The medical letter on drugs and therapeutics july 6 2015

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE
ISSUE
No.

1433
1472
Volume 56

July 6, 2015

IN THIS ISSUE

Drugs for Insomnia ............................................................................................................. p 95
Liletta – A Third Levonorgestrel-Releasing IUD ............................................................... p 99
Ryanodex – A New Dantrolene Formulation for Malignant Hyperthermia ...................... p 100
Eliglustat (Cerdelga) – An Oral Drug for Gaucher Disease ........................................ online only

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE

ISSUE No.

1433
1472
Volume 56

▶

July 6, 2015
Take CME Exams
ALSO IN THIS ISSUE

Liletta – A Third Levonorgestrel-Releasing IUD ................................................................p 99
Ryanodex – A New Dantrolene Formulation for Malignant Hyperthermia .......................p 100
Eliglustat (Cerdelga) – An Oral Drug for Gaucher Disease .........................................online only

Drugs for Insomnia

Pharmacological treatment of insomnia includes
prescription drugs, non-prescription medications, and
"natural" remedies. Behavioral approaches such as
cognitive behavioral therapy, which are not discussed
here, are also used. Pharmacologic treatment and
behavioral therapy are often combined.
BENZODIAZEPINE RECEPTOR AGONISTS — Zolpidem
(Ambien, and others), zaleplon (Sonata, and generics), and eszopiclone (Lunesta, and generics) are
not structural benzodiazepines, but they bind to
benzodiazepine receptors. All of them decrease
sleep latency and are approved for use in patients
with sleep-onset insomnia. Benzodiazepine receptor
agonists differ mainly in their duration of action (see
Table 1).
Zolpidem is the most widely prescribed hypnotic
in the US. The FDA has required manufacturers of
zolpidem to lower the recommended dose for women
and to recommend consideration of a lower dose

for men because of concerns about high serum
concentrations 8 hours after taking the drug that
could impair driving performance or cause falls in
the elderly.1 The FDA also recommends that patients
not drive or engage in other activities that require
mental alertness the day after taking extendedrelease zolpidem even in low doses because levels
can still remain high the next day.2 A low-dose
sublingual formulation of zolpidem (Intermezzo) is
the only hypnotic approved for treatment of insomnia
following middle-of-the-night awakening.3
The FDA has also recommended that the starting dose
of eszopiclone be reduced to 1 mg for both men and
women because one study found that taking an evening

dose of 3 mg impaired driving skills, memory, and
coordination for more than 11 hours.4
Adverse Effects – Benzodiazepine receptor agonists
can impair next-day performance, including driving.5
Complex sleep-related behaviors such as sleepwalking, sleep-eating, and sleep-driving may occur
without conscious awareness6,7; risk factors for these
behaviors include taking high doses of the drug,
taking it at times other than bedtime, and concurrent
use with other sedating drugs.8 Hallucinations have
been reported. Eszopiclone can leave an unpleasant
aftertaste. Some reports have associated use of
hypnotics, particularly zolpidem, with excess mortality
and an increased risk of cancer9,10; a cause-and-effect
relationship has not been established. Benzodiazepine
receptor agonists are classified as schedule IV
controlled substances; withdrawal, dependence, and

abuse can occur.
Drug Interactions – Zolpidem, eszopiclone, and
(minimally) zaleplon are metabolized by CYP3A4.
Concurrent administration with a CYP3A4 inhibitor,
such as clarithromycin (Biaxin, and generics), could
increase the risk of toxicity, but with zolpidem and
zaleplon the effect appears to be clinically insignificant.
Strong CYP3A4 inducers, such as rifampin (Rifadin,
and others), could decrease the effectiveness of
these drugs.11 Concurrent use of alcohol or other CNS
depressants increases the risk of CNS depression.
BENZODIAZEPINES — Benzodiazepines decrease
sleep latency and prolong the first two stages of sleep.
Like benzodiazepine receptor agonists, the differences
between the benzodiazepines are primarily in their
duration of action (see Table 1).
Adverse Effects – Benzodiazepines can impair
next-day performance, including driving.5,12 Complex
95

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The Medical Letter

July 6, 2015

Vol. 57 (1472)

®

Table 1. Some Hypnotics for Insomnia
Drug

Onset
of Action

Duration

Some Oral
Formulations

Usual
Hypnotic Dose

Dose in
Elderly

Pregnancy
Category* Cost1

Benzodiazepine Receptor Agonists
Eszopiclone – generic
Lunesta (Sunovion)

<30 min

intermediate

1, 2, 3 mg tabs

1-3 mg

1-2 mg

C

$9.60
124.20

Zaleplon – generic
Sonata (Pfizer)
Zolpidem –
immediate-release – generic
Ambien (Sanofi)
extended-release – generic
Ambien CR
sublingual – Edluar (Meda)

<30 min

ultra-short

5, 10 mg caps

10-20 mg

5 mg

C

4.60
68.60

<30 min

short

5, 10 mg tabs

5 mg

C

<30 min

short

6.25 mg

C

<30 min

short

6.25, 12.5 mg
ER tabs
5, 10 mg tabs

5 mg

C

0.70
132.00
47.50
132.00
106.00

20 min

ultra-short

1.75, 3.5 mg tabs

1.75 mg

C

83.10

20 min

short

5 mg/spray

Men: 5-10 mg
Women: 5 mg

Men: 6.25-12.5 mg
Women: 6.25 mg
Men: 5-10 mg
Women: 5 mg
Men: 3.5 mg
Women: 1.75 mg
Men: 5-10 mg
Women: 5 mg

5 mg

C

145.002

Intermezzo (Transcept)
oral spray – Zolpimist
(Amherst)
Benzodiazepines
Estazolam – generic
Flurazepam – generic
Temazepam – generic
Restoril (Mallinckrodt)
Triazolam – generic
Halcion (Pfizer)
Melatonin Receptor Agonist
Ramelteon – Rozerem
(Takeda)
Tricyclic Antidepressant
Doxepin – Silenor (Pernix)

Orexin Receptor Antagonist
Suvorexant – Belsomra
(Merck)

15-60 min

intermediate

1, 2 mg tabs

0.5-1 mg

X

10-30 min
30-60 min

long
intermediate

15 mg
7.5-15 mg

X
X

15-30 min

short

15, 30 mg caps
15-30 mg
7.5, 15, 22.5,
15-30 mg
30 mg caps
0.125, 0.25 mg tabs 0.125-0.25 mg
0.25 mg tabs

1-2 mg

6.00

0.125-0.25 mg

X

15-30 min

short

8 mg tabs

8 mg

8 mg

C

92.80

30 min

long

3, 6 mg tabs

6 mg

3 mg

C

102.60

30 min

intermediate

5, 10, 15, 20 mg tabs 10-20 mg

10-20 mg

C

87.70

5.00
0.90
138.80
21.90

17.803

ER = extended-release
*FDA pregnancy categories: C = risk cannot be ruled out; X = contraindicated during pregnancy
1. Approximate WAC for 10 days’ treatment with the lowest hypnotic dose or the lowest hypnotic dose for men. 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. June 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricingpolicy.
2. Cost of a 7.7-mL bottle that contains 60 5-mg sprays after 5 initial priming sprays.
3. Cost of five 0.25-mg tablets.

sleep-related behaviors and anterograde amnesia
may occur, particularly with triazolam (Halcion, and
generics). Aggressive behavior has been reported.13
In elderly patients, benzodiazepines can cause
weakness and impair coordination, and their use as
hypnotics has been associated with an increased
incidence of falls and hip fractures. Lethal overdoses
of oral benzodiazepines taken alone occur rarely;
fatalities almost always involve concurrent use of
opioid analgesics, alcohol, or other CNS depressants.14
Benzodiazepines are classified as schedule IV
controlled substances; dependence, tolerance, abuse,
and rebound insomnia can occur.
Drug Interactions – Most benzodiazepines (except
lorazepam, oxazepam, and temazepam) are metabolized to some extent by CYP3A4. Inhibitors of CYP3A4,
such as clarithromycin, can increase the risk of
benzodiazepine toxicity, and inducers, such as rifampin,
can decrease their effectiveness.11 Alcohol and other
96

CNS depressants increase the risk of benzodiazepineinduced CNS depression.
MELATONIN RECEPTOR AGONIST — Ramelteon
(Rozerem) is FDA-approved for sleep-onset insomnia.15
It has been used off-label for treatment of circadian
rhythm disorders. Clinical studies have shown
statistically significant but clinically modest improvements in sleep parameters.16 Comparative studies with
benzodiazepines or benzodiazepine receptor agonists
are lacking.
Adverse Effects – Common adverse effects of
ramelteon include dizziness, nausea, fatigue, and
headache. Increased serum prolactin and decreased
serum testosterone concentrations have been
reported. Unlike benzodiazepine receptor agonists
and benzodiazepines, ramelteon has no potential
for abuse and is not classified as a controlled
substance.


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Drug Interactions – Ramelteon is metabolized by
CYP1A2 and to a lesser extent by CYP2C9 and 3A4.
Concurrent administration of the selective serotonin
reuptake inhibitor (SSRI) fluvoxamine (Luvox, and
others), which is a strong CYP1A2 inhibitor, markedly
increases serum concentrations of ramelteon; they
should not be taken together. Other CYP1A2 inhibitors,
such as ciprofloxacin (Cipro, and others), could have

a similar effect. Drugs that inhibit CYP3A4 or 2C9
could also increase ramelteon serum concentrations
and the risk of toxicity. Rifampin, a potent inducer of
various CYP isozymes, decreases ramelteon serum
concentrations by 80% and presumably would
decrease its hypnotic effect.11
LOW-DOSE DOXEPIN — The tricyclic antidepressant
doxepin (Silenor) is the only antidepressant approved
by the FDA for the treatment of sleep-maintenance
insomnia.17 Its affinity for H1 histamine receptors
is thought to be largely responsible for its sedating
effect. In doses much lower than those used to treat
depression (3-6 mg vs 150-300 mg), it is claimed to
have a hypnotic effect without causing anticholinergic
and other typical tricyclic adverse effects. Some clinical
studies have demonstrated efficacy both in healthy
volunteers (51 minutes more total sleep time) and in
elderly patients with chronic insomnia.18
Adverse Effects – Residual next-day somnolence has
been reported with the 6-mg dose. Like ramelteon,
doxepin is not classified as a controlled substance.
Drug Interactions – Coadministration with cimetidine
(Tagamet, and others), an inhibitor of CYP2C19, 2D6,
and 1A2, can double doxepin serum concentrations; a
maximum doxepin dose of 3 mg is recommended for
patients taking cimetidine. Doxepin is contraindicated
for use with a monoamine oxidase inhibitor (MAOI) or
within two weeks of stopping one.
OREXIN RECEPTOR ANTAGONIST – The dual orexin
1 and 2 receptor antagonist suvorexant (Belsomra)

is FDA-approved for treatment of sleep-onset and
sleep-maintenance insomnia. Signaling of orexin
neuropeptides sustains wakefulness.19 Suvorexant
promotes sleep by blocking orexin neuropeptides
from binding to their receptors. Clinical studies have
shown that patients treated with the drug fall asleep
5-10 minutes sooner and stay asleep 15-25 minutes
longer than those given placebo.20 Loss of orexin
signaling has been associated with narcolepsy,
which is characterized by excessive daytime
sleepiness, cataplexy, hypnagogic and hypnopompic
hallucinations, and sleep paralysis.

Vol. 57 (1472)

July 6, 2015

Adverse Effects – Suvorexant is classified as a schedule
IV controlled substance. Its most serious side effect,
related to its long half-life, is next-day somnolence,
which may impair performance skills such as driving.
Cataplexy-like symptoms such as leg weakness
occurred in a few patients in clinical trials. Suvorexant
should be administered with caution to patients with
compromised respiratory function; it appears to be
safe in patients with mild to moderate COPD.21
Drug Interactions – Suvorexant is a substrate of
CYP3A4 and should not be administered with strong
CYP3A4 inhibitors, such as clarithromycin. In patients
taking moderate CYP3A4 inhibitors, such as fluconazole

(Diflucan, and generics), verapamil (Calan, and others),
or grapefruit juice, the recommended dose of suvorexant
is 5 mg, which can be increased to 10 mg if needed.
The efficacy of suvorexant may be reduced in patients
concomitantly taking a strong CYP3A4 inducer such as
carbamazepine (Tegretol, and generics).11 Suvorexant is
a P-glycoprotein inhibitor; concomitant administration
with digoxin increased digoxin serum concentrations.
Concurrent use of alcohol or other CNS depressants
increases the risk of CNS depression.
OTHER PRESCRIPTION DRUGS — A variety of drugs
are prescribed off-label for treatment of insomnia. The
most common are antidepressants such as trazodone
(Desyrel, and generics), mirtazapine (Remeron, and
generics), and amitriptyline (Elavil, and generics). There
is little evidence that these agents are effective in
treating insomnia not associated with depression.22,23
Second-generation antipsychotics such as quetiapine
(Seroquel, and others), ziprasidone (Geodon, and
generics), and olanzapine (Zyprexa, and others) have
also been prescribed for insomnia, but their adverse
effects make their use for treatment of insomnia alone
difficult to justify.24,25 The antiepileptic/neuropathic
analgesic gabapentin (Neurontin, and others), which
is FDA-approved for multiple indications, but not for
insomnia, may have a beneficial effect on sleep. Both
gabapentin and pregabalin (Lyrica), a related drug, have
been shown to increase slow-wave sleep and sleep
efficiency.26,27
NON-PRESCRIPTION PRODUCTS — Antihistamines –

Two first-generation antihistamines – diphenhydramine
(Nytol, Benadryl, and others) and doxylamine (Unisom,
and others) – are currently approved by the FDA as
“sleep aids” for sale without a prescription. They are also
marketed as hypnotics in combination products such as
Tylenol PM (acetaminophen plus diphenhydramine).
These drugs are sedating, but there is little acceptable
evidence that they improve the quality or duration of
97


The Medical Letter

®

sleep. Tolerance to the sedative effects of antihistamines
may develop rapidly. They can cause next-day sedation,
impairment of performance skills such as driving, and
anticholinergic effects, such as dry mouth and urinary
retention, which may be particularly troublesome in
elderly patients.28
Alcohol – Although widely used as a hypnotic, alcohol
causes initial CNS depression followed by rebound
excitation, which disrupts sleep. In addition, selfmedication with alcohol to relieve insomnia has led to
development of alcoholism.
Melatonin – Taken 3-5 hours before the desired
time of sleep onset, melatonin has been reported to
be effective in some patients with insomnia. It does
not appear to be effective when taken at bedtime. A
sustained-release formulation of melatonin (Circadin)

is approved for use in Europe; one study found it to
be more effective than placebo for use 2 hours before
bedtime in patients ≥65 years old.29 Melatonin is
only available as a dietary supplement in the US; the
hypnotic dose has not been established and the purity
of these products is unclear.
Herbal Products – Valerian root is claimed to be
a mild hypnotic that may improve the quality of
sleep, but some studies have found it ineffective. 30
Similarly, there is no convincing evidence that any
of the other “natural” remedies used for insomnia,
such as kava, L-tryptophan (5-HT), chamomile tea,
passion flower, coenzyme Q10, hops, lemon balm,
lavender, or skull cap, are effective for this purpose.31
No objective data have been published to date to
support the subjective claim of sleep improvement
attributed to cannabis or its various extracts. The
purity and optimal dosages of all these products are
unclear, and there is little if any information on their
safety during pregnancy.
ACUPUNCTURE — A recent review found that the
evidence for a beneficial effect of acupuncture for
treatment of insomnia was inconclusive.32 ■
1. FDA requires lower dosing of zolpidem. Med Lett Drugs Ther
2013; 55:5.
2. FDA Drug Safety Communication: FDA approves new label
changes and dosing for zolpidem products and a recommendation to avoid driving the day after using Ambien CR. Available
at: www.fda.gov/drugs/drugsafety/ucm352085.htm. Accessed
June 25, 2015.
3. Low-dose sublingual zolpidem (Intermezzo) for insomnia due

to middle-of-the-night awakening. Med Lett Drugs Ther 2012;
54:25.
4. In brief: lowering the dose of Lunesta. Med Lett Drugs Ther
2014; 56:48.
5. RN Hansen et al. Sedative hypnotic medication use and the

98

Vol. 57 (1472)

July 6, 2015

risk of motor vehicle crash. Am J Public Health 2015 June 11
(epub).
6. N Gunja. In the Zzz zone: the effects of Z-drugs on human performance and driving. J Med Toxicol 2013; 9:163.
7. N Gunja. The clinical and forensic toxicology of Z-drugs. J Med
Toxicol. 2013; 9:155.
8. JS Poceta. Zolpidem ingestion, automatisms, and sleep driving:
a clinical and legal case series. J Clin Sleep Med 2011; 7:632.
9. DF Kripke et al. Hypnotics’ association with mortality or cancer:
a matched cohort study. BMJ Open 2012; 2:e000850.
10. CH Kao et al. Relationship of zolpidem and cancer risk: a Taiwanese population-based cohort study. Mayo Clin Proc 2012; 87:430.
11. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
12. MJ Rapoport et al. Benzodiazepine use and driving: a metaanalysis. J Clin Psychiatry 2009; 70:663.
13. B Albrecht et al. Benzodiazepine use and aggressive behaviour:
a systematic review. Aust N Z J Psychiatry 2014; 48:1096.
14. M Jann et al. Benzodiazepines: a major component in unintentional prescription drug overdoses with opioid analgesics. J
Pharm Pract 2014; 27:5.
15. Ramelteon (Rozerem) for insomnia. Med Lett Drugs Ther 2005;

47:89.
16. A Kuriyama et al. Ramelteon for the treatment of insomnia in
adults: a systematic review and meta-analysis. Sleep Med
2014; 15:385.
17. Low-dose doxepin (Silenor) for insomnia. Med Lett Drugs Ther
2010; 52:79.
18. AD Krystal et al. Efficacy and safety of doxepin 3 and 6 mg in
a 35-day sleep laboratory trial in adults with chronic primary
insomnia. Sleep 2011; 34:1433.
19. JM Uslaner et al. Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. Sci Transl Med 2013; 5:179ra44.
20. Suvorexant (Belsomra) for insomnia. Med Lett Drugs Ther
2015; 57:29.
21. H Sun et al. Effects of suvorexant, an orexin receptor antagonist, on breathing during sleep in patients with chronic obstructive pulmonary disease. Respir Med 2015; 109:416.
22. MH Wiegand. Antidepressants for the treatment of insomnia: a
suitable approach? Drugs 2008; 68:2411.
23. WB Mendelson. A review of the evidence for the efficacy and
safety of trazodone in insomnia. J Clin Psychiatry 2005; 66:469.
24. ED Hermes et al. Use of second-generation antipsychotic
agents for sleep and sedation: a provider survey. Sleep. 2013;
36:597.
25. SL Anderson and JP Vande Griend. Quetiapine for insomnia: a review of the literature. Am J Health Syst Pharm 2014;
71:394.
26. CW Bazil. Gabapentin improves sleep in the presence of alcohol. J Clin Sleep Med 2005; 1:284.
27. I Hindmarch et al. A double-blind study in healthy volunteers to
assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep 2005; 28:187.
28. C Fox et al. Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc 2011; 59:1477.
29. AG Wade et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo
controlled trial on age and endogenous melatonin as predictors
of efficacy and safety. BMC Med 2010; 8:51.
30. DM Taibi et al. A systematic review of valerian as a sleep aid:

safe but not effective. Sleep Med Rev 2007; 11:209.
31. J Sarris and GJ Byrne. A systematic review of insomnia and
complementary medicine. Sleep Med Rev 2011; 15:99.
32. DK Cheuk et al. Acupuncture for insomnia. Cochrane Database
Syst Rev 2012; 9:CD005472.


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Liletta – A Third LevonorgestrelReleasing IUD

The FDA has approved Liletta, an intrauterine
device (IUD) that releases the synthetic progestin
levonorgestrel, for prevention of pregnancy for up to
3 years. The fourth IUD to be approved in the US, and
the third that releases levonorgestrel, Liletta is
comarketed by Actavis and Medicines360, a nonprofit
women's health pharmaceutical company. The wholesale cost of Liletta is similar to that of other IUDs (see
Table 1), but the manufacturer offers programs that
significantly reduce the cost for commercially-insured
patients and clinics serving low-income women.1
Pronunciation Key
Levonorgestrel: lee" voe nor jes' trel
Liletta: lye lett' uh

OTHER IUDs — IUDs provide convenient, long-term
contraception and a rapid return to fertility after removal.
ParaGard T 380A, a copper-containing IUD, Mirena,
which contains 52 mg of levonorgestrel, and Skyla,
which contains 13.5 mg of levonorgestrel, are FDAapproved for up to 10, 5, and 3 years of use, respectively.
Daily drug release rates decrease gradually from 20 mcg
to 10 mcg over 5 years with Mirena, and from 14 mcg to
5 mcg over 3 years with Skyla.2,3
THE NEW DEVICE — Liletta is the same size as Mirena
and slightly larger than Skyla. It has a 32x32mm T-shaped
plastic frame with a drug reservoir that, like Mirena,
contains 52 mg of levonorgestrel; the daily release rate of
levonorgestrel into the uterine cavity decreases gradually
from 18.6 mcg to 12.6 mcg over 3 years.
MECHANISM OF ACTION — Local progestogenic effects
that interfere with conception include thickening of
cervical mucus, inhibition of sperm capacitation and
survival, and changes in the endometrial lining.

July 6, 2015

A CLINICAL STUDY — Approval of Liletta was based on
a single-arm trial in 1751 women 16-45 years old. The
IUD was successfully inserted in 1714 women (97.9%).
The pregnancy rate for women aged 16-35 years,
calculated as the Pearl Index (number of pregnancies
per 100 woman-years), was the primary endpoint. The
Pearl Index for Liletta was 0.15 for the first year, and the
cumulative 3-year pregnancy rate was 0.55%. The trial

is ongoing and will evaluate the efficacy of Liletta over
7 years of use.4
ADVERSE EFFECTS — Adverse effects with Liletta
are similar to those with Mirena and Skyla.
Menstrual changes including spotting and irregular
or heavy bleeding are common, especially during
the first 3-6 months after insertion. Vaginal or
vulvovaginal infection, acne, headache or migraine,
nausea or vomiting, dyspareunia, depressed mood,
mood changes, and pain, discomfort, or tenderness
of the abdomen, breasts, or pelvis each occurred
in ≥5% of women in the pivotal trial. Symptomatic
ovarian cysts and pelvic infections, including endometritis, have been reported. Perforation can occur
during insertion of Liletta and may not be recognized
until a later date. Adverse events caused 12.3%
of women to discontinue use of Liletta within
3 years.4
Pregnancy that occurs with an IUD in place is likely
to be ectopic or result in miscarriage, sepsis, or premature labor and delivery. If an intrauterine pregnancy
occurs, the device should be removed.
INSERTION — Pregnancy must be ruled out before
inserting an IUD. Liletta can be inserted at any time
in women who are using an effective method of
contraception.5 A barrier method should be used for
7 days if Liletta is inserted after the seventh day of the

Table 1. Comparison of Intrauterine Devices (IUDs)
Failure
Rate with
Typical Use1

Advantages

Disadvantages

Cost2

ParaGard T 380A
10 years
(Teva Women's)
Liletta
3 years
(Actavis/Medicines360)
Mirena (Bayer)
5 years

0.8%

Nonhormonal

$739.00

0.15%3

Skyla (Bayer)

0.4%

Decreased menstrual bleeding and dysmenorrhea
Decreased menstrual bleeding and dysmenorrhea

Smaller T-frame and narrower
insertion tube

Irregular/heavy bleeding
and dysmenorrhea
Irregular bleeding in first 3-6
months; ovarian cysts
Irregular bleeding in first 3-6
months; ovarian cysts
Amenorrhea in only 6% of
users after one year

IUD

FDA-Approved
Maximum
Duration of Use

3 years

0.2%

625.004
811.005
650.005

1. Percent unintended pregnancy during first year of use. Adapted from J Trussel in RA Hatcher et al. Contraceptive Technology, 20th ed. revised, New York, NY: Ardent
Media, 2011.
2. Approximate WAC. Cost of insertion 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. June 5, 2015. Reprinted with permission by First Databank,

Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. DL Eisenberg et al. Contraception 2015; 92:10.
4. Liletta is available at a significantly lower cost to federally qualified clinics serving low-income women. Commercially-insured patients in the US may enroll in a savings
program that will subsidize up to $500 of the out-of-pocket cost of Liletta above $75 (www.lilettacard.com).
5. Patients without public or private insurance coverage for Mirena or Skyla who meet certain financial criteria may qualify to receive an IUD from the manufacturer at no cost
(www.archpatientassistance.org).

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The Medical Letter

menstrual cycle in a woman who was not previously
using hormonal or intrauterine contraception. Oral,
transdermal, or vaginal hormonal contraceptives
should be continued for 7 days after successful
placement, except when the IUD is inserted during
the hormone-free period of the previous method.
Patients switching from an injectable progestin
contraceptive to Liletta should use a barrier method
of contraception for 7 days after insertion if >13 weeks
have passed since the last injection. Liletta may be
inserted immediately after a first-trimester abortion
or miscarriage, but the prescribing information
recommends that it not be inserted after longer
pregnancies until at least 6 weeks have passed and
the uterus is fully involuted.

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July 6, 2015

Vol. 57 (1472)

®

Ryanodex – A New Dantrolene
Formulation for Malignant
Hyperthermia

The FDA has approved a new IV formulation of
dantrolene (Ryanodex – Eagle) for prevention and
treatment of malignant hyperthermia in adults and
children. The new formulation requires fewer vials,
less fluid volume, and less time for preparation and
administration than other available IV dantrolene
products (Dantrium, Revonto).
THE DISORDER — Malignant hyperthermia is a rare
hypercatabolic reaction characterized by uncontrolled
release of calcium ions in skeletal muscle cells that
most often occurs in genetically predisposed patients
who are exposed to certain inhaled anesthetics or the
muscle relaxant succinylcholine. Dantrolene, which
decreases calcium release from the sarcoplasmic
reticulum, has been a drug of choice for treatment of
malignant hyperthermia for many years.1
THE NEW FORMULATION — Ryanodex is available in
single-use vials containing 250 mg of dantrolene as a
lyophilized powder. Vials must be reconstituted with
5 mL of sterile water for injection (SWI; not bacteriostatic). Previously approved formulations contain only

CONCLUSION — Liletta, a new levonorgestrel-releasing
intrauterine device (IUD), offers effective contraception
for at least 3 years. It does not have any clinical
advantage over previously available hormonal IUDs, but
the manufacturer sponsors programs that may make it
more affordable than other IUDs for many women. ■
1. Liletta Patient Savings Program. Patient eligibility requirements. Terms and conditions available at: www.lilettacard.com.
Accessed June 25, 2015.
2. Choice of contraceptives. Treat Guidel Med Lett 2010; 8:89.
3. A new low-dose levonorgestrel-releasing IUD (Skyla). Med Lett
Drugs Ther 2013; 55:21.
4. DL Eisenberg et al. Three-year efficacy and safety of a new 52mg levonorgestrel-releasing intrauterine system. Contraception 2015; 92:10.
5. American College of Obstetricians and Gynecologists. ACOG
Practice Bulletin No 121: Long-acting reversible contraception:
implants and intrauterine devices. Obstet Gynecol 2011; 118:184.

20 mg of dantrolene per vial, and each vial requires
reconstitution with 60 mL of SWI. Ryanodex contains
less mannitol, which is used to increase urine output
in malignant hyperthermia, than Dantrium or Revonto.
Patients receiving the new formulation will require
supplementary doses of mannitol.1
ADVERSE EFFECTS — Dantrolene can cause flushing,
muscle weakness (including respiratory muscles),
dyspnea, dysphagia, somnolence, and dizziness. An
unpublished study in 61 healthy volunteers (summarized in the package insert) found the adverse effects
of Ryanodex to be generally similar to those of an older
IV dantrolene formulation, but immediate flushing,
dystonia, and dysphagia were more common and

declines in hand grip strength occurred more rapidly and
were more severe with Ryanodex.
CONCLUSION — Compared to other dantrolene
formulations used for treatment of malignant hyperthermia, Ryanodex is easier and faster to reconstitute
and requires less fluid volume for administration, but it
is more expensive, has a shorter shelf life, and requires
supplementary doses of mannitol. ■
1. Association of Surgical Technologists. Guideline statement
for malignant hyperthermia in the perioperative environment.
Revised January 2013. Available at: www.ast.org/AboutUs/
Guideline_Statements. Accessed June 25, 2015.

Table 1. Administration and Cost of IV Dantrolene
Formulation

Vials
Required1

Fluid Volume
Required1

Mannitol
Content/Vial

Shelf Life

Cost2
$798.00

Dantrium (Par)

9

540 mL

3000 mg

36 months

Revonto (US Worldmeds)

9

540 mL

3000 mg

36 months

630.00

Ryanodex (Eagle)

1

5 mL

125 mg

24 months

2300.00

1. Based on an initial 2.5 mg/kg dose for a 70-kg patient (www.ast.org/AboutUs/Guideline_Statements).
2. Approximate WAC for a 175-mg dose. 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. June 5, 2015.
Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.

100


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on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57 (Issue 1472)

▶

July 6, 2015

Eliglustat (Cerdelga) – An Oral
Drug for Gaucher Disease

The FDA has approved eliglustat (Cerdelga –

Genzyme), an oral glucosylceramide synthase inhibitor,
for treatment of adults with type 1 Gaucher disease.
Eliglustat is metabolized primarily by CYP2D6. Because
patients who are CYP2D6 ultra-rapid metabolizers may
not achieve therapeutic concentrations and a specific
dosage cannot be recommended for indeterminate
metabolizers, the FDA has approved the drug only
for patients who are extensive, intermediate, or poor
metabolizers of CYP2D6.
Pronunciation Key
Eliglustat: el” i gloo’ stat
Cerdelga: sir del’ guh

STANDARD TREATMENT — Patients with Gaucher
disease have a genetic deficiency of the lysosomal
enzyme glucocerebrosidase that leads to accumulation of glucosylceramide in the lysosomes
of reticuloendothelial cells, primarily in the liver,
spleen, and bone marrow. The most common
form of the disease (type 1) is characterized by
hepatosplenomegaly, hematologic disorders, and
bone involvement. The standard treatment for
Gaucher disease is enzyme replacement therapy with
taliglucerase (Elelyso),1 imiglucerase (Cerezyme),
or velaglucerase (Vpriv),2 which are all forms of the
enzyme glucocerebrosidase. These drugs are usually
administered as an IV infusion over 1-2 hours every
2 weeks. Substrate reduction therapy with miglustat
(Zavesca), an earlier glucosylceramide synthase
Table 1. Pharmacology
Class

Glucosylceramide synthase inhibitor

Formulation

84 mg capsules

Route

Oral

Mechanism of action

Inhibits glucosylceramide synthase

Tmax

1.5-2 hrs (EM); 3 hrs (PM)

Metabolism

Extensive; primarily by CYP2D6 and
to a lesser extent by CYP3A4

Elimination

Feces (51.4%); urine (41.8%)

Half-life (elimination)

~6.5 hrs (EM); ~8.9 hrs (PM)

EM = CYP2D6 extensive metabolizers; PM = CYP2D6 poor metabolizers

inhibitor, is an alternative for adults with mild to
moderate type 1 Gaucher disease who cannot receive
enzyme replacement therapy; its use has been limited
by severe side effects (diarrhea, weight loss, peripheral
neuropathy, tremor).
CLINICAL STUDIES — A double-blind trial (ENGAGE)
randomized 40 previously untreated patients ≥16
years old with type 1 Gaucher disease with baseline
splenomegaly and thrombocytopenia to eliglustat or
placebo for 9 months. The eliglustat group included 90%
extensive, 5% intermediate, and 5% ultra-rapid CYP2D6
metabolizers. At the end of the trial, mean spleen volume,
the primary endpoint, decreased by 27.8% in patients
taking eliglustat and increased by 2.3% in those taking
placebo. The mean hemoglobin level, mean liver volume,
and mean platelet count, all secondary endpoints, were
significantly improved in patients taking eliglustat
compared to those taking placebo.3
In a 1-year, open-label, noninferiority trial, 160
patients ≥18 years old who had been receiving
enzyme replacement therapy for at least 3 years
were randomized to oral eliglustat or IV enzyme
replacement therapy with imiglucerase. The eliglustat
group included 4% poor, 11% intermediate, 79%
extensive, and 4% ultra-rapid CYP2D6 metabolizers.
The composite primary endpoint was the percentage

of patients whose hemoglobin level, platelet count,
liver volume, and spleen volume remained stable
(≤1.5 g/dL decrease in hemoglobin, ≤25% decrease
in platelets, ≤20% increase in liver volume, and ≤25%
increase in spleen volume). After 12 months, eliglustat
was noninferior to imiglucerase in the percentage of
patients meeting the primary endpoint (85% vs 94%,
respectively).4
ADVERSE EFFECTS — Adverse effects occurring in
≥10% of patients in the two clinical trials included
fatigue, headache, nausea, diarrhea, back pain, pain in
the extremities, and upper abdominal pain.
DRUG INTERACTIONS — Eliglustat is a substrate
of CYP2D6 and CYP3A4. Because high serum concentrations of the drug can prolong the PR, QTc, and
e100

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The Medical Letter

July 6, 2015

Vol. 57 (1472)

®

Table 2. Recommendations for Use of Eliglustat with CYP Inhibitors
Concomitant Drug(s)

Recommended Eliglustat Dosage1
IM

EM

PM

Strong or moderate CYP2D6 inhibitor plus
strong or moderate CYP3A inhibitor

Contraindicated

Contraindicated

No dosage adjustment
needed

Strong or moderate CYP2D6 inhibitor

84 mg once/d

84 mg once/d

No dosage adjustment
needed

Strong CYP3A inhibitor

84 mg once/d

Contraindicated

Contraindicated

Moderate CYP3A inhibitor

84 mg once/d

Not recommended

Not recommended

Weak CYP3A inhibitor

No dosage adjustment
needed

No dosage adjustment
needed

Not recommended

EM = CYP2D6 extensive metabolizers; IM = CYP2D6 intermediate metabolizers; PM = CYP2D6 poor metabolizers
1. The usual dosage of eliglustat for CYP2D6 extensive and intermediate metabolizers is 84 mg twice/d. For CYP2D6 poor metabolizers, the usual dosage is
84 mg once/d.

QRS intervals, concurrent administration of inhibitors
of either enzyme5 must be avoided or approached with
caution; the FDA has made specific recommendations
for dosage adjustments depending on the patient’s

CYP2D6 metabolizer status (see Table 2).
Coadministration of eliglustat with strong CYP3A
inducers, such as rifampin, phenytoin, phenobarbital,
carbamazepine, and St. John’s wort, which markedly
decrease serum concentrations of the drug, is not
recommended for CYP2D6 extensive, intermediate, or
poor metabolizers.
Eliglustat is also an inhibitor of P-glycoprotein (P-gp)
and CYP2D6 and can increase serum concentrations
of drugs that are substrates of these pathways.
Patients taking digoxin, a P-gp substrate, should have
their digoxin serum concentrations measured before
starting treatment with eliglustat. The dose of digoxin
should be reduced by 30% if it is taken concurrently
with eliglustat and monitoring should be continued.
Eliglustat is not recommended for use in patients who
are also taking a class IA (e.g., procainamide) or a
class III (e.g., amiodarone) antiarrhythmic drug.
PREGNANCY — Eliglustat is classified as category
C (fetal anomalies in rats; no adequate studies in
women) for use during pregnancy.
DOSAGE, ADMINISTRATION, AND COST — CYP2D6
genotyping is required before dosage selection.
The recommended dosage of eliglustat is 84 mg
twice daily for extensive and intermediate CYP2D6
metabolizers and once daily for poor metabolizers.
The capsules should be swallowed whole, preferably

e101

with water, and should not be crushed, dissolved,
or opened. The drug is not recommended for use in
patients with pre-existing cardiac disease or long QT
syndrome.
The cost for 4 weeks' treatment with Cerdelga 84 mg
twice daily is $23,800. The cost of 4 weeks’ treatment
for a 70-kg patient at a dose of 60 units/kg is $34,892
with Cerezyme, $31,178 with Elelyso, and $30,294 with
Vpriv.6
CONCLUSION — Eliglustat (Cerdelga) offers an oral
alternative to IV enzyme replacement therapy for
treatment of type 1 Gaucher disease. It significantly
reduced spleen volume compared to placebo and
maintained blood counts and liver and spleen
volume in patients who switched from imiglucerase
(Cerezyme). ■
1. In brief: taliglucerase (Elelyso) for Gaucher disease. Med Lett
Drugs Ther 2012; 54:56.
2. In brief: velaglucerase (Vpriv) for Gaucher’s disease. Med Lett
Drugs Ther 2010; 52:36.
3. PK Mistry et al. Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized
clinical trial. JAMA 2015; 313:695.
4. TM Cox et al. Eliglustat compared with imiglucerase in patients
with Gaucher’s disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. Lancet 2015; 385:2355.
5. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
6. 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. June
5, 2015. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2015. www.fdbhealth.com/policies/drugpricing-policy.

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1.
Discuss the pharmacologic options available for treatment of insomnia and compare them based on their efficacy, dosage and administration, adverse effects, and
potential drug interactions.
2.
Review the efficacy and safety of the new levonorgestrel-releasing intrauterine device (Liletta) for prevention of pregnancy.
3.

Review the efficacy and safety of the new dantrolene formulation (Ryanodex) for treatment of malignant hyperthermia.
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Issue 1472 Questions

(Correspond to questions #1-10 in Comprehensive Exam #73, available January 2016)
Drugs for Insomnia

Liletta – A Third Levonorgestrel-Releasing IUD

1. Benzodiazepine receptor agonists:
a. are structural benzodiazepines
b. all decrease sleep latency
c. are all similar in their duration of action

d. all of the above

6. Which of the following IUDs does NOT release levonorgestrel?
a. Skyla
b. Paragard T 380A
c. Mirena
d. Liletta

2. Both benzodiazepines and benzodiazepine receptor agonists:
a. can impair next-day performance, including driving
b. can cause complex sleep-related behaviors
c. are classified as schedule IV controlled substances
d. all of the above

7. Compared to Skyla, Liletta:
a. is FDA-approved for a longer duration of use
b. has a smaller T-frame
c. releases a greater amount of active drug
d. all of the above

3. A 44-year-old man who has been taking Ambien for years read on
the internet that ramelteon (Rozerem) is a more natural way to treat
insomnia. He asks you if he should switch. You could tell him that:
a. ramelteon has been shown to be more effective than
Ambien in helping patients fall asleep sooner
b. ramelteon has been shown to be more effective than
Ambien in helping patients stay asleep longer
c. ramelteon has no potential for abuse and is not a
controlled substance
d. all of the above

8. A 26-year-old woman who had been taking an oral hormonal
contraceptive has Liletta inserted on day 10 of her menstrual
cycle. She asks whether she can stop taking the oral
contraceptive after insertion. You could tell her that she should:
a. continue taking the oral hormonal contraceptive for 7 days
after successful IUD placement
b. continue taking the oral hormonal contraceptive until the
estimated date of her next period
c. continue taking the oral hormonal contraceptive every
other day for 14 days until the IUD begins releasing
levonorgestrel at maximum levels
d. stop taking the oral hormonal contraceptive now because
the IUD begins releasing levonorgestrel immediately after
insertion

4. The most serious side effect of suvorexant (Belsomra) is:
a. next-day somnolence
b. angioedema
c. osteoporosis
d. hepatic injury
5. Used as sleep aids, first-generation antihistamines can cause:
a. impairment of performance, including driving
b. urinary retention
c. next-day sedation
d. all of the above

9. A possible advantage of Liletta over other hormonal IUDs is a
lower:
a. risk of venous thromboembolism

b. risk of ectopic pregnancy
c. risk of perforation
d. cost
Ryanodex – A New Dantrolene Formulation for Malignant Hyperthermia
10. Compared to other IV dantrolene formulations, Ryanodex:
a. requires less fluid volume for preparation
b. is more expensive
c. has a shorter shelf life
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-15-472-H01-P; Release: July 6, 2015, Expire: July 6, 2016
Comprehensive Exam 73: 0379-0000-16-073-H01-P; Release: January 2016, Expire: January 2017

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; 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
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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 nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
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