Rozerem (Ramelteon)
By Jack Keady
1. Back Ground
Insomnia is a neurological disorder that causes
difficulty falling asleep, staying a sleep, or negatively effects the overall
quality of a person’s sleep. Ramelteon, which is structurally based on the
naturally occurring melatonin, is a FDA approved drug that helps people
diagnosed with insomnia.1 Melatonin, which is produced by the pineal
gland, reaches peak synthesis and release at night, which helps lead to sleep.2
Melatonin has been explored as a sleep aid, but its half-life is very low,
due to how quickly it is broken down in the liver, which means the drug peaks
only after an hour to 90 minutes depending on dose.2 The
bioavailability, or amount of the drug that enters circulation, of melatonin
also varied widely for a single dose.2 The inconsistencies of pure
melatonin lead to a desire for a more stable melatonin derivative to help
people affected by insomnia.
2. Synthesis and Drug Target
Ramelteon, which’s brand name is Rozerem, was synthesized
in a series of experiments conducted by the Pharmaceutical Research Division of
Takeda Chemical Industries. The experiments were trying to synthesize a
compound with strong affinity for the MT1 receptor, and acted as an
antagonist for this receptor.3 MT1 is one of the
receptors melatonin binds to decreases wakefulness.3 The compound
also needed to show no affinity to other receptors, such as the MT3,
because at the time of the study it was unknown what purpose the MT3
receptor served.3
Multiple compounds were synthesized from preexisting
synthetic compounds, which were then tested for MT1 affinity in
Chinese Hamster Ovary cells expressing the desired receptor, MT3
affinity in Syrian hamster brains and peripheral organs, and overall efficacy
in freely moving cats.3 It was found that the compound (S)-(-)-22b
was the most potent and selective antagonist to the MT1 receptor,
which would later become known as Ramelton.3 While the drug was
designed to be selective for the MT1 receptor, it has also shown a
selectivity for the MT2 receptor in the brain.3
3. FDA Approval
The FDA approved Takeda Pharmaceutical’s new drug
application for an 8mg Rozerem pill on 07/22/2005.4 Rozerem originally
was granted an indication for the treatment of insomnia that is described as
difficulty with the onset of sleep.5 Clinical trials were conducted
for both chronic and transient insomnia.6 A group of 405 healthy
18-64 year olds with chronic insomnia underwent a double-blind placebo test
where the efficacy of 8-mg and 16-mg dozes of Rozerem were tested against a placebo.
The latency to persistent sleep was measured with polysomnography, and it was
found that 8-mg was efficacious, but 16-mg was not.6 A similar study
was conducted with 100 people, 65 years and older who have chronic insomnia,
with 4-mg and 8-mg of Rozerem, and both dozes were efficacious.6 For
transient insomnia 289 healthy adults between 18-64 underwent a double blind,
randomized placebo test, of 8-mg and 16-mg doses of Rozerem. The 8-mg dose was
found efficacious using polysomnography.6 All tests were conducted
in the United States.6
3.1 Adverse Reactions
There are a number of adverse reactions that were reported
during the clinical study. People reported: headaches, somnolence, fatigue, dizziness,
nausea, worsening insomnia, upper respiratory tract infection, diarrhea,
myalgia, depression, dysgeusia, anthralgia, influenza, and decreased blood
cholesterol.5 These are listed in order of prevalence with headache
being the most at 7%.5
Elderly patients could also be at an increased risk for
adverse reactions. A study found that elderly patients experienced a higher
maximum concentration, a longer half-life, and lower clearance of the drug.7
While this didn’t have any major pharmacokinetic implications, the increased
concentration and lower clearance could lead to prolonged and adverse effects
in the elderly.7
3.1 Food
Rozerem has a
low bioavailability, which can be significantly decreased if it is taken with
food.7 The maximum concentration is lowered and the time to reach
that concentration is increased if taken after eating a high fat meal.7
3.2 Overdose and Dependency
In the animal studies conducted there was
no signs of the development of dependency. Primates did not self-administer the
drug given the opportunity.5 There were no physical signs of
overdose when up to 160 mg, 20 times the daily dose, was administered during
animal trials.5
3.3 Drug interactions
CYP1A2 is the major enzyme in
the metabolism of Rozerem, with CYP2C and CYP3A4 also contribute to the
metabolism.6 Rozerem should not be taken with medication that
inhibits these enzymes, such as fluvoxamine, roframpin, ketoconazole, and fluconazole.6
There were no recorded significant clinical interactions between alcohol
and Rozerem, but alcohol inhibits deep REM sleep, which is the indication of
Rozerem.6 For this reason Rozerem should not be taken with alcohol.
4. Takeda
Pharmaceutical Company Limited
Takeda Pharmaceutical Company
Limited is headquartered in Japan and in 2017 brought in 1711.1 Bn ¥, about $16
Bn USD.8 Rozerem brought in 17.6 Bn ¥, about $160 million USD, which
is approximately 1% of total revenue.8 Takeda is the sole producer
of Ramelteon, the active agent in Rozerem.9 Takeda received the US
patent in 2000, and was rewarded the rights to the drug and multiple methods of
using a MT1 agonist as a treatment for insomnia, circadian rhythm
regulation, time zone change syndrome, and others.9
5. Market
Insomnia has a large economic
impact in the United States. It is estimated that 22.1% of adults suffer from
chronic insomnia according to the DSM-IV definition.10 This large
population costs an aggregate $100 billion USD a year in both direct costs of
treatment and indirect costs such as lost productivity.10 Currently Rozerem
is sold at an average of $15.11 a pill, which is competitive with other popular
sleep aids such as Ambien.11 Rozerem has
a major advantage to many other insomnia medications in the market place.
Because Rozerem targets the MT1
receptor, and not the GABA receptors there is a significantly lower risk of
abuse than benzodiazepine sleep aids.7 The only other MT1
receptor agonist in the market now is Hetlioz (tasimelteon), which is mostly
prescribed for people with Non-24-hour sleep-wake disorder (Non-24). [12][13]
While Hetlioz has the same mechanism of action, the medical indication for
Hetioz is Non-24, which predominately effects blind individuals and doesn’t
represent a large portion of the insomnia medication market. [13][14]
Despite the large insomnia market, Takeda is not
emphasizing Rozerem as an area of growth.8 As mentioned before Rozerem
generated 17.6 Bn ¥ of revenue in the 2017 fiscal year, which is a 0.7 %
decrease compared to 2016.8 While not explicitly stated in the financial
report, Takeda is most likely moving away from Rozerem because their patent
expire June 2019.15 Two companies, Dr. Reddy’s Lab SA and ACTAVIS
Labs FL INC, have generic forms of Ramelteon approved by the FDA, which leaves
little reason for Takeda to emphasize Rozerem as a revenue stream in the future.[16][17]
References
1. Buysse D, Bate
G, Kirkpatrick P. Ramelteon. Nature Reviews Drug Discovery. 2005,4:881-882.
2. Brzezinski A.
Melatonin in Humans. The New England Journal of Medicine. 1997;336:186-195.
doi: 10.1056/NEJM199701163360306
3. Uchikawa O,
Fukatsu K, Tokunoh R, et al. Synthesis of Tricyclic Indan Derivatives as
Melatonin Receptor Agonists. Journal of Medicinal Chemistry. 2002;45(19):4222-4239.
doi: 10.1021/jm0201159
4. Department of Heath & Human Services. (2005).
NDA 21-782 Approval. Rockville, MD: Food and Drug Administration
5. Center for Drug Evaluation and Research. (2005).
Application Number: 21-782, Approved Labeling. Food and Drug Administration
6. Center for Drug Evaluation and Research. (2005).
Application Number: 21-782, Medical Review. Food and Drug Administration
7. Schroeck JL,
Ford J, Conway EL, et al. Review of Safety and Efficacy of Sleep Medicines in
Older Adults. Clinical Therapeutics. 2016; 38(11):2340-2372. doi: https://doi.org/10.1016/j.clinthera.2016.09.010
8. Weber C, Sraoukos C, Iwasaki
M, Plump A. Strategic Focus & Superior Execution FY2017 Annual Results.
Takeda Pharmaceutical Company Limited. 2018. Retrieved from:
https://www.takeda.com/siteassets/system/investors/report/quarterlyannouncements/fy2017/fy2017-full-year-results/qr2017_q4_p01_en.pdf
9. United States Patent. (2000). Patent number:
6,034,239
10. Wickwire
E, Shaya F, Scharf S. Health economics of insomnia treatments: The return on
investment for a good night's sleep. Sleep Medicine Reviews. 2015, 30:72-82.
doi: http://dx.doi.org/10.1016/j.smrv.2015.11.004
11. Information
for Vermont Prescribers of Prescription Drugs: (Long Form). Takeda Pharmaceutical
Company Limited. 2018
12. Food
and Drug Administration Established
Pharmacologic Class (EPC) Text Phrase. FDA. 2016. Retrieved from:
13. Hetlioz Full
Prescribing Information. FDA, 2014. Refernce ID: 3672439
14. American Academy of Sleep
Medicine. ICSD - International classification of sleep disorders, revised:
Diagnostic and coding manual. American Academy of Sleep Medicine, 2001.
15. Food and Drug Administration. (2016). Orange Book: Approved Drug Products with Therapeutic Equivalence
Evaluations, Patent and Exclusivity for: N021782. Retrieved from: https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&Appl_No=021782&Appl_type=N
16. Food and Drug Administration. (2015) Drugs@FDA:
FDA Approved Drug Products. Retrieved from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=091610
17. Food and Drug Administration. (2013) Drugs@FDA:
FDA Approved Drug Products. Retrieved from:
WHat is the size of the market (in Dollars)? Are there any recent new patents for combination drugs or new formulations? Any warning letters for current manufacturers?
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