Treatment of Headaches During  Pregnancy and Lactation g y

10/12/2011
Treatment of Headaches During Pregnancy and Lactation
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y
Sylvia Lucas MD, PhD
University of Washington Medical Center
Seattle, Washington
November 13, 2011
Drug Safety During Pregnancy
Drugs and Pregnancy
• Peak prevalence of migraine occurs during women’s childbearing years
• Majority of migraineurs improve during pregnancy; 7% note onset during pregnancy
• Increase in age at which women become pregnant means more chronic medical conditions
• 60% of pregnancies are unplanned
• Pre‐pregnancy planning session: review prescription, OTC, supplements, caffeine, nicotine, alcohol use
– may need to change to safer drugs at their lowest effective dose
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Concept of Drug Safety during Pregnancy
• “Use in pregnancy is not recommended unless the potential benefits justify the potential risks to the fetus”
– “if benefit outweighs risk”
– Drug use during pregnancy could be considered D
d i
ld b
id d
“off label” – Drugs not tested on pregnant women
– Significant benefit to woman with severe migraine
– Risk difficult to ascertain, but document a “risk‐
benefit” conversation
US FDA Categories of Medication Risk in Pregnancy
A Controlled human studies show no risk
B No evidence of risk in humans, but no controlled studies
C Risk to humans has not been ruled out
D Positive evidence of risk to humans from human or animal studies
X Contraindicated in pregnancy
Some Limitations of FDA Rating Scale
• Information is difficult to interpret for use in counseling women on drug safety for the majority of drugs which are rated B or C
– Either animal studies have not demonstrated fetal risk but no controlled studies in pregnant women (B)
– Either studies in animals have shown adverse effects on fetus and there are no controlled studies in pregnant women or studies in women and/or animals are not available (C)
• Half of FDA‐approved drugs do not have a rating category
• Classification often not changed when new data are available (e.g. COC, bendectin, spermicides)
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FDA Categories to Avoid
• Category D
– Divalproex sodium, carbamazepine, tetracycline are known teratogens
– But also clonazepam, atenolol, and topirimate (new)
– NSAIDs become D in the 3rd trimester
• Category X
Category X
– Avoid ergotamine, methysergide and other ergot‐related drugs
• Decrease uterine blood flow (fetal hypoxia and growth retardation)
• Increase uterine muscle tone/contractions
– Dihydroergotamine not linked to increased risk of congenital malformation, but possible fetal bradycardia in late pregnancy
– Blue cohosh (yellow ginseng)‐uterine stimulant; CHF in infants
– Misoprostol‐uterine bleeding and abortion
– Ribivarin and Interferon alfa‐2B (Rebetron)‐potent teratogen
– Cholesterol‐lowering agents
Avoid Known Teratogens
• The Teratology Society has proposed that the FDA abandon the current classification in favor of evidence‐based narrative statements
• Defined as dysgenesis of fetal organs as D fi d d
i ff t l
evidenced either structurally or functionally (e.g. restricted growth, fetal death, carcinogenesis, malformation, brain function)
Teratogens can be Structural or Functional
• Potential structural abnormalities
– Thalidomide, MTX, ACE inhibitors, lithium, misoprostol, NSAIDS in the third trimester, tetracycline
• Potential functional abnormalities
– Carbamezepine, isotretinoin, phenytoin, valproic
acid, warfarin
• Functional effects at later exposure times
– Anticholinergic drugs, barbiturates, opioids, benzodiazepines
Koren G et al. NEJM 1998:338; 1128
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How Pregnancy Affects Drug Pharmacokinetic Properties
p
Variability of Drug Plasma Levels During Pregnancy
• Absorption
– Reduction in intestinal motility
– Increase in gastric pH
– No effect of pregnancy on bioavailability
• Distribution
– Increase in plasma volume
– Increase in fraction of drug unbound in plasma
– Albumin concentrations decrease during second trimester and continue to decline to about 70‐80% of normal values
– If clearance depends on protein binding, total concentration will underestimate unbound or active concentrations e.g. phenytoin and valproate
Effect of Pregnancy on Metabolism
First trimester
Second
trimester
Third trimester
CYP1A2
↓33%
↓50%
↓65%
CYP2A6
No data
↑54%
↑54%
CYP2C9
No data
No data
↑20%
CYP2C19
No data
↓50%
↓50%
↑50%
CYP2D6
No data
No data
CYP3A4
No data
No data
↑variability
UGT1A4 *
↑200% (65%
ind)
↑200% (65%
ind)
↑300% (90%
ind)
Renal clearance
↑20-65%
↑20-65%
↑20-65%
* Monotherapy (with inducers)
Table adapted from Anderson GD. Expert Opinion Drug Metab. Toxicol.2(6), 2006
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Hepatic Metabolism
Drugs/Probes
CYP1A2 ↓
Caffeine, clozapine, olanzapine
CYP2A6 ↑
Nicotine
CYP2C9 ↑
Phenytoin, losartan, celecoxib,
glyvuride, glipizide
CYP2C19 ↓
Proguanil, omeprazole,
pantoprozole
CYP2D6 ↑
Metoprolol, fluoxetine, nortriptyline
CYP3A4 ↑
Prednisolone*, nifedipine,
erythromycin*, eletriptan*,
saquinavir, verapamil*
UGT1A4 ↑
Lamotrigine
UGT2BB7 ↑
Morphine ,oxezepam, lorazepam?
*substrate of P-glycoprotein
Triptan Metabolism in Pregnancy
Drug
Metabolic Enzymes
Activity in
Pregnancy
Almotriptan
MAO-A
?
CYP3A4
↑
CYP2D6
↑
Eletriptan
CYP3A4
↑
Frovatriptan
CYP1A2
↓
Naratriptan
CYP450*
?
MAO-A
?
Rizatriptan
MAO-A
?
Sumatriptan
MAO-A
?
Zolmitriptan
CYP1A2
↓
MAO-A
?
Soldin OP et al. Ther Drug Monit 30:1, 2008
*
Specific enzymes not known
Triptan Studies in Human Pregnancy
• No human data suggest teratogenicity for any of the triptans
– 15% of a sumatriptan dose crosses the placenta over 4 hours (t½=2.5 hrs). Very small amounts will cross from mother to fetus by
amounts will cross from mother to fetus by passive transport
– Fetal 5‐HT1B/1D receptors develop through the third trimester, therefore it is not clear whether triptans could affect fetal development (Gupta S et al. J Hyperten. 24;2006)
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Pregnancy Registry Data
• Insufficient sample size and reporting bias
• Data available for 655 pregnancy exposures (594 suma, 57 nara, 4 Trex) as of Oct 31, 2010
• Most common adverse effects are spontaneous d
ff
abortion, preterm delivery, and low birth weight
• Not statistically significant except for preterm delivery significantly elevated with sumatriptan in Danish birth registry (Olesen C et al. Headache. 2000)
Birth Registries of Women Using Triptans
• Norwegian Mother and Child Cohort Study
– observational, prospective population‐based study of 69,929 pregnant women
– Standardized questionnaire of adverse pregnancy outcomes
– 2.2% of women used triptans
2 2% f
dt i t
d i
during pregnancy (1538 women), 2.7% (1538
) 2 7%
used trptans the 6 months prior to pregnancy (0.5% of prior users stopped when pregnant)
– No significant association between triptan therapy during the first trimester and major congenital malformations or any other adverse pregnancy outcome (slight risk atonic uterus in the mother)
– Also of interest, a significant number of women who used triptans
during pregnancy also used NSAIDs, paracetamol with and without codeine
(Nezvalova-Henriksen K, Spigset O, Norodeng H. Headache 50: 563-575, 2010)
Acute and Preventive Treatment of g
g
g
y
Migraine During Pregnancy
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Acute Treatment of Migraine in Pregnancy
Acute therapy: Mild to moderate, slow onset of pain
Medication
Caution
FDA Risk
Acetaminophen
Hepatotoxicity with
chronic use >200
mg/kg/d
B
Codeine
Sedation, respiratory
d
depression,
i
constipation, neonatal
withdrawal
C
Hydrocodone
B
Meperidine
C
NSAIDs (not 3rd)
Nausea, edema, GI
bleed, premature
closure of D.A.
B/C; D in 3rd
Acute Treatment of Migraine in Pregnancy
Acute therapy: Moderate to severe, rapid pain escalation/urgent care
Medication
Caution
FDA Risk
Triptans
Triptan sensation
C
Ondansetron
Rare transient
headache,
constipation, dizziness
Sedation, Diarrhea,
EPS
B
Sedation, respiratory
depression,
constipation,neonatal
withdrawal
B/C
Metoclopromide
Opioids (lozenges,
suppositories,
injectable)
B
Preventive Treatment of Migraine During Pregnancy
Medication
Propranolol,
metoprolol,
nadolol
Caution
FDA Risk
Maternal or fetal
hypotension, bradycardia,
weakness; depression,
peripheral edema with
verapamilil
C
Amitriptyline
Anticholinergic effects
C
Nortriptyline
May need dose increase
D
Fluoxetine
May need dose increase
C
Venlafaxine
Resp support and tube
feeding (few reports)
C
Verapamil
C
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Drug Safety During Lactation
Drug Safety During Lactation
• Safety and recommended use of a drug used during pregnancy may be completely different when its use is considered during lactation
• Dose of drug that the infant receives during breastfeeding is dependent on
–
–
–
–
Average plasma concentration of drug in mother Amount excreted into the breast milk
Amount excreted into the breast milk
Daily volume of milk ingested
Ability of the infant to absorb and eliminate drug
• Drug properties determine excretion
– Lipophilicity
– Protein binding
– Ionisation (e.g. pKa of a drug and “milk‐trapping”)
• Few drugs have clinical data: milk/plasma concentration ratio (M/P) model used as estimate
Risk Categories:
• American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk. Pediatrics 2001;108;776.
– Drugs for which the effect in nursing infants is unknown but may be of concern (Table 4)
but may be of concern (Table 4)
• Benzodiazepines, TCAs, SSRI, antipsychotics, lamotrigine, metoclopromide (concern for CNS function effect on infants)
– Drugs that have been associated with significant effects on some nursing infants and should be given to nursing mothers with caution (Table 5)
• Atenolol, aspirin, ergotamine, lithium, phenobarbital
– Maternal medication usually compatible with breastfeeding (Table 6)
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Dr. Hales’s Lactation Risk Category
• L1 Safest
– Studies show no risk or not orally bioavailable • L2 Safer
• L3 Moderately Safe
L3 M d t l S f
– Benefit > Risk
– New drugs go in L3
• L4 Possible Hazard
• L5 Contraindication
Using Medications and Mother’s Milk
(Hale, 13th edition, 2008)
Ibuprofen
Pregnancy Risk B, D in 3rd
Topiramate
C(
D)
Lactation Risk
L1 (Ideal)
L3
Infant Dose
75 mcg/kg/d
0 69 mg/kg/d
0.69
(theor)
Infant Dose (relat) 0.65%
24.5%
T1/2
1.8-2.5 h
18-24 h
Tmax
1-2 h
1.5-4 h
Protein Bound
>99%
15%
Drug Transfer into Breast Milk
• Protein binding of a drug is a useful and readily available measure of transfer of a drug into breast milk
• Using a series of 6 β
Using a series of 6 β‐blockers
blockers differing differing
significantly in lipophilicity, plasma and milk‐binding properties, Riant et al (Biochem Pharmacol. 35(24),1986) demonstrated that plasma protein binding was the major determinant of transfer of drug into breast milk
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Migraine Medication Lactation Risk
Medication with no significant levels measurable in infants:
Medication
% Maternal protein
binding
M/P*
Lactation Risk/AAP
Naproxen
99.7
0.01
Ibuprofen
99
-
Sertraline
99
0.89
p
Diazepam
98
0.2-2.7
Fluoxetine
95
0.29-0.67
Amitriptyline
95
1
Valproic acid
94
0.42
L2/ none
Propranolol
90
0.5
L2/ none
Verapamil
83-92
0.94
L2 /none
Eletriptan
85
0.25
L2 /none for suma
L3/ no information
L1 /none
L2/ conc in human milk
L3 /may
y be of concern
L2/ colic, irritability,
slow weight gain
L2/ may be of concern
*M/P is ratio of drug concentration in mother’s milk divided by concentration in plasma
Migraine Medication Lactation Risk
Medication with measurable levels in infants:
Medication
%Maternal protein
binding
M/P*
Gabapentin
<3
-
Atenolol
5
1.5-6.8
Metoprolol
Lactation
Risk/AAP
L2/ no info
L3/ cyanosis,
bradycardia
12
3-3.7
Sumatriptan
14-21
4.9
L3/ none
Topiramate
15
0.86
L3/ no info
Metoclopromide
30
0.5-4.1
Venlafaxine
30
-
L3/ no info
40
0.93
L5 /no info
76-80
-
L2/ no info
Zonisamide
Promethazine
L3/ conc in milk
L2/ conc in milk
* M/P is the ratio of drug concentration in mother’s milk divided by concentration in plasma
Protein‐binding of Triptans in Healthy Volunteers
Drug
Sumatriptan
Zolmitriptan
Naratriptan
Rizatriptan
Eletriptan
Almotriptan
Frovatriptan
Proteinbinding
14-21%
25%
20%
14%
85%
35%
15%
Unbound
Fraction (fu)
0.79-0.86
0.75
0.80
0.86
0.15
0.65
0.85
Data taken from package inserts
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Triptan Excretion in Nursing Mothers
Drug
Milk
Milk/Plasma
Mean
excretion
Sumatriptan
Human
5:1
0.21% of 6
mg SQ dose
Zolmitriptan
Rat
1:[email protected] hr
4:[email protected] 4 hr
Naratriptan
Rat
Rizatriptan
Rat
5:1
Almotriptan
Rat
1:[email protected] 0.5 hr
7:[email protected] hr
Frovatriptan
Eletriptan
Rat
4:1
Human
1:4
0.02% of 80
mg at 24 hr
Conclusions
• Offer counseling regarding medication use to women in their childbearing years
• For drugs with a narrow therapeutic range:
– metoprolol, fluoxetine, and nortriptyline may need a dose increase during pregnancy
– nicotine patch, omeprazole may need a dose decrease during pregnancy
• Document an explanation of medication risk and benefit
• Knowledge of protein‐binding properties of a drug can provide a quick method to estimate excretion in breast milk Thank you
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