Asenapine

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Structural formula
Structure of the asenapine
1: 1 mixture of (3a R , 12b R ) isomer (left) and (3a S , 12b S ) isomer (right)
General
Non-proprietary name Asenapine
other names
  • (3a S , 12b S ) - rel -5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H -dibenz [2,3: 6.7] oxepino [4,5- c ] pyrrole ( IUPAC )
  • (3a S *, 12b S *) -5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H -dibenz [2,3: 6.7] oxepino [4,5- c ] pyrrole
Molecular formula C 17 H 16 ClNO
External identifiers / databases
CAS number 65576-45-6
EC number 265-829-4
ECHA InfoCard 100,059,828
PubChem 9903970
ChemSpider 8079624
Wikidata Q416545
Drug information
ATC code

N05 AH05

Drug class

Atypical neuroleptic

Mechanism of action

u. a. Serotonin and dopamine antagonists

properties
Molar mass 285.77 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
06 - Toxic or very toxic 09 - Dangerous for the environment

danger

H and P phrases H: 301-315-319-335-400
P: 261-273-301 + 310-305 + 351 + 338
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Asenapine is a drug from the group of atypical neuroleptics , which u. a. Used in the treatment of moderate to severe manic phases in patients with bipolar disorder .

Clinical information

application areas

In the European Union (EU) asenapine is approved for the treatment of adults with bipolar disorder during moderate to severe manic episodes. In the USA, asenapine is also approved for the treatment of schizophrenia. In Switzerland , asenapine (trade name Sycrest) was granted on July 19, 2012 by Swissmedic .

Asenapine is administered sublingually: the sublingual tablet is placed under the tongue, where it dissolves completely after a few seconds and the active ingredient is absorbed through the mouth.

effectiveness

Clinical studies showed that asenapine reduced manic symptoms in one study over 3 weeks. This effect persisted for 12 weeks in the manic episode.

The effectiveness of asenapine is comparable to the effectiveness of olanzapine after 12 weeks. The sustained effects of asenapine were shown for a full year. In the approval studies, asenapine was less effective than olanzapine in the approved indication, but the safety profile was not improved. The Drugs Commission of the German Medical Association (AkdÄ) does not believe there is any therapeutic advantage. Due to insufficient effectiveness, asenapine was not approved for the schizophrenia indication, which was also applied for .

In patients who were partially unresponsive to monotherapy with lithium or valproic acid at therapeutic serum levels, the additional use of asenapine as adjunctive therapy to monotherapy with lithium or valproate resulted in superior efficacy.

Asenapine works very quickly; in clinical studies there was a measurable effect from day 2 in patients with symptoms of mania.

unwanted effects

Very common side effects are drowsiness and anxiety; Increased appetite and weight gain, fatigue, dulling, upset, urge to move, involuntary movements, Parkinson's-like disorders, dizziness, taste disorders, insensitivity to the mouth, elevated liver values ​​( GPT value) and muscle stiffness are also common. With the exception of mouth numbness, these side effects are well known for neuroleptics. The mouth numbness is related to the local anesthetic properties of asenapine, which is considered to be of little relevance. Compared to olanzapine, asenapine causes less pronounced weight gain and changes in metabolic parameters.

Studies

ARES and APOLLO

The monotherapy studies consisted of two studies each lasting 3 weeks (ARES-3A and ARES-3B). These studies compared the effectiveness of asenapine with placebo treatment in patients with acute manic or mixed episodes of bipolar I disorder.

After 3 weeks of therapy, the patients were able to take part in ARES-9, a 9-week follow-up study in which the patients received either asenapine twice a day in a dose of 5 mg or 10 mg or olanzapine once a day in one dose received from 5 to 20 mg. In contrast to the ARES-3A and ARES-3B studies, ARES-9 tested the non-inferiority of maintenance efficacy of asenapine versus olanzapine for up to 12 weeks.

Finally, patients who completed ARES-9 were able to participate in the 40-week ARES-40 extension study. ARES-40 was designed to verify the long-term safety of asenapine for up to 52 weeks.

The combination therapy studies included a 12-week treatment period in which asenapine plus lithium or valproic acid was compared with a placebo plus lithium or valproic acid. The aim was to treat patients with acute manic or mixed episodes in bipolar I disorder who did not fully respond to treatment with lithium or valproic acid alone. Patients who completed the APOLLO-12 study were then able to participate in the 40-week extension study APOLLO-40. The primary study objective of APOLLO-40 was to characterize the long-term safety and tolerability of asenapine for a period of up to 52 weeks.

Phase III (manic phases of bipolar disorder)

In particular, two randomized three-week short-term studies with asenapine are being assessed by the EMA. You are placebo-controlled and also have an olanzapine arm (A7501004 / NCT00159744 and A7501005 / NCT00159796). In addition, asenapine is being tested in a randomized 12-week study in addition to lithium or valproate (A7501008 / NCT00145470) and examined in several follow-up observations (nine weeks: A7501006 / NCT00143182, 40 weeks: A7501009 / NCT00145509, 40 weeks: A7501007 / NCT00159783)

In the two main short-term studies, patients with a DSM IV diagnosis of a manic or mixed phase of a bipolar I disorder will be included, who are included in a standard test that can be used to measure manic symptoms, the Young Mania Rating Scale (YMRS), at least Score 20 points. The YMRS checks 11 items, a maximum of 60 points can be achieved. The exclusion criteria of the studies include taking lithium, valproate or carbamazepine until shortly before the start of the study. Asenapine is tested in a dose of 5 to 10 mg twice a day, and olanzapine in a daily dose of 5 to 20 mg. The effectiveness is primarily examined by means of the change in the total point value of the YMRS. In both short-term studies, asenapine reduced the YMRS score in a statistically significant manner when compared with placebo (asenapine: -11.5; -10.8 placebo: -7.8; -5.5 olanzapine: -14.6; -12.6).

Pharmacological properties

Mechanism of action

The exact mechanism of action, as of other drugs effective in bipolar disorder, is not fully understood. Asenapine acts on many different receptors in the brain. An antagonistic effect at D 2 and 5-HT 2A receptors seems to be in the foreground.

Absorption and distribution in the body

Asenapine has only a very low bioavailability of less than 2% after oral ingestion and is therefore available as a sublingual tablet. The sublingual tablet is placed under the tongue until it is completely dissolved. The tablet dissolves in saliva within seconds.

chemistry

Chemical structure and isomerism

Asenapine is a tetracyclic chemical compound; it consists of a single, seven-membered oxepane ring to which two benzene - and a pyrrolidine ring fused are. One of the two benzene rings has a chlorine atom. The structure of asenapine is different from the structures of other atypical antipsychotics.

5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H -dibenz [2,3: 6,7] oxepino [4,5- c ] pyrrole contains two different stereocenters on the pyrrolidine ring. There are consequently four stereoisomers of this substance: the (3a R , 12b R ) form, the mirror image (3a S , 12b S ) form, the (3a R , 12b S ) form and the (3a S , 12b R )-Shape. The drug asenapine is a 1: 1 mixture ( racemate ) of the (3a R , 12b R ) form and the (3a S , 12b S ) form.

synthesis

Asenapine is produced from a diphenyl ether in a multistage synthesis according to van der Burg .

Commercial preparations

Asenapine was developed by Organon . Asenapine-containing finished medicinal products are sold in the EU under the trade name Sycrest by Lundbeck and in the USA under the name Saphris by MSD .

Manufacturers are Organon and Schering-Plow .

See also

Web links

Individual evidence

  1. ↑ a b data sheet Asenapine maleate from Sigma-Aldrich , accessed on March 21, 2011 ( PDF ).
  2. ↑ a b c EMA: Summary of Product Characteristics Asenapine / Sycrest 2010, (PDF; 330 kB)
  3. ↑ FDA: FDA Approves Saphris to Treat Schizophrenia and Bipolar Disorder. Retrieved November 7, 2012.
  4. ↑ swissmedic.ch: Sycrest®, Sublingualtabletten (Asenapinum) ( Memento from March 4, 2016 in the Internet Archive ), accessed on November 7, 2012.
  5. ↑ a b c Mc Intyre RS et al .: Asenapine versus olanzapine in acute mania: a double-blind extension study . In: Bipolar Disorders 2009: 11: 815-826 PMID 19832806 .
  6. ↑ a b c McIntyre RS et al .: J. Affect. Disord. 2010; 126: 358-65, PMID 20537396 .
  7. ↑ a b Medicines Commission of the German Medical Association (AkdÄ): New Medicines: Sycrest® (Asenapine) (PDF; 297 kB) from January 12, 2011.
  8. ↑ EMA: EPAR on Asenapine / Sycrest 2010, p. 62 ff, p. 69. (PDF; 1.2 MB)
  9. ^ McIntyre RS, Pharmacology and efficacy of asenapine for manic and mixed states in adults with bipolar disorder, Expert Rev. Neurother. 10 (5), 645-649 (2010)
  10. ↑ Brigitte M. Gensthaler, Sven Siebenand: New on the market: asenapine, bazedoxifene, bilastine, conestat alfa and vernakalant. Pharmaceutical newspaper , edition 01/2011.
  11. ↑ Sycrest: Summary of Product Characteristics , August 2016.
  12. ↑ EMA: EPAR on Asenapine / Sycrest 2010, p. 77, (PDF; 1.2 MB)
  13. ↑ EMA: EPAR on Asenapine / Sycrest 2010, p. 85, (PDF; 1.2 MB)
  14. ^ A b McIntyre RS et al .: Bipolar Disord. 2009; 11: 673-86, PMID 19839993 .
  15. ↑ a b McIntyre RS et al .: J. Affect. Disord. 2010; 122: 27-38, PMID 20096936 .
  16. ↑ Calabrese JR, Stet L, Kothari H et al. American Psychiatric Association (APA) 62nd Congress "Institute on Psychiatric Services". Poster. October 2010, Boston, MA, USA.
  17. ^ The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; P. 137, ISBN 978-0-911910-00-1 .
  18. ^ Willem J. van der Burg: Tetracyclic Derivaties and Pharmaceutical Compositions of Matter. US Patent No. 4,415,434 dated March 20, 1979.