R06AE03 - Cyclizine |
Propably not porphyrinogenic |
PNP |
Rationale
Cyclizine is a weak inhibitor of CYP2C9 in vitro. It is not an inducer or a mechanism-based inhibitor of any major CYP isoenzymes. Several references have listed it as safe for use in patients with acute porphyria.
Therapeutic characteristics
Cyclizine is indicated for the prevention and treatment of nausea and vomiting.
Side effects that have been reported (unknown frequency) are constipation, tachycardia, hepatic dysfunction, hypersensitivity hepatitis, somnolence, headache, dystonia, dyskinesia, tremor, convulsions, dizziness, decreased consciousness and paresthesia, disorientation, nervousness, insomnia, hypertension and hypotension.
Hepatic exposure
Probably irrelevant
Metabolism and pharmakokinetics
There are little data available on the pharmacokinetics of cyclizine, but data indicates that CYP2D6 might be involved in the metabolism of cyclizine to norcyclizine (Vella-Brincat 2012). Norcyclizine has little pharmacological effect compared to cyclizine and both have an elimination half-life of approximately 20 hours (SPC).
In vitro studies indicate that cyclizine is a weak inhibitor of CYP2C9 and CYP2D6. The inhibition of CYP2C9 required concentrations above that usually seen in plasma and indicates therefore that it has low likelihood of inducing drug-drug interactions with substrates of CYP2C9 (He 2002).
In the literature cyclizine is not reported to be an inducer or inhibitor of any of the quantitatively major CYP enzymes and the absence of such characteristics is also in accordance with review-papers (FDA, Pelkonen 2008, Isoherranen 2009, Hisaka 2010). No drug-drug interaction with cyclizine as a perpetrator has been reported in the literature.
Personal communication
M. Badminton: 2 reports of tolerance.
Published experience
Cyclizine is listed as safe for use in patients with acute porphyria (Eales 1979, Disler 1982, Moore 1997).
Cyclizine is listed as an option for the treatment of symptoms during an acute attack (Puy 2010).
IPNet drug reports
Uneventful use reported in 5 patients with acute porphyria.
References
- Scientific articles
- Disler, P. B., G. H. Blekkenhorst, et al. (1982). Guidelines for drug prescription in patients with the acute porphyrias. S Afr Med J 61(18): 656-660. #2817
- Eales, L. (1979). Porphyria and the dangerous life-threatening drugs. S Afr Med J 56(22): 914-917. #2904
- He, N., W. Q. Zhang, et al. (2002). Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes. Eur J Clin Pharmacol 57(12): 847-851. #2905
- Hisaka, A., Y. Ohno, et al. (2010). Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information. Pharmacol Ther 125(2): 230-248. #2906
- Isoherranen, N., H. Hachad, et al. (2009). Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database. Chem Res Toxicol 22(2): 294-298. #2907
- Moore, M. R. and R. J. Hift (1997). Drugs in the acute porphyrias--toxicogenetic diseases. Cell Mol Biol (Noisy-le-grand) 43(1): 89-94. #2822
- Pelkonen, O., M. Turpeinen, et al. (2008). Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol 82(10): 667-715. #2908
- Puy, H., L. Gouya, et al. (2010). Porphyrias. Lancet 375(9718): 924-937. #2909
- Vella-Brincat, J. W., E. J. Begg, et al. (2012). The pharmacokinetics and pharmacogenetics of the antiemetic cyclizine in palliative care patients. J Pain Symptom Manage 43(3): 540-548. #2912
- Drug interaction databases
- U.S.FoodandDrugAdministration(FDA). (16.09.2011). Drug Developement and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Retrieved 04.07.2013, from #2911
- Summary of Product Characteristics
- The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Cyclizine. #2910
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