Chemistry:Ziprasidone

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Short description: Antipsychotic medication
Ziprasidone
Ziprasidone.svg
Ziprasidone ball-and-stick model.png
Clinical data
Trade namesGeodon, Zeldox, Zipwell, other
AHFS/Drugs.comMonograph
MedlinePlusa699062
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, intramuscular injection (IM)
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60% (oral)[1]
100% (IM)
MetabolismLiver (aldehyde reductase)
Elimination half-life7 to 10 hours[2]
ExcretionUrine and feces
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H21ClN4OS
Molar mass412.94 g·mol−1
3D model (JSmol)
  (verify)
3D-animation of a ziprasidone molecule.
Ziprasidon Krka brand medicine.

Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder.[3] It may be used by mouth and by injection into a muscle (IM).[3] The IM form may be used for acute agitation in people with schizophrenia.[3]

Common side effects include dizziness, drowsiness, dry mouth, and twitches.[4][5] Although it can also cause weight gain, the risk is much lower than for other atypical antipsychotics.[6] How it works is not entirely clear but is believed to involve effects on serotonin and dopamine in the brain.[3]

Ziprasidone was approved for medical use in the United States in 2001.[3] The pills are made up of the hydrochloride salt, ziprasidone hydrochloride. The intramuscular form is the mesylate, ziprasidone mesylate trihydrate, and is provided as a lyophilized powder. In 2020, it was the 282nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[7][8]

Medical uses

Ziprasidone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia as well as acute mania and mixed states associated with bipolar disorder. Its intramuscular injection form is approved for acute agitation in schizophrenic patients for whom treatment with just ziprasidone is appropriate.[9]

In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, ziprasidone demonstrated mild-standard effectiveness. 15% more effective than lurasidone and iloperidone, approximately as effective as chlorpromazine and asenapine, and 9–13% less effective than haloperidol, quetiapine, and aripiprazole.[10] Ziprasidone is effective in the treatment of schizophrenia, though evidence from the CATIE trials suggests it is less effective than olanzapine, and equally as effective compared to quetiapine. There are higher discontinuation rates for lower doses of ziprasidone, which are also less effective than higher doses.[11]

Adverse effects

Ziprasidone (and all other second generation antipsychotics (SGAs)) received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.[12]

Sleepiness and headache are very common adverse effects (>10%).[4][5]

Common adverse effects (1–10%), include producing too much saliva or having dry mouth, runny nose, respiratory disorders or coughing, nausea and vomiting, stomach aches, constipation or diarrhea, loss of appetite, weight gain (but the smallest risk for weight gain compared to other antipsychotics[6]), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety.[4][5] Extrapyramidal symptoms are also common and include tremor, dystonia (sustained or repetitive muscle contractions), akathisia (the feeling of a need to be in motion), parkinsonism, and muscle rigidity; in a 2013 meta-analysis of 15 antipsychotic drugs, ziprasidone ranked 8th for such side effects.[13]

Ziprasidone is known to trigger mania in some bipolar patients.[14][15][16]

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.[12]

Recently, the FDA required the manufacturers of some atypical antipsychotics to include a warning about the risk of hyperglycemia and Type II diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone does not cause insulin resistance to the degree of other atypical antipsychotics, such as olanzapine. Weight gain is also less of a concern with ziprasidone compared to other atypical antipsychotics.[17][18][19][20] In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall.[12] According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2 kg (4.8 lbs), which is significantly lower than other atypical antipsychotics, making this medication better for patients that are concerned about their weight. In December 2014, the FDA warned that ziprasidone could cause a potentially fatal skin reaction, Drug Reaction with Eosinophilia and Systemic Symptoms, although this was believed to occur only rarely.[21]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[22] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[23] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[23] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[23] Symptoms generally resolve after a short period of time.[23]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[24] It may also result in reoccurrence of the condition that is being treated.[25] Rarely tardive dyskinesia can occur when the medication is stopped.[23]

Pharmacology

Pharmacodynamics

Ziprasidone[26]
Site Ki (nM) Action Ref
SERT 112 Blocker [26]
NET 44 Blocker [26]
DAT >10,000 ND [26]
5-HT1B 0.99–4.0 Partial agonist [27][26]
5-HT1D 5.1–9.0 Partial agonist [27][26]
5-HT1E 360–1,279 ND [27][26]
5-HT2A 0.08–1.4 Antagonist [28][29][27]
5-HT2B 27.2 Antagonist [26]
5-HT2C 0.72–13 Antagonist [29]
5-HT3 >10,000 ND [26]
5-HT5A 291 ND [26]
5-HT6 61–76 Antagonist [30][29]
5-HT7 6.0–9.3 Antagonist [26][30][29]
α1A 18 Antagonist [26][30]
α1B 9.0 Antagonist [26]
α2A 160 Antagonist [26][27][30]
α2B 48 Antagonist [26][27][30]
α2C 59–77 Antagonist [26][27][30]
β1 ≥2,570 ND [27][26]
β2 >10,000 ND [27][26]
D1 30–130 ND [26][29]
D2 4.8 Antagonist [31][29][30]
D2L 4.6 Antagonist [27][32]
D2S 4.2 Antagonist [27]
D3 7.2 Antagonist [31][29][27]
D4 0.8–105 Antagonist [31][29][26]
D4.2 28–39 Antagonist [32]
D4.4 14.9 Antagonist [33]
D5 152 ND [26]
H1 15–130 Antagonist [27][29][26]
H2 3,500 ND [26]
H3 >10,000 ND [26]
H4 >10,000 ND [26]
M1 ≥300 ND [34][26][29]
M2 ≥3,000 ND [34][26]
M3 ≥1,300 ND [34][30][26]
M4 ≥1,600 ND [34][26]
M5 ≥1,600 ND [34][26]
σ1 110 ND [27]
σ2 ND ND ND
Opioid >1,000 ND [27]
nACh >10,000 ND [26]
NMDA
(PCP)		 >10,000 ND [26]
VDCC >10,000 ND [26][27]
VGSC 2,620 ND [27]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except H3 (guinea pig), σ1 (guinea pig), opioid (rodent), NMDA/PCP (rat), VDCC, and VGSC.[26]

Correspondence to clinical effects

Ziprasidone mostly affects the receptors of dopamine (D2), serotonin (5-HT2A, partially 5-HT1A, 5-HT2C, and 5-HT1D)[1][35][36] and epinephrine/norepinephrine (α1) to a high degree, while of histamine (H1) - moderately.[37][38] It also somewhat inhibits reuptake of serotonin and norepinephrine, though not dopamine.[37][39]

Ziprasidone's efficacy in treating the positive symptoms of schizophrenia is believed to be mediated primarily via antagonism of the dopamine receptors, specifically D2. Blockade of the 5-HT2A receptor may also play a role in its effectiveness against positive symptoms, though the significance of this property in antipsychotic drugs is still debated among researchers.[40] Blockade of 5-HT2A and 5-HT2C and activation of 5-HT1A as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms.[41]; however, its effects on the 5-HT1A receptor may be limited as a study[42] found ziprasidone would likely "produce detectable occupancy [of 5-HT1A receptors] only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects." The relatively weak antagonistic actions of ziprasidone on the α1-adrenergic receptor likely in part explains some of its side effects, such as orthostatic hypotension. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks any anticholinergic side effects. Like most other antipsychotics, ziprasidone is sedating due primarily to serotonin and dopamine blockade.[43][44]

Pharmacokinetics

The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.[1]

After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier.[45] Steady state plasma concentrations are achieved within one to three days. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

The bioavailability of the drug is reduced by approximately 50% if a meal is not eaten before Ziprasidone ingestion.[12][46]

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4).[47] Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.[48][49]

Its biological half-life time is 10 hours at doses of 80–120 milligrams.[2]

History

Ziprasidone is chemically similar to risperidone,[50] of which it is a structural analogue.[51] It was first synthesized in 1987 at the Pfizer central research campus in Groton, Connecticut.[52]

Phase I trials started in 1995.[53] In 1998 ziprasidone was approved in Sweden.[54][55] After the FDA raised concerns about long QT syndrome, more clinical trials were conducted and submitted to the FDA, which approved the drug on February 5, 2001.[53][56][57]

Society and culture

Lawsuit

In September 2009, the U.S. Justice Department announced that Pfizer had been ordered to pay a historic fine of $2.3 billion as a penalty for fraudulent marketing of several drugs, including Geodon.[58] Pfizer had illegally promoted Geodon and submitted false claims to government health care programs for uses that were not medically accepted indications. The civil settlement also resolves allegations that Pfizer paid kickbacks to health care providers to induce them to prescribe Geodon, as well as other drugs. This was the largest civil fraud settlement in history against a pharmaceutical company.

References

  1. ↑ 1.0 1.1 1.2 "Ziprasidone hydrocloride: what role in the management of schizophrenia?". Journal of Central Nervous System Disease 3: 1–16. February 2011. doi:10.4137/JCNSD.S4138. PMID 23861634. 
  2. ↑ 2.0 2.1 "Ziprasidone in the treatment of mania in bipolar disorder". Neuropsychiatric Disease and Treatment 3 (6): 823–834. December 2007. doi:10.2147/NDT.S794. PMID 19300617. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Ziprasidone Monograph for Professionals" (in en). American Society of Health-System Pharmacists. https://www.drugs.com/monograph/ziprasidone.html. 
  4. ↑ 4.0 4.1 4.2 "Product Information: Zeldox IM (ziprasidone mesilate)". Australia Therapeutic Goods Administration. February 24, 2016. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06852-3. 
  5. ↑ 5.0 5.1 5.2 "Product Information: Zeldox (ziprasidone hydrochloride)". Australia Therapeutic Goods Administration. February 24, 2016. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05917-3&d=2016100716114622483. 
  6. ↑ 6.0 6.1 FDA Psychopharmacological Drugs Advisory Committee (July 19, 2000). "Briefing Document for Zeldoz Capsules". FDA. https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf. 
  7. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  8. ↑ "Ziprasidone - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Ziprasidone. 
  9. ↑ "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 US Dept of Justice. http://www.stopmedicarefraud.gov/pfizerfactsheet.html. 
  10. ↑ "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–962. September 2013. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
  11. ↑ "Effect of ziprasidone dose on all-cause discontinuation rates in acute schizophrenia and schizoaffective disorder: a post-hoc analysis of 4 fixed-dose randomized clinical trials". Schizophrenia Research 111 (1–3): 39–45. June 2009. doi:10.1016/j.schres.2009.03.009. PMID 19375893. 
  12. ↑ 12.0 12.1 12.2 12.3 "Geodon Prescribing Information". Pfizer, Inc.. http://www.pfizer.com/pfizer/download/uspi_geodon.pdf. 
  13. ↑ "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–962. September 2013. doi:10.1016/s0140-6736(13)60733-3. PMID 23810019. 
  14. ↑ "Ziprasidone-associated mania: a case series and review of the mechanism". Bipolar Disorders 5 (1): 72–75. February 2003. doi:10.1034/j.1399-5618.2003.02258.x. PMID 12656943. 
  15. ↑ "Ziprasidone-associated mania: a review and report of 2 additional cases". Clinical Neuropharmacology 28 (2): 83–86. 2005. doi:10.1097/01.wnf.0000159952.64640.28. PMID 15795551. 
  16. ↑ "Ziprasidone induction of hypomania in depression?". The American Journal of Psychiatry 159 (4): 673–674. April 2002. doi:10.1176/appi.ajp.159.4.673. PMID 11925314. 
  17. ↑ "Effects of six second generation antipsychotics on body weight and metabolism - risk assessment and results from a prospective study". Pharmacopsychiatry 42 (1): 29–34. January 2009. doi:10.1055/s-0028-1100425. PMID 19153944. 
  18. ↑ "Risk of diabetes mellitus associated with atypical antipsychotic use among Medicaid patients with bipolar disorder: a nested case-control study". Pharmacotherapy 27 (1): 27–35. January 2007. doi:10.1592/phco.27.1.27. PMID 17192159. 
  19. ↑ "Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers". Neuropsychopharmacology 33 (7): 1633–1641. June 2008. doi:10.1038/sj.npp.1301541. PMID 17712347. 
  20. ↑ "Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review". CNS Drugs 19 (Suppl 1): 1–93. 2005. doi:10.2165/00023210-200519001-00001. PMID 15998156. 
  21. ↑ "FDA Drug Safety Communication: FDA reporting mental health drug ziprasidone (Geodon) associated with rare but potentially fatal skin reactions". December 11, 2014. https://www.fda.gov/Drugs/DrugSafety/ucm426391.htm. 
  22. ↑ Joint Formulary Committee, BMJ, ed (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6. "Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse." 
  23. ↑ 23.0 23.1 23.2 23.3 23.4 (in en) Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. 2004. pp. 207–216. ISBN 9780198527480. https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207. 
  24. ↑ "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica 114 (1): 3–13. July 2006. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. 
  25. ↑ (in en) Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. 2013. p. 85. ISBN 9788847026797. https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85. 
  26. ↑ 26.00 26.01 26.02 26.03 26.04 26.05 26.06 26.07 26.08 26.09 26.10 26.11 26.12 26.13 26.14 26.15 26.16 26.17 26.18 26.19 26.20 26.21 26.22 26.23 26.24 26.25 26.26 26.27 26.28 26.29 26.30 26.31 26.32 26.33 "PDSP Ki Database". University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=ziprasidone&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query. 
  27. ↑ 27.00 27.01 27.02 27.03 27.04 27.05 27.06 27.07 27.08 27.09 27.10 27.11 27.12 27.13 27.14 27.15 27.16 Cite error: Invalid <ref> tag; no text was provided for refs named pmid8935801
  28. ↑ "1-Aminoindanes as novel motif with potential atypical antipsychotic properties". Bioorganic & Medicinal Chemistry Letters 18 (2): 489–493. January 2008. doi:10.1016/j.bmcl.2007.11.106. PMID 18160289. 
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 29.6 29.7 29.8 29.9 Cite error: Invalid <ref> tag; no text was provided for refs named pmid11513838
  30. ↑ 30.0 30.1 30.2 30.3 30.4 30.5 30.6 30.7 Cite error: Invalid <ref> tag; no text was provided for refs named pmid12629531
  31. ↑ 31.0 31.1 31.2 "Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors". Molecular Psychiatry 3 (2): 123–134. March 1998. doi:10.1038/sj.mp.4000336. PMID 9577836. 
  32. ↑ 32.0 32.1 "Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence". Neuropsychopharmacology 18 (2): 63–101. February 1998. doi:10.1016/S0893-133X(97)00112-7. PMID 9430133. 
  33. ↑ "[35S]Guanosine-5'-O-(3-thio)triphosphate binding as a measure of efficacy at human recombinant dopamine D4.4 receptors: actions of antiparkinsonian and antipsychotic agents". The Journal of Pharmacology and Experimental Therapeutics 282 (1): 181–191. July 1997. PMID 9223553. 
  34. ↑ 34.0 34.1 34.2 34.3 34.4 "Muscarinic mechanisms of antipsychotic atypicality". Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (7): 1125–1143. October 2003. doi:10.1016/j.pnpbp.2003.09.008. PMID 14642972. 
  35. ↑ "Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity". The Journal of Pharmacology and Experimental Therapeutics 275 (1): 101–113. October 1995. PMID 7562537. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7562537. 
  36. ↑ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th Edition. China: McGraw-Hill. 2011. pp. 406–410. ISBN 978-0-07-162442-8. 
  37. ↑ 37.0 37.1 Bipolar Psychopharmacotherapy: Caring for the Patient. John Wiley & Sons. June 24, 2011. p. 209. ISBN 978-1-119-95664-8. https://books.google.com/books?id=u0fO8RRIE1MC&pg=PT209. Retrieved May 13, 2012. 
  38. ↑ "From clinical research to clinical practice: a 4-year review of ziprasidone". CNS Spectrums 10 (11 Suppl 17): 1–20. November 2005. doi:10.1017/S1092852900019842. PMID 16381088. 
  39. ↑ "Pharmacological profile of neuroleptics at human monoamine transporters". European Journal of Pharmacology 368 (2–3): 277–283. March 1999. doi:10.1016/S0014-2999(99)00005-9. PMID 10193665. 
  40. ↑ Pharmakologie und Toxikologie: Arzneimittelwirkungen verstehen- Medikamente gezielt einsetzen; ein Lehrbuch für Studierende der Medizin, der Pharmazie und der Biowissenschaften, eine Informationsquelle für Ärzte, Apotheker und Gesundheitspolitiker. Georg Thieme Verlag. 2006. ISBN 978-3-13-368516-0. https://books.google.com/books?id=7ewS8QAClYEC&pg=PP1. Retrieved May 13, 2012. 
  41. ↑ Essentials of Clinical Psychopharmacology. American Psychiatric Pub. February 10, 2006. p. 297. ISBN 978-1-58562-243-6. https://books.google.com/books?id=i5zrVD1PAwEC&pg=PA297. Retrieved May 13, 2012. 
  42. ↑ "Occupancy of agonist drugs at the 5-HT1A receptor". Neuropsychopharmacology 29 (5): 847–859. May 2004. doi:10.1038/sj.npp.1300390. PMID 14985704. 
  43. ↑ "Serotonin 5-HT(2A) receptor antagonists in the treatment of insomnia: present status and future prospects". Drugs of Today 46 (3): 183–193. March 2010. doi:10.1358/dot.2010.46.3.1437247. PMID 20467592. 
  44. ↑ "Sedative effects of the dopamine D1 receptor agonist A 68930 on rat open-field behavior". NeuroReport 11 (6): 1269–1272. April 2000. doi:10.1097/00001756-200004270-00025. PMID 10817605. 
  45. ↑ "Ziprasidone (Professional Patient Advice)". https://www.drugs.com/ppa/ziprasidone.html. 
  46. ↑ "The effect of food on the absorption of oral ziprasidone". Psychopharmacology Bulletin 40 (3): 58–68. 2007. PMID 18007569. 
  47. ↑ "An overview of psychotropic drug-drug interactions". Psychosomatics 46 (5): 464–494. 2005. doi:10.1176/appi.psy.46.5.464. PMID 16145193. 
  48. ↑ "The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers". British Journal of Clinical Pharmacology 49 (Suppl 1): 65S–70S. 2000. doi:10.1046/j.1365-2125.2000.00157.x. PMID 10771457. 
  49. ↑ "The effects of ketoconazole on ziprasidone pharmacokinetics--a placebo-controlled crossover study in healthy volunteers". British Journal of Clinical Pharmacology 49 (Suppl 1): 71S–76S. 2000. doi:10.1046/j.1365-2125.2000.00156.x. PMID 10771458. 
  50. ↑ Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 2012-01-24. ISBN 9781609133450. https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA465. 
  51. ↑ "Atypicality of atypical antipsychotics". Primary Care Companion to the Journal of Clinical Psychiatry 7 (6): 268–274. 2005. doi:10.4088/pcc.v07n0602. PMID 16498489. 
  52. ↑ "Ziprasidone". The American Psychiatric Publishing textbook of psychopharmacology (4th ed.). Washington, D.C.: American Psychiatric Pub.. 2009. p. 641. ISBN 9781585623099. https://books.google.com/books?id=Xx7iNGdV25IC&pg=PA641. 
  53. ↑ 53.0 53.1 "Approval Package For: Application Number 20-919". FDA Center For Drug Evaluation And Research. May 26, 1998. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/20-919_geodon_biopharmr.pdf. 
  54. ↑ "First Approval For Pfizer's Zeldoxs". http://www.thepharmaletter.com/article/first-approval-for-pfizer-s-zeldox. 
  55. ↑ "Pfizer's Zeldox approvable in USA – Pharmaceutical industry news". The Pharma Letter. 13 September 2000. http://www.thepharmaletter.com/article/pfizer-s-zeldox-approvable-in-usa. 
  56. ↑ PsychoPharmacological Drugs Advisory Committee (19 July 2000). "FDA Background On ZeldoxTM (ziprasidone hydrochloride capsules) Pfizer, Inc.". Center for Drug Evaluation and Research (CDER). U.S. Food and Drug Administration. https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1b.pdf. 
  57. ↑ "Pfizer to Launch Zeldox in 9 European Union Countries Beginning Next Month". Pfizer Inc. http://www.prnewswire.com/news-releases/pfizer-to-launch-zeldox-in-9-european-union-countries-beginning-next-month-76154202.html. 
  58. ↑ "Justice Department Announces Largest Health Care Fraud Settlement in Its History". 2009-09-02. https://www.justice.gov/opa/pr/justice-department-announces-largest-health-care-fraud-settlement-its-history. 

Further reading



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