Human Data

In document Fluoxetine(原文) (Page 119-122)

3.4 Summary

3.4.1 Human Data In utero exposures

Case reports and case series reported adverse effects in infants exposed to fluoxetine in utero but the Expert Panel noted that such studies are not adequate for evaluating developmental effects of fluoxetine. The Expert Panel focused their evaluation of prenatal fluoxetine toxicity on studies with denominators, i.e., the sampling frame that was used for selecting study subjects could be identified.

The most complete study for evaluating toxicity in infants following prenatal exposure to fluoxetine was conducted by Chambers et al. (89). The study evaluated pregnancy outcomes in 228 women taking fluoxetine and a comparison group of 254 women exposed to either acetaminophen, dental x-ray, or < 1 oz. alcohol/week prior to learning of pregnancy. The fluoxetine group was divided into early or late exposures (before or after 25 weeks gestation, respectively). No difference in major mal-formations was found between liveborn infants exposed to fluoxetine in early gestation and controls.

However, the proportion of infants with multiple minor anomalies was increased. Late pregnancy exposures were associated with increased incidence of prematurity, reduced birth weight and length at full term, and poorer neonatal condition characterized by admission to special care nursery and adaptation problems (e.g., jitteriness, tachypnea, hypoglycemia, hypothermia, poor tone, respira-tory distress, weak or absent cry, or desaturation on feeding). Relative risks for late exposure were calculated by comparing late and early exposures and adjusting for numerous confounding factors.

Relative risks were 4.8 (95% CI: 1.1 – 20.8) for prematurity, 2.6 (95% CI: 1.1 – 6.9) for admission to a special care nursery, and 8.7 (95% CI: 2.9 – 26.6) for poor neonatal adaptation. Though conclusions about major malformations are limited by small sample size, the Expert Panel found this study to

Appendix II

have well-defined procedures and outcome measures and a thorough assessment of outcome com-pared to other studies. However, the Panel urged caution in interpreting the long-term implications of multiple minor anomalies. Also, the possible confounding effects of maternal depression need to be considered.

Two other large studies involving medical record reviews conducted by Simon et al. (104) and Ericson et al. (102) were felt to be well-designed and contribute to the utility of available data, although the Expert Panel noted that the medical record reviews in these studies do not provide outcome measures as strong as those in Chambers et al. (89).

Simon et al. (104) performed a record linkage study among members of a population based prepaid health plan to identify pregnancies for whom 1 or more prescriptions were filled for antidepressants within a 270 day interval before delivery. Significant reductions in gestational age at delivery (-0.9;

95% CI: -0.5,-1.3) were observed for women with SRI exposure (129/185 women using fluoxetine) during pregnancy in comparison to matched unexposed women after adjusting for maternal tobacco use, other substance use, race, and number of prior births. Risk of preterm birth dichotomized as

< 36 weeks gestation conferred a significantly increased risk for SRI exposure (OR:: = 4.38; 95% CI:

1.57, 12.22). Mean birth weights were significantly lower among SRI exposed infants in comparison to unexposed (-172 grams; 95% CI: -46, -299, controlling for the above potential confounders), but no effects were noted on birth weight when corrected for gestational age. None of these differences was significant when infants exposed to TCAs were compared with matched unexposed infants. The authors concluded that the observed effects are specific to SRI exposure rather than underlying maternal depression. The Expert Panel noted that the percent of preterm birth (<37 weeks) was comparable in the SRI- and TCA-exposed groups (10.3 and 10.0%, respectively). The absence of information on the full distribution of gestational age in each of the groups precludes a more meaningful interpretation of these data.

In a review of the Swedish Medical Birth Registry, Ericson et al. (102) found that use of antidepressants (fluoxetine [n = 15], other SRIs [n = 531], and non-SRI antidepressants [n = 438]) was associated with premature delivery (adjusted OR: 1.43, 95%; CI 1.14, 1.80), but no associations were noted by class of antidepressants; therefore, the authors suggested that the disease rather than the treatment was associated with prematurity. The Expert Panel believes that an alternative explanation for these findings is that a similar mode of action among these medications may be affecting the rate of prematurity.

The additional studies of prenatal fluoxetine toxicity were found to be limited by small numbers of subjects and/or study design. Though these studies alone were of limited utility, the Panel found some of the studies useful when evaluated together as a group, especially with better quality studies. No increase in major congenital malformations following in utero exposure was identified in any of the other studies reviewed by the Panel (19, 90, 96, 101, 104), although the Panel found the methods of most of these studies to be inadequate (i.e., limited sample size and statistical power for hypothesis testing) to detect a potentially important risk for congenital anomalies.

In a review of medical records, Cohen et al. (103) found that neonatal complications requiring admission to a special care nursery occurred in 1 of 11 (9%) pregnancies with first or second trimester exposure to fluoxetine vs. 16 of 53 (30%) pregnancies with third trimester exposure. Laine et al. (18) evaluated

sero-Appendix II

tonergic symptoms (e.g., myoclonus, restlessness, tremor, shivering, hyperreflexia, incoordination, and rigidity) in infants from ten fluoxetine- and ten citalopram-exposed pregnancies in which exposures were implied to have occurred during the period just prior to delivery. Compared to a control group (n = 20), there was no difference in pregnancy duration, but serotonergic symptoms were greater in the SRI group during the first 4 days of life; there was no difference at 2 weeks of age. The study by Oberlander et al. (110) found that 2-day-old infants exposed to SRIs (fluoxetine: n = 7, paroxetine: n = 11, sertraline:

n = 4) in utero responded to pain with less facial activity, a slower heart rate, and greater maintenance of cardiac modulation compared to control infants. It is not known if effects were due to prenatal brain alterations or continued presence of fluoxetine in infant blood. Findings from another study on a broader range of prenatal SRI exposures were consistent with these neonatal findings (112).

In contrast to the Chambers et al. study, Goldstein et al. (100) reported a lower incidence of neonatal irritability or jitteriness (4.5%) compared to other investigators and stated there were no apparent patterns of abnormal infant conditions in cases of fluoxetine exposure during the third trimester. The Goldstein study was not considered to be reliable due to methodologic limitations such as unstated but possibly large loss to follow-up and reliance for outcome data on reporters of questionable reliability.

Other neurotoxicity studies, limited by study design and found to be of little utility, suggested that prenatal fluoxetine exposure had no effect on neurodevelopment in children up 12 months (19) and 71 months of age (107, 109).

Although no differences were found by Simon et al. (104) in seizure disorder, motor delay, speech delay, or other motor abnormalities when comparing children with pregnancy exposure to fluoxetine and an unexposed reference group, the data collected to demonstrate this lack of developmental deficits were considered inadequate by the Expert Panel. No difference was found in birth weight or growth during the first 12 months for infants born to 11 women treated with 20 – 40 mg fluoxetine during pregnancy as compared to 10 control women (19), but the small size of this study provided limited power to detect differences. Breast milk exposures

Symptoms in infants breastfed by mothers taking fluoxetine were reported in case studies as outlined in Section 3.1.2. While some studies reported symptoms similar to those reported with prenatal exposure (e.g., hyperactivity, crying, irritability, reduced sleep, and poor feeding), no symptoms were reported in other breastfed infants exposed to fluoxetine. There were no controlled studies designed to evaluate symptoms in infants exposed to fluoxetine through breast milk.

In a well designed retrospective-cohort study conducted by Chambers et al. (113), it was found that infants nursed by mothers taking fluoxetine (n = 26) had a 392 g deficit in body weight gain (95% CI:

5 – 780 g), with weight gain at ~1.2 SD below control group (n = 38) values from 2 weeks to 6 months of age. However, all of the postnatally exposed infants had been prenatally exposed to fluoxetine in the third trimester, as contrasted to only 10.5% of the controls. Thus, the growth deficits found in this study may have been due to prenatal exposure or the effects attributed to postnatal exposure may have been partly due to residual levels of fluoxetine/norfluoxetine from third trimester exposure. A major strength of this study is that unlike most other fluoxetine studies which lack an unmedicated depressed comparison group, this study provides the only evidence of infant deficits specifically related to fluoxetine and not the underlying depressive disorder.

Appendix II Childhood exposures

Side effects in children taking fluoxetine are similar to those of adults and include manic reaction, hyperkinesia, rash, personality disorder, agitation, constipation, diarrhea, headache, nervousness, somnolence, insomnia, suicide attempt, depression, endometrial hyperplasia, hostility, euphoria, and migraine (4, 116). Additional side effects reported for children include thirst, hyperkinesia, epistaxis, urinary frequency, and menorrhagia (4). Some reviews expressed concern that children may be par-ticularly sensitive to excessive arousal and irritability (117-119). However, other studies did not find activation to be the most common side effect, as more commonly observed effects included gastroin-testinal effects, drowsiness, and headache (120, 122, 123).

In a medical review, the FDA (116) expressed concern about prolonged QTc interval and growth decrements in children taking fluoxetine. Although prolonged QTc interval was not replicated in later studies, the significance was found to be robust using Fridericia correction, which is unlikely to result in statistical significance for random variability. In addition the R-isomer of fluoxetine prolonged QTc intervals in adults. Therefore, the FDA Medical Officer believed prolonged QTc interval to be a true drug effect in children.

FDA concerns about growth decrements in children were based upon a 19-week study that reported height and weight increases of 1.0 cm and 1.2 kg in children treated with fluoxetine vs. 2.0 cm and 2.3 kg in control children (P = 0.008) (116). The original study examining growth in children was not available to CERHR. Impaired growth was reported in abstracts but there are no known published studies examining this endpoint.

In October, 2003, the FDA issued a Public Health Advisory regarding their review of suicidality in children taking fluoxetine or seven other antidepressant drugs (136). It was concluded that preliminary data suggest an excess of reports of suicidal ideation and suicide attempts and that additional data, analysis, and public discussion of available data on this issue are needed. In their latest Public Health Advisory, the FDA stated that the contribution of antidepressants to suicidal thinking and behavior is not yet clear, and cautioned clinicians, patients, families, and caregivers to closely monitor children or adults receiving fluoxetine or other antidepressants for worsening of depression or suicidal thoughts, especially during initiation of therapy and following dose adjustments (137). Manufacturers were asked to update their labels with stronger cautions and warnings about the need for monitoring of symptoms.

The Expert Panel finds the literature on childhood exposures to be markedly deficient due to small sample sizes, inadequate follow-up ranging from 6 to 13 weeks, high attrition, and multiple diagnoses.

Therefore, it is not possible to reach a conclusion regarding possible differences between fluoxetine and control treatments in the context of underlying methodologic limitations.

In document Fluoxetine(原文) (Page 119-122)