[SSRI-Research] FDA Alert: Effexor warnings added for neonatal adverse effects and suicidality r

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These poor children may wind up with floppy baby syndrom, autism, retardation,

adhd or a host of other possible diagnoses, which will all be rountinely

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JustSayNo

Wed, 30 Jun 2004 02:06:25 -0000

[sSRI-Research] FDA Alert: Effexor warnings added for neonatal adverse

effects and suicidality r

 

On June 28, the FDA and Wyeth issued a new MedWatch drug Alert to

healthcare professionals:

 

" Neonates exposed to Effexor, other SNRIs (Serotonin and

Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin

Reuptake Inhibitors), late in the third trimester of pregnancy have

developed complications requiring prolonged hospitalization,

respiratory support, and tube feeding. "

 

http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#effexor

 

Severe withdrawal symptoms in neonates who were exposed to an SSRI

antidepressant in the womb have been described in numerous case

reports at least since 1993. (See: Thisted)

 

Why is this the first time the FDA has seen fit to issue a warning to

physicians?

 

Among the disturbing reported symptoms suffered by newborn infants

exposed to an SSRI:

 

Chambers et al (1996) reported that 31.5% of 73 infants exposed to

Prozac in the third tri-mester exhibited symptoms of " poor neonatal

adaptation " including respiratory difficulties, irritability,

jitteriness, cyanosis (turning blue) on feeding.

 

Nordeg et al (2001) reported: Irritability, constant crying,

shivering, increased tonus (stiff limbs), eating and sleeping

difficulties, seizures.

 

Stiskal et al (2001) reported: jitteriness, vomiting, irritability,

hypoglycemia, necrotizing enterocolitis (severe bacterial infection

of intestine)

 

The Australian Drug Reaction Advisory Committee reported that as of

March 2001, there were 13 reports of antidepressant induced

withdrawal symptoms in newborns.

 

Isbister et al (2001) noted a similarity of symptoms between neonatal

withdrawal symptoms and adult serotonin toxicity.

 

Despite the fact that there are 317 reports on MEDLINE describing

various ill effects of antidepressants on infants, neither the FDA

nor the National Institute of Mental Health saw fit even to discuss

the problem publicly.

 

At a public meeting of FDA's pediatric advisory subcommittee, on

February 3-4, 2004, several panel members expressed concern about

withdrawal symptoms in neonates exposed to SSRIs.

 

By then, FDA officials surely knew about the review by expert panel

of the National Toxicology Program (NTP)-Center for the Evaluation of

Risks to Human Reproduction (CERHR). In April, 2004, the NTP-CERHR

panel issued a Report after examining all the available published

evidence about infants exposed to an antidepressant in utero and / or

breast fed by mothers taking an antidepressant:

 

The REPRODUCTIVE and DEVELOPMENTAL TOXICITY of FLUOXETINE

http://cerhr.niehs.nih.gov/news/fluoxetine/fluoxetine_final.pdf

 

The NTP-CERHR expert panel found reason for concern:

 

" 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, respiratory distress, weak or absent cry, or

desaturation on feeding). " The authors concluded that the observed

effects are specific to SRI exposure rather than underlying maternal

depression.

 

The CERHR panel report also noted the concerns expressed by FDA's

medical reviewer of the Prozac data. Specifically, FDA's expert

reviewer was concerned that children taking Prozac showed evidence of

developing cardiac abnormalities (QTc prolongation) and significant

impaired growth compared to those on placebo.

 

How do FDA officials explain their failure to warn healthcare

professionals and the public about documented risks of harm to

neonates whose mothers take an antidepressant?

 

On June 9, FDA's Pediatric Sub-committee of the Anti-infective Drugs

Advisory Committee met and issued strong recommendations requiring

expanded adverse drug reporting " for all products that are studied

under the Pediatric Exclusivity provisions. "

 

The committee also expressed concern that important negative

information or even acknowledgement of studies conducted in children

is not being noted in all of the labels of products having pediatric

studies.

 

The committee issued the following recommendations regarding SSRI /

SNRI neonatal withdrawal syndrome:

 

The committee strongly endorsed class labeling for the neonatal

toxicity/withdrawal syndrome related to in utero exposure of

SSRI/SNRI's. The members also strongly supported a package insert

for patients (pregnant or considering pregnancy) which provided

detailed information at the 6th to 8th grade level as to what is

known about the risk/benefit issues for the fetus/newborn and for the

mother when choices have to be made about the use of these agents in

pregnancy. The committee did not support a Public Health Advisory.

 

Strong support from the members was also provided regarding

professional education through professional groups regarding the

neonatal toxicity/withdrawal syndrome. In addition to Pediatric,

Obstetric and Psychiatric Professionals, providing information to

Family Medicine practitioners was also strongly emphasized.

 

The members felt there was an urgency to acquire research data

clarifying the nature of the neonatal syndrome. The few available

studies don't clearly distinguish between a " behavioral

teratogenicity " syndrome resulting from prolonged serotonin exposure

in utero vs. a simple " withdrawal syndrome " resulting from in

utero " serotonin toxicity. " It was felt that retrospective studies

would probably not have precise enough focused observations to

distinguish between these two syndromes, if in fact there are two

separate syndromes.

 

Although retrospective studies might provide incidence/prevalence

data, the members felt that prospective detailed, longitudinal and

long term studies, including if possible, in utero physiologic fetal

data are urgently needed. For example, information regarding the

long term effects on older children following fetal exposure to

SSRI/SNRIs has not been studied in enough detail.

 

It was suggested that the NICHD Center for Research for Mothers and

Children might be a perfect fit for such studies. Other ongoing

epidemiologic studies of infants relative to genetic/teratogenic

follow-up were also suggested as ongoing mechanisms to study the

effects of these agents on newborn infants.

 

Although ideal, the use of randomized controlled trials of SSRIs for

the treatment of maternal depression for the specific purpose of

defining the effects on the fetus and newborn, is a complex issue

which would take much more discussion involving psychiatrists and

obstetricians. From one of the speakers the members were made aware

of a potential study comparing SSRIs vs. light therapy of depression

in pregnancy. Following women who chose no therapy or alternate

pharmacologic or light therapy might provide a control group.

 

See: http://www.fda.gov/ohrms/dockets/ac/04/minutes/2004-4050M1.htm

 

 

How do FDA officials explain that only Wyeth has issued a warning

about neonatal withdrawal symptoms--inasmuch as the risk and

potential harm--has been documented in all antidepressants?

 

How do FDA officials explain the agency's failure to enforce its

request to ALL antidepressant drug manufacturers to issue safety

warnings about suicidal risks for children, adolescents and adults

prescribed their drugs?

 

To date, neither Pfizer (manufacturer of Zoloft / sertraline) nor Eli

Lilly (manufacturer of Prozac / fluoxetine) seem to have issued new

warnings as their drugs are not listed on FDA's 2004 MedWatch safety

web page.

 

Articles cited:

 

* Thisted E, Ebbesen F. (1993) Malformations, withdrawal

manifestations, and hypoglycaemia after exposure to valproate in

utero. Arch Dis Child. Sep;69(3 Spec No):288-91.

*Chanbers CD, et al. (1996) Birth outcomes in pregnant women taking

fluoxetine. N Engl Med 335:1010–1015.

*Nordeng H, et al (2001) Neonatal withdrawal syndrome after in utero

exposure to selective serotonin reuptake inhibitors. Acta Paediatry;

90(3):288-91.

*Stiskal JA, et al (2001) Neonatal paroxetine withdrawal syndrome.

Arch Dis Child Fetal Neonatal Ed, 84(2):F134-5.

 

 

Contact: Vera Hassner Sharav

Tel: 212-595-8974

e-mail: veracare

 

 

 

CDER MEDWATCH LISTSERV [MEDWATCHLIST]

Monday, June 28, 2004 2:21 PM

FDA MedWatch - Effexor (venlafaxine) warnings added for

neonatal effects and suicidality risk

 

MedWatch - The FDA Safety Information and Adverse Event Reporting

Program

 

FDA and Wyeth Pharmaceuticals notified healthcare professionals of

revisions to the WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION

sections of Effexor (venlafaxine) labeling to alert healthcare

providers of two important safety issues.

 

Neonates exposed to Effexor, other SNRIs (Serotonin and

Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin

Reuptake Inhibitors), late in the third trimester of pregnancy have

developed complications requiring prolonged hospitalization,

respiratory support, and tube feeding. Such complications can arise

immediately upon delivery

 

Patients with major depressive disorder, both adult and pediatric,

may experience worsening of their depression and/or the emergence of

suicidal ideation and behavior (suicidality), whether or not they are

taking antidepressant medications. The warning recommends patients

being treated with antidepressants be observed closely for clinical

worsening and suicidality, especially at the beginning of a course of

drug therapy, or at the time of dose changes, either increases or

decreases.

 

Read the MedWatch 2004 safety summary, including links to the " Dear

Healthcare Professional " letter and the highlighted Effexor labeling,

at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#effexor

SSRI-Research/