorption and long duration
of action, it does not have to be administered at the
same time each day and can be given without regard
to meals. The other long-acting insulins, detemir and
glargine, must be given at the same time each day.
163

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


Revised 12/7/16: In Table 3, footnote 1 was changed to: "Approximate WAC for 30 days' treatment with 40 units/day in prefilled pens."

The Medical Letter

®

Vol. 57 (1483)

December 7, 2015

Table 3. Long-Acting Insulin Analogs
Dosage
Frequency

Onset
of Action

Duration
of Action Cost1

Insulin degludec – Tresiba (Novo Nordisk) 3 mL FlexTouch pen (100, 200 units/mL)

once/d

1-9 hrs

>42 hrs

Insulin detemir – Levemir (Novo Nordisk)
Insulin glargine – Lantus (Sanofi)
Toujeo (Sanofi)

once/d or bid2 1-4 hrs
once/d3
1-4 hrs
once/d3
1-6 hrs

Drug

Available Formulations
10 mL vial; 3 mL FlexTouch pen (100 units/mL)
10 mL vial; 3 mL SoloStar pen (100 units/mL)
1.5 mL SoloStar pen (300 units/mL)

12-20 hrs
22-24 hrs
24-36 hrs

$355.00
298.20
298.20
335.50

1. Approximate WAC for 30 days' treatment with 40 units/day in prefilled pens. 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. November 5, 2015. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
2. The once-daily dose should be administered with the evening meal or at bedtime. With twice-daily dosing, the second dose can be administered with the evening
meal, at bedtime, or 12 hours after the morning dose.
3. The dose can be administered at any time of day, but must be injected at the same time each day.

In patients with type 1 diabetes not already using a
long-acting insulin, the recommended starting dose
of insulin degludec is one-third to one-half of the total
daily insulin dose; the remainder of the total daily insulin
dose should be administered as a short-acting insulin
divided and given with meals. In insulin-naive type
2 diabetes patients, the recommended starting dose
of insulin degludec is 10 units once daily. In patients
with type 1 or type 2 diabetes already receiving insulin,
the dose is the same as the current total daily dose of
intermediate- or long-acting insulin. The dose of insulin
degludec can be increased every 3-4 days as needed.
CONCLUSION — Insulin degludec (Tresiba) is

noninferior to insulin glargine (Lantus) and insulin
detemir (Levemir) in lowering HbA1c, and it may
cause less nocturnal hypoglycemia. Its relatively long
half-life permits once-daily dosing and, unlike insulin
detemir and insulin glargine, it does not have to be
injected at the same time each day. ■

▶

Drugs Past Their Expiration Date

Healthcare providers are often asked if drugs can
be used past their expiration date. Because of legal
restrictions and liability concerns, manufacturers do
not sanction such use and usually do not even comment on the safety or effectiveness of their products
beyond the date on the label. Since our last publication
on this subject,1 more data have become available.
SAFETY — There are no published reports of
human toxicity due to ingestion, injection, or topical
application of a current drug formulation after its
expiration date. Renal tubular damage has been
reported with use of degraded tetracycline in a
formulation that is no longer available.2
THE EXPIRATION DATE — The manufacturer's expiration
date is based on the stability of the drug in the original
sealed container. The date does not necessarily mean
that the drug was found to be unstable after a longer
164

1. Drugs for type 2 diabetes. Treat Guidel Med Lett 2014; 12:17.

2. Concentrated insulin glargine (Toujeo) for diabetes. Med Lett
Drugs Ther 2015; 57:69.
3. H Haahr and T Heise. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet 2014; 53:787.
4. S Heller et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type
1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet 2012; 379:1489.
5. B Zinman et al. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized,
treat-to-target trial (BEGIN Once Long). Diabetes Care 2012;
35:2464.
6. L Meneghini et al. The efficacy and safety of insulin degludec
given in variable once-daily dosing intervals compared with
insulin glargine and insulin degludec dosed at the same time
daily: a 26-week, randomized, open-label, parallel-group, treatto-target trial in individuals with type 2 diabetes. Diabetes Care
2013; 36:858.
7. A Philis-Tsimikas et al. Effect of insulin degludec versus sitagliptin in patients with type 2 diabetes uncontrolled on oral antidiabetic agents. Diabetes Obes Metab 2013; 15:760.

period; it only means that real-time data or extrapolations from accelerated degradation studies indicate
that the drug in the closed container will still be stable
at that date. Most drug products have a labeled shelf life
of 1-5 years, but once the original container is opened,
the expiration date on that container no longer applies.
STABILITY — Data from the US Department of Defense/
FDA Shelf Life Extension Program, which tests the stability of drug products past their expiration date, have
shown that 2650 of 3005 lots (~88%) of 122 different
products stored in their unopened original containers
remained stable for an average of 66 months after their
expiration date.3 Of these, 312 lots (~12%) remained
stable for >4 years after the expiration date. Failure on
the basis of potency, pH, water content, dissolution,
physical appearance, or presence of impurities
occurred in 479 lots (~18%), but none failed within 1

year. Potassium iodide, which has been extensively
stockpiled for use in a radiation emergency, has shown
no significant degradation over many years.4


The Medical Letter

®

HEAT, HUMIDITY, AND LONG-TERM STORAGE —
Storage in high heat and/or humidity can accelerate
the degradation of some drug formulations, but in
one study, captopril tablets, theophylline tablets
(Theo-Dur, and others), and cefoxitin sodium powder
for injection (Mefoxin, and others), stored at 40°C
and 75% relative humidity, remained stable for 1.5-9
years beyond their expiration dates.5 In another study,
theophylline retained 90% of its potency 30 years past
its expiration date.6 A study of eight products that
had been stored in their unopened original containers
for 28-40 years past expiration found that 12 of 14
active ingredients had retained ≥90% of their original
potency; aspirin retained <5% of its potency and
amphetamine <60%.7
LIQUID DRUGS — Solutions and suspensions are
generally less stable than solid dosage forms, but
in one report, four outdated samples of atropine
solution (three up to 12 years past expiration and one
>50 years past expiration) were all found to contain
significant amounts of the drug.8 Drugs in solution

that have become cloudy or discolored or show signs
of precipitation, particularly injectables, should not
be used. Suspensions are especially susceptible
to freezing. Limiting factors with ophthalmic drugs
include evaporation of the solvent and the continued
ability of the preservative to inhibit microbial growth.9
Epinephrine solutions in EpiPen auto-injectors may
lose potency after the expiration date. In a study of
34 pens that had expired 1-90 months previously, the
decrease in epinephrine content was proportional
to the number of months past the expiration date.10
One study found that pens 3-36 months past their
expiration dates contained 84.2-101.5% of the labeled
dose,11 but a study of pens stored in EMS vehicles
that had expired 1-11 years previously found that
only 12.6-31.3% of the labeled dose remained.12 No
data are available on other epinephrine auto-injectors
such as Auvi-Q.13
CONCLUSION — When no suitable alternative is
available, outdated drugs may be effective. How much
potency they retain varies with the drug, the lot, the
preservatives (if any), and the storage conditions,
especially heat and humidity; many solid dosage
formulations stored under reasonable conditions in
their original unopened containers retain ≥90% of their
potency for at least 5 years after the expiration date
on the label, and sometimes much longer. Solutions
and suspensions are generally less stable. There are
no reports of toxicity from degradation products of
currently available drugs. ■

Vol. 57 (1483)

December 7, 2015

1. Drugs past their expiration date. Med Lett Drugs Ther 2009;
51:100.
2. GW Frimpter et al. Reversible “Fanconi syndrome” caused by
degraded tetracycline. JAMA 1963; 184:111.
3. RC Lyon et al. Stability profiles of drug products extended beyond labeled expiration dates. J Pharm Sci 2006; 95:1549.
4. US Department of Health and Human Services. Guidance for federal agencies and state and local governments: potassium iodide
tablets shelf life extension. Available at: www.fda.gov/downloads/
Drugs/Guidances/ucm080549.pdf. Accessed November 24, 2015.
5. G Stark et al. A study of the stability of some commercial solid dosage forms beyond their expiration dates. Pharm J 1997; 258:637.
6. R Regenthal et al. The pharmacologic stability of 35-year old
theophylline. Hum Exp Toxicol 2002; 21:343.
7. L Cantrell et al. Stability of active ingredients in long-expired
prescription medications. Arch Intern Med 2012; 172:1685.
8. JG Schier et al. Preparing for chemical terrorism: stability of injectable atropine sulfate. Acad Emerg Med 2004; 11:329.
9. GD Novack. Can I use those eyedrops after the expiration date?
Ocul Surf 2015; 13:169.
10. FE Simons et al. Outdated EpiPen and EpiPen Jr autoinjectors:
past their prime? J Allergy Clin Immunol 2000; 105:1025.
11. O Rachid et al. Epinephrine doses contained in outdated epinephrine auto-injectors collected in a Florida allergy practice.
Ann Allergy Asthma Immunol 2015; 114:354.
12. A Stonemen et al. Stability of epinephrine in expired EpiPen
products from EMS ambulances. Available at: http://abstracts.
aaps.org/Verify/AAPS2014/PosterSubmissions/W5370.pdf.
Accessed November 24, 2015.
13. In brief: Auvi-Q – a new epinephrine auto-injector. Med Lett

Drugs Ther 2013; 55:13.

▶

Deoxycholic Acid (Kybella) for
Double Chin

The FDA has approved the use of subcutaneous
injections of deoxycholic acid (Kybella – Kythera/
Allergan) to improve the appearance of moderate
to severe convexity or fullness associated with submental fat (double chin) in adults. It is the first drug
approved for this indication.
Pronunciation Key
Kybella: kye bell’ uh

MECHANISM OF ACTION — Deoxycholic acid is an
endogenous bile acid that solubilizes dietary fat
in the gut.1 Kybella contains synthetically derived
deoxycholic acid. When the drug is injected into
subcutaneous fat tissue, it solubilizes lipids in
adipocyte membranes. The resulting cytolysis induces
an inflammatory response that clears cell debris.2
Table 1. Pharmacology
Class

Cytolytic

Formulation

2 mL single patient use vials (10 mg/mL)

Route

Subcutaneous

Tmax

18 minutes

Metabolism

Not significantly metabolized

Elimination

In feces with endogenous deoxycholic acid

165


The Medical Letter

®

CLINICAL STUDIES — Approval of deoxycholic
acid was based on the results of two unpublished,
randomized, placebo-controlled trials (REFINE-1 and
REFINE-2), which are summarized in the package
insert. A total of 1,022 healthy adults 19-65 years
old with a BMI ≤40 kg/m2 and moderate to severe

submental fullness (grade 2 or 3 on a scale of 0 to
4) were randomized to a maximum of 6 treatment
sessions with deoxycholic acid or placebo. The mean
age was 49 years, mean BMI was 29 kg/m2, and 85% of
the subjects were women. In the two trials, a 2-grade
improvement on a composite of clinician and patient
ratings of submental fat 12 weeks after the final
treatment occurred in 13.4% and 18.6% of patients
treated with deoxycholic acid, and in <0.1% and 3.0%
of those treated with placebo. A 1-grade composite
response also occurred in more patients treated
with the active drug (70.0% and 66.5% vs 18.6% and
22.2% with placebo). Significantly more patients
treated with deoxycholic acid had a ≥10% reduction
in submental fat measured by MRI.
ADVERSE EFFECTS — The most common adverse
effects of Kybella injections, occurring in at least 20%
of patients and at a higher rate than with placebo,
were edema, bruising, pain, numbness, erythema,
and induration at the injection site, which sometimes
lasted for more than 30 days. Marginal mandibular
nerve injury (asymmetric smile, facial muscle
weakness) occurred in 4% and dysphagia occurred in
2% of patients treated with the drug; all but one case
resolved without treatment.
PREGNANCY — There are no adequate studies of
Kybella in pregnant women. In animal studies, no fetal
harm was observed in rats at doses up to 5 times
the maximum recommended human dose, but an
increased incidence of missing intermediate lung lobe

was found in rabbit fetuses at doses 2-fold higher
than the maximum recommended human dose.
DOSAGE, ADMINISTRATION, AND COST — Each 2-mL
vial of Kybella contains 20 mg of deoxycholic acid.
The recommended dosage is 2 mg/cm2 administered
as 0.2-mL injections 1 cm apart. The drug should
be injected into the subcutaneous fat tissue of the
desired treatment area; injection into the dermis
may cause skin ulceration. Patients may receive a
maximum of 6 treatments, spaced at least 1 month
apart, with no more than 50 injections (10 mL)
given per single treatment session. According to the
manufacturer, the cost of one 2-mL vial of Kybella is
$300; six treatment sessions at the maximum dose
would cost $9,000 for the drug alone.
166

Vol. 57 (1483)

December 7, 2015

CONCLUSION — Deoxycholic acid injections (Kybella)
can improve the appearance of unwanted submental
fat in some patients, but the safety of injecting a
cytolytic drug in the vicinity of vital structures remains
to be established. ■
1. U Wollina and A Goldman. ATX-101 for reduction of submental
fat. Expert Opin Pharmacother 2015; 16:755.
2. B Ascher et al. Efficacy, patient-reported outcomes and safety
profile of ATX-101 (deoxycholic acid), an injectable drug for the

reduction of unwanted submental fat: results from a phase III,
randomized, placebo-controlled study. J Eur Acad Dermatol
Venereol 2014; 28:1707.

▶

Ferric Citrate (Auryxia) for
Hyperphosphatemia

The FDA has approved ferric citrate (Auryxia –
Keryx), an oral phosphate binder, for treatment of
hyperphosphatemia in patients with chronic kidney
disease (CKD) on dialysis. It is the second iron-based
phosphate binder to be approved in the US, and the
first that causes significant systemic absorption of
iron. Auryxia is not FDA-approved for treatment of
iron deficiency anemia.
Pronunciation Key
Auryxia: awe rik' see uh

STANDARD TREATMENT — Dialysis treatment and
limitation of elemental phosphate intake (typically to
750-1000 mg/day) are somewhat effective in lowering
serum phosphorus levels, but addition of an oral
phosphate binder is often needed. Whether phosphatebinding drugs can improve clinical outcomes has not
been established.
Calcium-based phosphate binders such as calcium
acetate (PhosLo, and others) are effective in reducing
serum phosphate levels, but they can cause adverse
gastrointestinal effects and hypercalcemia, and their

use has been associated with an increased rate of
vascular calcification.1,2 Sevelamer carbonate (Renvela)3
and lanthanum carbonate (Fosrenol)4 are generally
preferred in patients with hypercalcemia, but they can
also cause adverse gastrointestinal effects, and the
long-term effects of possible lanthanum accumulation
in human bone and other tissues are unknown. The
iron-based phosphate binder sucroferric oxyhydroxide
(Velphoro) appears to be as effective as sevelamer
carbonate in reducing serum phosphorus levels, with
a lower daily pill burden.5 Use of magnesium-based
phosphate binders has been limited by the occurrence of
hypermagnesemia with respiratory arrest.6 Aluminumbased agents can cause systemic aluminum toxicity
and are rarely prescribed for long-term use.


The Medical Letter

Vol. 57 (1483)

®

December 7, 2015

Table 1. Some Oral Drugs for Hyperphosphatemia
Drug

Available Formulation

Usual Adult Dosage

Cost1

Calcium acetate – PhosLo Gelcaps
(Fresenius Medical Care)
Eliphos (Hawthorn)
Phoslyra (Fresenius Medical Care)

667 mg caps (169 mg Ca)

$189.50

667 mg tabs
667 mg/5 mL oral solution

2001-2668 mg
(507-676 mg Ca)
with each meal

Ferric citrate – Auryxia (Keryx)

1 g tabs (210 mg ferric iron)

1101.60

Lanthanum carbonate – Fosrenol (Shire)

500, 750, 1000 mg chewable tabs;
750, 1000 mg packets
800 mg tabs; 0.8, 2.4 g packets

8-9 g/d (1680-1890 mg Fe)
in 3 divided doses with meals
500-1000 mg tid
with meals2
1600-3200 mg tid
with meals
500 mg tid with meals2

Sevelamer carbonate – Renvela (Genzyme)
Sucroferric oxyhydroxide – Velphoro
(Fresenius Medical Care)

500 mg chewable tabs

133.60
251.20

841.20
924.10
897.80

1. Approximate WAC for 30 days’ treatment with the lowest usual 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. November 5, 2015.
Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
2. Tablets must be chewed completely before swallowing.

PHARMACOLOGY — Ferric iron binds to dietary
phosphate in the GI tract; the resulting precipitate is
eliminated in feces. Unlike sucroferric oxyhydroxide,

administration of ferric citrate results in significant
iron absorption.7
CLINICAL STUDIES — In an open-label trial, 441
patients with CKD and hyperphosphatemia on
peritoneal dialysis or hemodialysis were randomized
in a 2:1 ratio to receive ferric citrate or an active control
(sevelamer carbonate and/or calcium acetate)
for 52 weeks. Reductions in serum phosphorus
levels were similar in both groups. Compared to
patients in the control group, those taking ferric
citrate required significantly lower doses of IV iron
and erythropoiesis-stimulating agents to maintain
similar hemoglobin concentrations.7
ADVERSE EFFECTS — Diarrhea occurred in 21% of
patients taking ferric citrate in clinical trials. Nausea,
vomiting, constipation, and cough each occurred in
>5% of patients. In the open-label trial, 21% of patients
taking ferric citrate and 14% of those taking an active
control discontinued treatment due to adverse effects.
Ferric citrate may cause excessive increases in iron
stores. Iron parameters should be measured before
starting the drug and monitored during treatment,
with doses of IV iron products and erythropoiesisstimulating agents adjusted accordingly. Auryxia is
contraindicated for use in patients with iron overload
syndromes such as hemochromatosis.
PREGNANCY — Ferric citrate is classified as category B (no adequate studies in animals or women;
risk unknown) for use during pregnancy. Iron
overdose in pregnant women may increase the risk
of spontaneous abortion, gestational diabetes, and
fetal malformations.

DRUG INTERACTIONS — Iron-containing products such
as ferric citrate can interfere with the absorption of
other drugs taken concurrently. Doxycycline should be
taken at least one hour before and ciprofloxacin should
be taken at least two hours before or after ferric citrate.
Levofloxacin, calcitriol, doxercalciferol, digoxin, and
warfarin can be taken concomitantly with ferric citrate.
DOSAGE AND ADMINISTRATION — The recommended
starting dosage of ferric citrate is 2 g (420 mg ferric
iron) three times daily with meals. The daily dose can be
titrated at weekly intervals in decrements or increments
of 1-2 g as needed; the maximum dose is 12 g/day.
CONCLUSION — In patients with chronic kidney
disease on dialysis, ferric citrate (Auryxia) appears to
be as effective as sevelamer carbonate (Renvela) and
calcium acetate (PhosLo, and others) in reducing serum
phosphorus levels, but may not be as well tolerated.
Ferric citrate has a greater daily pill burden than
sucroferric oxyhydroxide (Velphoro), the other ironbased phosphate binder approved for this indication,
but its use may permit reductions in the dosage of IV
iron products and erythropoiesis-stimulating agents. ■
1. L Liu et al. The effects of non-calcium-based phosphate binders versus calcium-based phosphate binders on cardiovascular calcification and bone remodeling among dialysis patients:
a meta-analysis of randomized trials. Ren Fail 2014; 36:1244.
2. K Wada and Y Wada. Evaluation of aortic calcification with lanthanum carbonate vs. calcium-based phosphate binders in maintenance hemodialysis patients with type 2 diabetes mellitus: an openlabel randomized controlled trial. Ther Apher Dial 2014; 18:353.
3. In brief: sevelamer-based phosphate binders. Med Lett Drugs
Ther 2008; 50:13.
4. Phosphate binders. Med Lett Drugs Ther 2006; 48:15.
5. Sucroferric oxyhydroxide (Velphoro) for hyperphosphatemia.
Med Lett Drugs Ther 2014; 56:76.

6. M Tonelli et al. Oral phosphate binders in patients with kidney
failure. N Engl J Med 2010; 362:1312.
7. JB Lewis et al. Ferric citrate controls phosphorus and delivers
iron in patients on dialysis. J Am Soc Nephrol 2015; 26:493.

167


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▶

®

Nivolumab (Opdivo) plus Ipilimumab
(Yervoy) for Metastatic Melanoma

The FDA has approved the combined use of the
programmed death receptor-1 (PD-1) blocking
antibody nivolumab (Opdivo)1 and the anti-CLA-4
antibody ipilimumab (Yervoy)2 for treatment of BRAF
V600 wild-type unresectable or metastatic melanoma.
This is the first immunotherapy combination to be
approved for treatment of any type of cancer.
Pronunciation Key
Nivolumab: ni voe' loo mab"
Opdivo: op dee' voe
Ipilimumab: ip" i lim' ue mab
Yervoy: yur voi

CLINICAL STUDIES — Approval of nivolumab plus
ipilimumab was based on the results of a doubleblind trial in 142 patients with previously untreated
unresectable or metastatic melanoma (109 patients
with BRAF V600 wild-type tumors were included
in the primary efficacy analysis); the combination
significantly improved the objective response
rate (61% vs 11%) and median progression-free
survival (not yet reached vs 4.4 months) compared
to ipilimumab alone. A complete response was
achieved in 22% of patients receiving both drugs
compared to 0% of those receiving ipilimumab alone.
Similar results were reported in 33 patients with
BRAF mutation-positive tumors who were eligible
for the study, but were not included in the primary
efficacy analysis.3
Another double-blind trial in 945 patients with
previously untreated unresectable or metastatic
melanoma compared nivolumab plus ipilimumab,
ipilimumab alone, and nivolumab alone. Median
progression-free survival was 11.5 months with
both drugs, 2.9 months with ipilimumab alone,
and 6.9 months with nivolumab alone. Nivolumab
monotherapy was as effective as nivolumab plus
ipilimumab in patients with tumors positive for the
PD-1 ligand (median progression-free survival was
14.0 months in both groups), but not in patients with
PD-L1-negative tumors (5.3 months with nivolumab
vs 11.2 months with both drugs).4,5
In a follow-up of a dose-finding study (available only
as an abstract), the overall survival rate at 12 months

in the subset of patients with advanced or metastatic
melanoma who received the FDA-approved dose of
nivolumab plus ipilimumab was 75%.6
ADVERSE EFFECTS — In the pivotal trial of combined
use of nivolumab and ipilimumab, common adverse
168

Vol. 57 (1483)

December 7, 2015

effects included diarrhea, rash, fatigue, pruritus,
colitis, and nausea. Grade 3 or 4 adverse effects
occurred in 54% of patients who received nivolumab
plus ipilimumab and in 24% of those who received
ipilimumab alone.3
DOSAGE, ADMINISTRATION, AND COST — The
recommended dosage for treatment of BRAF V600
wild-type unresectable or metastatic melanoma
is nivolumab 1 mg/kg and ipilimumab 3 mg/kg IV
every 3 weeks for 4 doses, followed by nivolumab
3 mg/kg every 2 weeks until disease progression or
unacceptable toxicity occurs. The cost for a single
dose of both drugs is $35,242.50.7
CONCLUSION — Combined use of nivolumab (Opdivo)
and ipilimumab (Yervoy) is more effective than
ipilimumab alone in previously untreated patients
with BRAF V600 wild-type unresectable or metastatic
melanoma. The combination offers a new option for
first-line treatment of metastatic melanoma. ■

1. Nivolumab (Opdivo) for metastatic melanoma and metastatic
NSCLC. Med Lett Drugs Ther 2015; 57:85.
2. Ipilimumab (Yervoy) for metastatic melanoma. Med Lett Drugs
Ther 2011; 53:51.
3. MA Postow et al. Nivolumab and ipilimumab versus ipilimumab
in untreated melanoma. N Engl J Med 2015; 372:2006.
4. Addendum: nivolumab (Opdivo) for metastatic melanoma and
metastatic NSCLC. Med Lett Drugs Ther 2015; 57:94.
5. J Larkin et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373:23.
6. M Sznol et al. Updated survival, response and safety data
in a phase 1 dose-finding study (CA209-004) of concurrent
nivolumab (nivo) and ipilimumab (ipi) in advanced melanoma.
Presented at: The Society for Melanoma Research - 12th
International Melanoma Congress (SMR) 2015, November 1821, San Francisco, California.
7. Approximate WAC for a 70-kg patient. Cost of administration
not included. 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. November
5, 2015. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2015. www.fdbhealth.com/policies/drugpricing-policy.

Corrections
Eloctate for Hemophilia A (Med Lett Drugs Ther 2015; 57:143)
In the table on page 144, the indications and half-life listed
for Nuwiq were erroneously taken from the European package insert. The table has been revised online to reflect the US
prescribing information. The cost for Nuwiq has also been
updated.
A Sumatriptan Patch (Zecuity) for Migraine (Med Lett Drugs Ther
2015; 57:151)
In the introduction on page 151, the triptans were referred to
as serotonin (5-HT) receptor antagonists; they are 5-HT1B/1Dreceptor agonists.

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Review the efficacy and safety of deoxycholic acid (Kybella) for treatment of double chin.
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Issue 1483 Questions
(Correspond to questions #111-120 in Comprehensive Exam #73, available January 2016)
Deoxycholic Acid (Kybella) for Double Chin

Insulin Degludec (Tresiba) – A New Long-Acting Insulin for
Diabetes
1. Which of the long-acting human insulin analogs has the longest
duration of action?
a. insulin detemir (Levemir)
b. insulin glargine (Lantus)
c. concentrated insulin glargine (Toujeo)
d. insulin degludec (Tresiba)
2. A 43-year-old woman with type 2 diabetes currently well
controlled on metformin, sitagliptin, and insulin glargine has
seen advertisements for insulin degludec and asks you if she
should switch. You could tell her that:
a. insulin degludec is more effective than insulin glargine in
lowering HbA1c
b. insulin degludec causes more hypoglycemia than insulin
glargine
c. insulin degludec has a longer duration of action than insulin
glargine so she only needs to take it every other day
d. unlike insulin glargine, insulin degludec does not have to
be taken at the same time each day
3. Compared to the addition of sitagliptin in patients with type 2
diabetes taking oral antidiabetic drugs, insulin degludec:
a. is more effective in lowering HbA1c
b. is less effective in lowering HbA1c
c. causes less hypoglycemia
d. causes more GI adverse effects
Drugs Past Their Expiration Date
4. Preservation of the potency of drugs well past the expiration
date has been associated with:

a. storage in their original containers
b. solid dosage forms
c. low heat and humidity
d. all of the above
5. Toxicity associated with use of currently available drug
formulations past their expiration date:
a. has not been reported
b. has mainly been renal
c. has mainly been gastrointestinal
d. has involved multiple organ systems

6. Adverse effects reported with the use of subcutaneous
injections of deoxycholic acid include:
a. bruising
b. marginal mandibular nerve injury
c. dysphagia
d. all of the above
7. A 65-year-old man with a BMI of 35 kg/m2 asks you about
using Kybella to improve the appearance of his double chin. You
could tell him that:
a. it was less effective than placebo in clinical trials
b. it has not been studied in men
c. the clinical trials included mostly women with an average
age of 49 years and an average BMI of 29 kg/m2
d. all of the above
Ferric Citrate (Auryxia) for Hyperphosphatemia
8. Ferric citrate increases concentrations of:
a. phosphorus
b. calcium
c. iron

d. all of the above
9. The most common adverse effect of ferric citrate is:
a. constipation
b. nausea
c. diarrhea
d. hypercalcemia
Nivolumab (Opdivo) plus Ipilimumab (Yervoy) for Metastatic
Melanoma
10. Compared to ipilimumab alone, combined use of nivolumab and
ipilimumab in patients with BRAF V600 wild-type metastatic
melanoma has:
a. increased the objective response rate
b. prolonged progression-free survival
c. increased the incidence of grade 3 or 4 adverse effects
d. all of the above

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EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
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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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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,
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