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Interaction Pearls: 5 Reasons to be on your Pharmacists’ Good Side

Interaction Pearls: 5 Reasons to be on your Pharmacists’ Good Side. By Arianne Lareau (M.Sc.), Julie Morin (M.Sc.), Audrey Séguin (M.Sc.), and Andréanne Vincent (M.Sc.), Presented by Audrey Séguin Santa Cabrini Hospital. Disclosure. No conflict of interest. Patient Case No.1 50 y-old ♂.

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Interaction Pearls: 5 Reasons to be on your Pharmacists’ Good Side

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  1. Interaction Pearls: 5 Reasons to be on your Pharmacists’ Good Side By Arianne Lareau (M.Sc.), Julie Morin (M.Sc.), Audrey Séguin (M.Sc.), and Andréanne Vincent (M.Sc.), Presented by Audrey Séguin Santa Cabrini Hospital

  2. Disclosure No conflict of interest

  3. Patient Case No.150 y-old ♂ • Medical Hx: • Schizophrenia, HTA, DLP, DB II, HBP • Smoker (1 pack/day), ⍉ Alcohol, ⍉ Drugs • No known allergies • Medication: • Clozapine 300 mg once a day • Atorvastatine 40 mg once a day • Ramipril 5mg once a day • Metformin 500 mg twice daily • Tamsulosin 0,4 mg once a day • Admitted for severe urosepsis • Abx: Piperacilline-Tazobactam 3g IV q6h

  4. Patient Case No.1Part I • On day 4: • New onset of aSx tachycardia (pulse 120), and mild drowsiness. • Normal blood pressure, no fever. • No laboratory abnormalities • Normal electrolytes • Creatinine 70 umol/L and stable • WBC and neutrophils are decreasing • Normal liver function • Normal ECG What’s happening?

  5. Clozapine • Atypical antipsychotic • Metabolism : extensively hepatic via the CYP1A2 (primarily), 2C19, 3A4 and 2D6. • Metabolites have limited or no activity • Non-dose dependant adverse effects • Sialorrhea • Agranulocytosis • Hypotension* • Dose-dependant adverse effects • Tachycardia • Drowsiness    • Seizures *speed titration dependant

  6. Cigarette smoking • Strong inducer of the CYP1A2 • ≥ 7 cigarettes/day : enzymatic induction of CYP 1A2 and UDP-glucuronosyl-transferases (UGT) • Clozapine plasmatic concentration ⬇ 33 to 75% • Upon smoking cessation: clozapine plasmatic concentration ⬆ 57 to 72 % Nicotine replacement therapy does NOT solve the problem

  7. What is recommended in the literature ? • if patient smokes ≥ 20 cigarettes/day or marijuana abuse • ⬇ 40% clozapine dose in the first 4 days (10%/day) • if patient smokes between 7 - 19 cigarettes • No clinical data, based on clinical judgement • ⬇ 25 - 33% clozapine dose in the first 4 days (10%/day) What is recommended based on our clinical experience ? • The decision to decrease the dose of clozapine is based on many factors : • Clozapine dosage of the patient (high vs low dose) • Is the patient smoking during his/her hospital stay? • Will the patient continue smoking after hospital discharge?

  8. What did we do? • MD + pharmacist decided to keep the same clozapine dose BECAUSE : • Patient has a low clozapine dose • Patient wants to keep smoking at discharge • The patient discharge is planed in less than 48h

  9. Patient case No.1Part II • Urine cultures are available : • E coli (S) to ciprofloxacin and amoxicilline-clavulanate • Piperacilline-tazobactam is changed to ciprofloxacin 500 mg PO twice daily (total duration of antibiotic = 10 days) • Hospital discharge Is everything OK?

  10. Ciprofloxacin • Fluoroquinolone • CYP1A2 inhibitor • Can ⬆ plasmatic concentration of clozapine by 30 - 500 % in 48h • No interaction with moxifloxacin and levofloxacin

  11. What did we do? • Changed Ciprofloxacin for Amoxicillin-clavulanate 875mg PO twice daily.

  12. Patient case No.245 y-old ♀ • Medical Hx: • Obesity (BMI = 32 kg/m2) • Epilepsy in childhood. No anticonvulsant since she was 20 years old. • DVTs x 2, • 1st DVT secondary to use of hormone therapy • Last DVT 2 months ago complicated by PE (unprovoked) • Medication: • Apixaban 5mg twice daily for life • Admitted for new onset of epilepsy • At the emergency room she received an IV phenytoin loading dose • She is now stabilized on IV phenytoin 5 mg/kg/day for the last 48h • The plan is to switch IV phenytoin  PO for long term management • A follow up in neurology in 6 weeks is scheduled

  13. Phenytoin • Strong CYP inducer (including the 3A4) • Also induces the P-glycoprotein (P-gp)

  14. Apixaban • Apixaban is metabolized via CYP3A4, and P-gp (to a lesser extent) • DOAC’s plasmatic concentration: • ⬇ Dabigatran 66% • ⬇ Rivaroxaban up to 50% • ⬇ Apixaban 54% • ⬇ Edoxaban 34%

  15. What is recommended in the literature ? • AVOID this combination • Switch to warfarin and close follow-up of INR + Phenytoin concentration • Warfarin ⬆ levels of Phenytoin and Phenytoin ⬇ effect of Warfarin • Other antiepileptic medication to avoid because of CYP and P-gp induction: carbamazepine and phenobarbital What is recommended based on our clinical experience ? • A loading dose of phenytoin would be reasonable • Not many IV anticonvulsant options for the acute phase • Delay before enzymatic induction takes between 7 to 14 days • DOAC + phenytoin should be avoided in chronic management of a condition requiring therapeutic anticoagulation

  16. What did we do? • Consider switching to levetiracetam PO • No interaction

  17. Patient case No.370 y-old, ♀ • Medical Hx : • Epilepsy, HTA, DB II, COPD • Hospitalized 2 months ago for pneumonia • History of Penicillin allergy • Medication: • Fosinopril 20 mg PO once a day • Metformin 500 mg PO three times a day • Sitagliptine 50 mg PO once a day • Carbamazepine 200 mg PO three time a day • Valproic acid 1000 mg PO at breakfast and before bedtime + 500 mg PO at dinner • Tiotropium 18 mcg 1 inhalation once a day • Admitted to ICU for MI

  18. Patient case No.3Part I • Treatment: • Aspirin 160mg + Ticagrelor 180mg loading doses • PCI  DES on the left coronary artery • Metoprolol 50 mg po twice daily • Rosuvastatin 40 mg po once a day • Aspirin 80 mg PO once a day • Ticagrelor 90 mg PO twice daily • Enoxaparin 40 mg SC once a day • Pantoprazole 40mg po once a day

  19. Ticagrelor • Platelet inhibition: P2Y12 receptor antagonist. • Not a prodrug (compared to clopidogrel and prasugrel). • Doesn’t need metabolic activation for antiplatelet activity. • Approximately ⅓ of the parent drug is metabolized into an active metabolite AR-C124910XX by CYP3A4/A5.

  20. Carbamazepine • Anticonvulsant • Substrate of the CYP3A4 • Also a strong inducer of CYP3A4 and to a lesser extent of CYP1A2, CYP2B6, and UGT1A1 • Effect on ticagrelor: • ⬇ Cmax of 73% • ⬇ AUC of 86% • ⬇ T1/2 of 7hrs to 3hrs • Ticagrelor active metabolite/parent drug ratio = ⬆ by 4X

  21. What is recommended in the literature ? • AVOID this combination • What is recommended base on our clinical experience ? • Switch to another P2Y12 inhibitor that do not undergo metabolic transformation by CYP3A4 • Clopidogrel or Prasugrel are alternatives • Clopidogrel = pro-drug. Activated by CYP2C19 • Prasugrel = pro-drug. Activated by oxidation. NOT metabolized by CYP 450. • Don’t forget to give a loading dose.

  22. What did we do? • MD + pharmacist decided to switch from TICAGRELOR to CLOPIDOGREL. • Clopidogrel was chosen over Prasugrel because of the bleeding risk factors (woman, age 70)

  23. Patient case No.3Part II • 5 days later: hyperthermia, leucocytosis, tachypnea • Normal renal and hepatic function • Septic evaluation: including blood cultures, procalcitonin and a pulmonary X-ray. • Suspicion of nosocomial pneumonia Empiric antibiotherapy started: • Meropenem 1g IV q8h STAT (history of PNC known) • Vancomycin 1g IV q12h

  24. Pharmacist’s reaction

  25. Interaction between Valproic acid and Carbapenems • The capacity of the VPAGase is different between the carbapenems. • Mean ⬇ [valproate] of 80% with meropenem ; 69% with ertapenem; 51% with imipenem/cilastatin • Rapid onset: 24-48hrs after adding Meropenem or Ertapenem. Up to 5 days after adding Imipenem. • VPA levels return to baseline only 8 to 14 days after carbapenem discontinuation.

  26. What should we do? • Double valproic acid doses and close follow-up levels? • Change Meropenem for Imipenem/Cilastatin? • Decrease Meropenem doses and monitor patient closely? • Change Meropenem for another class of antibiotic?

  27. Double the dose of Valproic acid? • The interaction persists (subtherapeutic levels of Valproate) despite use of increased doses. NO

  28. Change for Imipenem/Cilastatin? • Seems to be a better candidate, BUT • imipenem is the most epileptogenic carbapenem • at least 50% drop of Valproate levels NO

  29. Decrease Meropenem doses and Monitor • Interaction is NOT dose-dependent • 33 to 48% of subjects had worsening of their seizures NO

  30. Change the class of Abx • When possible! • If the use of a carbapenem is inevitable, some experts recommend adding an antiepileptic such as Levetiracetam which should be continued at least for 2 weeks after discontinuation of the carbapenem. YES

  31. What did we do? • After further investigation of the PNC allergy history, the patient had a small rash in childhood, with no respiratory Sx. • Kept the same anticonvulsants • Changed Meropenem for Piperacilline-tazobactam 4g IV q6h

  32. Thank you for your attention!

  33. References • Benoît Rouleau, Philippe Vincent, Josée Martel. Le monitorage thérapeutique de la clozapine : une nécessité clinique, Pharmactuel Vol. 41 N° 2 Mars - Avril 2008 • Morgan Snyder and Tawny Smith (2011) Case Report: The clinical implications of clozapine and cigarette smoking. Mental Health Clinician: November 2011, Vol. 1, No. 5, pp. 107-109. • Claudia Stöllberger, Josef Finsterer. Interactions between non-vitamin K oral anticoagulants and antiepileptic drugs. Epilepsy Research 126 (2016) 98–101. • Ishikawa T, Otaki H, Mizuta S, Kuriyama M, Onomura O, Higuchi N, Nakashima MN, Nakashima M, Ohyama K. Computational study of the competitive binding of valproic acid glucuronide and carbapenem antibiotics to acylpeptide hydrolase. Drug Metab Pharmacokinet. 2017 Aug;32(4):201-207. doi: 10.1016/j.dmpk.2017.04.002. Epub 2017 Apr 30. PubMed PMID: 28734645. • Huang CR, Lin CH, Hsiao SC, Chen NC, Tsai WC, Chen SD, Lu YT, Chuang YC. Drug interaction between valproic acid and carbapenems in patients with epileptic seizures. Kaohsiung J Med Sci. 2017 Mar;33(3):130-136. doi: 10.1016/j.kjms.2016.12.001. Epub 2017 Jan 11. PubMed PMID: 28254115. • Wu CC, Pai TY, Hsiao FY, Shen LJ, Wu FL. The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations. Ther Drug Monit. 2016 Oct;38(5):587-92. doi: 10.1097/FTD.0000000000000316. PubMed PMID: 27322166.

  34. References • Angiolillo DJ, Rollini F, Storey RF, Bhatt DL, James S, Schneider DJ, Sibbing D, So DYF, Trenk D, Alexopoulos D, Gurbel PA, Hochholzer W, De Luca L, Bonello L, Aradi D, Cuisset T, Tantry US, Wang TY, Valgimigli M, Waksman R, Mehran R, Montalescot G, Franchi F, Price MJ. International Expert Consensus on Switching Platelet P2Y12 Receptor-Inhibiting Therapies. Circulation. 2017 Nov 14;136(20):1955-1975. doi: 10.1161/CIRCULATIONAHA.117.031164. Epub 2017 Oct 30. Review. PubMed PMID: 29084738. • Teng R, Mitchell P, Butler K. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects.Eur J Clin Pharmacol. 2013 Apr;69(4):877-83. doi: 10.1007/s00228-012-1436-x. Epub 2012 Oct 24. PubMed PMID: 23093043. • Dobesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2014 Oct;34(10):1077-90. doi: 10.1002/phar.1477. Epub 2014 Aug 28. Review. PubMed PMID: 25164528; PubMed Central PMCID: PMC4282310.

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