Pregabalin

Pregabalin
Systematic (IUPAC) name
(S)-3-(Aminomethyl)-5-methylhexanoic acid
Clinical data
Pronunciation /priˈɡæbəlᵻn/
AHFS/Drugs.com International Drug Names
MedlinePlus a605045
Licence data US FDA:link
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Dependence
liability		 Moderate[1]
Addiction
liability		 Low to moderate[1]
Routes of
administration		 oral
Pharmacokinetic data
Bioavailability ≥90%
Protein binding Nil
Metabolism Negligible
Metabolites N-methylpregabalin[2]
Onset of action 1.5 hours[3]
Biological half-life 6.3 hours[3]
Excretion Renal
Identifiers
CAS Number 148553-50-8 YesY
ATC code N03AX16
PubChem CID 5486971
DrugBank DB00230 YesY
ChemSpider 4589156 YesY
UNII 55JG375S6M YesY
KEGG D02716 YesY
ChEBI CHEBI:64356 N
ChEMBL CHEMBL1059 YesY
Synonyms Isobutyl GABA
Chemical data
Formula C8H17NO2
Molar mass 159.23 g.mol−1
 NYesY (what is this?)  (verify)

Pregabalin, also known as β-isobutyl-γ-Aminobutyric acid (beta-isobutyl-GABA) is used to treat epilepsy, neuropathic pain, fibromyalgia and generalized anxiety disorder.[4][5] Its use for epilepsy is as an add-on therapy for partial seizures with or without secondary generalization in adults.[6]

Common side effects include: sleepiness, confusion, trouble with memory, poor coordination, dry mouth, problem with vision, and weight gain.[5] Potentially serious side effects include angioedema, drug misuse, and an increased suicide risk.[5]

Pregabalin is a derivative of the neurotransmitter γ-Aminobutyric acid (GABA) and a potent gabapentinoid. It is a close structural analogue of GABA, as well as of GABOB (beta-hydroxy-GABA), baclofen (beta-(4-chlorophenyl)-GABA), and phenibut (beta-phenyl-GABA).[7][8] It is a ion channel modulator that has rapid analgesic, anticonvulsant, and anxiolytic effects. Pregabalin is a central nervous system depressant that has potential for abuse. The Drug Enforcement Administration (DEA) placed pregabalin, including its salts, and all products containing pregabalin into Schedule V of the Controlled Substances Act (CSA).[9][10][11]

Pregabalin was originally marketed as Lyrica and is marketed under a number of brand names worldwide.[12] As of 2015 no generic version is available in the United States.[5] In the United States it costs about 300-400 USD per month.[5]

Medical uses

A package of 150 mg pregabalin capsules (Finland)

Seizures

Pregabalin is useful when added to other treatments, when those other treatments are not controlling partial epilepsy.[13] Its use alone is less effective than some other seizure medications.[14]

It is unclear how it compares to gabapentin for this use.[14]

Neuropathic pain

The European Federation of Neurological Societies recommends pregabalin as a first line agent for the treatment of pain associated with diabetic neuropathy, post-herpetic neuralgia, and central neuropathic pain.[15] A minority obtain substantial benefit, and a larger number obtain moderate benefit.[16] Other first line agents, including gabapentin and tricyclic antidepressants, are given equal weight as first line agents, and unlike pregabalin, are available as less expensive generics.[17]

Pregabalin is not recommended for certain other types of neuropathic pain such as pain that of trigeminal neuralgia or HIV infection[18] and its use in cancer-associated neuropathic pain is controversial.[18] There is no evidence for its use in the prevention of migraines and gabapentin has been found not to be useful.[19] It has been examined for the prevention of post-surgical chronic pain, but its utility for this purpose is controversial.[20][21]

Pregabalin is generally not regarded as efficacious in the treatment of acute pain.[16] In clinical trials examining the utility of pregabalin for the treatment of acute post-surgical pain, no effect on overall pain levels was observed, but people did require less morphine and had fewer opioid-related side effects.[20]

Anxiety disorders

The World Federation of Biological Psychiatry recommends pregabalin as one of several first line agents for the treatment of generalized anxiety disorder, but recommends other agents such as SSRIs as first line treatment for obsessive-compulsive disorder and post-traumatic stress disorder.[22] It appears to have anxiolytic effects similar to benzodiazepines with less risk of dependence.[23][24]

Therapeutic effects of pregabalin appear after 1 week of use and is similar in effectiveness to lorazepam, alprazolam, and venlafaxine, but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychic and somatic anxiety symptoms.[25] Long-term trials have shown continued effectiveness without the development of tolerance, and, in addition, unlike benzodiazepines, it has a beneficial effect on sleep and sleep architecture, characterized by the enhancement of slow-wave sleep.[25] and produces less severe cognitive and psychomotor impairment; it also has a low potential for abuse and dependence and may be preferred over the benzodiazepines for these reasons.[25][26]

Side effects

Pregabalin has been shown to produce therapeutic effects that are similar to other controlled substances. In a study with recreational users of sedative and hypnotic drugs, a 450 mg dose of pregabalin resulted in subjective ratings of a "good drug effect" and "high" and "liking" similar to 30 mg of diazepam. In clinical studies, pregabalin showed a side effect profile similar to other central nervous system depressants.[27]

Adverse drug reactions associated with the use of pregabalin include:[28][29]

Discontinuation

Following abrupt or rapid discontinuation of pregabalin, some people reported symptoms suggestive of physical dependence. The FDA determined that the substance dependence profile of pregabalin, as measured by a patient physical withdrawal checklist, was quantitatively less than benzodiazepines.[27] Even people who have discontinued short term and or long term use of pregabalin have experienced withdrawal symptoms, including insomnia, headache, nausea, anxiety, diarrhea, flu like symptoms, nervousness, major depression, pain, convulsions, hyperhidrosis and dizziness.[31]

Overdose

Several renal failure patients developed myoclonus while receiving pregabalin, apparently as a result of gradual accumulation of the drug. Acute overdosage may be manifested by somnolence, tachycardia and hypertonicity. Plasma, serum or blood concentrations of pregabalin may be measured to monitor therapy or to confirm a diagnosis of poisoning in hospitalized patients.[32][33][34]

Drug interactions

No interactions have been demonstrated in vivo. The manufacturer notes some potential pharmacological interactions with opioids, benzodiazepines, barbiturates, ethanol (alcohol), and other drugs that depress the central nervous system. ACE inhibitors may enhance the adverse/toxic effect of Pregabalin. Antidiabetic Agents (Thiazolidinedione): Pregabalin may enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione).[35]

Pharmacology

Pharmacodynamics

Pregabalin binds to the α2δ subunit of voltage-gated calcium channels in the central nervous system. Although, pregabalin is an analogue of GABA, it does not bind directly to GABAA, GABAB, or benzodiazepine receptors. Nor does it block sodium channels and is not active at opioid receptors. Gabapentinoids, such as pregabalin, are α2δ subunit voltage-gated calcium channel modifiers that affect GABA. In contrast to the distribution of α2δ-1 and α2δ-2 subunits binding correlates partially with GABAergic neurons.[36] Pregabalin promotes the production of GABA and increases neural GABA levels by producing a dose dependent increase in glutamate decarboxylase (GAD), an enzyme involved in GABA biosynthesis, that converts glutamate into GABA in a single step.[37] Pregabalin increases the density of GABA transporter proteins and increases the rate of functional GABA transport.[38]

Both α2δ subunit binding sites are also known for three other different gabapentinoids. That being gabapentin, gabapentin enacarbil, and phenibut. Recently, phenibut, a close analogue of pregabalin, has been found to similarly bind to the α2δ subunit of voltage-gated calcium channels and phenibut inhibits these channels similarly to gabapentin and pregabalin.[39] Baclofen (β-(4-chlorophenyl)-GABA) has also been found to do this, but relatively weakly.[39] Moreover, it has been found that the antinociceptive effects of phenibut in rodents are mediated not by GABAB receptor but by blockade of α2δ subunit-containing voltage-gated calcium channels, implicating this action as an important mediator of the effects of phenibut.[39] Phenibut has the same structure of baclofen (lacking only a chlorine atom in the para-position of the phenyl group) and includes the phenylethylamine structure. Pregabalin has instead the phenyl group substituted with the isobutyl group. Making both phenibut and baclofen close analogues of pregabalin.[40] As such, phenibut is a gabapentinoid.[41][42][43]

Pregabalin is approximately 2.5 times more potent and binds more strongly to the receptors than gabapentin.[44] The biological half-life for pregabalin is 6.3 hours.

Pharmacokinetics

Absorption

Pregabalin is rapidly absorbed when administered on an empty stomach, with peak plasma concentrations occurring within one hour. Pregabalin oral bioavailability is estimated to be greater than or equal to 90% and is independent of dose. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by approximately 25 to 30% and a delay in Tmax (time to reach Cmax) to approximately 2.5 hours. Administration with food, however, has no clinically significant effect on the extent of absorption.[2]

Distribution

Pregabalin has been shown to cross the blood–brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the volume of distribution of pregabalin for an orally administered dose is approximately 0.56 L/kg and is not bound to plasma proteins.[2]

Metabolism

Pregabalin undergoes negligible metabolism in humans.[45] In experiments using nuclear medicine techniques, it was revealed that approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The major metabolite is N-methylpregabalin.[2]

Excretion

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.[2] Renal clearance of pregabalin is 73 mL/minute.[46]

History

Pregabalin was invented by medicinal chemist Richard Bruce Silverman at Northwestern University in the United States.[47] The drug was approved in the European Union in 2004. Pregabalin received U.S. FDA approval for use in treating epilepsy, diabetic neuropathic pain, and postherpetic neuralgia in December 2004, and appeared on the U.S. market in fall 2005.[48]

In June 2007, the FDA approved Lyrica as a treatment for fibromyalgia. It was the first drug to be approved for this indication and remained the only one until duloxetine gained FDA approval for the treatment of fibromyalgia in June 2008.[49]

Generic versions of pregabalin became available in Russia in 2011,[50] in Canada in 2013, and are expected to become available in the European Union and the U.S. in 2016 and 2018 respectively.[51]

Society and culture

Legal status

Regulatory approval

In the United States, the Food and Drug Administration (FDA) has approved pregabalin for adjunctive therapy for adults with partial onset seizures, management of postherpetic neuralgia and neuropathic pain associated with spinal cord injury and diabetic peripheral neuropathy, and the treatment of fibromyalgia.[55] Pregabalin has also been approved in the European Union and Russia (but not in US) for treatment of generalized anxiety disorder.[56][57]

Marketing

Pregabalin is marketed by Pfizer under the trade name Lyrica. Pfizer described in an SEC filing that the drug could be used to treat epilepsy, postherpetic neuralgia, diabetic peripheral neuropathy and fibromyalgia. Lyrica was promoted for other uses which had not been approved by medical regulators up until 2009. For this practice, with three other drugs, Pfizer was fined a record amount of US$2.3 billion by the Department of Justice.[58] Lyrica sales reached a record US$3.063 billion in 2010.[59] Lyrica is one of four drugs which Pharmacia & Upjohn, a subsidiary of Pfizer, in 2009 pleaded guilty to misbranding "with the intent to defraud or mislead". Pfizer agreed to pay US$2.3 billion (GB£1.4 billion) in settlement, and entered a corporate integrity agreement. Pfizer illegally promoted the drugs and caused false claims to be submitted to government healthcare programs for uses that were not approved by the U.S. Food and Drug Administration (FDA).[58]

Intellectual property

Northwestern University invented pregabalin and holds a patent on it, which it exclusively licensed to Pfizer.[60][61] That patent, along with others, was challenged by generic manufacturers and was upheld in 2014, giving Pfizer exclusivity for Lyrica in the US until 2018.[62][63]

Other names

Other trade names include:

See also

References

  1. 1 2 Schifano F (2014). "Misuse and abuse of pregabalin and gabapentin: cause for concern?". CNS Drugs 28 (6): 491–6. doi:10.1007/s40263-014-0164-4. PMID 24760436. Gabapentinoids (e.g. pregabalin and gabapentin) are widely used in neurology, psychiatry and primary healthcare ... Although at therapeutic dosages gabapentinoids may present with low addictive liability levels...
  2. 1 2 3 4 5 "Summary of product characteristics" (PDF). European Medicines Agency. 6 March 2013. Retrieved 6 May 2013.
  3. 1 2 http://www.clevelandclinicmeded.com/medicalpubs/pharmacy/septoct2005/pregabalin.htm
  4. ↑ Frampton, JE (September 2014). "Pregabalin: a review of its use in adults with generalized anxiety disorder.". CNS Drugs 28 (9): 835–54. doi:10.1007/s40263-014-0192-0. PMID 25149863.
  5. 1 2 3 4 5 "Pregabalin". The American Society of Health-System Pharmacists. Retrieved Oct 23, 2015.
  6. ↑ Benkert, Otto; Hippius, Hanns (2006). Kompendium Der Psychiatrischen Pharmakotherapie (in German) (6th ed.). Springer. ISBN 978-3-540-34401-8.
  7. ↑ Lapin I (2001). "Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug". CNS Drug Rev 7 (4): 471–81. doi:10.1111/j.1527-3458.2001.tb00211.x. PMID 11830761.
  8. ↑ Jensen B, Regier LD, editors. RxFiles : Drug comparison charts. 7th ed. Saskatoon, SK: RxFiles, 2010; p.78
  9. ↑ "Schedules of controlled substances: placement of pregabalin into schedule V. Final rule". Fed Regist 70: 43633–5. July 2005. PMID 16050051.
  10. ↑ "Title 21 CFR - PART 1308 - Section 1308.15 Schedule V". usdoj.gov.
  11. ↑ http://www.deadiversion.usdoj.gov/fed_regs/rules/2005/fr0728.htm
  12. ↑ Drugs.com international listings for pregabalin Page accessed Feb 15, 2016
  13. ↑ Pulman, J; Hemming, K; Marson, AG (12 March 2014). "Pregabalin add-on for drug-resistant partial epilepsy". The Cochrane database of systematic reviews 3: CD005612. doi:10.1002/14651858.CD005612.pub3. PMID 24623260.
  14. 1 2 Zhou, Q; Zheng, J; Yu, L; Jia, X (17 October 2012). "Pregabalin monotherapy for epilepsy". The Cochrane database of systematic reviews 10: CD009429. doi:10.1002/14651858.CD009429.pub2. PMID 23076957.
  15. ↑ Attal N, Cruccu G, Baron R, et al. (September 2010). "EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision". Eur. J. Neurol. 17 (9): 1113–e88. doi:10.1111/j.1468-1331.2010.02999.x. PMID 20402746.
  16. 1 2 Moore, RA; Straube, S; Wiffen, PJ; Derry, S; McQuay, HJ (Jul 8, 2009). "Pregabalin for acute and chronic pain in adults". The Cochrane database of systematic reviews (3): CD007076. doi:10.1002/14651858.CD007076.pub2. PMC 4167351. PMID 19588419.
  17. ↑ Finnerup, NB; Sindrup SH; Jensen TS (September 2010). "The evidence for pharmacological treatment of neuropathic pain". Pain 150 (3): 573–81. doi:10.1016/j.pain.2010.06.019. PMID 20705215.
  18. 1 2 Bennett, M.I. (November 2013). "Pregabalin for acute and chronic pain in adults.". Pain Med 14 (11): 1681–8. doi:10.1111/pme.12212. PMID 23915361.
  19. ↑ Linde, M; Mulleners, WM; Chronicle, EP; McCrory, DC (Jun 24, 2013). "Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults.". The Cochrane database of systematic reviews 6: CD010609. doi:10.1002/14651858.CD010609. PMID 23797675.
  20. 1 2 Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J (August 2012). "The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis". Anesth. Analg. 115 (2): 428–42. doi:10.1213/ANE.0b013e318249d36e. PMID 22415535.
  21. ↑ Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I (2013). "Pharmacotherapy for the prevention of chronic pain after surgery in adults". Cochrane Database Syst Rev 7: CD008307. doi:10.1002/14651858.CD008307.pub2. PMID 23881791.
  22. ↑ Wensel TM, Powe KW, Cates ME (March 2012). "Pregabalin for the treatment of generalized anxiety disorder". Ann Pharmacother 46 (3): 424–9. doi:10.1345/aph.1Q405. PMID 22395254.
  23. ↑ Owen, Richard T. (September 2007). "Pregabalin: its efficacy, safety and tolerability profile in generalized anxiety". Drugs of Today 43 (9): 601–10. doi:10.1358/dot.2007.43.9.1133188. PMID 17940637. Retrieved 2012-01-22.
  24. ↑ Bandelow B, Sher L, Bunevicius R, et al. (June 2012). "Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care". Int J Psychiatry Clin Pract 16 (2): 77–84. doi:10.3109/13651501.2012.667114. PMID 22540422.
  25. 1 2 3 Bandelow, B.; Wedekind, D.; Leon, T. (Jul 2007). "Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention". Expert Rev Neurother 7 (7): 769–81. doi:10.1586/14737175.7.7.769. PMID 17610384.
  26. ↑ Owen, RT. (Sep 2007). "Pregabalin: its efficacy, safety and tolerability profile in generalized anxiety". Drugs Today (Barc) 43 (9): 601–10. doi:10.1358/dot.2007.43.9.1133188. PMID 17940637.
  27. 1 2 3 Drug Enforcement Administration, Department of Justice (July 2005). "Schedules of controlled substances: placement of pregabalin into schedule V. Final rule". Federal register 70 (144): 43633–5. PMID 16050051. Retrieved 2012-01-22.
  28. ↑ Pfizer Australia Pty Ltd. Lyrica (Australian Approved Product Information). West Ryde: Pfizer; 2006.
  29. ↑ Rossi, Simone, ed. (2006). Australian Medicines Handbook, 2006. Australian Medicines Handbook. ISBN 978-0-9757919-2-9.
  30. ↑ "Medication Guide (Pfizer Inc.)" (PDF). U.S. Food and Drug Administration. June 2011. Retrieved 2011-11-06.
  31. ↑ "Lyrica Capsules". medicines.org.uk.
  32. ↑ Murphy, N.G.; Mosher, L. (2008). "Severe myoclonus from pregabalin (Lyrica) due to chronic renal insufficiency". Clinical Toxicology 46 (7): 594. doi:10.1080/15563650802255033.
  33. ↑ Yoo, Lawrence; Matalon, Daniel; Hoffman, Robert S.; Goldfarb, David S. (2009). "Treatment of pregabalin toxicity by hemodialysis in a patient with kidney failure". American Journal of Kidney Diseases 54 (6): 1127–30. doi:10.1053/j.ajkd.2009.04.014. PMID 19493601.
  34. ↑ Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Biomedical Publications. pp. 1296–1297. ISBN 978-0-9626523-7-0.
  35. ↑ Pregabalin. In: Lexi-Drugs [database on the Internet]. Hudson (OH): Lexi-Comp, Inc.; 2007 [cited 2015 Oct 29].
  36. ↑ Dolphin, Annette C. (2012). "Calcium channel auxiliary α2δ and β subunits: Trafficking and one step beyond". Nature Reviews Neuroscience 13. doi:10.1038/nrn3311. Errata is: Dolphin, Annette C. (2012). "Calcium channel auxiliary α2δ and β subunits: Trafficking and one step beyond". Nature Reviews Neuroscience 13 (9): 664. doi:10.1038/nrn3317.
  37. ↑ "Aristopharma Ltd. - Product Details". aristopharma.com.
  38. ↑ DBA Quality Care Products LLC, Lake Erie Medical. "LYRICA 200 mg". DailyMed. Lake Eric Medical DBA Quality Care Products LLC. Retrieved 27 September 2015.
  39. 1 2 3 Zvejniece, Liga; Vavers, Edijs; Svalbe, Baiba; Veinberg, Grigory; Rizhanova, Kristina; Liepins, Vilnis; Kalvinsh, Ivars; Dambrova, Maija (2015). "R-phenibut binds to the α2–δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects". Pharmacology Biochemistry and Behavior 137: 23–29. doi:10.1016/j.pbb.2015.07.014. ISSN 0091-3057. PMID 26234470.
  40. ↑ Nelson, LS (2008). "Phenibut Withdrawal – A Novel 'Nutritional Supplement'". Clinical Toxicology 46 (7): 605. doi:10.1080/15563650802255033.
  41. ↑ Elaine Wyllie; Gregory D. Cascino; Barry E. Gidal; Howard P. Goodkin (17 February 2012). Wyllie's Treatment of Epilepsy: Principles and Practice. Lippincott Williams & Wilkins. p. 423. ISBN 978-1-4511-5348-4.
  42. ↑ Honorio Benzon; James P. Rathmell; Christopher L. Wu; Dennis C. Turk; Charles E. Argoff; Robert W Hurley (11 September 2013). Practical Management of Pain. Elsevier Health Sciences. p. 1006. ISBN 978-0-323-17080-2.
  43. ↑ Slava Lapin (30 July 2009). From the Inside. Luniver Press. p. 209. ISBN 978-1-905986-11-8. Retrieved 6 November 2010.
  44. ↑ McMahon, Stephen B (2013). Wall and Melzack's textbook of pain (6th ed.). Philadelphia, PA: Elsevier/Saunders. p. 515. ISBN 9780702040597.
  45. ↑ McElroy, Susan L.; Keck, Paul E.; Post, Robert M., eds. (2008). Antiepileptic Drugs to Treat Psychiatric Disorders. INFRMA-HC. p. 370. ISBN 978-0-8493-8259-8.
  46. ↑ "LYRICA – pregabalin capsule". DailyMed. U.S. National Library of Medicine. September 2010. Retrieved 6 May 2013.
  47. ↑ Lowe, Derek. "Getting To Lyrica". In The Pipeline. Science. Retrieved 21 November 2015.
  48. ↑ Dworkin, Robert H.; Kirkpatrick, Peter (June 2005). "Pregabalin" (PDF). Nature Reviews Drug Discovery 4 (6): 455–456. doi:10.1038/nrd1756. PMID 15959952. Retrieved 2012-01-22.
  49. ↑ "Living with Fibromyalgia, Drugs Approved to Manage Pain". U.S. Food and Drug Administration. 2008-07-18. Retrieved 2011-11-06.
  50. ↑ "Pregabalin-containing Medicines.". Russian State Register of Medicinal Products (in Russian). Retrieved 9 July 2015.
  51. ↑ "Pfizer Wins Ruling to Block Generic Lyrica Until 2018". Retrieved December 8, 2014.
  52. ↑ "Title 21 CFR - PART 1308 - Section 1308.15 Schedule V". usdoj.gov.
  53. ↑ Felleskatalogen (7 May 2015). "Lyrica". felleskatalogen.no.
  54. ↑ Chalabianloo, F; Schjøtt J (January 2009). "Pregabalin and its potential for abuse". Journal of the Norwegian Medical Association 129 (3): 186–187. doi:10.4045/tidsskr.08.0047. PMID 19180163.
  55. ↑ "Pfizer to pay $2.3 billion to resolve criminal and civil health care liability relating to fraudulent marketing and the payment of kickbacks". Stop Medicare Fraud, US Dept of Health & Human Svc, and of Justice. Retrieved 2012-07-04.
  56. ↑ Bandelow, Borwin; Wedekind, Dirk; Leon, Teresa (July 2007). "Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention". Expert Review of Neurotherapeutics 7 (7): 769–781. doi:10.1586/14737175.7.7.769. PMID 17610384. Retrieved 2011-11-06.
  57. ↑ "Pfizer's Lyrica Approved for the Treatment of Generalized Anxiety Disorder (GAD) in Europe" (Press release). Retrieved 2011-11-06.
  58. 1 2 "Pfizer agrees record fraud fine". BBC News. 2 September 2009. Retrieved 6 November 2011.
  59. ↑ "Portions of the Pfizer Inc. 2010 Financial Report". Sec.gov (edgar archives). Retrieved 2011-11-06.
  60. ↑ Jacoby, M. (2008). "Financial Windfall from Lyrica". Chemical & Engineering News 86 (10): 56–61. doi:10.1021/cen-v086n010.p056.
  61. ↑ "Patent US6197819 - Gamma amino butyric acid analogs and optical isomers".
  62. ↑ Susan Decker for Bloomberg News. Feb 6, 2014. Pfizer Wins Ruling to Block Generic Lyrica Until 2018
  63. ↑ Decision: Pfizer Inc. (PFE) v. Teva Pharmaceuticals USA Inc., 12-1576, U.S. Court of Appeals for the Federal Circuit (Washington)

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