Interaction Pearls: 5 Reasons to be on your Pharmacists Good Side By Arianne Lareau (M.Sc.), Julie Morin (M.Sc.), Audrey Sguin (M.Sc.), and Andranne Vincent (M.Sc.), Presented by Audrey Sguin Santa Cabrini Hospital Disclosure No conflict of interest Patient Case No.1 50 y-old Medical Hx:
Schizophrenia, HTA, DLP, DB II, HBP Smoker (1 pack/day), Alcohol, Drugs Alcohol, Alcohol, Drugs 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 Patient Case No.1 Part 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 Whats happening? 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 Cigarette smoking
Strong inducer of the CYP1A2 7 cigarettes/day : enzymatic induction of CYP 1A2 and UDPglucuronosyl-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 What is recommended in the literature ? if
patient smokes 20 cigarettes/day or marijuana abuse if 40% clozapine dose in the first 4 days (10%/day) 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? 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 Patient case No.1 Part 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? Ciprofloxacin Fluoroquinolone CYP1A2 inhibitor Can plasmatic concentration of clozapine by 30 - 500 % in 48h
No interaction with moxifloxacin and levofloxacin What did we do? Changed Ciprofloxacin for Amoxicillin-clavulanate 875mg PO twice daily. Patient case No.2 45 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 Phenytoin
Strong CYP inducer (including the 3A4) Also induces the P-glycoprotein (P-gp) Apixaban Apixaban is metabolized via CYP3A4, and P-gp (to a lesser extent) DOACs plasmatic concentration: Dabigatran 66%
Rivaroxaban up to 50% Apixaban 54% Edoxaban 34% 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 What did we do? Consider switching to levetiracetam PO No interaction Patient case No.3 70 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 Patient case No.3 Part 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 Ticagrelor Platelet inhibition: P2Y12 receptor antagonist. Not a prodrug (compared to clopidogrel and prasugrel).
Doesnt need metabolic activation for antiplatelet activity. Approximately of the parent drug is metabolized into an active metabolite AR-C124910XX by CYP3A4/A5. 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
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. Dont forget to give a loading dose. 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) Patient case No.3
Part 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 Pharmacists reaction 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. What should we do? a) Double valproic acid doses and close follow-up levels? b)
Change Meropenem for Imipenem/Cilastatin? c) Decrease Meropenem doses and monitor patient closely? d) Change Meropenem for another class of antibiotic? Double the dose of Valproic acid? NO The interaction persists (subtherapeutic levels of Valproate) despite use of increased doses.
Change for Imipenem/Cilastatin? NO Seems to be a better candidate, BUT imipenem is the most epileptogenic carbapenem at least 50% drop of Valproate levels Decrease Meropenem doses and Monitor NO
Interaction is NOT dose-dependent 33 to 48% of subjects had worsening of their seizures Change the class of Abx YES 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. 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 Thank you for your attention! References Benot Rouleau, Philippe Vincent, Jose Martel. Le monitorage thrapeutique de la clozapine : une ncessit 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 Stollberger, Josef Finsterer. Interactions between non-vitamin K oral anticoagulants and antiepileptic drugs. Epilepsy Research 126 (2016) 98101. 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. 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.
