Nabiximols

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Nabiximols
INN: Tetrahydrocannabinol Botanical Drug Substance [1]
THC.svg
Cannabidiol.svg
Chemical structures of tetrahydrocannabinol (top) and cannabidiol (bottom)
Combination of
Tetrahydrocannabinol Cannabinoid
Cannabidiol Cannabinoid
Clinical data
Trade names Sativex
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)
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Canadian packaging of a case of Sativex vials Sativex - Canadian box front.jpg
Canadian packaging of a case of Sativex vials

Nabiximols (USAN, [2] trade name Sativex) is a specific Cannabis extract that was approved in 2010 as a botanical drug in the United Kingdom. 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. [3] [4] 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. [5] [6] Nabiximols is a combination drug standardized in composition, formulation, and dose. Its principal active components are the cannabinoids: tetrahydrocannabinol (THC) and cannabidiol (CBD). Each spray delivers a dose of 2.7 mg THC and 2.5 mg CBD.

Contents

In 2003, GW Pharmaceuticals partnered with Bayer to market the drug under the brand name Sativex. In 2011, GW licensed the rights to commercialise nabiximols to Novartis for Asia (excluding China and Japan), Africa and the Middle East (excluding Israel). [7]

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; [8] [9] but, in August 2014, the NHS in Wales agreed to fund Sativex for people with multiple sclerosis. [10]

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. [11] 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, [12] and also for pain due to cancer. [13] [14]

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. [15]

In 2013, France legalized the use of cannabinoids in medicine, Sativex is the first one to be sold under prescription. [16] Nevertheless, as of June 2016 this drug had still not actually been sold in pharmacies there. [17]

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. [18] A 2009 meta-analysis of six studies found large variations of effectiveness, with a – statistically non-significant – trend towards a reduction of spasticity. [19] 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. [20] A 2021 study, however, showed “clinically relevant symptomatic results” [21]

Nabiximols has also been studied for cancer pain resistant to opioids. While adjuvant use of nabiximols was safe in 3 trials for cancer pain, [22] [23] [24] data regarding efficacy were mixed, and the drug failed to meet its primary endpoint for this purpose in its first Phase III trial. [25]

Side effects

In early clinical trials, nabiximols has generally been well tolerated. [26] [27] [28] 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. [18] A systematic review has shown no evidence is available about the negative effect of Nabiximols on cognition ability [29]

Licensing

GW Pharmaceuticals were issued a license to cultivate cannabis for the manufacturing of Sativex in the United Kingdom (UK), granting them the sole legal right to research in aerosolized cannabis derived therapeutics, which became commercially viable in April 2013, when the UK Government scheduled the Sativex formulation to part IV of the UK Drugs Act. [30]

See also

Related Research Articles

<span class="mw-page-title-main">Multiple sclerosis</span> Disease that damages the myelin sheaths around nerves

Multiple sclerosis (MS) is an autoimmune disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, vision loss, eye pain, muscle weakness, and loss of sensation or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks or building up over time. In the relapsing forms of MS, between attacks, symptoms may disappear completely, although some permanent neurological problems often remain, especially as the disease advances. In the progressive forms of MS, bodily function slowly deteriorates and disability worsens once symptoms manifest and will steadily continue to do so if the disease is left untreated.

<span class="mw-page-title-main">Tetrahydrocannabinol</span> Chemical compound

Tetrahydrocannabinol (THC) is a terpenoid found in cannabis. It is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Its chemical formula C21H30O2 includes compounds, the term THC usually refers to the delta-9-THC isomer with chemical name (−)-trans-Δ9-tetrahydrocannabinol. It is a colorless oil.

<span class="mw-page-title-main">Medical cannabis</span> Marijuana used medicinally

Medical cannabis, or medical marijuana (MMJ), is cannabis and cannabinoids that are prescribed by physicians for their patients. The use of cannabis as medicine has not been rigorously tested due to production and governmental restrictions, resulting in limited clinical research to define the safety and efficacy of using cannabis to treat diseases.

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.

<span class="mw-page-title-main">Interferon beta-1a</span> Cytokine in the interferon family

Interferon beta-1a is a cytokine in the interferon family used to treat multiple sclerosis (MS). It is produced by mammalian cells, while interferon beta-1b is produced in modified E. coli. Some research indicates that interferon injections may result in an 18–38% reduction in the rate of MS relapses.

<span class="mw-page-title-main">Cannabidiol</span> Phytocannabinoid discovered in 1940

Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. As of 2022, clinical research on CBD included studies related to the treatment of anxiety, addiction, psychosis, movement disorders, and pain, but there is insufficient high-quality evidence that cannabidiol is effective for these conditions. CBD is also sold as a herbal dietary supplement promoted with unproven claims of particular therapeutic effects.

<span class="mw-page-title-main">Tetrahydrocannabivarin</span> Homologue of tetrahydrocannabinol

Tetrahydrocannabivarin is a homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of pentyl (5-carbon), making it non-psychoactive in lower doses. It has been shown to exhibit neuroprotective activity, appetite suppression, glycemic control and reduced side effects compared to THC, making it a potential treatment for management of obesity and diabetes. THCV was studied by Roger Adams as early as 1942.

<span class="mw-page-title-main">Nabilone</span> Synthetic cannabinoid

Nabilone, sold under the brand name Cesamet among others, is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It mimics tetrahydrocannabinol (THC), the primary psychoactive compound found naturally occurring in Cannabis.

<span class="mw-page-title-main">Levonantradol</span> Chemical compound

Levonantradol (CP 50,556-1) is a synthetic cannabinoid analog of dronabinol (Marinol) developed by Pfizer in the 1980s. It is around 30 times more potent than THC, and exhibits antiemetic and analgesic effects via activation of CB1 and CB2 cannabinoid receptors. Levonantradol is not currently used in medicine as dronabinol or nabilone are felt to be more useful for most conditions, however it is widely used in research into the potential therapeutic applications of cannabinoids.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS). Several therapies for it exist, although there is no known cure.

<span class="mw-page-title-main">Signs and symptoms of multiple sclerosis</span> Neurological signs and symptoms

Multiple sclerosis can cause a variety of symptoms: changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, or difficulty moving; difficulties with coordination and balance; problems in speech (dysarthria) or swallowing (dysphagia), visual problems, fatigue and acute or chronic pain syndromes, bladder and bowel difficulties, cognitive impairment, or emotional symptomatology. The main clinical measure in progression of the disability and severity of the symptoms is the Expanded Disability Status Scale or EDSS.

<span class="mw-page-title-main">Laquinimod</span> Chemical compound

Laquinimod is an experimental immunomodulator developed by Active Biotech and Teva. It is being investigated as an oral treatment for multiple sclerosis (MS) and Huntington's disease.

Geoffrey William Guy is a British pharmacologist, physician, businessman and academic, who co-founded GW Pharmaceuticals and has developed treatments using compounds found in cannabis, which are the first cannabis-based medicines approved by and available on the British National Health Service (NHS).

<span class="mw-page-title-main">Dexanabinol</span> Chemical compound

Dexanabinol is a synthetic cannabinoid derivative in development by e-Therapeutics plc. It is the "unnatural" enantiomer of the potent cannabinoid agonist HU-210. Unlike other cannabinoid derivatives, HU-211 does not act as a cannabinoid receptor agonist, but instead as an NMDA antagonist. It therefore does not produce cannabis-like effects, but is anticonvulsant and neuroprotective, and is widely used in scientific research as well as currently being studied for applications such as treating head injury, stroke, or cancer. It was shown to be safe in clinical trials and is currently undergoing Phase I trials for the treatment of brain cancer and advanced solid tumors.

<span class="mw-page-title-main">Dronabinol</span> Generic name of Δ9-THC in medicine

Dronabinol (INN), also known under the trade names Marinol and Syndros, is a generic name for the molecule of delta-9-tetrahydrocannabinol in the pharmaceutical context. It has indications as an appetite stimulant, antiemetic, and sleep apnea reliever and is approved by the FDA as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting only.

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<span class="mw-page-title-main">GW Pharmaceuticals</span>

GW Pharmaceuticals Limited is a British pharmaceutics company known for its multiple sclerosis treatment product nabiximols which was the first natural cannabis plant derivative to gain market approval in any country. Another cannabis-based product, Epidiolex, was approved for treatment of epilepsy by the US Food and Drug Administration in 2018. It is a subsidiary of Jazz Pharmaceuticals.

<span class="mw-page-title-main">Botanical drug</span> Plant ingredients marketed for treatment of a disease

A botanical drug is defined in the United States Federal Food, Drug, and Cosmetic Act as a botanical product that is marketed as diagnosing, mitigating, treating, or curing a disease; a botanical product in turn, is a finished, labeled product that contains ingredients from plants. Chemicals that are purified from plants, like paclitaxel, and highly purified products of industrial fermentation, like biopharmaceuticals, are not considered to be botanical products.

<span class="mw-page-title-main">Cannabis in Sweden</span> Use of cannabis in Sweden

Cannabis in Sweden is illegal for all purposes. It is illegal for recreational purposes, for most medical purposes and possession of even small amounts of cannabis is a criminal offence. Consequently, limited medical usage of cannabis-based drugs is only allowed for specific conditions.

Medical cannabis research includes any medical research on using cannabis. Different countries conduct and respond to medical cannabis research in different ways.

References

  1. ↑ "DDrare: Database of Drug Development for Rare Diseases". ホーム (in Japanese). 2016-12-28. Retrieved 2024-03-23.{{cite web}}: Text "DDrare" ignored (help)
  2. ↑ "Statement on a non-proprietary name" (PDF). United States Adopted Names Council.
  3. ↑ "Nabiximols". UK Medicines Online.[ permanent dead link ] Page accessed Feb 3, 2016
  4. ↑ "Sativex (nabiximols) - factsheet". Multiple Sclerosis Trust. October 2014.
  5. ↑ Itin C, Barasch D, Domb AJ, Hoffman A (May 2020). "Prolonged oral transmucosal delivery of highly lipophilic drug cannabidiol". International Journal of Pharmaceutics. 581: 119276. doi:10.1016/j.ijpharm.2020.119276. PMID   32243971. S2CID   214785913.
  6. ↑ Itin C, Domb AJ, Hoffman A (October 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 Opinion on Drug Delivery. 16 (10): 1031–1035. doi:10.1080/17425247.2019.1653852. PMID   31393180. S2CID   199505274.
  7. ↑ "GW signs Sativex cannabis-based drug deal with Novartis". The Telegraph. 11 April 2011. Retrieved 12 July 2012.
  8. ↑ Ryan S (4 June 2011). "Sussex MS sufferers call for drug funding". Argus (Sussex, UK). Retrieved 8 June 2011.
  9. ↑ "Sativex rejected by healthcare provider". Lincolnshire. 20 June 2011. Archived from the original on 22 June 2011. Retrieved 20 June 2011.
  10. ↑ "Wales NHS to offer MS cannabis drug Sativex". 15 August 2014. Retrieved 18 August 2014.
  11. ↑ "Sativex (nabiximols)". Swedish Medical Products Agency. Archived from the original on 2014-01-01.
  12. ↑ "Multiple Sclerosis". GW Pharmaceuticals\. Archived from the original on 2011-08-11. Retrieved 24 July 2011.
  13. ↑ "Cancer Pain". GW Pharmaceuticals. Archived from the original on 2011-09-27. Retrieved 24 July 2011.
  14. ↑ "Sativex - Investigational Cannabis-Based Treatment for Pain and Multiple Sclerosis Drug Development Technology". www.drugdevelopment-technology.com. Retrieved 2008-08-08.
  15. ↑ Olszewska D, Kidawa M. "Sativex - lek z marihuany". Krajowe Biuro Do Spraw Przeciwdziałania Narkomanii.
  16. ↑ "France Legalizes Marijuana-Based Drug To Treat Multiple Sclerosis". HunffingtonPost. Retrieved 4 June 2015.
  17. ↑ "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.
  18. 1 2 Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2011/2012(in German)
  19. ↑ Lakhan SE, Rowland M (December 2009). "Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review". BMC Neurology. 9: 59. doi: 10.1186/1471-2377-9-59 . PMC   2793241 . PMID   19961570.
  20. ↑ Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D (April 2014). "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. PMC   4011465 . PMID   24778283.
  21. ↑ D'hooghe M, Willekens B, Delvaux V, D'haeseleer M, Guillaume D, Laureys G, et al. (June 2021). "Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience". BMC Neurology. 21 (1): 227. doi: 10.1186/s12883-021-02246-0 . PMC   8218396 . PMID   34157999. S2CID   235496708.
  22. ↑ Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, et al. (May 2012). "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 . PMID   22483680.
  23. ↑ Lynch ME, Cesar-Rittenberg P, Hohmann AG (January 2014). "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 . PMID   23742737.
  24. ↑ Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT (August 2013). "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 . PMID   23141881.
  25. ↑ Underwood G (9 January 2015). "Last stage failure for Otsuka and GW Cancer Pain Drug". Pharmafile. Retrieved 2016-12-07.
  26. ↑ Wade DT, Makela P, Robson P, House H, Bateman C (August 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". Multiple Sclerosis. 10 (4): 434–441. doi:10.1191/1352458504ms1082oa. PMID   15327042. S2CID   1378674.
  27. ↑ Wade DT, Makela PM, House H, Bateman C, Robson P (October 2006). "Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis". Multiple Sclerosis. 12 (5): 639–645. doi:10.1177/1352458505070618. PMID   17086911. S2CID   16175440.
  28. ↑ Wade DT, Robson P, House H, Makela P, Aram J (February 2003). "A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms". Clinical Rehabilitation. 17 (1): 21–29. doi:10.1191/0269215503cr581oa. PMID   12617376. S2CID   1414988.
  29. ↑ Motaghi E, Ghasemi-Pirbaluti M, Rashidi M, Alasvand M, Di Ciano P, Bozorgi H (March 2023). "The effect of tetrahydrocannabinol:cannabidiol oromucosal spray on cognition: a systematic review". European Journal of Clinical Pharmacology. 79 (3): 371–381. doi:10.1007/s00228-023-03454-y. PMID   36700997. S2CID   256273374.
  30. ↑ "GWPharma - GW Pharmaceuticals' cannabinoid-medicine Sativex® moved to Schedule 4 of UK Drugs Act". Archived from the original on 2013-10-29. Retrieved 2013-11-27.
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