Drugs in Milk S

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.
`