Drug Safety in Pregnancy and Lactation Lecture January 26, 2024 PDF

Drug Safety in Pregnancy and Lactation Pharmacotherapeutics Course PharmD Program, University of Toronto January 26, 2024 Jonathan Zipursky MD PhD FRCPC Divisions of General Internal Medicine and Clinical Pharmacology & Toxicology Ass...

Drug Safety in Pregnancy and Lactation Pharmacotherapeutics Course PharmD Program, University of Toronto January 26, 2024 Jonathan Zipursky MD PhD FRCPC Divisions of General Internal Medicine and Clinical Pharmacology & Toxicology Assistant Professor, Temerty Faculty of Medicine University of Toronto Adjunct Scientist, ICES and Sunnybrook Research Institute 1 Disclosures Expert opinions and testimony related to the safety and effectiveness of drugs. None of that work involves the topics presented today. Funding from First Exposure program at the DLSPH 2  Objectives 1. Pharmacokinetic changes that occur in pregnancy 2. Review pitfalls & principles of drug safety in pregnancy 3. Discuss an approach to drug safety in lactation 4. Introduce resources for drug safety in pregnancy/lactation 3 Pharmacokinetic changes occurring in pregnancy 4  Table 1. Physiological changes during pregnancy: effects on drug disposition Pariente G, Leibson T, Carls A, Adams-Webber T, Ito S, et al. (2016) Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review. PLOS Medicine 13(11): e1002160. https://doi.org/10.1371/journal.pmed.1002160 https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002160 Table 1. Physiological changes during pregnancy: effects on drug disposition From: Serum Creatinine Levels Before, During, and After Pregnancy JAMA. 2019;321(2):205-207. doi:10.1001/jama.2018.17948 Mean Serum Creatinine Concentrations With 50th, 75th, and 95th Percentile Values Among 243 534 Women With Singleton Pregnancies and Apparently Healthy Renal FunctionA, Dashed curves indicate upper and lower 95% CI bounds. B, Values adjacent to each curve indicate the percentile-specific corresponding serum creatinine values at each time point. To convert creatinine values to mg/dL, divide by 88.4. Examples of CYP changes Examples: 1. Lithium 2. SSRIs (e.g., citalopram) GFR increases at end of T2 and into T3 ↓ [Lithium] Plasma volume expands At delivery and postpartum there is a ↑ [Lithium] drop in GFR and rapid volume contraction Metabolism mostly by hepatic CYP enzymes, which are induced especially ↓ [SSRI] beyond 20 wks gestation May necessitate increase in dose of SSRI (but drug levels do not always correlate with symptoms) Principles & Pitfalls of Drug Safety in Pregnancy 11 Teratogen Human teratogens are agents/substances/exposures which cause physical/functional defects (harmful effects) in the human fetus *Greek teras = monster Known Teratogens Alcohol (Ethanol) Misoprostol Carbamazepine Mycophenolate Cytotoxic chemotherapy Phenytoin DES Thalidomide Isotretinoin Trimethoprim Lithium Valproic Acid Methimazole Warfarin Methotrexate 16 Known Teratogens continued… 17 Mobius syndrome (misoprostol) 18 Risk Evaluation and Mitigation Strategies (REMS) (Zipursky 2020) 19 Drug Use in Pregnancy 20  Drug use in pregnancy in COMMON 8/10 pregnant women take a prescription medication 9/10 pregnant women take any drug in pregnancy (Palmsten 2015) 21 Drug use in pregnancy in COMMON (Smolina 2015, Pham-Huy 2021) 22 Prescription drug use by trimester (Smolina 2015) 23 A case study – Ondansetron in pregnancy 24  Case 34-year-old woman, G2P1, at 11 weeks gestation presents to clinic with worsening nausea/vomiting Currently taking doxylamine/pyridoxine TSH normal Had previously used ondansetron (Zofran) for nausea but is worried about safety in early pregnancy. 25 26 Safety for parent vs. safety for baby Conception Spontaneous abortion Fetal growth restriction Teratogenicity Neonatal drug withdrawal Long term neurodevelopmental Childhood 27  Step 1: Baseline Risk of Congenital Malformations 3% risk of major congenital malformations at birth Risk factors: Genetic abnormalities Consanguinity *Drugs/Environmental (e.g., radiation) exposures Nutrition/Resource poor settings In utero infections Maternal age Disease: Diabetes 28 Step 2: Critical period in development 29 Step 3: Assessment of causality (Bradford Hill) 30 (Franks 2020) Shepard Criteria  Step 3: Key Shepard Criteria 1. Proven exposure at a critical time 2. Consistent findings in ≥ 2 epidemiologic studies 3. Specific syndrome 4. Rare exposures associated with rare defect 32  33 (Pastuszak 1998) Step 4: Hierarchy of Evidence 34 Step 4: Hierarchy of Evidence xx Level 5 35  Step 5: Confounding by indication “Clinical indication for selecting a particular treatment (eg, severity of the illness) also affects the outcome.” 37 (Kyriacou 2016) Step 5: Confounding by indication continued… 1.Propensity score methods 2. Active user designs 3. Unique to pregnancy – compare to drug use at a different time in pregnancy (or pre-preg) 38 Active user Exposures during other time periods Step 6: What’s the alternative? Uncontrolled disease (-) drug Controlled disease (+) drug 40 Summary - Ondansetron Ondansetron (Zofran) is as 3rd/4th-line treatment for N/V pregnancy Low (if any) concern about association with congenital malformations 41 BREAK 42 Approach to Drug Safety in Lactation 43 “The question is never, does the drug enter breast milk…but rather how much” Dr. Shinya Ito Professor of Pediatrics The Hospital for Sick Children 44 Factors affecting drug transfer into breast milk Passive diffusion down a concentration gradient Pharmacokinetic (PK) factors affecting the transfer of drugs into breast milk: Lipophilicity Molecular weight Protein binding Drug pKa (measure of acidity) & milk pH Drug bioavailability Volume of distribution 45 Milk : Plasma ratio (M/P ratio) 46  AUC milk AUC plasma  Pitfalls of the MP ratio Measuring drug concentrations in milk at different times will yield different estimations Drug concentrations in breast milk after a single dose versus at steady-state. Challenging to interpret for drugs taken intermittently (e.g., opioids). Does not account for the quantity of milk ingested by the infant Does not account for infant drug clearance 49 Relative Infant Dose (RID) RID Safe 25% ***None of this accounts for infant drug clearance (e.g., renal function) which is a more important determinant of drug accumulation after ingestion 50 Drugs contraindicated in breastfeeding Chemotherapeutics Radioisotopes Lithium Gold salts Iodine Oral retinoids Amiodarone Ergotamine Bromocriptine (decrease production) Drugs of abuse 51 Infant factors (GI tract and proteases) 52 Studying drug safety in lactation First principles (RID, PK studies) Case studies/series Population-based studies & RCTs are exceedingly rare 53 A case study – Opioids and breastfeeding 54  Case 34-year-old woman, G2P1, at 48 hours postpartum from a cesarean delivery. She is breastfeeding and is prescribed Percocet (oxycodone/acetaminophen) to be take PRN every 6 hours. Still experiencing significant surgical site pain at discharge. Worried about potential adverse effects to the baby 55 Mix of Opioids Prescribed Postpartum (Narcotic Monitoring System Data) 100 90 80 Type of drug filled postpartum (%) 70 60 Oxycodone 50 Morphine Hy dromorphone 40 Codeine 30 Other (tramadol, fentany l) 20 10 0 2012 2013 2014 2015 2016 2017 2018 2019 2020 Year Proportions of codeine, morphine, oxycodone, hydromorphone, tramadol, and fentanyl prescribed to postpartum women (N=85,852) in Ontario, by year. 56 (Zipursky BMJ 2023)  Neonatal risks of postpartum opioid use Regulatory bodies and societies have focused predominantly on risks of neonatal CNS and respiratory depression related to opioids ingested via breastfeeding All opioids pass into breast milk to varying degrees – RID between 1 – 7% Opioid Primary metabolic pathway RID (%)† Morphine UGT2B7 2.5-7.5% Codeine CYP2D6 0.3-1.2% Oxycodone CYP3A4 (2D6, minor) 2.6-7.6% Tramadol CYP2D6 2.3% Fentanyl CYP3A4 1.2% Hydromorphone UGT 0.7% 57 (Ito 2018; Zipursky 2020) Codeine was characterized as particularly unsafe during lactation Lancet 2006 Mother in this case was found to have a CYP2D6*2/*2 UM genotype Toxic serum concentration of morphine (70 ng/mL) and elevated morphine in breastmilk (87 ng/mL) Child died from opioid toxicity due to enhanced maternal conversion of codeine to morphine with subsequent passage of large amounts of morphine in breast milk 58 2020) (Koren 2006; Zipursky 59 Infants born to mothers prescribed opioids were no more likely to be hospitalized in the ensuing 30 days 61 (Zipursky BMJ 2023) Summary – Approach to Opioid Use in Breastfeeding First principles approach – Relative infant Dose, volume ingested by infant, drug clearance Population based data – Infant harm related to small amounts of opioid passed through breast milk is unlikely 62 Resources for Drug Safety in Pregnancy and Lactation 63 LactMed (NIH) & free app 65 “A reinvented program should be modernized and aligned with the expanding complexities associated with providing perinatal care. We envision a national and interprofessional collaborative effort among clinical and research experts in reproductive drug safety...The evidence-based counselling services should be complemented by open access and searchable databases to adapt to how patients and physicians may prefer to access information…mandate more patient and public involvement to ensure the program is meeting the most relevant needs of Canadians.” www.firstexposure.ca  Drug information service Website Counselors Research Drug safety in pregnancy clinic Pre-pregnancy counseling Intrapartum Drugs in lactation Database to collect clinical information + ICES connection Drug Safety in Pregnancy Clinic @ Sunnybrook M4 Friday mornings 9-12 Integrated into our Clinical Pharmacology rotation, with the hope to expand to other trainees in the future One of our Sunnybrook pharmacists has been working with the team New referrals: Fax: 416-480-5616 70  Acknowledgements David Juurlink Michelle Hladunewich Shinya Ito Nan Okun Tara Gomes Lynfa Stroud Peter Austin Anne McLeod Joel Ray Jenny Blake Muhammad Mamdani Wendy Katherine Karl Everett Ping Li Andrew Calzavara Andrea Pang Mike Paterson Dave Comartin 71  Contact Jonathan Zipursky MD PhD FRCPC IC/ES Central G1 48, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 T 416-480-6100 X 3798 F 416-480-6048 E [email protected] @JonZipursky 72 Questions