Drugs in Milk Jason Sauberan Jason S b Sauberan, , PharmD PharmD h [email protected] Goals ◦ Understand basic Understand basic milk distribution principles milk distribution principles.. ◦ Use of information resources. ◦ Application of evidence to patient care. Objectives • Name potentially dangerous drugs. • Answer common patient questions. • Navigate different clinical scenarios. Outline 1. 2. 3. 4. Basic milk distribution principles F Forecasting milk distribution & infant exposure ti ilk di t ib ti & i f t Sources of reliable information S Specific medications ifi di ti ◦ Drugs of abuse ◦ Opiates ◦ Safe and surprisingly safe How does a drug get into milk? gg NeoReviews 2004;5(4) Drug factors enhancing transfer to milk ◦ Low molecular weight L l l i h ◦ High lipophilicity ◦ Low plasma protein binding ◦ Weak bases (milk pH 7.0‐7.2) ◦ High, prolonged maternal [serum] THE BALANCE OF FACTORS Protein P t i Bound B d Weak Acid Water Soluble Large Size Short t ½ BLOODSTREAM Low Binding Lo Weak Base Lipid Soluble Small Size Long t ½ Active Transport BREAST MILK Determining infant exposure Conc. Step 1: Step 1 calculate infant “dose” Cmilkave (mg/L) ∙ milk intake (L/kg/d) = dose (mg/kg/d) Begg EJ et al. BJCP. 1999 48(2): 142– 147. hours Step 2 Step 2: calculate relative infant dose (RID) ◦ RID = infant/maternal dose (mg/kg/day) alternate RID infant milk dose/infant treatment dose ◦ alternate RID = infant milk dose/infant treatment dose Judging infant risk ◦ RID < 10% usually safe and acceptable Consider ◦ maternal dose ◦ distribution factors ◦ Tmax – pump and dump? ◦ OK if maternal drug once daily and has short t½ if ld d il dh h ½ ◦ Pointless with long t½ or frequent dosing p min ◦ Better plan is to feed at C ◦ Oral bioavailability – neonatal ◦ Postnatal age g ◦ Individual infant clinical characteristics SERUM PENICILLLIN Huang NN. J Pediatrics. 1953;42(6):65768. Kearns GL, et al. NEJM. 2003;349(12):1157 67 Anderson PO, et al. Clin Ped 2003;42(4):325-40. Where can I find reliable information? LactMed ◦ toxnet.nlm.nih.gov Medication and Mothers’ Milk (Hale) ( ) ◦ www.infantrisk.com Reprotox ◦ www.reprotox.org Drugs in Pregnancy & Lactation (Briggs) Breastfeeding (Lawrence & Lawrence) g( ) # Of Med dications Hale LactMed Briggs AAP Reprotox ePocrates FDB Lexi-Comp Clin-eGuide PDR Akus & Bartick. Ann Pharm 2007;41(9):1352-60. Akus & Bartick. Ann Pharm 2007;41(9):1352-60. http://www.mothertobabyca.org/ Case example #1 MOB with CVC placed postoperatively after c‐hyst for percreta o Broad spectrum abx for GI infection, develops Candida CLABSI. o OB resident asks which is safer in breastfeeding? Ampho B or Micafungin? Micafungin Ampho B PB >99% PB >95% MW 1292Da MW 924 Da F <1% F <10% Case example #2 MOB with DM‐2, used insulin during pregnancy, switching postpartum to her pre pregnancy oral sulfonylurea; glimepiride. o She asks if OK to breastfeed? Glimep Glyb Glip Cmilk ‐ BLQ BLQ ADR ‐ N N PB 99% 99% 99% MW 490 Da 494 Da 446 Da F 100% 95% 95 100% Case example #3 MOB with chronic pain, suffered during pregnancy on intermittent Percocet. At 21 d PP wants to switch to pre‐pregnancy fentanyl patch since her OB told her it was safer than codeines . patch since her OB told her it was safer than “codeines” Baby hx: 34 wk, SGA, transient hyperbili and hypoglycemia, Baby hx “mild” NAS mild NAS, overly sedated from NAS tx, poor feeder. overly sedated from NAS tx poor feeder Fentanyl RID <1 Cmilk (mcg/L) 0‐0.4 ADR none PB 80 85 80‐85 MW 337 t ½ 4 F 33% 7* * Case report, fentanyl p , y patch 100 mcg/hr, term baby Incompatible drugs? ① HIV » Malawi PMTCT (MMWR 2013;16(8):148-51) » ZDV, 3TC, LPV/RTV, ABC, NVP, EFV ,3 , / , , , : minimal‐no exposure p (CROI 2013, Curr HIV Res. 2013;11(2):102-25.) • ARVs to avoid in neonates: ATV (hyperbili), TNV (osteopenia) I tibl d ? Incompatible drugs? ②Radiopharmaceuticals p ((NRC 2001,, ICRP 2004)) » Iodine 131, Gallium 67, Thallium 201 ‐ contraindicated » Most others: resume BF p 6‐24 hrs ③ Cancer chemotherapy – see Hale book, appendix A; predict when agent out of mom’s body (>5 x t½) to resume breastfeeding resume breastfeeding. • Cyclophosphamide: max t ½ = 12 hr, resume BF after 72 hours ④ Recreational Drugs: Nicotine, meth, cocaine, THC g , , , (Breastfeeding Med 2009;4(4):225-8. ABM Clinical Protocol #21) I tibl d ? Incompatible drugs? THC during lactation NEJM 1982;307(13):819-20. ◦ Max milk 340 mcg/L = 50 mcg/kg/d ingestion by infant ◦ RID ≈ 2‐3 % assuming maternal 180 mg/d (2‐3 mg/kg/d) ◦ “normal development” in case infants (n=2) “normal development” in case infants (n 2) ◦ M:P = 8 (60 mcg/L vs. 7 mcg/L) Hepatic metabolism by CYP 2C9, 3A4 – low activity in baby Hepatic metabolism by CYP 2C9, 3A4 NDI from THC and breastfeeding? ◦ NO: (n=27), 77% monthly‐weekly, 23% daily. Tennes K, et al. 1985 ◦ 34% of screened subjects reported using THC during pregnancy ◦ YES: (n= 56), only with daily or QOD use Astley & Little 1990 ◦ 1.5% of screened subjects reported using THC during pregnancy Incompatible drugs? p g THC during lactation Astley & Little. Neurotoxicol Teratol. 1990;12(2):161-8. Ito S, et al. Biology of the Neonate 2001;80(3):219-22. Rosy Antimicrobials ◦ PCNs, cephs, penems, clindamycin, macrolides, AMG, vancomycin, FQs PCN h li d i lid AMG i FQ ◦ Amphotericin B, fluconazole, nystatin ◦ Acyclovir, oseltamivir, zanamivir ◦ Isoniazid, rifamycins, ethambutol, PZA More data needed but probably OK p y ◦ Linezolid, fosfomycin ◦ Echinocandins ◦ (Val)ganciclovir Controversial ◦ SMX, nitrofurantoin, metronidazole Rosy Cardiovascular HTN ◦ ◦ ◦ ◦ ◦ ◦ Methyldopa Shorter acting  blockers : labetalol, metoprolol CCB : nifedipine, amlodipine ACEI : enalapril, benazapril HCTZ (<50 mg/day) Magnesium Anticoagulants ◦ Heparin, LMWH, lepirudin ◦ Warfarin, low dose aspirin Antiarrhythmics ◦ Digoxin, flecainide, amiodarone Digo in flecainide amiodarone (monitor thyroid fxn, serum TDM) (monitor th roid f n ser m TDM) Rosy Gastrointestinal ◦ H2 blockers (ranitidine, famotidine) & PPIs bl k ( i idi f idi ) & PP ◦ Antacids ◦ Antiemetics: prochlorperazine, ondansetron A ti ti hl i d t ◦ Promethazine? Avoid if possible due to lactation suppression ◦ Anti diarrhea: loperamide ◦ Avoid: Bismuth subsalicylate (Kaopectate®) Rosy Sleeping pills ◦ Short acting, minimally metabolized benzodiazepines: Short acting minimally metabolized benzodiazepines: oxazepam, lorazepam, zolpidem ◦ Trazodone ◦ OTC – doxylamine, diphenhydramine, dimenhydranate. Vaccines MMWR 2011; 60 (2): 26. 2004;53(5);103‐105 ◦ MMR, Varicella, LAIV – OK ◦ Yellow fever – (usually) not OK; Small pox – not OK Vitamin K ◦ Milk 1‐3 mcg/L, formula 60‐100 mcg/L ◦ Maternal supplement 5 mg/day  milk 80 mcg/L Greer, et al. Pediatrics 1997;99(1):88–92. Rosy Transplant immunosuppressants Transplant immunosuppressants ◦ Cyclosporine, tacrolimus, azathioprine, mycophenolate Cyclosporine tacrolimus azathioprine mycophenolate Diabetes ◦ Insulin, metformin, glyburide Insulin metformin glyburide Thyroid ◦ Levothyroxine, PTU, methimazole L th i PTU thi l Same day or dental surgery ◦ Lidocaine Lid i ± epii ◦ Propofol, midazolam ◦ Fentanyl, morphine Fentanyl morphine Thorny Methylergonovine ◦ 83 cases of breastfed infant toxicity reported to the manufacturer. ◦ HTN, brady/tachycardia, convulsions, seizures, emesis, diarrhea, cramps. ◦ Onset: > 2 days of continued maternal use (2‐7 days). ◦ Manufacturer: do not breastfeed during treatment. Manufacturer: do not breastfeed during treatment ◦ LactMed: avoid continued methylergonovine use once milk is in. If not possible, withhold breastfeeding until g 12 hours after the last dose. Thorny Methadone maintenance ◦ RIDs RID 1 to 3% in most studies, 5 to 6% in a few 1 to 3% i o t t die 5 to 6% i fe ◦ Infant dose 10‐40 mcg/kg/day ◦ Very low infant serum levels V l i f t l l ◦ Neutral or positive effects on NAS ◦ Illicit polypharmacy? Illi it l h ? ◦ High dose? Am J Obstet Gynecol 2009;200(1):70.e1-5 Thorny Opioid analgesics All have ideal chemical properties for transmission to breastmilk. Harm/fatalities have been reported. Preferred: morphine hydromorphone Preferred Preferred: morphine, hydromorphone Careful: Hydrocodone, Oxycodone Careful ◦ Active metabolites (CYP2D6) ( ) ◦ Wide variety in infant t1/2 ◦ Higher bioavailability Thorny Opioid analgesics RID HC: 1.6% (0.7 9%, n=30 RID HC: 1 6% (0 7–22.4, 95% CI), range 0.2 4 95% CI) range 0 2‐9% n=30 ◦ “worst case scenario” ~ 100 mcg/kg/day potential exposure from 8 maternal Vicodin tabs/day (includes hydromorphone metabolite exposure). Sauberan JB, et al. Obstet Gynecol. 2011;117(3):611‐7. RID OC: 1‐3%, n=5/50 RID OC: 1 3% n=5/50 [Milk] OC (48‐72h PNA): 35 mcg/L (2‐129 mcg/L) ◦ “worst case scenario?” 20 mcg/kg/day from maternal g g Percocet 4‐6 tabs per day. n=<50 ◦ “Up to 90 mg/day OK up to 3d PNA” ?? Seaton S, et al. Aust N Z J Obstet Gynaecol. 2007;47(3):181‐5. Thorny ‐‐ Antidepressants Thorny Drug AD Class RID (%) ADR (y/n) FDA status Sertraline SSRI <1 n unknown risk Paroxetine SSRI 1‐2 n caution Escitalopram SSRI 5.3 n caution Citalopram SSRI 55‐10 10 y* caution, ADR Fluoxetine SSRI 6‐12 y* not rec Duloxetine SNRI <1 n not rec V l f i Venlafaxine SNRI 6 6‐12 n D/C Trazodone ‐ <1 n caution, not rec Mirtazapine ‐ 1‐2 n caution Bupropion ‐ 2 y† D/C TCA 1‐2 n unknown risk Nortriptyline * * Abnormal sleep patters, colic, poor feeding, detectable infant serum levels † One report of seizure like activity Thorny Antidepressants Preferred: sertraline, paroxetine, escitalopram, Preferred: sertraline paro etine escitalopram duloxetine, nortriptyline. Concerning: fluoxetine, citalopram, venlafaxine, Concerning: fluoxetine citalopram venlafaxine bupropion. Problems ◦ Don’t want to change what worked antenatal ◦ Neonatal SSRI toxicity/withdrawal syndrome?? to icit / ithdra al s ndrome?? ◦ Jitteriness, vomiting, irritable, inconsolable, shivering, eating/sleeping problems; first 1 2 days PNA. eating/sleeping problems; first 1‐2 days PNA Antidepressant withdrawal * More likely to occur when AD used during pregnancy + breastfeeding Vs. just breastfeeding. * Less likely to experience jitteriness and muscle stiffness with longer t1/2 ADs. * Occurs infrequently, mild, self‐limiting. Occurs infrequently mild self‐limiting Total (%) Once per week Once daily Multiple times daily Jitteriness 10 2 6 2 Vomiting 10 3 5 2 Irritable 25 8 11 6 Poor Eat/sleep 13 3 5 5 Stiffness 5 2 2 1 Shivering 5 3 1 1 0.3 0.1 0.1 0.1 Symptom Convulsions Hale TW, et al. Breastfeeding Med. 2010;5(6):283‐8.