Medication and Alcohol Use and Breastfeeding

Medications, Alcohol, and Breastfeeding

Thomas W. Hale, R. Ph., Ph.D. University Distinguished Professor Department of Pediatrics Associate Dean of Research Director, InfantRisk Center Texas Tech University School of Medicine

Disclosures

• Dr. Hale had a financial arrangement with Biohaven Pharmaceuticals which is not discussed in this presentation

2 2

4 Plasma Cell

From Day 3 to Day 4 Postpartum

•Benefit of Breastfeeding is Important. •Depends on 3 major factors • Choice of Drug (penicillin vs anticancer drugs) • Age of the infant • Premature…some risk • Older infant…minimal risk • Volume of milk • Colostrum….minimal risk • Full breastfeeding… some risk • Late stage lactation…minimal risk • Exposure in utero? • Prior Dependence or Tolerance

Pharmacokinetics and Drug Levels in Milk

• Molecular weight of drug really matters • Drugs > 800 daltons enter milk poorly • Drugs < 300 daltons may enter milk easily • Protein Binding: • Higher the binding the poorer the levels in milk • pKa • Higher the pKa the more drug is trapped in milk. • “Ion trapping” • Vd • Higher the Vd, the lower the levels in milk • They’re all in the periphery, not in plasma

• Lipid Solubility • More lipid soluble, the higher drug levels in milk • Plasma levels • The Higher, the more drug enters milk • The Lower, the less enters milk (fluticasone) • Transport processes are poorly understood • At least 5 drugs are thought to be transported but 4 do not attain clinical levels • Ranitidine, Cimetidine, Iodine, Nitrofurantoin, Acyclovir

Other Kinetic Factors

• Oral Bioavailability • How much is absorbed and ends up in Plasma. • Oral, IM, Rectal bioavailability are often different • Drug exposure via milk depends on the oral absorption of the drug in the infant AND then how much gets past the liver. • Monoclonal Antibodies (minimal to nil) • Morphine (26%) • Large proteins unabsorbed (heparin, etanercept, etc) • Sumatriptan (14%) • Domperidone (13%) • Tetracyclines (most poorly absorbed in milk) • Stability in GI tract of infant is important • Proton pump inhibitors are unstable at low pH. • Monoclonal antibodies are unstable due to proteases in GI tract

Nucleus

Capillary

Drugs with Apparent Transporters (Influx Transporters)

Iodine Acyclovir Cimetidine Nucleus Nitrofurantoin Ranitidine ???

Capillary

Copyright T.W.Hale, 2021 6 Extracellular Proteins Transported IgA Protein IgM, IgG (minimally) Transporters Nucleus Prolactin IGF-1 ????

Capillary

Plasma Cell

Some Suggestions

•Always evaluate stage of lactation. • Premature infant…higher risk • First 4 days, low milk volume…..low risk • Late stage… low milk volume….low risk • Calculate and use the Relative Infant Dose. If less than 10% then it is probably safe.

Infant dose (milk) ( mg/kg/day) RID = Maternal dose (mg/kg/day)

• Avoid estrogen-containing products • Evidence of low milk production is poor! • Progestin-only mini pills preferred. • Progestin receptors not present in ‘lactating tissues’ • If suppression occurs, you can stop immediately. • Depo-Provera • Some controversy about lowering production (early postnatally), but not proven. • Do not use early postpartum, use oral BCP first, then Depo

Birth Control Products • Levonorgestrel (Mirena IUD) • Plasma concentration of levonorgestrel produced by Mirena are even lower than those produced by LNG contraceptive implants and with oral contraceptives. • Work by thinning uterine lining, inhibit sperm, create mucus plug in cervix • In 163 and 157 women who received Mirena intrauterine systems, or a Copper T380A intrauterine device respectively, no change in breastfeeding rate, infant growth, or infant development was noted over 12 months.1 • Only approximately 0.1% of the serum dose of LNG has been reported to transfer via milk to infants.2 • Increased endometrial copper concentrations have been noted in a study of 95 breastfeeding mothers with copper intrauterine devices, but no change was noted in the serum or milk copper concentrations. • The data from the levonorgestrel-only intrauterine devices suggests minimal to no effect on breastfeeding. • Several recent studies have reviewed the impact of Levonorgestrel IUDs on breastfeeding and have found no changes in breastfeeding rates.

1. Shaamash AH, Sayed GH, Hussien MM, Shaaban MM. Contracep 2005 Nov; 72(5):346-51. 2. Haukkamaa M, Holma P. Leiras Clinical Study Report 1996

• Penicillins, Cephalosporins are generally safe • Dicloxacillin, Flucloxacillin, Cloxacillin good for mastitis. • Erythromycin is unsafe due to elevated risk of hypertropic pyloric stenosis • Azithromycin is probably OK. • Doxycycline ( short term < 3-4 weeks) Possible dental staining in infant • Clindamycin: safe… RID = 0.8% - 1.8% • Good for most MRSA • Fluoroquinolones • Ciprofloxacin - use cautiously. • Ofloxacin, Norfloxacin, Levofloxacin. • Resistance limits the use of these agents today. • Metronidazole • Levels moderate but are considered safe. Commonly used in neonates. • All may induce changes in intestinal Flora…diarrhea, candida overgrowth. • Avoid prolonged use, >6 weeks ??

Anticonvulsants

• Lamotrigine (Lamictal): • Commonly used in BIPOLAR syndrome • RID= 9.2-18%; probably safe; safest after 1 month • Evaluate infants with RASH !!!! • Valproic acid( Depakene, Depakote): • RID= 1.4-1.7%; UNSAFE; avoid in moms at risk for pregnancy. • Could reduce IQ in infants. • Levetiracetam (Keppra): • RID= 3.3 – 7.8%; probably safe; levels fall quickly in infants postpartum. Very popular now. • Topiramate (Topamax): • RID= 24.68% - 55.65%; probably safe, but monitor infant levels. • Moderate doses are important.

Copyright T.W.Hale, 2021 9 Ethanol • Approximately half of all lactating women in Western countries occasionally consume alcohol while breastfeeding. • Alcohol intake inhibits the milk ejection reflex (Reduces Oxytocin Release), causing a temporary decrease in milk yield. • Concentration in breastmilk is equal to that of blood. • The amount of alcohol presented to nursing infants through breast milk is approximately 5-16% of the weight- adjusted maternal dose, and even in a theoretical case of binge drinking, the children would not be subjected to clinically relevant amounts of alcohol. • Alcohol transfers into human milk readily, with an average milk/plasma ratio of about 1. This does not necessarily mean that the dose of alcohol in milk is high, only that the levels in plasma correspond closely with those in milk. • The absolute amount (dose) of alcohol transferred into milk is generally low and is a function of the maternal level. • In 12 breastfeeding mothers who ingested 0.3 g/kg of ethanol in orange juice (equivalent to 1 can of beer for the average-sized woman), the mean maximum concentration of ethanol in milk was 320 mg/L.1 • This produced a 23% reduction (156 to 120 mL) in breast milk production following ingestion of beer • In another group of five women, who consumed 0.4 g/kg at one setting, milk and maternal plasma levels were similar. Levels of alcohol in milk averaged 0.44 g/L at peak and fell to 0.09 g/L at 180 minutes.2 • Adult metabolism of alcohol is approximately 1 oz of pure ethanol in 3 hours. • A good rule is 2 hours for each drink consumed. • Chronic or heavy consumers of alcohol should not breastfeed.

1. Mennella JA, Beauchamp GK. The transfer of alcohol to human milk. Effects on flavor and the infant's behavior. N Engl J Med. 1991;325(14):981-985. 2. da-Silva VA, Malheiros LR, Moraes-Santos AR, Barzano MA, McLean AE. Ethanol pharmacokinetics in lactating women. Braz J Med Biol Res. 1993 Oct;26(10):1097-1103.

Ho E, Collantes A, Kapur BM, Moretti M, Koren G. Alcohol and breast feeding: calculation of time to zero level in milk. Biol Neonate. 2001;80(3):219-22. doi: 10.1159/000047146. PMID: 11585986. 20

Copyright T.W.Hale, 2021 10 Vaccinations MMR Safe Yellow Fever Safer than getting disease Hepatitis B Safe Hepatitis A Safe DPT Safe Flumist Probably safe Influenza Safe Varicella Safe Inactivated Safe Polio Safe Covid Vaccines Gardasil (HPV) Safe Covid-19 Presumably Safe

Antihypertensives

• Preferred Beta Blockers • Preferred: Metoprolol, Labetalol, Propranolol • AVOID:) Acebutolol, Atenolol (poor choice) • Preferred Calcium Channel blockers • Nifedipine, Nimodipine, Verapamil, Nitrendipine • ACE inhibitors • Avoid in very premature infants. Suppresses nephron development in 3rd trimester. • Captopril, Enalapril, Benazepril are preferred in breastfeeding mothers. • Aldomet, hydralazine are fine. • Labetalol- diuretic, may produce hypoglycemia in infants. • WATCH the dose with these products !!!!!!!!

Copyright T.W.Hale, 2021 11 Morphine/Heroin & Breastfeeding • Dose to infant ranges all over. Research data is poor. • Doses as high as 15 mg IV/IM have produced relative infant doses as high as 35% and milk levels of 50 µg/100 mL. • Few untoward effects have been noted at normal doses • These are not the doses potentially used by addicts. • Poor oral bioavailability (< 30%), due to sequestration (75%) in the infant’s liver limits systemic levels in infant. • Infants under 1 month of age have a prolonged elimination half- life and decreased clearance of morphine relative to older infants. • The clearance of morphine and its elimination begins to approach adult values by 2 months of age. High doses over prolonged periods could lead to sedation and respiratory problems in newborn infants. • SAFE to use cautiously

1. Feilberg VL, Rosenborg D, Broen Christensen C, et al. Excretion of morphine in human breast milk. Acta Anaesthesiol Scand. 1989;33:426–8. 2. Ito S. Opioids in breast milk: Pharmacokinetic principles and clinical implications. J Clin Pharmacol. 2018;58 Suppl 10:S151–S163.

Codeine • Use of codeine in breastfeeding moms Highly controversial following Koren paper in 2006 of a mother with rapid metabolism.1 • Koren Paper was recently retracted by journal after extensive controversy. • Question surrounding this paper was how did the baby get that much codeine AND acetaminophen from milk?????. • We don’t think infant ingestion was due to “milk” intake ??? • As a case of unintended consequences, the Scheduling of Codeine dramatically INCREASED the number of acetaminophen/codeine 300/30 mg and 300/60 mg combination products prescribed by 597% and 1056%, respectively, in the months after the FDA rescheduling of hydrocodone, oxycodone, etc to CII. • The OB residents couldn’t write for Hydrocodone, so they wrote for Codeine!

1. Koren, G., Cairns, J., Chitayat, D., Gaedigk, A. & Leeder, S.J. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine‐prescribed mother. Lancet 368, 704 (2006). 2. Zipursky J, Juurlink DN. The Implausibility of Neonatal Opioid Toxicity from Breastfeeding. Clin Pharmacol Ther. 2020 Nov;108(5):964-970. doi: 10.1002/cpt.1882. Epub 2020 Jun 25. PMID: 32378749.

• Opioid with long half-life • Half-life = 13-55 hours • Methadone is a potent and very long-acting opiate analgesic. It is primarily used to prevent withdrawal in opiate addiction. • In 12 breastfeeding women on methadone maintenance doses ranging from 20-80 mg/day, the mean concentration of methadone in milk was 116 (72- 160) µg/L respectively. This equates to a mean of 2.79% of the maternal dose per day. • Excellent study of 8 women with doses of 40-105 mg/d • Relative infant dose = 2.8% • Always ASK the DOSE !!!!!! • Newborn Infant or Infant that STOPs breastfeeding will go through withdrawal

Buprenorphine

• Buprenorphine (Belbuca, Probuphine, Buprenex ) • Lots of recent interest in this drug. • Treatment of withdrawal • Treatment of chronic pain syndromes • Buprenorphine is a potent, long-acting narcotic agonist and antagonist and may be useful as a replacement for methadone treatment in addiction • Buprenorphine + Naloxone = Suboxone • Partial mu agonist. Poor addictive properties. • Slow onset, weak agonist. • Buccal film, transdermal patch, tablet • Maintenance treatment of moderate to severe opioid use disorder • Less euphoria, physical dependence, ceiling effect, milk withdrawal • Higher affinity for receptor than other opiates • RID= 0.09 – 2.52%

• Hydrocodone • Potency (1.5-2 X morphine) • 30 fold less active than its active metabolite Hydromorphone. • Subject to rapid metabolism, but still good choice. • The total dosage to infants was estimated at 0.7% of their neonatal therapeutic dose, suggesting that standard maternal doses are clinically irrelevant to the infant.

• Hydrocodone is still generally recommended that for treatment of postpartum pain, and doses should be limited to no more than 30 mg/day. If higher doses are required, then the infant should be closely monitored for possible untoward complications such as sedation and apnea. Doses more than 40 mg/day should be avoided.8

• RID= 2.21% - 3.7%

1. Sauberan JB, Anderson PO, Lane JR, et al. Breast milk hydrocodone and hydromorphone levels in mothers using hydrocodone for postpartum pain. Obstet Gynecol. 2011 Mar;117(3):611-617.

Other Opiates Used and Abused

• Oxycodone • Hydromorphone (Dilaudid) • Potency (1.5-2 X morphine) • Not metabolized to more potent • Significant euphoria metabolites • Highly addictive • Potency (7-10 X morphine) • 5-10 mg every 6 hours as needed. • Caution in breastfeeding • RID= 1-4.56% mothers • Fentanyl • RID = 0.67% • Generally shorter term use although patches are available. • Following dose of 4 mg q 4 h, • Potency = 80-100 X morphine respiratory depression in 6 day • Rapid onset, short half-life old breastfed infant. • 25-35 µg IV every 30-60 min as • Naloxone provided recovery. needed. • RID= 2.9-5%

Copyright T.W.Hale, 2021 14 Other Analgesics • Ketamine (Intranasal 28 mg) • Pain Surgical Pain Control • Rapid Acting Analgesic. Few hemodynamic problems. • Excellent analgesia with minimal respiratory problems. • No data are available on the transfer of ketamine into human milk. • Rapid redistribution out of plasma in 10-15 minutes. • Short half-life of 2.5 hours. It is poorly oral bioavailable. • GREAT for treatment-resistant depression • Esketamine Nasal spray. Just FDA approved • Side Effects: Sedation, dissociation, hypertension • Levels in milk are likely LOW. (Need samples) • Dexmedetomidine • Dexmedetomidine is a selective alpha-2 adrenergic agonist used for sedation of initially intubated and mechanically ventilated patients in the intensive care unit and sedation of non-intubated patients prior to and/or during procedures. • Infusion in one breastfeeding mom(Mayo Clinic), levels in milk ranged from 15 – 89 picograms/mL. • Dose 45 µg stat, followed by 0.7 µg/kg/hr

Analgesics Overview

• Hydrocodone, morphine are generally safe in breastfeeding mothers. • Codeine use still controversial, but probably safe in most moms • Hydromorphone is super potent, respiratory depression reported. • Avoid High doses of Oxycodone (apnea).Highly addictive. • Fentanyl levels in milk are low. Urine levels in infants are measureable, but may not be relevant. • Buprenorphine is a potent, long-acting narcotic agonist and antagonist, but probably quite safe. RID = 0.09 – 2.52% • Tramadol: Probably safe. Levels minimal, RID =2.86% • Ibuprofen, Ketorolac, and acetaminophen are Ok • Meperidine is poor choice due to neonatal sedation, neurobehavioral delay.

• Newest Anticonvulsants •Topiramate (Topamax) • RDA = 24 % but plasma levels were low to undetectable in infants. •Lamotrigine (Lamictal) • RID: 9.2 - 18.3 % • Observe for rash. (Stevens-Johnson Syndrome) • Thus far no complications • Infant levels tend to fall after few weeks exposure. •Valproic acid. Avoid due to neurobehavioral complications.

Monoclonal Antibodies

• IgG1-4 look-alike drugs used to treat: • Crohn’s, Ulcerative Colitis, MS, Cancer, chronic Migraine, etc, etc. • Most are IgG 1 derivatives. Data thus far seem OK. • One is IgG4 (Tysabri) risky

• Transfer into milk is generally negligible: • Studies on etanercept, infliximab, certolizumab, rituximab, vedolizumab show minimal levels in milk. • ORAL absorption probably minimal due to Proteases in GI tract. • No studies on numerous other Monoclonals.

• Vitamins are probably necessary in premature infants. • IM Vitamin K is mandatory to prevent hemorrhagic disease of the newborn. • Oral Vitamin K is too slow. Support IM injections. • Vitamin D is probably necessary but proper dosing is mandatory. • Mom would require > 8000 IU/day to significantly change her milk levels. • Excessive doses can lead to Vitamin D toxicity. • Infant needs own dose 400 IU/day. • B complex are probably necessary but do not overdose. • High dose Vitamin A is risky (> 10,000 IU/day) ???

Radiocontrast Agents •Sometimes used in CT and MRI scans •Product is highly Iodinated but iodine is not released. Its covalently bound. •Iodine in OVERDOSE is dangerous to infant. • Avoid iodine supplements !!!! •Contrast agents are rapidly cleared from body (1-4 hours) •Only limited transfer into milk •NONE orally bioavailable •Not necessary to stop breastfeeding, but one pump and discarding at 2-3 hours is OK.

Radiocontrast Agents and Milk Concentrations

Drug Dose Milk Significance Bioavail. (Cmax) Gadopentetate* 6.5 g 3.09 µmol/L Dose = 0.023% 0.8% Iohexol 0.77 35 mg/L Absorption Nil; < 0.1% g/kg Iopanoic Acid 2.77 g 20.8 mg 0.08% of Nil maternal dose

Metrizamide 5.06 g 32.9 mg/L 0.02% of 0.4% maternal dose

Metrizoate 580 mg 14mg/L 0.3% of Nil maternal dose

* Gadolinium ion….not iodinated. 36

Copyright T.W.Hale, 2021 18 Radioactive Agents •Some are not hazardous (Technetium, wait <24 h) • 6 h half life. WEAK emitter ! •Radioactive Iodides are EXTREMELY hazardous • (I-131, I-125) • 27% goes to Milk, 27% goes to Mom’s thyroid •Close contact restrictions apply to some agents • Iodine •Best to call InfantRisk Center. •Stop Breastfeeding with radioactive Iodides • Before procedure is best. Reduces irradiation of breast tissues.

131Iodine Concentration in Breasts

Radioactive 131Iodine Close Contact Restrictions Treatment of Hyperthyroidism (assuming 50% uptake)*,**

RADIATION DOSE 10 mCi 15 mCi 20mCi 30mCi

Sleeping restriction (6 feet separation 3 nights 6 nights 8 nights 11 nights sleeping arrangement) for adult.

Sleeping restriction (6 feet separation of sleeping arrangement) for infant, children, 15 nights 18 nights 20 nights 23 nights and pregnant women.

Close contact restriction (6 feet separation) 1 day 1 day 2 days 5 days from children and pregnant women.

Treatment of !yroid cancer remnant ablation (assuming 2% uptake) (No thyroid)*,**

39 RADIATION DOSE 50 mCi 100 mCi 150mCi 200mCi

Sleeping restriction (6 feet separation 1 night 1 night 2 nights 4 nights sleeping arrangement) for adult.

Sleeping restriction (6 feet separation of sleeping arrangement) for infant, children, 6 nights 13 nights 18 nights 21 nights and pregnant women. CloseX Rays contact restriction (6 feet separation) 1 day 1 day 1 day 1 day from children and pregnant women. Adapted• from American !yroid Association Taskforce On Radioiodine Safety, Sisson JC, Freitas J, McDougallX-rays IR, are Dauer high LT, Hurley energy JR, Brierley electromagnetic JD, Edinboro CH, Rosenthalwaves D, that !omas can MJ, Wexler JA, passAsamoah through E, Avram AM, many Milas M,materials Greenlee C. includingRadiation safety human in the treatment tissue. of patients with thyroid diseases by radioiodine ¹³¹I: practice recommendations of the American !yroid Association. !•yroid.X-rays 2011 ionize Apr;21(4):335-46. matter Epub with 2011 which Mar 18. they interact, by ejecting * electronsIMPORTANT: from !e recommendations their atoms. in the table above were derived by calculating the dose and time required to limit the eﬀective dose to the infant below 1 mSv. Please be advised, • Important:these recommendations X rays still PASS permit athrough minimal amount body. of radiation While transfer they to maythe infant that damageis considered tissues, safe by the authorities.they leave An average no radioactiveadult American is exposedresidue to 6.2 that mSv/year wouldaccording harm to the Nuclear an infant. Regulatory Commission. !e only way to totally avoid any radiation is to wait for all of it to decay (5-10 half-lives). Exposure of 1 mSv slightly increases the • Thusincidence …no of cancer hazard to 1 in10,000 to breastmilk people. or infant. ** !e half-life of I-131 is around 8 days. To avoid all radiation exposure to the breastfed infant, close contact must be avoided for at least 5 half-lives, ie. 40 days.

• Heparin transfer is nil. • Low Molecular Weight heparins are OK. Transfer is low. Observe for blood in feces. • Enoxaparin, Dalteparin, Tinzaparin • Warfarin levels in milk are negligible. • Antiplatelet agents…some caution. (Agrylin) • Long lasting effect on platelets. • Clopidogrel (Plavix). Binds to platelet COX irreversibly much like aspirin. No levels yet. • Low dose Aspirin OK. 81 mg or 325 mg/day • No acetylsalicylic acid in milk. • Rivaroxiban(Xarelto) RID = 4-5% • Apixaban RID= 14-21 %

Drugs to Avoid

•Drugs of abuse •Radioactive drugs • Cocaine •Discontinue briefly • Heroin •Radioactive I-131, I-125 • Phencyclidine •Discontinue • Hallucinogens breastfeeding. • Ergot alkaloids •Estrogens, Antiestrogens • Migraine preps • Ergotamine • Cabergoline •Pseudoephedrine •Anti-cancer drugs 42