Nabiximols

Nabiximols (USAN,[1] trade name Sativex) is a specific Cannabis extract that was approved in 2010 as a botanical drug in the United Kingdom despite a lack of convincing evidence of effectiveness for spasticity reduction (see below). Nabiximols is sold as a mouth spray intended to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis; it was developed by the UK company GW Pharmaceuticals.[2][3] In 2019 it was proposed that following application of the spray, nabiximols is washed away from the oral mucosa by the saliva flow and ingested into the stomach, with subsequent absorption from the gastro-intestinal tract.[4][5] Nabiximols is a combination drug standardized in composition, formulation, and dose. Its principal active cannabinoid components are the cannabinoids: tetrahydrocannabinol (THC) and cannabidiol (CBD). Each spray delivers a dose of 2.7 mg THC and 2.5 mg CBD.

Nabiximols
Chemical structures of tetrahydrocannabinol (top) and cannabidiol (bottom)
Combination of
TetrahydrocannabinolCannabinoid
CannabidiolCannabinoid
Clinical data
Trade namesSativex
Routes of
administration		Oromucosal spray
ATC code
Legal status
Legal status
  • AU: S8 (Controlled drug)
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
UNII
CompTox Dashboard (EPA)
 NY (what is this?)  (verify)
Canadian packaging of a case of Sativex vials

In May 2003 GW Pharmaceuticals and Bayer entered into an exclusive marketing agreement for GW's cannabis-based medicinal extract product, to be marketed under the brand name Sativex. "Bayer has obtained exclusive rights to market Sativex in the UK. In addition, Bayer has the option for a limited period to negotiate the marketing rights in other countries in European Union and selected other countries around the world."

In April 2011, GW licensed to Novartis the rights to commercialise nabiximols in Asia (excluding China and Japan), Africa and the Middle East (excluding Israel).[6]

Availability

In June 2010, the Medicines and Healthcare products Regulatory Agency of the United Kingdom licensed nabiximols as a prescription-only medicine for the treatment of spasticity due to multiple sclerosis. This regulatory authorization represents the world's first full regulatory approval for the medicine. The spray is being marketed in the UK by Bayer Schering Pharma. Many people with MS cannot receive nabiximols due to local National Health Service (NHS) resistance to its funding;[7][8] but, in August 2014, the NHS in Wales agreed to fund Sativex for people with multiple sclerosis.[9]

Nabiximols was also approved in Spain for MS spasticity in the second half of 2010 and was launched in that country in March 2011. It was approved in the Czech Republic in April 2011, in Germany in May 2011, in Denmark in June 2011 and in Sweden in January 2012 to people with MS who have not responded adequately to other medication for spasticity.[10] It has also been recommended for approval in Italy and Austria with formal approvals expected in these countries during 2011. In Spain and other European markets (excluding the UK), nabiximols will be marketed by Almirall.

In Canada, nabiximols has been approved by Health Canada for the treatment of MS spasticity. It has also received a licence with conditions (NOC/c) for two additional uses: as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis,[11] and also for pain due to cancer.[12][13]

Nabiximols is available in a number of countries as an unlicensed medicine, which enables doctors to prescribe the product to people who they consider may benefit. The product has been exported from the UK to a total of 28 countries to date.

In February 2007, GW and Otsuka Pharmaceutical announced an exclusive agreement for Otsuka to develop and market the drug in the United States. The first large scale US Phase IIb trial, Spray Trial, for people with cancer reported positive results in March 2010. GW and Otsuka have now commenced the Phase III development of nabiximols in cancer pain.

In December 2012, Sativex was approved in Poland.[14]

In 2013, France legalized the use of cannabinoids in medicine, Sativex is the first one to be sold under prescription.[15] Nevertheless, as of June 2016 this drug had still not actually been sold in pharmacies there.[16]

Effectiveness

Of the two preliminary Phase III studies investigating the treatment of people with MS, one showed a reduction of spasticity of 1.2 points on the 0–10 points rating scale (versus 0.6 points under placebo), the other showed a reduction of 1.0 versus 0.8 points. Only the first study reached statistical significance. The Phase III approval study consisted of a run-in phase where the response of individuals to the drug was determined. The responders (42% of subjects) showed a significant effect in the second, placebo controlled, phase of the trial.[17] A 2009 meta-analysis of six studies found large variations of effectiveness, with a – statistically non-significant – trend towards a reduction of spasticity.[18] A systematic review in 2014 by the American Academy of Neurology found that nabiximols was 'probably effective' for spasticity, pain, and urinary dysfunction, but wasn't supported for tremor.[19]

Nabiximols has also been studied for cancer pain resistant to opioids. Adjuvant use was safe and effective in 3 trials for cancer pain,[20][21][22] however the drug failed to meet its primary endpoint for this purpose in its first Phase III trial.[23]

Side effects

In early clinical trials, nabiximols has generally been well tolerated.[24][25][26] The most common adverse effects in Phase III trials were dizziness (25%), drowsiness (8%) and disorientation (4%); 12% of subjects stopped taking the drug because of the side effects. No investigations regarding the potential for dependence are available, but such a potential is unlikely considering the pharmacological properties of the two components.[17]

Licensing

GW Pharmaceuticals were issued a unique license to cultivate cannabis for the manufacturing of Sativex in the UK, granting them the sole legal right to research in aerosolized cannabis derived therapeutics, which in April 2013 became commercially viable when the UK Government scheduled the Sativex formulation to part IV of the UK Drugs Act.[27]

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See also

References
  1. United States Adopted Names Council: Statement on a non-proprietary name
  2. UK Medicines Online Nabiximols Page accessed Feb 3, 2016
  3. Multiple Sclerosis Trust. October 2014 Sativex (nabiximols) - factsheet
  4. Itin, Constantin; Barasch, Dinorah; Domb, Abraham; Hoffman, Amnon (2020). "Prolonged oral transmucosal delivery of highly lipophilic drug cannabidiol". Int J Pharm. 581: 119276. doi:10.1016/j.ijpharm.2020.119276. PMID 32243971.
  5. Itin, Constantin; Domb, Abraham; Hoffman, Amnon (2019). "A meta-opinion: cannabinoids delivered to oral mucosa by a spray for systemic absorption are rather ingested into gastro-intestinal tract: the influences of fed / fasting states". Expert Opin Drug Deliv. 16: 1031–1035. doi:10.1080/17425247.2019.1653852. PMID 31393180.
  6. "GW signs Sativex cannabis-based drug deal with Novartis". The Telegraph. 11 April 2011. Retrieved 12 July 2012.
  7. Ryan, Siobhan (4 June 2011). "Sussex MS sufferers call for drug funding". Argus (Sussex, UK). Retrieved 8 June 2011.
  8. "Sativex rejected by healthcare provider". Lincolnshire. 20 June 2011. Archived from the original on 22 June 2011. Retrieved 20 June 2011.
  9. "Wales NHS to offer MS cannabis drug Sativex". 15 August 2014. Retrieved 18 August 2014.
  10. Sativex (nabiximols), Swedish Medical Products Agency Archived 2014-01-01 at the Wayback Machine
  11. GW Pharmaceuticals. "Multiple Sclerosis Archived 2011-08-11 at the Wayback Machine". Accessed 24 July 2011.
  12. GW Pharmaceuticals. "Cancer Pain Archived 2011-09-27 at the Wayback Machine" Accessed 24 July 2011.
  13. "Sativex - Investigational Cannabis-Based Treatment for Pain and Multiple Sclerosis Drug Development Technology". www.drugdevelopment-technology.com. Retrieved 2008-08-08.
  14. Olszewska, Dorota; Kidawa Michał. "Sativex - lek z marihuany". Krajowe Biuro Do Spraw Przeciwdziałania Narkomanii.
  15. "France Legalizes Marijuana-Based Drug To Treat Multiple Sclerosis". HunffingtonPost. Retrieved 4 June 2015.
  16. "Cannabis thérapeutique : pourquoi le Sativex n'est-il toujours pas vendu en France ?". Sciences et Avenir. Archived from the original on 2016-05-10. Retrieved 6 June 2016.
  17. Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2011/2012 (in German)
  18. Lakhan, Shaheen E; Rowland, Marie (2009). "Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review". BMC Neurol. 9: 59. doi:10.1186/1471-2377-9-59. PMC 2793241. PMID 19961570.
  19. Koppel, Barbara S.; Brust, John C. M.; Fife, Terry; Bronstein, Jeff; Youssof, Sarah; Gronseth, Gary; Gloss, David (2014-04-29). "Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology". Neurology. 82 (17): 1556–1563. doi:10.1212/WNL.0000000000000363. ISSN 1526-632X. PMC 4011465. PMID 24778283.
  20. Portenoy, Russell K.; Ganae-Motan, Elena Doina; Allende, Silvia; Yanagihara, Ronald; Shaiova, Lauren; Weinstein, Sharon; McQuade, Robert; Wright, Stephen; Fallon, Marie T. (2012-05-01). "Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial". The Journal of Pain. 13 (5): 438–449. doi:10.1016/j.jpain.2012.01.003. ISSN 1528-8447. PMID 22483680.
  21. Lynch, Mary E.; Cesar-Rittenberg, Paula; Hohmann, Andrea G. (2014-01-01). "A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain". Journal of Pain and Symptom Management. 47 (1): 166–173. doi:10.1016/j.jpainsymman.2013.02.018. ISSN 1873-6513. PMID 23742737.
  22. Johnson, Jeremy R.; Lossignol, Dominique; Burnell-Nugent, Mary; Fallon, Marie T. (2013-08-01). "An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics". Journal of Pain and Symptom Management. 46 (2): 207–218. doi:10.1016/j.jpainsymman.2012.07.014. ISSN 1873-6513. PMID 23141881.
  23. "Last stage failure for Otsuka and GW Cancer Pain Drug". Pharmafile. 2015-09-01. Retrieved 2016-12-07.
  24. Wade D, Makela P, Robson P, House H, Bateman C (2004). "Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients". Mult Scler. 10 (4): 434–41. doi:10.1191/1352458504ms1082oa. PMID 15327042.
  25. Wade D, Makela P, House H, Bateman C, Robson P (2006). "Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis". Mult Scler. 12 (5): 639–45. doi:10.1177/1352458505070618. PMID 17086911.
  26. Wade D, Robson P, House H, Makela P, Aram J (2003). "A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms". Clin Rehabil. 17 (1): 21–9. doi:10.1191/0269215503cr581oa. PMID 12617376.
  27. "Archived copy". Archived from the original on 2013-10-29. Retrieved 2013-11-27.CS1 maint: archived copy as title (link)
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