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Nabiximols (USAN,[1] trade name Sativex) is a specific extract of Cannabis that was approved as a botanical drug in the United Kingdom in 2010 as a mouth spray to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis; it was developed by the UK company GW Pharmaceuticals.[2][3] The drug is a pharmaceutical product standardised 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. 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).[4]

Contents

1 Availability 2 Effectiveness 3 Side effects 4 Licensing 5 See also 6 References 7 External links

Availability[edit] 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;[5][6] but, in August 2014, the NHS in Wales agreed to fund Sativex for people with multiple sclerosis.[7] 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.[8] 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,[9] and also for pain due to cancer.[10][11] 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.[12] In 2013, France legalized the use of cannabinoids in medicine, Sativex is the first one to be sold under prescription.[13] Nevertheless, at least until June 2016, this drug was never actually sold in pharmacies there.[14] Effectiveness[edit] 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.[15] A 2009 meta-analysis of six studies found large variations of effectiveness, with a – statistically non-significant – trend towards a reduction of spasticity.[16] 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.[17] Nabiximols has also been studied for cancer pain resistant to opioids. Adjuvant use was safe and effective in 3 trials for cancer pain,[18][19][20] however the drug failed to meet its primary endpoint for this purpose in its first Phase III trial.[21] Side effects[edit] In early clinical trials, nabiximols has generally been well tolerated.[22][23][24] 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.[15] Licensing[edit] 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.[25] See also[edit]

Medical cannabis Nabilone Dronabinol Hortapharm B.V.

References[edit]

^ United States Adopted Names Council: Statement on a nonproprietary name ^ UK Medicines Online Nabiximols Page accessed Feb 3, 2016 ^ Multiple Sclerosis Trust. October 2014 Sativex (nabiximols) - factsheet ^ "GW signs Sativex cannabis-based drug deal with Novartis". The Telegraph. 11 April 2011. Retrieved 12 July 2012.  ^ Ryan, Siobhan (4 June 2011). "Sussex MS sufferers call for drug funding". Argus (Sussex,UK). Retrieved 8 June 2011.  ^ "Sativex rejected by healthcare provider". Lincolnshire. 20 June 2011. Archived from the original on 22 June 2011. Retrieved 20 June 2011.  ^ "Wales NHS to offer MS cannabis drug Sativex". 15 August 2014. Retrieved 18 August 2014.  ^ Sativex (nabiximols), Swedish Medical Products Agency Archived 2014-01-01 at the Wayback Machine. ^ GW Pharmaceuticals. "Multiple Sclerosis". Accessed 24 July 2011. ^ GW Pharmaceuticals. "Cancer Pain" Accessed 24 July 2011. ^ "Sativex - Investigational Cannabis-Based Treatment for Pain and Multiple Sclerosis Drug Development Technology". www.drugdevelopment-technology.com. Retrieved 2008-08-08.  ^ Olszewska, Dorota; Kidawa Michał. "Sativex - lek z marihuany". Krajowe Biuro Do Spraw Przeciwdziałania Narkomanii.  ^ "France Legalizes Marijuana-Based Drug To Treat Multiple Sclerosis". HunffingtonPost. Retrieved 4 June 2015.  ^ "Cannabis thérapeutique : pourquoi le Sativex n'est-il toujours pas vendu en France ?". Sciences et Avenir. Retrieved 6 June 2016.  ^ a b Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2011/2012 (in German) ^ 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.  ^ 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.  ^ 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.  ^ 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.  ^ 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.  ^ "Last stage failure for Otsuka and GW Cancer Pain Drug". Pharmafile. 2015-09-01. Retrieved 2016-12-07.  ^ 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.  ^ 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.  ^ 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.  ^ http://www.gwpharm.com/GW%20Pharmaceuticals%20cannabinoid-medicine%20Sativex%20moved%20to%20Schedule%204%20of%20UK%20Drugs%20Act.aspx

External links[edit]

GW Pharmaceuticals Website

v t e

Analgesics (N02A, N02B)

Opioids

Opiates/opium

Codeine# (+paracetamol, +aspirin) Morphine# (+naltrexone) Opium Laudanum Paregoric

Semisynthetic

Acetyldihydrocodeine Benzylmorphine Buprenorphine (+naloxone) Desomorphine Diamorphine (heroin) Dihydrocodeine (+paracetamol) Dihydromorphine Ethylmorphine Hydrocodone (+paracetamol, +ibuprofen, +aspirin) Hydromorphinol Hydromorphone Nicocodeine Nicodicodeine Nicomorphine Oxycodone (+paracetamol, +aspirin, +ibuprofen, +naloxone, +naltrexone) Oxymorphone Thebacon

Synthetic

Alfentanil Alphaprodine Anileridine Butorphanol Carfentanil Dextromoramide Dextropropoxyphene Dezocine Fentanyl# (+fluanisone) Ketobemidone Levorphanol Lofentanil Meptazinol Methadone# Nalbuphine NFEPP Pentazocine Pethidine (meperidine) Phenadoxone Phenazocine Piminodine Piritramide Propiram Remifentanil Sufentanil Tapentadol Tilidine Tramadol

Paracetamol-type

Acetanilide‡ Bucetin‡ Butacetin‡ Paracetamol (acetaminophen)# Parapropamol‡ Phenacetin‡ Propacetamol‡

NSAIDs

Propionates

Fenoprofen Flurbiprofen Ibuprofen# Ketoprofen Naproxen Oxaprozin

Oxicams

Meloxicam Piroxicam

Acetates

Diclofenac Indometacin Ketorolac Nabumetone Sulindac Tolmetin

COX-2 inhibitors

Celecoxib Etoricoxib Lumiracoxib Parecoxib Rofecoxib ‡ Valdecoxib ‡

Fenamates

Meclofenamic acid Mefenamic acid

Salicylates

Aspirin (acetylsalicylic acid)# (+paracetamol/caffeine) Benorylate Diflunisal Ethenzamide Magnesium salicylate Salicin Salicylamide Salsalate Wintergreen (methyl salicylate)

Pyrazolones

Aminophenazone‡ Ampyrone Metamizole (dipyrone) Nifenazone Phenazone Propyphenazone (+paracetamol/caffeine)

Others

Glafenine

Cannabinoids

Cannabidiol Cannabis Nabilone Nabiximols Tetrahydrocannabinol (dronabinol)

Ion channel modulators

Calcium blockers

Gabapentin Gabapentin enacarbil Pregabalin Ziconotide

Sodium blockers

Carbamazepine Lacosamide Local anesthetics (e.g., cocaine, lidocaine) Mexiletine Nefopam Tricyclic antidepressants (e.g., amitriptyline#)

Nav1.7/1.8-selective: DSP-2230§ Funapide§ PF-05089771§ Raxatrigine§

Potassium openers

Flupirtine

Myorelaxants

Carisoprodol Chlorzoxazone Cyclobenzaprine Mephenoxalone Methocarbamol Orphenadrine

Others

Analgesic adjuvant Analgecine Camphor Capsaicin Clonidine Ketamine Menthol Methoxyflurane Nefopam Proglumide Tricyclic antidepressants (e.g., amitriptyline#)

#WHO-EM ‡Withdrawn from market Clinical trials:

†Phase III §Never to phase III

v t e

Cannabinoid receptor modulators

Receptor (ligands)

CB1

Agonists (abridged; see here for more): 2-AG 2-AGE (noladin ether) 11-Hydroxy-THC α-Amyrin β-Amyrin AB-CHMINACA AM-1172 AM-1220 AM-1221 AM-1235 AM-2201 AM-2232 Anandamide Arvanil AZ-11713908 Cannabinol CB-13 CP 47,497 CP 55,940 Dimethylheptylpyran DEA ECG EGCG Epicatechin Gallocatechol (gallocatechin) Honokiol HU-210 JWH-007 JWH-015 JWH-018 JWH-073 Kavain L-759,633 Levonantradol Menabitan Nabilone Nabitan NADA O-1812 Oleamide Pravadoline Serinolamide A THC (dronabinol) UR-144 WIN 55,212-2 Yangonin

Antagonists: AM-251 AM-6545 Cannabidiol Cannabigerol Drinabant Falcarinol (carotatoxin) Hemopressin Ibipinabant LY-320,135 MK-9470 NESS-0327 O-2050 Otenabant PF-514273 PipISB Rimonabant Rosonabant Surinabant Taranabant THCV TM-38837 VCHSR Virodhamine

Antibodies: Brizantin (Бризантин) Dietressa (Диетресса)

Unknown/unsorted: MAFP

CB2

Agonists: 2-AG 2-AGE (noladin ether) 3,3'-Diindolylmethane 4-O-Methylhonokiol α-Amyrin β-Amyrin A-796,260 A-834,735 A-836,339 AM-1172 AM-1221 AM-1235 AM-1241 AM-2232 Anandamide AZ-11713908 Cannabinol Caryophyllene CB-13 CBS-0550 CP-55,940 GW-405,833 (L-768,242) GW-842,166X HU-308 JTE 7-31 JWH-007 JWH-015 JWH-018 JWH-73 JWH-133 L-759,633 L-759,656 Magnolol MDA-19 Nabitan NADA PF-03550096 S-444,823 SER-601 Serinolamide A UR-144 Tedalinab THC (dronabinol) THCV Tetrahydromagnolol Virodhamine

Antagonists: 4-O-Methylhonokiol AM-630 BML-190 Cannabidiol Honokiol JTE-907 SR-144,528 WIN 54,461 WIN 56,098

NAGly (GPR18)

Agonists: Abnormal cannabidiol ACPA AM251 Anandamide Cannabidiol NADGly THC (dronabinol) O-1602

Antagonists: CID-85469571 O-1918

GPR55

Agonists: 2-AGE (noladin ether) 2-ALPI Abnormal cannabidiol AM-251 CID1011163 CID1252842 CID1792579 CP 55,940 GSK-494581A Lysophosphatidylinositol ML-184 ML-185 ML-186 O-1602 Oleoylethanolamide Palmitoylethanolamide THC (dronabinol)

Antagonists: Cannabidiol CID-16020046 ML-191 ML-192 ML-193 O-1918 PSB-SB-487 PSB-SB-1202 PSB-SB-1203 Tetrahydromagnolol

GPR119

Agonists: 2-Oleoylglycerol Anandamide APD668 AR-231,453 AS-1269574 MBX-2982 N-Oleoyldopamine Oleoylethanolamide Olvanil PSN-375,963 PSN-632,408

Transporter (modulators)

eCBTs

Inhibitors: 5'-DMH-CBD AM-404 AM-1172 Arachidonoyl serotonin Arvanil Cannabidiol Guineensine LY-2183240 O-2093 OMDM-2 Paracetamol (acetaminophen) SB-FI-26 UCM-707 URB-597 VDM-11 WOBE490 WOBE491 WOBE492

Enzyme (modulators)

FAAH

Inhibitors: 4-Nonylphenylboronic acid AACOCF3 AM-404 Arachidonoyl serotonin BIA 10-2474 Biochanin A Genistein IDFP JNJ-1661010 JNJ-42165279 JZL-195 Kaempferol LY-2183240 MAFP Palmitoylisopropylamide Paracetamol (acetaminophen) PF-3845 PF-04457845 PF-750 SA-47 SA-57 TAK 21d TC-F 2 UCM710 URB-597

Activators: PDP-EA

MAGL

Inhibitors: ABX-1431 IDFP JJKK 048 JW 642 JZL-184 JZL-195 JZP-361 KML 29 MAFP MJN110 NAM Pristimerin URB-602

ABHD6

Inhibitors: JZP-169 JZP-430 KT182 KT185 KT195 KT203 LEI-106 ML294 ML295 ML296 UCM710 WWL-70

ABHD12

Inhibitors: Betulinic acid Maslinic acid MAFP Oleanolic acid Orlistat (tetrahydrolipstatin) Ursolic acid

Others

Precursors: Phosphatidylethanolamine NAPE Diacylglycerol

Others: 2-PG (directly potentiates activity of 2-AG at CB1 receptor) ARN-272 (FAAH-like anandamide transporter inhibitor)

See also Receptor/signaling modulators Cannabinoids (cannabin

.