The present study was designed to define the kinetic behavior of fluoxetine N-demethylation in human liver microsomes and to identify the isoforms of cytochrome p450 (CYP) involved in this metabolic pathway. The kinetics of Ne formation of norfluoxetine was determined in human liver microsomes from six genotyped CYP2C19 extensive metabolizers (EM). The correlation studies between the fluoxetine N-demethylase activity and various CYP enzyme activities were performed. Selective inhibitors or chemical probes of various cytochrome P-450 isoforms were also employed. The kinetics of norfluoxetine formation in all liver microsomes were fitted by a single-enzyme Michaelis-Menten equation (mean Km=32 umol/L +/- 7 umol/L). Significant correlations were found between N-demethylation of fluoxetine at both 25 umol/L and 100 umol/L and 3-hydroxylation of tolbutamide at 250 micromol/L (r1=0.821, P1=0.001; r2=0.668, P2=0.013), respectively, and S-mephenytoin 4'-hydroxylase activity (r=0.717, P=0.006) at high substrate concentration of 100 umol/L. S-mephenytoin (SMP) (a CYP2C19 substrate) at high concentration and sulfaphenazole (SUL) (a selective inhibitor of CYP2C9) substantially inhibited norfluoxetine formation. The reaction was minimally inhibited by coincubation with chemical probe, inhibitor of CYP3A4 (triacetyloleandomycin, TAO). The inhibition of fluoxetine N-demethylation at high substrate concentration (100 umol/L) was greater in PM livers than in EM livers (73 % vs 45 %, P < 0.01) when the microsomes were precoincubated with SUL plus TAO. Cytochrome p450 CYP2C9 is likely to be a major CYP isoform catalyzing fluoxetine N-demethylation in human liver microsomes at a substrate concentration close to the therapeutic level, while polymorphic CYP2C19 may play a more important role in this metabolic pathway at high substrate concentration.
The exact metabolic fate of fluoxetine has not been fully elucidated. The drug appears to be metabolized extensively, probably in the liver, to norfluoxetine and several other metabolites. Norfluoxetine (desmethylfluoxetine) the principal metabolite, is formed by N-demethylation of fluoxetine, which may be under polygenic control. The potency and selectivity of norfluoxetine's serotonin-reuptake inhibiting activity appear to be similar to those of the parent drug. Both fluoxetine and norfluoxetine undergo conjugation with glucuronic acid in the liver, and limited evidence from animals suggests that both the parent drug and its principal metabolite also undergo O-dealkylation to form p-trifluoromethylphenol, which subsequently appears to be metabolized to hippuric acid.
IDENTIFICATION: Fluoxetine is a selective serotonin reuptake inhibitor used as an antidepressant agent. It is soluble in: water, methanol, chloroform and insoluble in hexane, ethyl acetate and benzene. HUMAN EXPOSURE: Main risks and target organs: Fluoxetine is safer in overdose than most other classes of antidepressants. In overdosage, most patients experience only mild neurological and gastroenterological symptoms; significant cardiovascular toxicity is unusual. The serotonergic effects of fluoxetine may be enhanced by combination with other antidepressants, monoamine oxidase inhibitors, carbamazepine or lithium and produce a life-threatening serotoninergic syndrome comprising hyperthermia, tremor and convulsions. Summary of clinical effects: Drowsiness, tremor, headache, blurred vision, dizziness, restlessness, and rarely, seizures and coma. Nausea, vomiting, abdominal pain. Bradycardia, mild hypertension or hypotension. Contraindications: Absolute: Hypersensitivity to fluoxetine. Coadministration of sumatriptan, non-specific monoamine oxidase inhibitors and B-specific monoamine oxidase inhibitors. Relative: Combination therapy with A-specific monoamine oxidase inhibitors or other antidepressants. Pregnancy or lactation. Routes of entry: Oral: Fluoxetine is administered orally. Absorption by route of exposure: Fluoxetine hydrochloride is readily absorbed from the gastrointestinal tract with peak plasma concentrations appearing from 6 to 8 hours after oral administration. The systemic bioavailability is greater than 85 % and does not appear to be affected by food. Distribution by route of exposure: Fluoxetine is widely distributed throughout the body. Plasma protein binding is 94 %. Biological half-life by route of exposure: Fluoxetine has a relatively long and highly variable half-life ranging from 1 to 4 days after a single dose and averaging nearly 70 hours; patients receiving high doses over long periods of time may exhibit prolonged elimination half-lives. The half-life of its active metabolite, norfluoxetine, is about 7 to 9 days. Metabolism: Fluoxetine is extensively metabolized in the liver to a desmethyl metabolite, norfluoxetine, which has activity similar to fluoxetine. Peak plasma concentrations of the active metabolite, norfluoxetine, occur around 76 hours after ingestion. Elimination and excretion: The primary route of elimination appears to be further hepatic metabolism to inactive metabolites which are conjugated and then excreted in the urine. Mode of action: Toxicodynamics: Fluoxetine is a potent inhibitor of serotonin re-uptake by Central Nervous System neurones and may interact with other drugs or circumstances which cause serotonin release. The enhancement of the serotonergic effects may produce a life-threatening serotonin syndrome. Pharmacodynamics: Fluoxetine specifically inhibits neuronal re-uptake of serotonin, thus increasing the concentration of the serotonin at the synapse and reinforcing of serotonergic neuronal transmission. Fluoxetine has little effect on other neurotransmitters. Fluoxetine has no direct effect on the heart. Carcinogenicity: Human studies: there is no evidence of carcinogenicity in patients taking fluoxetine. Teratogenicity: Human studies: a study of 128 women exposed to fluoxetine during the first trimester showed no increase in major fetal malformations. It is not known, however, if the drug is a human teratogen. A neonate whose mother had been taking fluoxetine during most of her pregnancy suffered tachypnea, emesis, continuous crying, irritability, tremor and increased muscle tone; the symptoms resolved within 96 hours. Fluoxetine and norfluoxetine are excreted in breast milk. The effects on the infant are uncertain. Caution should be exercised when fluoxetine is administered to a nursing mother. Interactions: Drug interactions with fluoxetine have been reported with L-tryptophan, L-dopa; monoamine oxidase inhibitors: selegiline, tranylcypromine; tricyclic antidepressants; selective serotonin re-uptake inhibitors: trazodone, zimeldine; benzodiazepines: alprazolam, diazepam; buspirone, lithium, anticonvulsants: carbamazepine, phenytoin, valproate; pentazocine, dextromethorphan, fenfluramine, calcium channel blockers, benztropine, cyproheptadine, clarithromycin. Cannabis, ethanol and LSD. At least 14 days should elapse between discontinuing a MAO-inhibiting antidepressant and introducing fluoxetine. Conversely, because of the long half-life of fluoxetine and its metabolite, norfluoxetine, it is recommended that at least 5 weeks should elapse between discontinuation of fluoxetine and the introduction of a MAO inhibitor. Main adverse effects: The major adverse effects reported with therapeutic doses of fluoxetine are primarily those of headache, insomnia, nausea, and nervousness. Less common adverse effects include tremors, sweating, dry mouth, anxiety, drowsiness, and diarrhea. ANIMAL/PLANT STUDIES: Carcinogenicity: Animal studies: fluoxetine was not carcinogenic in rats and mice at doses ten times the recommended daily dose for 24 months. Teratogenicity: Animal studies: in rats, fluoxetine and norfluoxetine cross the placenta and distribute within the fetus during the periods of organogenesis and postorganogenesis. Levels in fetal tissue are approximately half the corresponding maternal concentrations. Fluoxetine does not impair the fetal growth in rats or rabbits at doses nine and eleven times the maximum daily human dose respectively. Mutagenicity: In vitro: fluoxetine and norfluoxetine did not show mutagenicity in the Ames test. There was no induction of sister-chromatid exchange in the bone marrow of the Chinese Hamster.
◉ 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. A safety scoring system finds fluoxetine use to be possible during breastfeeding, although others do not recommend its use. 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, agitation, irritability, poor feeding, and poor weight gain.
Mothers taking an SSRI during pregnancy and postpartum may have more difficulty breastfeeding, although this might be a reflection of their disease state. These mothers 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.
◉ 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 a pediatrician observer, who was the infant’s father. However, the mother and the infant’s 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. 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. Maternal fluoxetine 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 the infant 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.
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 infants 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. The reaction was probably caused by fluoxetine and breastfeeding might have contributed to maintaining the high fluoxetine levels after birth.
A woman with narcolepsy took sodium oxybate 4 grams each night at 10 pm and 2 am as well as fluoxetine 20 mg and cetirizine 5 mg daily throughout pregnancy and postpartum. She breastfed her infant except for 4 hours after the 10 pm oxybate dose and 4 hours after the 2 am dose. She either pumped breastmilk or breastfed her infant just before each dose of oxybate. The infant was exclusively breastfed or breastmilk fed for 6 months when solids were introduced. The infant was evaluated at 2, 4 and 6 months with the Ages and Stages Questionnaires, which were withing the normal range as were the infant's growth and pediatrician's clinical impressions regarding the infant's growth and development.
Two women were treated with fluoxetine 20 mg daily during the third trimester of pregnancy and during breastfeeding. Pediatric evaluations including neurologic assessments and brain ultrasound were conducted during the first 24 hours postpartum. Further follow-up was conducted at 6 or more months of age. Infant clinical status was comparable to unexposed infants from the same pediatric department.
◉ Effects on Lactation and Breastmilk:Fluoxetine has caused increased prolactin levels and galactorrhea in nonpregnant, nonnursing patients. Euprolactinemic galactorrhea has also been reported. 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.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575; fluoxetine n = 21) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.
Elevated plasma phenytoin concentrations resulting in symptoms of toxicity have been reported when fluoxetine was used concurrently with phenytoin; caution and close monitoring are suggested.
Because of the possibility that fluoxetine may inhibit the metabolism of astemizole, leading to increased blood levels and risk of cardiac arrhythmias, including torsades de pointes, concurrent use is not recommended.
Both increased and decreased lithium concentrations, as well as some cases of lithium toxicity, have been reported with concomitant fluoxetine use; close monitoring of lithium concentrations is recommended.
Fluoxetine hydrochloride appears to be well absorbed from the GI tract following oral administration. The oral bioavailability of fluoxetine in humans has not been fully elucidated to date, but at least 60-80% of an oral dose appears to be absorbed. However, the relative proportion of an oral dose reaching systemic circulation unchanged currently is not known. Limited data from animals suggest that the drug may undergo first-pass metabolism and extraction in the liver and/or lung following oral administration. In these animals (beagles), approximately 72% of an oral dose reached systemic circulation unchanged. Food appears to cause a slight decrease in the rate, but not the extent of absorption of fluoxetine in humans.
Distribution of fluoxetine and its metabolites into human body tissues and fluids has not been fully characterized. Limited pharmacokinetic data obtained during long term administration of fluoxetine to animals suggest that the drug and some of its metabolites, including norfluoxetine, are widely distributed in body tissues, with highest concentrations occurring in the lungs and liver. The drug crosses the blood-brain barrier in humans and animals. In animals, fluoxetine: norfluoxetine ratios reportedly were similar in the cerebral cortex, corpus striatum, hippocampus, hypothalamus, brain stem, and cerebellum 1 hr after administration of single dose of the drug.
