LETTER TO THE EDITORS

On the possible interaction between vaccines and drugs

Paolo Pellegrino & Carla Carnovale & Valentina Perrone & Dionigi Salvati & Marta Gentili &Tatiana Brusadelli & Marco Pozzi & Stefania Antoniazzi & Emilio Clementi & Sonia Radice

Received: 14 November 2013 /Accepted: 17 November 2013 /Published online: 5 December 2013# Springer-Verlag Berlin Heidelberg 2013

Dear Sirs,Reduction in the hepatic cytochrome P450 system activity hasbeen described after a vaccination in previous studies [1, 2].While the mechanism behind such reduction was explained asthe consequence of the activity of inflammatory cytokines onthe mRNA level of hepatic cytochromes [3], it is unclear whateffect this interaction may have in the clinical practice.

To date, only few reports describe significant changes indrug pharmacokinetics after the administration of a vaccine [4,5], and small cohort studies reported contrasting results inpatients treated with drugs that may be influenced by thisinteraction [6, 7, 10–12]. Moreover, it is unclear how theeffects of vaccines on hepatic cytochrome P450 system activ-ity affect patients who present risk factors such as age orgenetic predisposition [1, 2].

To explore this issue further, we used the Vaccine AdverseEvent Reporting System (VAERS) database, which collectsinformation about adverse events following the administrationof vaccines and is useful to detect rare vaccine-related adverseevents [8].

We carried out a search of all reports consistent with avaccine–drug interaction resulting in an adverse drug reaction,

in a detectable increase of drug serum level, or in a change ofdrug-related biomarkers such as the International NormalizedRatio (INR).

As the patients were treated with more than a single drug inmany of the cases, we considered only those cases in whichthere was no mention of recent therapy variation, or there wasan explicit statement about the absence of variations.

As highlighted in Table 1, we retrieved and validated 28reports. Among these, 12 were related to an increase of INR,and ten described an increase of serum level of phenytoin,carbamazepine and theophylline (Table 1). The remaining sixcases described an adverse drug reaction attributed to aninteraction between the vaccine and the drugs (Table 1). Asexpected, considering previous observations [1], we foundthat most of the cases occurred in elderly patients and withinthe first weeks after vaccine administration.

Aitken et al. recently observed that human CYP2C8, 2C9,2C18, 2C19, 2B6, and 3A4 mRNA expression is down-regulated by inflammatory cytokines [3], which are also re-leased as result of a vaccination [1, 2].

As one or more of these hepatic cytochromes metabolizesphenytoin, theophylline and carbamazepine, a reduction intheir expression due to vaccination may explain the increasedlevel of these drugs that we observed after vaccination. Inagreement, other studies showed an increase in phenytoinserum level after vaccination with pertussis vaccine [10] andsuccessive studies confirmed this finding in other drugs suchas theophylline [11, 12].

The increased INR we observed with warfarin may also beexplained by the vaccination. Warfarin is metabolized primar-ily by CYP2C9, and a reduction in the activity of this hepaticcytochrome may result in an increase of INR [9]. The reducedactivity of this enzyme due to genetic polymorphisms [9], aswell as the presence of other variants that may affect thecytokines response to vaccination, may create a subgroup ofpatients at higher risk for this interaction than the ones ob-served in our analysis.

Paolo Pellegrino and Carla Carnovale contributed equally to this work.

P. Pellegrino :C. Carnovale :V. Perrone :D. Salvati :M. Gentili :T. Brusadelli : E. Clementi (*) : S. Radice (*)Unit of Clinical Pharmacology, Department of Biomedical andClinical Sciences, University Hospital “Luigi Sacco”, Università diMilano, Via GB Grassi 74, 20157 Milan, Italye-mail: emilio.clementi@unimi.ite-mail: sonia.radice@unimi.it

M. Pozzi : E. ClementiScientific Institute, IRCCS E.Medea, 23842 Bosisio Parini, LC, Italy

S. AntoniazziIRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico,Milan 20122, Italy

Eur J Clin Pharmacol (2014) 70:369–371DOI 10.1007/s00228-013-1616-3

Taken together, these observations indicate a possible riskof drug–vaccine interactions due to cytochrome inhibitionbased on vaccine-induced increase of cytokines. It is likelyto assume the presence of specific risk factors for these inter-actions, such as age and genetic basis. Further analyses arerequired to better assess these findings.

Acknowledgments The financial support by the Italian MedicinesAgency, AIFA, and the Centre of Pharmacovigilance of Regione Lom-bardia (ViGer project, Vigilanza in Geriatria, to EC) and the ItalianMinistry of Health (RC 2013 to EC) is gratefully acknowledged.

Conflict of interest We declare no conflict of interest.

References

1. Pellegrino P, Carnovale C, Borsadoli C, Danini T, Speziali A, PerroneV, Antoniazzi S, Pozzi M, Clementi E, Radice S (2013) Two cases ofhallucination in elderly patients due to a probable interaction betweenflu immunization and tramadol. Eur J Clin Pharmacol 69(8):1615–1616

2. Hayney MS, Buck JM (2002) Effect of age and degree of immuneactivation on cytochrome P450 3A4 activity after influenza immuni-zation. Pharmacotherapy 22(10):1235–1238

3. Aitken AE, Morgan ET (2007) Gene-specific effects of in-flammatory cytokines on cytochrome P450 2C, 2B6 and 3A4mRNA levels in human hepatocytes. Drug Metab Dispos35(9):1687–1693

4. Robertson WC Jr (2002) Carbamazepine toxicity after influenzavaccination. Pediatr Neurol 26(1):61–63

Table 1 Cases from the VAERS database

Vaccine Drug Adverse drug reaction Other drugs Lab data

Hepatitis b Triamterene; hydrochlorothiazide Rash, itching Yes No

Influenza Theophylline Elevated serum level Yes Yes

Influenza Theophylline Elevated serum level No Yes

Influenza Theophylline Elevated serum level Yes Yes

Influenza Carbamazepine Elevated serum level Yes Yes

Influenza Carbamazepine Elevated serum level Yes Yes

Dtap+Hepb+Ipv Theophylline Elevated serum level No No

Influenza Enalapril Therapeutic failure Yes No

Influenza Phenytoin Elevated serum level Yes Yes

Influenza Phenytoin Elevated serum level Yes Yes

Influenza Phenytoin Elevated serum level Yes Yes

Influenza Theophylline Elevated serum level Yes Yes

Hepatitis b Unknown Possible interaction ? No

Hepatitis ba Imitramine Hallucinations, drug interaction No No

MMRa Imitramine Hallucinations, drug interaction No No

Td adsorbeda Imitramine Hallucinations, drug interaction No No

Zoster Sumatriptan Therapeutic failure No No

Influenza Cyclosporine (Ophthalmic) Headaches and facial twitching No No

Influenza Warfarin Increased INR No Yes (INR)

Influenza H1N1 Warfarin Increased INR No Yes (INR)

Influenza H1N1 Warfarin Increased INR Yes Yes (INR)

Influenza Warfarin Increased INR Yes Yes (INR)

Influenza Warfarin Increased INR Yes Yes (INR)

Influenza Warfarin Increased INR Yes Yes (INR)

Zoster Warfarin Increased INR Yes Yes (INR)

Influenza Warfarin Increased INR Yes Yes (INR)

Pneumococcus Warfarin Increased INR No Yes (INR)

Zoster Warfarin Increased INR No Yes (INR)

Zoster Warfarin Increased INR No Yes (INR)

Influenza Warfarin Increased INR Yes Yes (INR)

MMR measles, mumps, and rubella vaccine; Dtap +Hepb +Ipv diphtheria & tetanus toxoids/acellular pertussis vaccine/poliovirus vaccine inactivated/hepatitis b vaccine; Td adsorbed tetanus and diphtheria toxoids adsorbed; INR International Normalized Ratioa Same patients

370 Eur J Clin Pharmacol (2014) 70:369–371

5. Kuo AM, Brown JN, Clinard V (2012) Effect of influenza vaccina-tion on international normalized ratio during chronic warfarin thera-py. J Clin Pharm Ther 37(5):505–509

6. Jackson ML, Nelson JC, Chen RT, Davis RL, Jackson LA, VaccineSafety Datalink Investigators (2007) Vaccines and changes in coag-ulation parameters in adults on chronic warfarin therapy: a cohortstudy. Pharmacoepidemiol Drug Saf 16(7):790–796

7. Raj G, Kumar R, McKinney WP (1995) Safety of intramuscularinfluenza immunization among patients receiving long-term warfarinanticoagulation therapy. Arch Intern Med 155(14):1529–1531

8. http://vaers.hhs.gov/index [last access 10/31/13]

9. Johnson JA, Cavallari LH (2013) Pharmacogenetics and cardiovas-cular disease—implications for personalized medicine. PharmacolRev 65(3):987–1009

10. Renton KW (1979) The deleterious effect of Bordetella pertussisvaccine and poly(rI.rC) on the metabolism and disposition of phe-nytoin. J Pharmacol Exp Ther 208(2):267–270

11. Meredith CG, Christian CD, Johnson RF, Troxell R, Davis GL,Schenker S (1985) Effects of influenza virus vaccine on hepatic drugmetabolism. Clin Pharmacol Ther 37(4):396–401

12. Jann MW, Fidone GS (1986) Effect of influenza vaccine on serumanticonvulsant concentrations. Clin Pharm 5(10):817–820

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