NATIONAL PERINATAL ASSOCIATION CONFERENCE 2014 - Medications and Lactation: Principles for Safe Practice for the Clinician – Evelyn Fulmore, Pharm.D., McLeod Regional Medical Center
Medications and Lactation: Principles for Safe Practice for the Clinician
Medications and Lactation: Principles for Safe Practice for the Clinician – Evelyn Fulmore, Pharm.D., McLeod Regional Medical Center
1. Medications and Lactation: Principles
for Safe Practice for the Clinician
Evelyn Fulmore, Pharm.D.
McLeod Regional Medical
Center
Florence, SC
2. Disclosures
No financial relationships or duality of
interest to disclose
I will be discussing use of agents to improve
milk supply (galactagogues)
3. Learning Objectives
Basic physiology of lactation and
mechanisms of medication entry into
mother’s breast milk
Factors to consider when selecting
medications during lactation
Role of galactagogues in lactation induction
Tips in utilizing and interpreting available
lactation drug information resources
7. Factors Affecting Amount of Drug
Received by the Infant
Milk yield
Colostrum versus Mature milk
Concentration of drug in the milk
How well the breast was emptied during the
previous feeding
Infants ability to absorb, detoxify, and excrete
the drug
17. Drugs That Aid in Milk Production:
Galactagogues
Herbals: Fenugreek
Metoclopramide (Reglan)
Domperidone (Motillium)
Synthetic Oxytocin nasal spray
18. Galactagogues
Used to increase breast milk supply
Need to determine the etiology of low milk
supply
Ensure proper breastfeeding technique
Only use with adequate milk removal
Must evaluate for medical co-morbidities
(e.g. hypothyroidism, retained placenta)
19. Herbal: Fenugreek
Trigonella foenum graecum
MOA: stimulate sweat production;
Phytoestrogen and Diosgenin - increase
milk flow
Tea (bitter taste), capsule or tablet
Sweat and urine (maple syrup smell)
Caution use in Asthma or diabetes
Contains coumarin (interact with
NSAIDS)
No scientific data
20. Domperidone (Motillium)
Not approved for use in the US
MOA: increase prolactin ® milk production
Maternal safety has not been established
FDA warning concerning reports of QT
interval prolongation, cardiac arrest, sudden
death (IV formulation)
Clinical trial showed increase breastmilk
volume without affecting nutrient composition
Campbell-Yeo M. Effect of Domperidone on Compositiono of Preterm Human
Breast Milk. Pediatrics 2010; 125 (1):e107-e114
21. Metoclopramide (Reglan)
Most commonly used
MOA: increase prolactin
Caution: clearance of metoclopramide in the
neonate is prolonged can result in side
effects (methemoglobinemia)
Short term use recommended (1-3 weeks)
Common dosing: 1st day – 10 mg, 2nd day – 10
mg bid, thereafter 10 mg tid
22. Synthetic Oxytocin Nasal Spray
Hormone (synthetically derived)
MOA: causes release of milk from milk
glands to the ducts (helps empty the breast)
Prepared by compounding Rx (10 unit/ml)
Dose: 1-2 sprays each nostril before breast
feeding or pumping
27. Definitions of Breast Feeding
Recommendations
Compatible
Hold Breast Feeding
No (limited) Human Data – Probably Compatible
No (limited) Human Data – Potential Toxicity
No (limited) Human Data – Potential Toxicity
(Mother)
Contraindicated
Briggs GG et. al. Drugs iinn PPrreeggnnaannccyy aanndd
LLaaccttaattiioonn,, 22000088;; 88tthh eeddiittiioonn
33. Values Used to Estimate Infant Drug
Exposure
Milk to Plasma Ratio (M/P)
– Ratio of the concentration of drug in mother’s milk divided by the
concentration in the mother’s plasma
– M/P <1 is preferred
Theoretical Infant Dose (TID)
– Multiply the milk concentration x daily milk intake of the infant
– Compared to the usual maintenance pediatric dose
Relative Infant Dose (RID)
– Divide the infant’s dose via milk (mg/kg/day) by the mother’s dose
(mg/kg/day)
– Assumes daily milk intake of 150 ml/kg/day
– RID<10% is considered safe
– Exception: fluconazole, metronidazole (have a high RID but are
non toxic)
39. The Transfer of Drugs and Other Chemicals Into Human Milk
Committee on Drugs
Pediatrics 2001;108;776
CLINICAL REPORT
The Transfer of Drugs and Therapeutics Into Human
Breast Milk: An Update on Selected Topics
Hari Cheryl Sachs, MD, FAAP* and COMMITTEE ON DRUGS
Pediatrics; originally published online August 26, 2013;
DOI: 10.1542/peds.2013-1985
42. Narcotics/Opiates
Case controlled studies evaluating long term
developmental outcomes are needed
Breastfeeding should be supported if:
– “stable” and compliant with methadone or
buprenorphine +/- naloxone (Subutex®, Suboxone®)
– negative maternal urine toxicology test at delivery
except for prescribed medications
– plan to continue substance abuse treatment in the
postpartum period
– do not have medical contraindication to breastfeeding
Breastfeeding Medicine 2009; 4(4):225-228
45. Antidepressants:
SSRIs and SNRIs
Limited to small case studies
Paroxetine and sertraline produced low RID 0.5-3%
Fluoxetine, citalopram, venlafaxine have variable
RID near to equal 10%
Preference hierarchy: sertraline, paroxetine,
citalopram, venlafaxine, fluoxetine
Watch for uneasy sleep, colic, irritability, poor
feeding, drowsiness
Breastfeeding Medicine 2008; 3 (1): 44-52
46. Relative Infant Dose (RID) of Commonly
Prescribed Antidepressants
Antidepressant Relative Infant Dose (%)
Buproprion (Wellbutrin) 2
Citalopram (Celexa) 3-10
Desvenlafaxine (Khedezla) 5.5-8.1
Duloxetine (Cymbalta) <1
Escitalopram (Lexapro) 3-6
Fluoxetine (Prozac) <12
Fluvoxamine (Luvox) <2
Mirtazapine (Remeron) 0.5-3
Paroxetine (Paxil) 0.5-3
Sertraline (Zoloft) 0.5-3
Venlafaxine (Effexor) 6-9
Chad L et.al. Update on antidepressant use during breastfeeding. Canadian Fam Physician 2013; 59: 633-634.
48. Antiepileptic meds:
Topiramate and Levetiracetam
5 mother child pairs on Topiramate
– mean milk:plasma ratio 0.86
– Topiramate concentrations in infant were low
– 4 of 5 mothers also taking carbamazepine (inducer)
8 women on Levetiracetam
– Milk and plasma concentration equal
– Levetiracetam concentrations in infants were low
Ohman I et.al. Topiramate kinetics during delivery and lactation. Epilepsia 2002; 43:
1157-1160
Johannasen SI et.al. Levetiracetam concentrations in serum and breast milk at birth and
during lactaction. Epilepsia 2005; 46: 775-777
52. Diabetes Meds:
Glyburide and Glipizide
Nonrandomized controlled study
Single dose of glyburide (5 or 10 mg, n=8)
Daily dose of glyburide or glipizide (5 mg; n=5)
No glyburide was found in milk
Mean infant exposure < 1.5%
Blood glucose levels were normal
Glyburide and glipizide compatible with
breastfeeding
Feig DS et.al. Transfer of glyburide and glipizide into
breast milk. Diabetes Care 2005; 28:1851-5
58. References
1. Buck, ML. Drugs in Pregnancy and Lactation: Literature an Resource Update. Pediatric
Pharm., 2010;16 (1): 1-5.
2. Burkey BW. Evaluating Medication Use in Pregnancy and Lactation: What Every
Pharmacist Should Know. J Pediatric Pharmacol Ther 2013; 18(3):247-258.
3. Chad L et.al. Update on Antidepressant Use During Breastfeeding. Canadian Family
Physician, 2013; 59: 633-634.
4. Feig DS et. al. Oral Antidiabetic Agents in Pregnancy and Lactation: A Paradigm Shift?
The Annals of Pharmacotherapy, 2007:41(7): 1174-1180.
5. Glatstein MM et. al. Use of Hypoglycemic Drugs During Lactation. Canadian Family
Physician, 2009; 55: 371-373.
6. Glueck CJ et.al. Growth, Motor, and Social Development in Breast and Formula-fed
Infants of Metformin-treated Women with Polycystic Ovarian Syndrome. J Pediatrics,
2006; 148(5):628-32.
7. Sachs et.al. AAP Committee on Drugs: The Transfer of Drugs and Therapeutics Into
Human Breast Milk: An Update on Selected Topics. Pediatrics, 2013; 132 (3): e796-
e809.
8. Mathhew JL. Effect of Maternal Antibiotics on Breast feeding Infants. Postgrad Med
Journal, 2004; 80:196-200.
59. References
9. Mortel M and Mehta SD. Systematic Review of the Efficacy of Herbal Galactogogues.
Journal of Human Lactation,2013;29(2):154-162.
10. Pack AM. Therapy Insight: Clinical Management of Pregnant Women with Epilepsy. Nat
Clin Pract Neurol, 2006; 2(4):190-200.
11. Wagner CL. Human Milk and Lactation. Medscape, 2012.
12. The Academy of Breastfeeding Medicine (ABM) Protocol Committee. ABM Clinical
Protocol #18: Use of Antidepressants in Nursing Mothers. Breast Feeding Medicine,
2008;3(1):44-52.
13. The Academy of Breastfeeding Medicine (ABM) Protocol Committee. ABM Clinical
Protocol #21: Guidelines for Breastfeeding and the Drug-Dependent Woman. Breast
Feeding Medicine, 2009;4(4):225-228.
14. The Academy of Breastfeeding Medicine (ABM) Protocol Committee. ABM Clinical
Protocol #9. Use of Galactogogues in Initiating or Augmenting the Rate of Maternal Milk
Secretion. Breast Feeding Medicine, 2011;6(1):41-49.
60. Medications and Lactation: Principles
for Safe Practice for the Clinician
Evelyn Fulmore, Pharm.D.
McLeod Regional Medical
Center
Florence, SC
Editor's Notes
During the 1st 10-14 days, large gaps exist between alveolar cells which enhance drug absorption. This will be important in considering breastfeeding the preterm infant.
The most important factor in infant exposure through breast milk is the amount of medication in the mother’s serum.Pass from the maternal plasma compartment through capillary wall into the alveolar cells to penetrate the breast milk.
We will spend a few moments to review each of these factors that determine penetration into medications into breast milk.
Drugs that are very lipid soluble penetrate in milk in higher concentrations almost without exception. Of particular interest are the drugs that are active in the CNS. CNS active drugs invariably have the unique characteristics required to enter milk. Therefore, if a drug is active in the CNS, higher levels in milk are expected; although the amounts still are often subclinical. Examples include drugs like Diazepam and Phenobarbital.
The molecular weight of a medication is a significant determinant as to the entry of that medication into human milk. Medications with small MWs (&lt;200 daltons) can easily pass into milk traversing small pores in the cell walls of the mammary epithelium. Examples of low MW drugs include: alcohol, amphetemines, diet pills. Drugs with higher molecular weights must traverse the membrane by dissolving in the cell’s lipid membranes, which may significantly reduce milk levels. Examples include Heparin, Enoxaparin, Insulin, Remicade. Larger molecular weight or size agents are preferred due to the reduced amounts that enter into the milk compartment.
Protein binding also plays an important role. Drugs circulate in the maternal plasma, either bound to albumin or freely soluble in the plasma. It is the free component “unbound fraction” that transfers into milk, while the bound fraction stays in the maternal circulation. Examples: warfarin and many NSAIDs. Levels are reduced in milk simply because they are excluded from the milk compartment. This is one of the single most important physiologic parameters to consider when choosing a safe medication for a nursing mother.
Once a drug has entered the mother’s milk and has been ingested by the infant, it must traverse or pass through the infant’s GI tract prior to absorption. Some drugs are poorly stable in this environment due to the proteolytic enzymes and acids present in the infant’s stomach. Examples of drugs with low oral bioavailability in the infant include. Aminoglycosides, heparin, insulin, omeprazole, and other large peptide drugs. Other drugs are poorly absorbed by the infant’s gastrointestinal tract and do not enter the infant’s blood stream. Thus oral bioavailability is a useful tool to estimate just how much of the drug will be absorbed by the infant. Realize also that some drugs that exert their action in the GI tract may produce local side effects in the infant causing diarrhea, constipation, or PMC.
Drugs are trapped in milk (ion trapping) due to the low pH of human milk (7-7.2). With drugs with a high pKa, the ionic state of the drug changes and stops its exit back into the maternal circulation. This is important for weak basic drugs, such as barbiturates (like phenobarbital with high pKa).
In the US it is estimated that 15% of breast feediing mothers use herbal galactagogues. Four herbs (shatavari, tobangun, fenugreek, milk thistle) with potential use as galactagogues have been studied. Currently the Academy of Breast feeding Medicine does not recommend use of herbals as galactagogues.
Fenugreek seeds contain hormone precursors that increase milk supply. Scientists do not know for sure how this happens. Some believe it is possible because breasts are modified sweat glands, and fenugreek stimulates sweat production. It has been found that fenugreek can increase a nursing mother&apos;s milk supply within 24 to 72 hours after first taking the herb. Once an adequate level of milk production is reached, most women can discontinue the fenugreek and maintain the milk supply with adequate breast stimulation. Many women today take fenugreek in a pill form (ground seeds placed in capsules). The pills can be found at most vitamin and nutrition stores and at many supermarkets and natural foods stores. Fenugreek can also be taken in tea form, although tea is believed to be less potent than the pills and the tea comes with a bitter taste that can be hard to stomach. Fenugreek is not right for everyone. The herb has caused aggravated asthma symptoms in some women and has lowered blood glucose levels in some women with diabetes.
The Milk to Plasma Ratio is the ratio of the concentration of the drug in the mother’s milk divided by the concentration in the mother’s plasma. If high (&gt;1-5), it is useful as an indicator of drugs that may sequester in milk in high levels. If low (&lt;1), it is a good indicator that only minimal levels of the drug are transferred into milk. While it is best to choose drugs with low M/P ratios, the amount of the drug which transfers is largely determined by the level of drug in the mother’s plasma compartment. Even with high M/P ratios and low maternal plasma levels, the amount of drug that transfers can be low. The Theoretical Infant Dose is a value calculated by multiplying the milk concentration x the daily milk intake of the infant. This value is then compared to published usual maintenance pediatric doses. Lastly, the Relative Infant Dose (RID) is a value calculated by dividing the infant’s dose via milk (mg/kg/day) by the maternal dose (mg/kg/day). This weight normalizing method indicates approximately how much of the “maternal dose” the infant is receiving. In the literature, some investigators do not normalize this value by weight so be careful we making comparisons.
The transfer of venlafaxine into breastmilk studied by Newport and colleagues in 13 infant-mother pairs showed a mean milk:plasma ratio of 275.3%. The highest venlafaxine and desvenlafaxine concentration in breastmilk occurred an average of 8 hours after a maternal dose. Infant plasma concentrations of venlafaxine/desvenalfaxine were 37.1% of the maternal plasma concentrations, with a theoretical infant dose of 0.208 mg/kg/day. No adverse effects were reported. The considerable transfer of drug into breastmilk suggests the need for confirmatory studies and caution when prescribing this drug in clinical practice.
On the basis of small studies, including single-dose studies, case reports and short-term studies, phenytoin, carbamazepine and valproate are probably safe. These AEDs are all moderately to highly protein-bound, and are not transferred in high concentrations in breast milk. A small study of four infants indicates that lamotrigine might be transferred to the infant through breast milk in concentrations similar to those seen in the mother, as lamotrigine is extensively metabolized by glucuronidation, which is immature in infants. Given these findings, infants who are breastfed by mothers receiving lamotrigine should be monitored.
In eight women receiving levetiracetam, concentrations of the drug were approximately equal in milk and plasma.[51] In their babies, however, levels of levetiracetam in the serum were very low, indicating extensive transfer in milk and rapid elimination of levetiracetam in infants. Similarly, 2-3 weeks after delivery in five mother-child pairs in which the mother was treated with topiramate, the mean milk : maternal plasma concentration ratio of topiramate was 0.86,[52] yet topiramate concentrations of the drug in the infants were very low, indicating efficient elimination by the infant. It should be noted, however, that in this small study four of the five mothers were also taking carbamazepine, which induces metabolism of topiramate, as well as inducing fetal metabolism in general (including metabolism of carbamazepine).