Fluoxetine use while Breastfeeding
Drugs containing Fluoxetine: Prozac, Sarafem, Symbyax, Prozac Weekly, Selfemra, Rapiflux
Fluoxetine Levels and Effects while Breastfeeding
Summary of Use during Lactation
The average amount of drug in breastmilk is higher with fluoxetine than with most other SSRIs and the long-acting, active metabolite, norfluoxetine, is detectable in the serum of most breastfed infants during the first 2 months postpartum and in a few thereafter. Adverse effects such as colic, fussiness, and drowsiness have been reported in some breastfed infants. Decreased infant weight gain was found in one study, but not in others. No adverse effects on development have been found in a few infants followed for up to a year.
If fluoxetine is required by the mother, it is not a reason to discontinue breastfeeding. If the mother was taking fluoxetine during pregnancy or if other antidepressants have been ineffective, most experts recommend against changing medications during breastfeeding. Otherwise, agents with lower excretion into breastmilk may be preferred, especially while nursing a newborn or preterm infant. The breastfed infant should be monitored for behavioral side effects such as colic, fussiness or sedation and for adequate weight gain. Mothers taking an SSRI during pregnancy and postpartum may have more difficulty breastfeeding and may need additional breastfeeding support. Breastfed infants exposed to an SSRI during the third trimester of pregnancy have a lower risk of poor neonatal adaptation than formula-fed infants.
Fluoxetine is metabolized to norfluoxetine which has antidepressant activity that is considered to be equal to fluoxetine.
Maternal Levels. In a pooled analysis of serum levels from published studies and 1 unpublished case, the authors found that 20 mothers taking an average daily dosage of 28 mg (range 10 to 80 mg) had an average milk fluoxetine level of 76 mcg/L (range 23 to 189 mcg/L). Using the average dosage and milk level data from this paper, an exclusively breastfed infant would receive an estimated 2.4% of the maternal weight-adjusted dosage of fluoxetine; however, the substantial contribution of norfluoxetine was not considered. In one of the studies included in the pooled analysis that measured both fluoxetine and norfluoxetine in 14 mothers, the average daily infant dosage in breastmilk was about 7% (range 3 to 12%) of the mother's weight-adjusted dosage.
Eleven women taking fluoxetine 20 to 40 mg daily during pregnancy and lactation had trough milk fluoxetine and norfluoxetine levels measured on day 4, week 2 and month 2 postpartum. When standardized to a 20 mg daily dosage, total drug concentration in breastmilk ranged from 75.4 to 91.5 mcg/L at the 3 times. The authors estimated that an exclusively breastfed infant would receive a minimum of 2.4% and 3.8% of the maternal weight-adjusted dosage of the drug and metabolite combined with this maternal dosage regimen at 2 weeks and 2 months of age, respectively.
In 1 mother who was 11 weeks postpartum and taking fluoxetine in a daily dosage of 20 mg, the authors estimated that an exclusively breastfed infant would receive 3.3% of the maternal weight-adjusted dosage.
At 2 months postpartum, 7 mothers taking an average of 24 mg of fluoxetine daily had average breastmilk levels of 63.7 mcg/L of fluoxetine and 103.8 mcg/L of norfluoxetine. These data indicate that a fully breastfed infant would receive 25 mcg/kg daily of fluoxetine plus norfluoxetine. This value would be about 6.3% of the maternal weight-adjusted dosage.
Twenty-three nursing mothers who were taking fluoxetine in an average dose of 21 mg daily for a minimum of 4 weeks and averaging 3.7 months postpartum had random foremilk samples (n = 30) analyzed for R- and S-isomers of fluoxetine and norfluoxetine. The weight-adjusted dosages of these infants (average 91% breastfed) were calculated to be 0.54% and 0.57% of the maternal weight-adjusted dosage for fluoxetine and norfluoxetine, respectively. The concentrations of the active S-isomer in milk were about 1.9 times that of the R- isomer.
Data from 24 women on the excretion of fluoxetine and norfluoxetine into milk from two previously published studies were combined and reanalyzed using NONMEM. Data from the two original papers were previously included in a pooled analysis reported above. Simulations of the data indicated that a fully breastfed infant would receive a median of 0.017 mg/kg daily of fluoxetine plus norfluoxetine. This resulted in a median weight-adjusted percentage of 5.9% of the maternal dosage, with a 99th percentile value of 23%.
Infant Levels. In a pooled analysis of 22 mother-infant pairs from published and unpublished cases, the authors found that infants had an average of 7% (range 0 to 59%) of their mothers' fluoxetine plasma levels; 4 of the 22 infants (18%) had a plasma level greater than 10% of the mothers' which was defined by the authors as being elevated.
Eleven breastfed (6 exclusively; 5 supplemented) infants with an average age of 24.6 weeks (range 5 to 36 weeks) whose mothers were taking an average of 27.3 mg daily of fluoxetine all had measurable norfluoxetine serum levels averaging 3.2 mcg/L (range 1.4 to 8.7 mcg/L) which was 3.2% of average maternal norfluoxetine serum levels. One infant also had a detectable fluoxetine level of 2.6 mcg/L.
The breastfed (extent not stated) infants of 11 women taking fluoxetine 20 to 40 mg daily during pregnancy and lactation had trough milk fluoxetine and norfluoxetine levels measured on day 4, week 2 and month 2 postpartum. At 2 weeks of age, fluoxetine was detectable in the serum of 2 of the infants in concentrations of 7.1% of the average maternal serum level. Norfluoxetine was detectable in the serum of all infants in average concentrations of 38% of the average maternal serum level. At 2 months of age, no infant had detectable fluoxetine levels; norfluoxetine was detectable in the serum of all infants in concentrations averaging 6.5% of the average maternal serum level.
At 2 months postpartum, the breastfed infants of 7 mothers taking an average of 24 mg of fluoxetine daily had an average serum levels of 2 mcg/L of fluoxetine and 8.5 mcg/L of norfluoxetine which was about 9% of the maternal serum norfluoxetine level.
Thirty serum levels were obtained from 23 infants with an average age of 3.7 months and breastfed an average of 91% by mothers who had been taking fluoxetine in an average dose of 21 mg daily for at least 4 weeks. Six of 7 infants had detectable serum levels in the first month, 6 of 8 in the second month and 2 of 14 thereafter. The ratio of infant to maternal serum levels of fluoxetine plus S-norfluoxetine dropped rapidly during the first month and was less than 10% by 2 months of age. Infant serum levels of S-fluoxetine and S-norfluoxetine were about 3 times as high as the R-isomers during the first 2 months. Only norfluoxetine could be detected after this time and the S- to R-isomer ratio fell to about 1.4.
Effects in Breastfed Infants
Colic, decreased sleep, vomiting and watery stools occurred in a 6-day-old breastfed infant probably caused by maternal fluoxetine. Two other reports of colic in breastfed infants, a 1.76-month-old and a 2-month-old, were possibly caused by fluoxetine in breastmilk. The older of the two also exhibited hyperactivity.
Another case of possible increased irritability in a 3-month-old was noted by one pediatrician observer; however, the mother and another pediatrician disagreed.
Occurrence of hyperglycemia and glycosuria in a 5-month-old, possibly from fluoxetine in breastmilk was reported to the Australian Adverse Drug Reaction Advisory Committee.
A 3-day-old breastfed infant was difficult to arouse, ceased rooting behavior, decreased nursing, and was moaning and grunting. Although the infant had been exposed in utero and was somewhat drowsy during the first 2 days of life, symptoms became worse after the mother's milk came in on day 3. These effects were probably caused by fluoxetine in breastmilk.
Possible drug-induced seizure-like activity and cyanosis occurred in a breastfed 3-week-old breastfed infant whose mother was taking fluoxetine, carbamazepine and buspirone during pregnancy and breastfeeding.
One observational report of 4 infants found no apparent neurological abnormalities following exposure to fluoxetine in milk for 12 to 52 weeks.
A retrospective, case-control, cohort study compared the weights of the infants of mothers who took fluoxetine during pregnancy and breastfed for at least 2 weeks postpartum to the infants of mothers who took fluoxetine during pregnancy and did not breastfeed. Compared to controls, decreased weight gain occurred among the 26 infants exposed postpartum to fluoxetine in breastmilk, although the weights were still in the normal range.
A prospective study of 51 nursing women taking fluoxetine and 63 nursing women who took no fluoxetine found no effect on weight gain, but reported a greater frequency of unspecified side effects in the infants of mothers who took fluoxetine. This study's results have been reported only in abstract form, so some details are lacking.
In a prospective study of 40 women who took fluoxetine throughout pregnancy, 21 breastfed their infants (extent and duration not stated). Testing of the infants at 15 to 71 months of age found no differences in cognitive, language or temperament measurements between infants who were breastfed and those who were not.
In a study comparing the 31 infants of depressed mothers who took an SSRI during pregnancy for major depression with 13 infants of depressed mothers who did not take an SSRI, mental development and most motor development in both groups was normal at follow-up averaging 12.9 months. Three of the treated mothers took fluoxetine in doses averaging 23.3 mg daily for an average of 3 months while breastfeeding their infants. Psychomotor development was slightly delayed compared to controls, but the contribution of breastfeeding to abnormal development could not be determined.
Platelet serotonin levels were measured in 11 mothers and their breastfed infants after 4 to 12 weeks of fluoxetine therapy. Maternal dosages ranged from 20 to 40 mg daily. Ten of the infants were under 6 months of age and 4 were under 3 months of age at the start of therapy; 6 were exclusively breastfed. Although maternal platelet serotonin levels were decreased from 157 mcg/L to 23 mcg/L by fluoxetine therapy, average infant serotonin levels were 217 mcg/L before and 230 mcg/L after maternal therapy. These findings indicate that the amount of fluoxetine ingested by the infants was not sufficient to affect serotonin transport in platelets in most breastfed infants. However, 3 infants experienced drops in platelet serotonin of 13, 24 and 60%, respectively. The latter infant was the only one with measurable fluoxetine plasma levels as well as norfluoxetine, but had no discernible adverse effects. One other infant had a delay in motor development at 24 weeks, but had normal mental development; 6 other infants were within 1 standard deviation of normal in both measures when tested between 24 and 56 weeks of age. Platelets and neurons both have the same serotonin transporter, so this effect on platelet serotonin might indicate potential effects on the nervous system of some breastfed infants.
Twenty-nine mothers who took fluoxetine in an average dosage of 34.6 mg daily for depression or anxiety starting no later than 4 weeks postpartum, breastfed their infants exclusively for 4 months and at least 50% during months 5 and 6. Their infants had 6-month weight gains that were normal according to national growth standards and mothers reported no abnormal effects in their infants.
One study of side effects of SSRI antidepressants in nursing mothers found no adverse reactions that required medical attention in one infant whose mother was taking fluoxetine. No specific information on maternal fluoxetine dosage, extent of breastfeeding or infant age was reported.
Eleven infants who were breastfed (extent and duration not stated) during maternal use of fluoxetine for depression (n = 5) or panic disorder (n = 6) had normal weight gain at 12 months of age that was not significantly different from a control group of infants whose mothers took no psychotropic medications. Neurologic development was also normal at 12 months of age.
In 1 breastfed (extent not stated) infant aged 11 weeks whose mother was taking fluoxetine 20 mg daily, no adverse reactions were noted clinically at the time of the study.
A small study compared the reaction to pain in infants of depressed mothers who had taken an SSRI during pregnancy alone or during pregnancy and nursing to a control group of unexposed infant of nondepressed mothers. Infants exposed to an SSRI either prenatally alone or prenatally and postnatally via breastmilk had blunted responses to pain compared to control infants. Seven of the 30 infants were exposed to fluoxetine. Because there was no control group of depressed, nonmedicated mothers, an effect due to maternal behavior caused by depression could not be ruled out. The authors stressed that these findings did not warrant avoiding drug treatment of depression during pregnancy or avoiding breastfeeding during SSRI treatment.
An infant was born to a mother taking fluoxetine 40 mg daily, oxycodone 20 mg 3 times daily, and quetiapine 400 mg daily. The infant was breastfed 6 to 7 times daily and was receiving 120 mcg of oral morphine 3 times daily for opiate withdrawal. Upon examination at 3 months of age, the infant's weight was at the 25th percentile for age, having been at the 50th percentile at birth. The authors attributed the weight loss to opiate withdrawal. The infant's Denver developmental score was equal to his chronological age.
An uncontrolled online survey compiled data on 930 mothers who nursed their infants while taking an antidepressant. Infant drug discontinuation symptoms (e.g., irritability, low body temperature, uncontrollable crying, eating and sleeping disorders) were reported in about 10% of infants. Mothers who took antidepressants only during breastfeeding were much less likely to notice symptoms of drug discontinuation in their infants than those who took the drug in pregnancy and lactation.
A cohort of 247 infants exposed to an antidepressant in utero during the third trimester of pregnancy were assessed for poor neonatal adaptation (PNA). Of the 247 infants, 154 developed PNA. Infants who were exclusively given formula had about 3 times the risk of developing PNA as those who were exclusively or partially breastfed. Fifteen of the infants were exposed to fluoxetine in utero.
A late preterm infant was born to a mother who took fluoxetine 60 mg daily throughout pregnancy and during exclusive breastfeeding. At 7 days of age, the infant was found to be having jerking movements, with hypertonia and hyperreflexia as well as tachypnea and compensated metabolic acidosis. The infant's Finnegan scores were the range of 7 to 10. On day 8 of life, the infant had a serum fluoxetine level of 120 mcg/L, which is similar to therapeutic adult levels. Breastfeeding was discontinued and after 5 days of formula feeding the infant's Finnegan scores had decreased to a range of 3 to 6. After 10 days of formula, most symptoms had subsided. At 3 months of age, the infant was growing and developing normally. The infant's symptoms were attributed to serotonin syndrome caused by the high levels of fluoxetine rather than to withdrawal. Breastfeeding might have contributed to maintaining the high fluoxetine levels after birth.
Effects on Lactation and Breastmilk
Fluoxetine has caused increased prolactin levels and galactorrhea in nonpregnant, nonnursing patients. In a study of cases of hyperprolactinemia and its symptoms (e.g., gynecomastia) reported to a French pharmacovigilance center, fluoxetine was found to have a 3.6-fold increased risk of causing hyperprolactinemia compared to other drugs. Preliminary animal and in vitro studies found that fluoxetine may have some estrogenic activity. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
In a small prospective study, 8 primiparous women who were taking a serotonin reuptake inhibitor (SRI; 3 taking fluoxetine and 1 each taking citalopram, duloxetine, escitalopram, paroxetine or sertraline) were compared to 423 mothers who were not taking an SRI. Mothers taking an SRI had an onset of milk secretory activation (lactogenesis II) that was delayed by an average of 16.7 hours compared to controls (85.8 hours postpartum in the SRI-treated mothers and 69.1 h in the untreated mothers), which doubled the risk of delayed feeding behavior compared to the untreated group. However, the delay in lactogenesis II may not be clinically important, since there was no statistically significant difference between the groups in the percentage of mothers experiencing feeding difficulties after day 4 postpartum.
A case control study compared the rate of predominant breastfeeding at 2 weeks postpartum in mothers who took an SSRI antidepressant throughout pregnancy and at delivery (n = 167) or an SSRI during pregnancy only (n = 117) to a control group of mothers who took no antidepressants (n = 182). Among the two groups who had taken an SSRI, 33 took citalopram, 18 took escitalopram, 63 took fluoxetine, 2 took fluvoxamine, 78 took paroxetine, and 87 took sertraline. Among the women who took an SSRI, the breastfeeding rate at 2 weeks postpartum was 27% to 33% lower than mother who did not take antidepressants, with no statistical difference in breastfeeding rates between the SSRI-exposed groups.
Alternate Drugs to Consider
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