Hydroxyzine

Hydroxyzine
Names
Pronunciation/haɪˈdrɒksɪziːn/
Trade namesAtarax, Vistaril,[1] others
Other namesUCB-4492
IUPAC name
  • (±)-2-(2-{4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl}ethoxy)ethanol
Clinical data
Drug classFirst generation antihistamine[2]
Main usesItchiness, anxiety, nausea[3]
Side effectsSleepiness, headache, dry mouth[3][4]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Dependence riskVery low[5]
Pregnancy
category
  • US: N (Not classified yet)[6]
    Routes of
    use    		By mouth, intramuscular injection
    Defined daily dose75 mg[7]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa682866
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    BioavailabilityHigh
    Protein binding93%
    MetabolismLiver
    MetabolitesCetirizine, others
    Elimination half-lifeAdults: 20.0 hours[8][9]
    Children: 7.1 hours[8]
    ExcretionUrine, feces
    Chemical and physical data
    FormulaC21H27ClN2O2
    Molar mass374.91 g·mol−1
    3D model (JSmol)
    SMILES
    • Clc1ccc(cc1)C(c2ccccc2)N3CCN(CC3)CCOCCO
    InChI
    • InChI=1S/C21H27ClN2O2/c22-20-8-6-19(7-9-20)21(18-4-2-1-3-5-18)24-12-10-23(11-13-24)14-16-26-17-15-25/h1-9,21,25H,10-17H2 checkY
    • Key:ZQDWXGKKHFNSQK-UHFFFAOYSA-N checkY

    Hydroxyzine, sold under the brand names Atarax and others, is a medication of the antihistamine type.[3] It is used in the treatment of itchiness, anxiety, and nausea, including that due to motion sickness.[3] It; however, is less preferred to newer antihistamines such as cetirizine or loratadine for hives.[10] It is used either by mouth or injection into a muscle.[3]

    Common side effects include sleepiness, headache, and a dry mouth.[3][4] Serious side effects may include QT prolongation.[4] It is unclear if use during pregnancy or breastfeeding is safe.[3] Hydroxyzine works by blocking the effects of histamine.[4] It is a first generation antihistamine in the piperazine family of chemicals.[3][2]

    It was first made by Union Chimique Belge in 1956 and was approved for sale by Pfizer in the United States later that year.[3][11] In the United Kingdom 28 doses cost less than a pound.[4] In the United States the wholesale cost in 2018 was about 0.05 USD per dose.[12] In 2017, it was the 99th most commonly prescribed medication in the United States, with more than seven million prescriptions.[13][14]

    Medical uses

    (a-c) Papules and pustules on body (d-f) Treatment with hydroxyzine by mouth

    Hydroxyzine is used in the treatment of itchiness, anxiety, and nausea due to motion sickness.[3]

    A systematic review concluded that compared with other anxiolytic agents (benzodiazepines and buspirone), hydroxyzine was equivalent in efficacy, acceptability, and tolerability.[15]

    Hydroxyzine can also be used for the treatment of allergic conditions, such as chronic urticaria, atopic or contact dermatoses, and histamine-mediated pruritus. These have also been confirmed in both recent and past studies to have no adverse effects on the liver, blood, nervous system, or urinary tract.[16]

    Use of hydroxyzine for premedication as a sedative has no effects on tropane alkaloids, such as atropine, but may, following general anesthesia, potentiate meperidine and barbiturates, and use in pre-anesthetic adjunctive therapy should be modified depending upon the state of the individual.[16]

    In other cases, the usage of hydroxyzine is as a form of non-barbiturate tranquilizer[17] used in the pre-operative sedation and treatment of neurological disorders, such as psychoneurosis and other forms of anxiety or tension states.[17]

    Dosage

    The defined daily dose is 75 mg by mouth or by injection.[7] The typical dose in adults is 25 to 50 mg twice per day with half that dose being recommended in older people.[18] Treatment should generally be for less than two weeks.[18]

    Contraindications

    The administration of hydroxyzine in large amounts by ingestion or intramuscular administration during the onset of pregnancy can cause fetal abnormalities—when administered to pregnant rats, mice and rabbits, hydroxyzine caused abnormalities such as hypogonadism with doses significantly above that of the human therapeutic range.[19] In humans, a significant dose has not yet been established in studies, and by default, the Food and Drug Administration (FDA) has introduced contraindication guidelines in regard to hydroxyzine.[19] Similarly the use in those at risk from or showing previous signs of hypersensitivity is also contraindicated.[19] Hydroxyzine is contraindicated for intravenous (IV) injection, as it has shown to cause hemolysis.

    Other contraindications include the administration of hydroxyzine alongside depressants and other compounds which affect the central nervous system.[19] and if absolutely necessary, it should only be administered concomitantly in small doses.[19] If administered in small doses with other substances, such as mentioned, then patients should refrain from using dangerous machinery, motor vehicles or any other practice requiring absolute concentration, in accordance with safety law.[19]

    Studies have also been conducted which show that long-term prescription of hydroxyzine can lead to tardive dyskinesia after years of use, but effects related to dyskinesia have also anecdotally been reported after periods of 7.5 months,[20] such as continual head rolling, lip licking and other forms of athetoid movement. In certain cases, elderly patients' previous interactions with phenothiazine derivatives or pre-existing neuroleptic treatment may have had some contribution towards dyskinesia at the administration of hydroxyzine due to hypersensitivity caused due to the prolonged treatment,[20] and therefore some contraindication is given to the short-term administration of hydroxyzine to those with previous phenothiazine use.[20]

    Side effects

    Several reactions have been noted in manufacturer guidelines—deep sleep, incoordination, sedation, calmness, and dizziness have been reported in children and adults, as well as others such as hypotension, tinnitus, and headaches.[21] Gastro-intestinal effects have also been observed, as well as less serious effects such as dryness of the mouth and constipation caused by the mild antimuscarinic properties of hydroxyzine.[21]

    Central nervous system problems such as hallucinations or confusion have been observed in rare cases, attributed mostly to overdosage.[22][21] Such properties have been attributed to hydroxyzine in several cases, particularly in patients treated for neuropsychological disorders, as well as in cases where overdoses have been observed. While there are reports of the "hallucinogenic" or "hypnotic" properties of hydroxyzine, several clinical data trials have not reported such side effects from the sole consumption of hydroxyzine, but rather, have described its overall calming effect described through the stimulation of areas within the formatio reticularis. The hallucinogenic or hypnotic properties have been described as being an additional effect from overall central nervous system suppression by other CNS agents, such as lithium or ethanol.[23]

    The effect of hydroxyzine has also been tested on the ability of humans in the registration and storage of memory, and was used in comparison with relatively safe drugs, such as lorazepam, to illustrate the effects of benzodiazepines, which are thought to have adverse effects on the capacity of memory storage. Hydroxyzine was found to have no adverse effects on memory in relation to lorazepam, which caused several deficiencies in the capacity of memory storage.[24]

    In a comparative study with lorazepam on memory effects, patients who had taken hydroxyzine experienced sedative effects like drowsiness, but recalled that they felt capable, attentive and able to continue with a memory test under these conditions.[24] Conversely, those under the effects of lorazepam felt unable to continue due to the fact they felt out of control with its effects; 8 out of 10 patients describing tendencies of problems with balance and control of simple motor functions.[24]

    Somnolence with or without vivid dreams or nightmares may occur in users with antihistamine sensitivities in combination with other CNS depressants. Hydroxyzine exhibits anxiolytic and sedative properties in many psychiatric patients. Other studies have suggested that hydroxyzine acts as an acute hypnotic, reducing sleep onset latency and increasing sleep duration — also showing that some drowsiness did occur. This was observed more in female patients, who also had greater hypnotic response.[25]

    Because of potential for more severe side effects, this drug is on the list to avoid in the elderly.[26]

    In 2015, the European Medicines Agency (EMA) announced a small but definite risk of QT prolongation associated with the use of hydroxyzine. This side effect is more likely to occur in people with pre-existing cardiac disease, or with the use of other medicines known to prolong the QT interval.

    Pharmacology

    Pharmacodynamics

    Hydroxyzine[27]
    SiteKi (nM)SpeciesRef
    5-HT2A170 (IC50)Rat[28]
    5-HT2CNDNDND
    α1460 (IC50)Rat[28]
    D1>10,000Mouse[29]
    D2378
    560 (IC50)    		Mouse
    Rat    		[29]
    [28]
    H12.0–19
    6.4
    100 (IC50)    		Human
    Bovine
    Rat    		[30][31][32]
    [33]
    [28]
    H2NDNDND
    H3NDNDND
    H4>10,000Human[31]
    mACh4,600
    10,000
    10,000 (IC50)
    6,310 (pA2)
    3,800    		Human
    Mouse
    Rat
    Guinea pig
    Bovine    		[34]
    [29]
    [28]
    [35]
    [33]
    VDCC≥3,400 (IC50)Rat[28]
    Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

    Hydroxyzine's predominant mechanism of action is as a potent and selective histamine H1 receptor inverse agonist.[36][37] This action is responsible for its antihistamine and sedative effects.[36][37] Unlike many other first-generation antihistamines, hydroxyzine has very low affinity for the muscarinic acetylcholine receptors, and in accordance, has low or no propensity for producing anticholinergic side effects.[33][37][38][39] In addition to its antihistamine activity, hydroxyzine has also been shown to act more weakly as an antagonist of the serotonin 5-HT2A receptor, the dopamine D2 receptor, and the α1-adrenergic receptor.[28][36] The weak antiserotonergic effects of hydroxyzine likely underlie its usefulness as an anxiolytic,[40] as other antihistamines without such properties have not been found to be effective in the treatment of anxiety.[41]

    Hydroxyzine crosses the blood–brain barrier easily and exerts effects in the central nervous system.[36] A positron emission tomography (PET) study found that brain occupancy of the H1 receptor was 67.6% for a single 30 mg dose of hydroxyzine.[42] In addition, subjective sleepiness correlated well with the brain H1 receptor occupancy.[42] PET studies with antihistamines have found that brain H1 receptor occupancy of more than 50% is associated with a high prevalence of somnolence and cognitive decline, whereas brain H1 receptor occupancy of less than 20% is considered to be non-sedative.[43]

    Pharmacokinetics

    Hydroxyzine can be administered orally or via intramuscular injection. When given orally, hydroxyzine is rapidly absorbed from the gastrointestinal tract. The effect of hydroxyzine is notable in 30 minutes.

    Pharmacokinetically, hydroxyzine is rapidly absorbed and distributed in oral and intramuscular administration, and is metabolized in the liver; the main metabolite (45%), cetirizine, is formed through oxidation of the alcohol moiety to a carboxylic acid by alcohol dehydrogenase, and overall effects are observed within one hour of administration. Higher concentrations are found in the skin than in the plasma. Cetirizine, although less sedating, is non-dialyzable and possesses similar anti-histaminergic properties. The other metabolites identified include a N-dealkylated metabolite, and an O-dealkylated 1/16 metabolite with a plasma half-life of 59 hours. These pathways are mediated principally by CYP3A4 and CYP3A5.[44] "In animals, hydroxyzine and its metabolites are excreted in feces via biliary elimination."[45]

    Administration in geriatrics differs from the administration of hydroxyzine in younger patients; according to the FDA, there have not been significant studies made (2004), which include population groups over 65, which provide a distinction between elderly aged patients and other younger groups. Hydroxyzine should be administered carefully in the elderly with consideration given to possible reduced elimination.[22]

    Similarly, the use of sedating drugs alongside hydroxyzine can cause oversedation and confusion if administered in large amounts—any form of treatment alongside sedatives should be done under supervision of a doctor.[17][22]

    The Tmax of hydroxyzine is about 2.0 hours in both adults and children and its elimination half-life is around 20.0 hours in adults and 7.1 hours in children.[8][9] Another study found that the elimination half-life of hydroxyzine in adults was as short as 3 hours, but this may have been due to methodological limitations.[46]

    Chemistry

    Hydroxyzine is a member of the diphenylmethylpiperazine class of antihistamines.

    Analogues

    Analogues of hydroxyzine include buclizine, cetirizine, cinnarizine, cyclizine, etodroxizine, meclizine, and pipoxizine among others.

    Synthesis

    Hydroxyzine is synthesized by the alkylation of 1-(4-chlorobenzhydryl)piperazine with 2-(2-Chloroethoxy)ethanol:[47]

    Society and culture

    Cost

    In the United Kingdom 28 doses cost less than a pound.[4] In the United States the wholesale cost in 2018 was about 0.05 USD per dose.[12] In 2017, it was the 99th most commonly prescribed medication in the United States, with more than seven million prescriptions.[13][14]

    • Hydroxyzine costs (US)
      Hydroxyzine costs (US)
    • Hydroxyzine prescriptions (US)
      Hydroxyzine prescriptions (US)

    Brand names

    Hydroxyzine preparations require a doctor's prescription. The drug is available in two formulations, the pamoate and the dihydrochloride or hydrochloride salts. Vistaril, Equipose, Masmoran, and Paxistil are preparations of the pamoate salt, while Atarax, Alamon, Aterax, Durrax, Tran-Q, Orgatrax, Quiess, and Tranquizine are of the hydrochloride salt.

    References

    1. ↑ "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 2020-10-20. Retrieved 2020-08-05.
    2. 1 2 "Hydroxyzine". pubchem.ncbi.nlm.nih.gov. Archived from the original on 13 August 2020. Retrieved 4 March 2020.
    3. 1 2 3 4 5 6 7 8 9 10 "Hydroxyzine Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 27 March 2019. Retrieved 21 Nov 2018.
    4. 1 2 3 4 5 6 British national formulary : BNF 74 (74 ed.). British Medical Association. 2017. p. X. ISBN 978-0857112989.
    5. ↑ Hubbard, John R.; Martin, Peter R. (2001). Substance Abuse in the Mentally and Physically Disabled. CRC Press. p. 26. ISBN 9780824744977. Archived from the original on 2020-08-01. Retrieved 2019-08-20.
    6. ↑ "Hydroxyzine Use During Pregnancy". Drugs.com. 4 May 2020. Archived from the original on 30 October 2020. Retrieved 17 May 2020.
    7. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 22 January 2021. Retrieved 30 August 2020.
    8. 1 2 3 Paton DM, Webster DR (1985). "Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines)". Clin. Pharmacokinet. 10 (6): 477–97. doi:10.2165/00003088-198510060-00002. PMID 2866055.
    9. 1 2 Simons FE, Simons KJ, Frith EM (1984). "The pharmacokinetics and antihistaminic of the H1 receptor antagonist hydroxyzine". J. Allergy Clin. Immunol. 73 (1 Pt 1): 69–75. doi:10.1016/0091-6749(84)90486-x. PMID 6141198.
    10. ↑ Fein, MN; Fischer, DA; O'Keefe, AW; Sussman, GL (2019). "CSACI position statement: Newer generation H1-antihistamines are safer than first-generation H1-antihistamines and should be the first-line antihistamines for the treatment of allergic rhinitis and urticaria". Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. 15: 61. doi:10.1186/s13223-019-0375-9. PMID 31582993.
    11. ↑ Shorter E (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 9780195368741. Archived from the original on 2020-01-02. Retrieved 2016-09-23.
    12. 1 2 "NADAC as of 2018-11-21". Centers for Medicare and Medicaid Services. Archived from the original on 2019-06-01. Retrieved 21 Nov 2018.
    13. 1 2 "The Top 300 of 2020". ClinCalc. Archived from the original on 12 February 2021. Retrieved 11 April 2020.
    14. 1 2 "Hydroxyzine - Drug Usage Statistics". ClinCalc. Archived from the original on 8 July 2020. Retrieved 11 April 2020.
    15. ↑ Guaiana G, Barbui C, Cipriani A (8 Dec 2010). "Hydroxyzine for generalised anxiety disorder". Cochrane Database Syst. Rev. (12): CD006815. doi:10.1002/14651858.CD006815.pub2. PMID 21154375.
    16. 1 2 United States Food & Drug Administration, (2004), p1
    17. 1 2 3 Dolan CM (1958). "Management of Emotional Disturbances — Use of Hydroxyzine (Atarax®) in General Practice". Calif. Med. 88 (6): 443–4. PMC 1512309. PMID 13536863.
    18. 1 2 "HYDROXYZINE oral - Essential drugs". medicalguidelines.msf.org. Archived from the original on 2 March 2021. Retrieved 30 August 2020.
    19. 1 2 3 4 5 6 United States Food & Drug Administration, (2004), p2
    20. 1 2 3 Clark BG, Araki M, Brown HW (1982). "Hydroxyzine‐associated tardive dyskinesia". Ann. Neurol. 11 (4): 435. doi:10.1002/ana.410110423. PMID 7103423.
    21. 1 2 3 UCB South-Africa, et al., (2004)
    22. 1 2 3 United States Food & Drug Administration, (2004), p3
    23. ↑ Anderson PO, Knoben JE, Troutman WG (2002). Handbook of Clinical Drug Data (10th ed.). New York: McGraw-Hill Medical. pp. 794-6. ISBN 9780071363624.
    24. 1 2 3 De Brabander A, Deberdt W (1990). "Effect of hydroxyzine on attention and memory". Human Psychopharmacology. 5 (4): 357–62. doi:10.1002/hup.470050408.
    25. ↑ Alford C, Rombaut N, Jones J, Foley S, Idzikowski C, Hindmarch I (1992). "Acute effects of hydroxyzine on nocturnal sleep and sleep tendency the following day: A C‐EEG study". Human Psychopharmacology. 7 (1): 25–35. doi:10.1002/hup.470070104. {{cite journal}}: Unknown parameter |displayauthors= ignored (help)
    26. ↑ "NCQA's HEDIS Measure: Use of High Risk Medications in the Elderly" (PDF). NCQA.org. 2008. Archived from the original (PDF) on 1 February 2010. Retrieved 22 Feb 2010.
    27. ↑ Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 March 2021. Retrieved 14 Aug 2017.
    28. 1 2 3 4 5 6 7 Snowman AM, Snyder SH (1990). "Cetirizine: actions on neurotransmitter receptors". J. Allergy Clin. Immunol. 86 (6 Pt 2): 1025–8. doi:10.1016/S0091-6749(05)80248-9. PMID 1979798.
    29. 1 2 3 Haraguchi K, Ito K, Kotaki H, Sawada Y, Iga T (1997). "Prediction of drug-induced catalepsy based on dopamine D1, D2, and muscarinic acetylcholine receptor occupancies". Drug Metab. Dispos. 25 (6): 675–84. PMID 9193868. Archived from the original on 2021-08-28. Retrieved 2010-09-25. {{cite journal}}: Unknown parameter |displayauthors= ignored (help)
    30. ↑ Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P (2002). "Binding characteristics of cetirizine and levocetirizine to human H1 histamine receptors: contribution of Lys191 and Thr194" (PDF). Mol. Pharmacol. 61 (2): 391–399. doi:10.1124/mol.61.2.391. PMID 11809864. Archived from the original (PDF) on 2019-02-19. Retrieved 2020-05-05. {{cite journal}}: Unknown parameter |displayauthors= ignored (help)
    31. 1 2 Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R (2005). "Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist". J. Pharmacol. Exp. Ther. 314 (3): 1310–21. doi:10.1124/jpet.105.087965. PMID 15947036. {{cite journal}}: Unknown parameter |displayauthors= ignored (help)
    32. ↑ Anthes JC, Gilchrest H, Richard C, Eckel S, Hesk D, West RE, Williams SM, Greenfeder S, Billah M, Kreutner W, Egan RE (2002). "Biochemical characterization of desloratadine, a potent antagonist of the human histamine H1 receptor". Eur. J. Pharmacol. 449 (3): 229–37. doi:10.1016/s0014-2999(02)02049-6. PMID 12167464. {{cite journal}}: Unknown parameter |displayauthors= ignored (help)
    33. 1 2 3 Kubo N, Shirakawa O, Kuno T, Tanaka C (1987). "Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay". Japanese Journal of Pharmacology. 43 (3): 277–82. doi:10.1254/jjp.43.277. PMID 2884340. {{cite journal}}: Unknown parameter |displayauthors= ignored (help)
    34. ↑ Cusack B, Nelson A, Richelson E (1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology. 114 (4): 559–65. doi:10.1007/bf02244985. PMID 7855217.
    35. ↑ Orzechowski RF, Currie DS, Valancius CA (2005). "Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models". Eur. J. Pharmacol. 506 (3): 257–64. doi:10.1016/j.ejphar.2004.11.006. PMID 15627436.
    36. 1 2 3 4 Szepietowski J, Weisshaar E (2016). Itin P, Jemec GB (eds.). Itch - Management in Clinical Practice. Current Problems in Dermatology. Vol. 50. Karger Medical and Scientific Publishers. pp. 1–80. ISBN 9783318058895. Archived from the original on 2021-02-26. Retrieved 2017-10-09.
    37. 1 2 3 Hosák L, Hrdlička M, et al. (2017). Psychiatry and Pedopsychiatry. Charles University in Prague, Karolinum Press. p. 364. ISBN 9788024633787.
    38. ↑ Berger FM (1957). "The Chemistry and Mode of Action of Tranquilizing Drugs". Ann. N. Y. Acad. Sci. 67 (10): 685–700. Bibcode:1957NYASA..67..685B. doi:10.1111/j.1749-6632.1957.tb46006.x. PMID 13459139.
    39. ↑ Tripathi KD (2013). Essentials of Medical Pharmacology. JP Medical Ltd. p. 165. ISBN 9789350259375.
    40. ↑ Stein DJ, Hollander E, Rothbaum BO, eds. (2009). Textbook of Anxiety Disorders. American Psychiatric Publishing, Inc. p. 196. ISBN 9781585622542.
    41. ↑ Lamberty Y, Gower AJ (2004). "Hydroxyzine prevents isolation-induced vocalization in guinea pig pups: comparison with chlorpheniramine and immepip". Pharmacol. Biochem. Behav. 79 (1): 119–24. doi:10.1016/j.pbb.2004.06.015. PMID 15388291.
    42. 1 2 Tashiro M, Kato M, Miyake M, Watanuki S, Funaki Y, Ishikawa Y, Iwata R, Yanai K (2009). "Dose dependency of brain histamine H1 receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [11C]doxepin". Human Psychopharmacology. 24 (7): 540–8. doi:10.1002/hup.1051. PMID 19697300. {{cite journal}}: Unknown parameter |displayauthors= ignored (help)
    43. ↑ Yanai K, Tashiro M (2007). "The physiological and pathophysiological roles of neuronal histamine: an insight from human positron emission tomography studies". Pharmacol. Ther. 113 (1): 1–15. doi:10.1016/j.pharmthera.2006.06.008. PMID 16890992.
    44. ↑ "Ucerax (hydroxyzine hydrochloride) 25 mg film-coated tablets. Summary of product characteristics" (PDF). Irish Medicines Board. 2013. Archived from the original (PDF) on 22 February 2014. Retrieved 9 Feb 2014.
    45. ↑ "VISTARIL® (hydroxyzine pamoate) Capsules and Oral Suspension" (PDF). pfizer.com. 2006. Archived from the original (PDF) on 3 July 2007. Retrieved 7 Mar 2007. The extent of renal excretion of VISTARIL has not been determined
    46. ↑ Kacew S (1989). Drug Toxicity & Metabolism In Pediatrics. CRC Press. p. 257. ISBN 9780849345647.
    47. ↑ H. Morren, U.S. Patent 2,899,436 (1959); H. Morren, DE 1049383  (1954); H. Morren, DE 1061786  (1954); H. Morren, DE 1068262  (1954); H. Morren, DE 1072624  (1954); H. Morren, DE 1075116  (1954).
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