10/12/2011 Treatment of Headaches During Pregnancy and Lactation g 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 1 10/12/2011 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) 2 10/12/2011 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 3 10/12/2011 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 4 10/12/2011 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) 5 10/12/2011 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 6 10/12/2011 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 7 10/12/2011 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) 8 10/12/2011 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 9 10/12/2011 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 10 10/12/2011 Triptan Excretion in Nursing Mothers Drug Milk Milk/Plasma Mean excretion Sumatriptan Human 5:1 0.21% of 6 mg SQ dose Zolmitriptan Rat 1:1@1 hr 4:1@ 4 hr Naratriptan Rat Rizatriptan Rat 5:1 Almotriptan Rat 1:1@ 0.5 hr 7:1@6 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 11