Lamotrigine

Drug Levels and Effects:




Summary of Use during Lactation:


Breastfed infants whose mothers are taking lamotrigine have relatively high plasma lamotrigine levels, averaging 30 to 35% of maternal serum levels; infant plasma levels up to 50% of maternal levels have been reported. Neonates are particularly at risk for high plasma levels because their ability to metabolize the drug by glucuronidation is limited, plasma protein binding is relatively low, and maternal plasma and milk levels can rise dramatically in the immediate postpartum period if the dosage is not reduced to the prepregnancy dosage.[1][2] Mild thrombocytosis has been reported in some infants and withdrawal symptoms can occur if breastfeeding is abruptly discontinued. One case of severe apnea occurred in a breastfed 16-day-old whose mother was taking a high dose of the drug. Additionally, lamotrigine can cause rare, but potentially fatal skin reactions, although none has been reported in breastfed infants.

If lamotrigine is required by the mother, it is not necessarily a reason to discontinue breastfeeding, because many infants have been breastfed without adverse reactions. However, breastfed infants should be carefully monitored for side effects such as apnea, rash, drowsiness or poor sucking, including measurement of serum levels to rule out toxicity if there is a concern. Monitoring of the platelet count may also be advisable. If an infant rash occurs, breastfeeding should be discontinued until the cause can be established.


Drug Levels:


In published reports of anticonvulsant use during breastfeeding, most women were taking a combination of anticonvulsants. Some other anticonvulsants (e.g., phenytoin, carbamazepine) stimulate the metabolism of other drugs including anticonvulsants, whereas others (e.g., valproic acid) inhibit the metabolism of other drugs. Therefore, the relationship of the maternal dosage to the concentration in breastmilk can be quite variable, making calculation of the weight-adjusted percentage of maternal dosage less meaningful than for other drugs in this database.

Maternal Levels.

An epileptic woman took oral lamotrigine 300 mg daily throughout pregnancy and postpartum. After 6 weeks postpartum, the dosage was reduced to 200 mg daily. Breastmilk lamotrigine levels (time with respect to the doses not stated) on a dose of 300 mg daily ranged from 2.4 to 6.5 mg/L. After reducing the maternal dosage to 200 mg daily, the milk levels were 1.95 and 1.26 mg/L at days 64 and 92 postpartum, respectively.[3]

An epileptic woman was taking lamotrigine at a dosage of 300 mg daily in the last half of pregnancy and postpartum. At 2 weeks postpartum, breastmilk samples taken before the morning dose, before and after nursing, were 5.6 and 5.7 mg/L, respectively.[4]

Thirty-four women with 35 births had breastmilk lamotrigine levels monitored. Specific dosages and milk levels were not reported in the abstract, but the authors stated that they calculated that some of the infants received a mg/kg dosage that would be expected to produce therapeutic serum levels. However, infant serum levels were not reported.[5]

Nine epileptic mothers with 10 pregnancies taking lamotrigine in daily dosages averaging 411 mg daily (range 100 to 800 mg daily) had their breastmilk lamotrigine levels monitored between days13and 18 postpartum before and after nursing. (One of the mothers had her first of 2 pregnancies reported previously in reference [3]) Three of the women were also taking other anticonvulsants that induce lamotrigine metabolism; one was taking valproic acid that inhibits lamotrigine metabolism. The average prenursing breastmilk level was 7.4 mg/L (range 1 to 8.2 mg/L), 11.8 hours after the previous dose. The average postnursing level was 5.6 mg/L (range 1 to 8.2 mg/L); one mother had taken a dose during nursing. The authors estimated that these exclusively breastfed infants would receive between 0.2 and 1 mg/kg daily or about 9% (range 2 to 20%) of the maternal weight-adjusted dosage.[1][6]

Six nursing mothers who were taking lamotrigine in an average dosage of 6.3 mg/kg daily (range 1.75 to 12.5 mg/kg daily)collected milk over 1 to 2 dosage intervals. The mean infant daily dosage of lamotrigine in breastmilk was 0.45 mg/kg daily (range 0.1 to 0.75 mg/kg daily) which was 7.6% (range 5.7 to 9.9%) of the maternal weight-adjusted dosage.[7]

A hospital laboratory evaluated all requests for lamotrigine concentration measurements. Mothers were taking between 50 to 500 mg of lamotrigine daily in the postpartum period. Milk concentrations ranged from 0.3 to 10.3 mg/L.[8]

Twenty-four nursing mothers taking lamotrigine had serum and breastmilk concentrations measured on several occasions. The average lamotrigine dosage was 387 mg daily (range 50 to 800 mg daily) or 5.93 mg/kg daily (range 0.99 to 14.34 mg/kg daily). The average breastmilk concentration of all samples was 3.4 mg/L (range 0.5 to 11.8 mg/L). The authors estimated that an exclusively breastfed infant would receive an average dosage of 0.51 mg/kg daily which was equivalent to 9.2% (range 3.1 to 21.1%) of the maternal weight-adjusted maternal dosage. Among 16 women who donated multiple serial milk samples, the peak milk concentrations occurred about 3 hours after the dose and averaged 2.3 times the average minimum milk concentration.[9]

Four women who were taking lamotrigine during pregnancy and postpartum had their milk analyzed for lamotrigine twice between 1 to 12 weeks postpartum. Maternal dosages ranged from 250 to 900 mg daily and milk concentrations ranged from 2.8 to 8 mg/L.[10]

A mother was taking 875 mg of lamotrigine daily at term and her dose was slowly reduced by 25 mg/day at weekly intervals beginning 2 weeks postpartum. On day 22 postpartum with a dose of 600 mg daily, her milk lamotrigine level was 7.68 mg/L13hours after a dose and on day 25, it was 10.06 mg/L 3.5 hours after the same dose. From days 28 to 64 postpartum on doses of 525 to 575 mg/day, milk samples contained 7.02 to 8.71 mg/L of lamotrigine 12 to 14 hours after a dose. The authors estimated that the infant's daily dosage on day 22 was 1.15 mg/kg, equating to 13% of the maternal weight-adjusted dosage.[11]

A mother treated for epilepsy during pregnancy and breastfeeding had lamotrigine measured in several blood and milk samples during the first month postpartum. She was receiving 400 mg of lamotrigine daily which corresponded to a dose of 5.3 mg/kg daily at birth increasing to 6.5 mg/kg daily at 1 month due to postpartum weight loss. Milk lamotrigine levels ranged from 7.8 to 11.5 mg/L on 4 occasions during the first month.[12][13]

Infant Levels.

An infant was exclusively breastfed from day 2 of age during maternal treatment with lamotrigine 300 mg daily. Infant total serum level at 2 days of age was 2.8 mg/L (free drug 1.2 mg/L), reflecting transplacental passage. Serum levels taken periodically 2 to 3 hours after the morning dose and 1 to 2 hours after breastfeeding ranged from 1.7 to 2.7 mg/L (free drug 0.73 to 1 mg/L). After maternal dosage reduction to 200 mg daily and 50% formula supplementation, total serum levels on days 64 and 92 dropped to 1.54 and 0.75 mg/L (free drug 0.53 and 0.24 mg/L), respectively. Infant serum levels were undetectable (total <0.2 mg/l;="" free=""><0.1 mg/l)="" on="" days="" 144="" and="" 145="" with="" only="" one="" breastfeeding="">

The 2-week old breastfed infant of a mother taking lamotrigine 300 mg daily had a level of 1.4 mg/L before the mother's morning dose.[4]

The plasma levels of 10 breastfed infants of 9 mothers taking lamotrigine during pregnancy and postpartum were monitored after birth. Most were breastfed from day 1 or 2 of age. Their transplacentally acquired plasma levels which were similar to maternal plasma levels at birth, generally dropped slightly over the first 72 hours of life. Infant plasma levels 2 to 3 weeks postpartum averaged 1.7 mg/L (range 0.5 to 3.3 mg/L) before nursing about 11.8 hours after the previous maternal dose and 1.5 mg/L (range <0.5 to="" 2.5="" mg/l)="" after="" nursing.="" infant="" plasma="" levels="" averaged="" 30%="" (range="" 23="" to="" 50%)="" of="" their="" mothers'="" plasma="" levels="" at="" that="">

Four infants of mothers taking lamotrigine monotherapy during pregnancy and lactation for partial seizures had their plasma levels monitored on day 10 of age (sampling time with respect to dose or nursing not reported). Maternal dosages were 200,400,750, and 800 mg and the respective infant's serum levels were <1, 1.8,="" 2,="" and="" 1.3="" mg/l.="" repeat="" levels="" in="" 2="" infants="" at="" 2="" months="" of="" age="" were="" 1.7="" and="" 1.9="" mg/l="" (previously="" 1.8="" and="" 1.3="" mg/l,="" respectively).="" infant="" plasma="" levels="" ranged="" from="" 0="" to="" 43%="" of="" maternal="" plasma="" levels="" at="" 10="" days="" of="" age="" and="" 20="" and="" 23%="" of="" maternal="" levels="" at="" 2="" months="" when="" they="" were="" partially="" breastfed,="" each="" receiving="" formula="" for="" 2="" or="" 3="" feedings="">

Six infants with a median age of 4.1 months (range 0.1 to 5.1 months) were breastfed during maternal use of lamotrigine in an average dosage of 6.3 mg/kg daily. Five were exclusively breastfed and one was about 50% breastfed. Single serum levels taken at various times after the maternal dose averaged 0.6 (range 0.3 to 0.9 mg/L) which averaged 18% (range 3 to 33%) of maternal serum levels.[7]

A hospital laboratory evaluated all requests for lamotrigine concentration measurements. Mothers were taking between 50 to 500 mg of lamotrigine daily. Infant serum concentrations averaged 88% of their mothers' serum concentrations at delivery , and averaged 45 to 55% of their mothers' serum concentrations at 3, 7, 14 and 30 days after delivery, although the percentage of infants who were breastfed was not stated. Infants who were breastfed (extent not stated) had serum concentrations ranging from <0.1 to="" 12.7="">

Simultaneous infant and maternal serum lamotrigine concentrations were obtained from 12 mother-infant pairs during maternal use of lamotrigine. Total infant serum concentrations of lamotrigine averaged 18.3% of maternal serum concentrations, but unbound infant serum concentrations averaged 30.9% of maternal levels, probably because the drug was less bound in the infants' serum. In 4 mother-infant pairs who had simultaneous serum sampling at delivery and again during the first 4 weeks postpartum, infant/maternal serum concentration ratios averaged 12.2 (total) and 6.2 (unbound) times higher at delivery than at the second sampling. These decreases indicate that exposure to lamotrigine during breastfeeding is much less than exposure during pregnancy.[9]

Four breastfed infants (extent not stated), whose mothers were taking lamotrigine in dosages ranging from 250 to 900 mg daily, had serum lamotrigine concentrations measured twice after breastfeeding between 1 and 12 weeks postpartum. The median serum concentration in the infants was 2.2 mg/L (range 1.7 to 3.3 mg/L), which was 26% of the median maternal serum concentrations.[10]

An infant was fully breastfed by a mother taking lamotrigine during pregnancy and postpartum. The infant had a serum concentration of 7.7 mg/L at 12 hours of life and 5.8 mg/L on day 3 of life while his mother was taking 875 mg daily of lamotrigine. On day 16, 4 hours after the maternal dose and 3 hours after breastfeeding, the infant's serum concentration was 4.9 mg/L with a maternal dose of 850 mg daily. Breastfeeding was terminated on day 17 because of an severe apneic episode in the infant; on day 22, the infant's serum concentration was 1.3 mg/L and on day 25 it was 0.5 mg/L.[11]

A mother treated for epilepsy during pregnancy and breastfeeding was receiving 400 mg of lamotrigine daily which corresponded to a dose of 5.3 mg/kg daily at birth and increasing to 6.5 mg/kg daily at 1 month due to postpartum weight loss. Her breastfed (extent not stated) infant had a serum lamotrigine concentration of13.6 mg/L at birth, 12.7 mg/L at 4 days of age and then stabilized between 6.7 to 6.9 mg/L from days 6 to 32 of age. The initial high levels were probably due to transplacental transmission. The later concentrations corresponded to 44 to 49% of the maternal serum concentrations.[12][13] The same authors reported on 21 women who were taking lamotrigine during pregnancy and lactation and their infants. At 6 to 10 days postpartum, the infants' serum lamotrigine concentrations ranged from 0% to 74% of maternal serum concentrations.[14]

A computer simulation of 300 cases in which the mother was receiving 200 mg of lamotrigine daily estimated that a fully breastfed infant would receive an average of 2 mg of lamotrigine daily and develop average serum concentration of 1 mg/L.[15]

Three breastfed preterm infants whose mothers were taking lamotrigine 200 mg daily had serum lamotrigine levels measured. One infant whose mother was taking no other drugs, had undetectable serum lamotrigine. The other two infants were twins whose mother was taking other unspecified medications for bipolar disorder. They reportedly had serum levels "within the therapeutic range". Whether the infants were exposed prenatally was not stated.[16]

An analysis was performed of paired infant and maternal serum lamotrigine concentrations obtained 6 to 10 days after delivery in 21 postpartum mothers and their breastfed (extent not stated) infants. The ratio of infant to maternal serum concentrations ranged from 0.0 to 0.74. No correlation was found between breastmilk concentrations and infant serum concentrations of lamotrigine. The authors attributed the wide range to differences in the activity of metabolizing enzymes in the breastfed infants.[17]


Effects in Breastfed Infants:


One infant was exclusively breastfed from day 2 of life during maternal lamotrigine 300 mg daily, which was decreased at 6 weeks postpartum to 200 mg daily and 50% formula was introduced. Examinations every 4 weeks showed normal development and no evidence of mental retardation or neurologic deficits. An electroencephalogram at 4 weeks of age showed no signs of pathology.[3]

A breastfed infant whose mother was taking lamotrigine 300 mg daily during pregnancy and postpartum had no observable adverse effects up to 5 months of age.[4]

The same authors reported 9 previously unreported infants who were breastfed during maternal lamotrigine therapy (dosage range 100 to 800 mg daily) with no adverse effects.[1][6]

Thirty-five pregnancies in 34 mothers who were taking lamotrigine during pregnancy were monitored. An unstated fraction of them breastfed their infants. No adverse effects in infants were observed.[5]

An exclusively breastfed infant whose mother was taking lamotrigine 200 mg and levetiracetam 2.5 g daily during pregnancy and lactation appeared healthy to the investigators throughout the 6- to 8-week study period.[18]

The breastfed infant of a woman taking lamotrigine 300 mg daily developed normally during the first 4 months of life and no adverse effects were observed.[19]

A 6-week-old infant developed apparent withdrawal symptoms after abrupt weaning by a mother who was taking lamotrigine 200 mg daily during late pregnancy and postpartum. Symptoms included loss of appetite, neuromotor hyperexcitability and irritability. Symptoms occurred 2 weeks after weaning and were completely alleviated within 48 hours after instituting lamotrigine 1 mg/kg daily in the infant. Neuromotor development of the infant normalized 1 month after discontinuing therapy.[20] The reaction is rated as probably caused by lamotrigine in breastmilk.

Six infants with a median age of 4.1 months (range 0.1 to 5.1 months) were breastfed during maternal use of lamotrigine in an average dosage of 6.3 mg/kg daily. Five were exclusively breastfed and one was about 50% breastfed. No adverse effects were noted by the mothers or the attending pediatricians. A clinical pediatric assessment in 3 of the infants also revealed no adverse effects.[7]

Thirty infants whose mothers were taking lamotrigine were followed during breastfeeding. None of the infants developed a rash. Among infants who were monitored by laboratory testing, no abnormalities in liver tests, electrolytes (</span>n= 10) or hematocrits (</span>n= 8) were noted. Elevated platelet counts were observed in 7 of 8 infants tested (average age 3.8 weeks, range 2 to 10 weeks), with no adverse clinical effects.[9]

A mother was taking 875 mg of lamotrigine daily at term and her dose was slowly reduced by 25 mg/day at weekly intervals beginning 2 weeks postpartum. Her infant was fully breastfed and on day 16 postpartum while she was taking 850 mg daily, the infant experienced a severe apneic episode requiring cardiac compressions to maintain perfusion and was responsive only to painful stimuli. The infant's mother was taking a high dosage and had extensive drug excretion into breastmilk, and the infant's serum concentration was at the high end of the therapeutic range for children, but the fact that no adverse effects had occurred prior to day 16 could not be explained. Lamotrigine was assessed to be the probable causes of the apneic episode.[11]

In a long-term study on infants exposed to anticonvulsants during breastfeeding, no difference in average intelligence quotient at 3 years of age was found between infants who were breastfed (</span>n= 30) and those not breastfed (</span>n= 36) when their mothers were taking lamotrigine.[21]

Three women with bipolar disorder breastfed their infants during pregnancy and breastfeeding. One took 50 mg daily at term and increased her dose to 200 mg within one month. She reportedly breastfed her infant exclusively for 12 months. An unrelated infant rash occurred at 4 months of age, but the infant's growth and development were normal at 18 months of age. Another woman took lamotrigine 250 mg daily while she breastfed (extent not stated) her infant for several weeks. The infant's growth and development were normal at 18 months of age. The third mother also took 250 mg daily while breastfeeding (extent not stated) for at least 15 months. At 4 months of age, the infant developed a rash on the neck that resolved spontaneously; the infant's growth and development were normal at 15 months of age.[22]

Five breastfed preterm infants were reported whose mothers were taking lamotrigine. Transient elevation of liver enzymes occurred in twins whose mother was taking other unspecified medications for bipolar disorder. No adverse effects were seen in the other infants.[16]


Possible Effects on Lactation:


Relevant published information was not found as of the revision date.


Alternate Drugs to Consider:


Dependent on patient and condition being treated.


References:


1. Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia. 2000;41:709-13. PMID:10840403
2. Liporace J, Kao A, D'Abreu A. Concerns regarding lamotrigine and breast-feeding. Epilepsy Behav. 2004;5:102-5. PMID:14751214
3. Rambeck B, Kurlemann G, Stodieck SRG et al. Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child. Eur J Clin Pharmacol. 1997;51:481-4. PMID:9112063
4. Tomson T, Ohman I, Vitols S. Lamotrigine in pregnancy and lactation: a case report. Epilepsia. 1997;38:1039-41. PMID:9579945
5. Berry DJ. The disposition of lamotrigine throughout pregnancy. Ther Drug Monit. 1999;21:450. Abstract 90.
6. Ohman I, Tomson T, Vitols S. Lamotrigine (LTG) pharmacokinetics during delivery and lactation. Ther Drug Monit. 1999;21:478. Abstract 201.
7. Page-Sharp M, Kristensen JH, Hackett LP et al. Transfer of lamotrigine into breast milk. Ann Pharmacother. 2006;40:1470-1. Letter. PMID:16868219
8. Ivana K, Milan G, Blanka K, Hana B. Therapeutic monitoring of lamotrigine during delivery, in the neonatal period, and during lactation. Ther Drug Monit. 2007;29:477. Abstract 52.
9. Newport DJ, Pennell PB, Calamaras MR et al. Lamotrigine in breast milk and nursing infants: determination of exposure. Pediatrics. 2008. PMID:18591203
10. Fotopoulou C, Kretz R, Bauer S et al. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res. Epilepsy Res. 2009;85:60-4. PMID:19272754
11. Nordmo E, Aronsen L, Wasland K et al. Severe apnea in an infant exposed to lamotrigine in breast milk. Ann Pharmacother. 2009;43:1893-7. PMID:19826099
12. Kacirova I, Grundmann M, Brozmanova H. [Drug interaction between lamotrigine and valproic acid used at delivery and during lactation - A case report]. Klin Farmakol Farm. 2010;24:222-5.
13. Kacirova I , Grundmann M, Brozmanova H. Drug interaction between lamotrigine and valproic acid used at delivery and during lactation - a case report. Basic Clin Pharmacol Toxicol. 2011;109:134. Abstract.
14. Kacirova I , Grundmann M, Brozmanova H. Serum levels of lamotrigine in breastfeeding mothers, maternal milk and nursed infants. Basic Clin Pharmacol Toxicol. 2011;109:134. Abstract.
15. Cibert M, Gouraud A, Vial T, Tod M. A physiologically-based pharmacokinetic model to predict neonate exposure to drugs during breast-feeding: application to lamotrigine. Fundam Clin Pharmacol. 2010;24 (Suppl. 1):246. Abstract.
16. Precourt A , Morin C. Use of lamotrigine during breastfeeding: descriptive analysis of our population and report of five cases of premature neonates. Breastfeed Med. 2011;6 (Suppl 1):S-18. Abstract.
17. Kacirova I , Grundmann M, Brozmanova H. Serum levels of lamotrigine in breastfeeding mothers, maternal milk and nursed infants. Basic Clin Pharmacol Toxicol. 2011;109:135-6. Abstract.
18. Johannessen SI, Helde G, Brodtkorb E. Levetiracetam concentrations in serum and in breast milk at birth and during lactation. Epilepsia. 2005;46:775-7. PMID:15857447
19. Gentile S. Lamotrigine in pregnancy and lactation. Arch Women Ment Health. 2005;8:57-8. PMID:15868389
20. Popescu L, Marceanu M, Moleavin I. Withdrawal of lamotrigine caused by sudden weaning of a newborn: a case report. Epilepsia . 2005;46 (Suppl 6):407. Abstract.
21. Meador KJ, Baker GA, BrowningNet al. Effects of breastfeeding in children of women taking antiepileptic drugs. Neurology. 2010;75:1954-60. PMID:21106960
22. Wakil L, Epperson CN, Gonzalez J et al. Neonatal outcomes with the use of lamotrigine for bipolar disorder in pregnancy and breastfeeding: a case series and review of the literature. Psychopharmacol Bull. 2009;42:91-8. PMID:19752842



Substance Identification:




Substance Name:

Lamotrigine

CAS Registry Number:

84057-84-1

Drug Class:


  • Anticonvulsants

  • Antimanic Agents

  • Antidepressive Agents


  • Administrative Information:




    LactMed Record Number:


    399


    Last Revision Date:


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