A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Sarafem Side Effects, and Drug Interactions - Fluoxetine Hydrochloride
Sarafem Side Effects, and Drug Interactions - Fluoxetine Hydrochloride
SIDE EFFECTS
In one of three placebo-controlled trials of fluoxetine in
PMDD, treatment-emergent adverse events reporting rates were assessed. The information
from Table 1 included under
SIDE EFFECTS
is based on data from this trial
at the recommended dose of SARAFEM (SARAFEM 20 mg, N=104; placebo, N=108). In
addition, a broader set of information on treatment-emergent adverse events
in the population of female patients, 18 to 45 years of age from the US placebo-controlled
depression, OCD, and bulimia clinical trials, is presented for comparison (Table
2).
Adverse events were recorded by clinical investigators using
descriptive terminology of their own choosing. Consequently, it is not possible
to provide a meaningful estimate of the proportion of individuals experiencing
adverse events without first grouping similar types of events into a limited
(i.e., reduced) number of standardized event categories.
In the tables and tabulations that follow, COSTART Dictionary
terminology has been used to classify reported adverse events. The stated frequencies
represent the proportion
of individuals who experienced, at least once, a treatment-emergent
adverse event of the type listed. An event was considered treatment-emergent
if it occurred for the first time or worsened while receiving therapy following
baseline evaluation. It is important to emphasize that events reported during
therapy were not necessarily caused by it.
The prescriber should be aware that the figures in the tables
and tabulations cannot be used to predict the incidence of side effects in the
course of usual medical practice where patient characteristics and other factors
differ from those that prevailed in the clinical trials. Similarly, the cited
frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures,
however, do provide the prescribing physician with some basis for estimating
the relative contribution of drug and nondrug factors to the side effect incidence
rate in the population studied.
Incidence in a Placebo-Controlled PMDD Clinical Trial--Table
1 enumerates the most common treatment-emergent adverse events associated with
the use of SARAFEM 20 mg (incidence of at least 5% for SARAFEM 20 mg and greater
than placebo) for the treatment of PMDD.
TABLE 1: MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE
IN A PMDD PLACEBO-CONTROLLED CLINICAL TRIAL
| |
Percentage of patients reporting event
|
|
Body System/ Adverse Event *
|
SARAFEM 20 mg (N=104)
|
Placebo (N=108)
|
|
Body as a Whole
|
|
|
|
Headache
|
13
|
9
|
|
Asthenia
|
12
|
3
|
|
Pain
|
9
|
7
|
|
Accidental injury
|
8
|
4
|
|
Infection
|
7
|
4
|
|
Digestive System
|
|
|
|
Nausea
|
13
|
7
|
|
Nervous System
|
|
|
|
Insomnia
|
9
|
7
|
|
Dizziness
|
7
|
4
|
|
Nervousness
|
7
|
4
|
|
Thinking abnormal†
|
6
|
--
|
|
Respiratory System
|
|
|
|
Rhinitis
|
23
|
17
|
|
Pharyngitis
|
10
|
6
|
*Included are events reported by at least 5% of patients taking
SARAFEM 20 mg, except the following events, which had an incidence on placebo
> SARAFEM 20 mg: diarrhea and flu syndrome.
†Thinking abnormal is the COSTART term that captures
concentration difficulties. --Incidence less than 0.5%.
Incidence in US Depression, OCD, and Bulimia Placebo-Controlled
Clinical Trials (excluding data from extensions of trials)--Table 2 enumerates
the most common treatment-emergent adverse events associated with the use of
fluoxetine up to 80 mg (incidence of at least 2% for fluoxetine and greater
than placebo) in female patients ages 18 to 45 years from US placebo-controlled
clinical trials in the treatment of depression, OCD, and bulimia.
TABLE 2 : TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
FEMALE PATIENTS AGES 18 to 45 YEARS IN US DEPRESSION, OCD, AND BULIMIA PLACEBO-CONTROLLED
CLINICAL TRIALS
| |
Percentage of patients reporting event
|
|
Body System/Adverse Event*
|
Fluoxetine (N=1145)
|
Placebo (N=553)
|
|
Body as a Whole
|
|
|
|
Headache
|
24
|
21
|
|
Asthenia
|
14
|
6
|
|
Flu syndrome
|
7
|
3
|
|
Abdominal pain
|
6
|
5
|
|
Accidental injury
|
4
|
3
|
|
Fever
|
3
|
2
|
|
Cardiovascular System
|
|
|
|
Palpitation
|
3
|
2
|
|
Vasodilatation
|
3
|
1
|
|
Digestive System
|
|
|
|
Nausea
|
27
|
11
|
|
Anorexia
|
11
|
4
|
|
Dry mouth
|
11
|
8
|
|
Diarrhea
|
10
|
7
|
|
Dyspepsia
|
7
|
5
|
|
Constipation
|
5
|
3
|
|
Vomiting
|
3
|
2
|
|
Metabolic and Nutritional Disorders
|
|
|
|
Weight loss
|
3
|
1
|
|
Nervous System
|
|
|
|
Insomnia
|
24
|
11
|
|
Nervousness
|
14
|
10
|
|
Anxiety
|
13
|
9
|
|
Somnolence
|
13
|
6
|
|
Tremor
|
12
|
1
|
|
Dizziness
|
11
|
5
|
|
Libido decreased
|
4
|
1
|
|
Abnormal dreams
|
3
|
2
|
|
Thinking abnormal†
|
3
|
2
|
|
Respiratory System
|
|
|
|
Pharyngitis
|
6
|
5
|
|
Yawn
|
5
|
--
|
|
Skin and Appendages
|
|
|
|
Sweating
|
8
|
3
|
|
Rash
|
5
|
3
|
|
Special Senses
|
|
|
|
Abnormal vision
|
3
|
1
|
|
Urogenital System
|
|
|
|
Urinary frequency
|
2
|
1
|
*Included are events reported by at least 2% of patients taking
fluoxetine, except the following events, which had an incidence on placebo >
fluoxetine (depression, OCD, and bulimia combined): back pain, cough increased,
depression (includes suicidal thoughts), dysmenorrhea, flatulence, infection,
myalgia, pain, pruritus, rhinitis, sinusitis.
†Thinking abnormal is the COSTART term that captures
concentration difficulties. --Incidence less than 0.5%.
Associated with Discontinuation in a Placebo-Controlled PMDD
Clinical Trial--The most common adverse event (incidence at least 2% for SARAFEM
20 mg and greater than placebo) associated with discontinuation in a PMDD placebo-controlled
trial was nausea (3% for SARAFEM 20 mg, N=104 and 1% for placebo, N=108). In
this clinical trial, more than one event may have been recorded as the cause
of discontinuation.
Associated with Discontinuation in US Depression, OCD, and
Bulimia Placebo-Controlled Clinical Trials (excluding data from extensions of
trials)--In female patients age 18 to 45 years in US depression, OCD, and bulimia
placebo-controlled clinical trials combined, which collected a single primary
event associated with discontinuation (incidence at least 1% for fluoxetine
and at least twice that for placebo), insomnia (1%, N=561) was the only event
reported.
Female Sexual Dysfunction with SSRIs--Although changes in sexual
desire, sexual performance, and sexual satisfaction often occur as manifestations
of a mood-related disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that SSRIs can cause such untoward
sexual experiences. Reliable estimates of the incidence and severity of untoward
experiences involving sexual desire, performance, and satisfaction are difficult
to obtain, however, in part because patients and physicians may be reluctant
to discuss them. Accordingly, estimates of the incidence of untoward sexual
experience and performance, cited in product labeling, are likely to underestimate
their actual incidence. For example, in women (age 18 to 45) receiving fluoxetine
for indications other than PMDD, decreased libido was seen at an incidence of
4% for fluoxetine compared to 1% for placebo. There have been spontaneous reports
in women (age 18 to 45) taking fluoxetine for indications other than PMDD of
orgasmic dysfunction, including anorgasmia.
There are no adequate and well-controlled studies examining
sexual dysfunction with fluoxetine treatment.
While it is difficult to know the precise risk of sexual dysfunction
associated with the use of SSRIs, physicians should routinely inquire about
such possible side effects.
Other Events Observed In US Clinical Trials--Following
is a list of all treatment-emergent adverse events reported at anytime by females
and males taking fluoxetine in all US clinical trials for conditions other than
PMDD as of May 8, 1995 (10,782 patients) except (1) those listed in the body
or footnotes of Tables 1 or 2 above or elsewhere in labeling; (2) those for
which the COSTART terms were uninformative or misleading; (3) those events for
which a causal relationship to fluoxetine use was considered remote; (4) events
occurring in only one patient treated with fluoxetine and which did not have
a substantial probability of being acutely life-threatening; and (5) events
that could only occur in males.
Events are classified within body system categories using the
following definitions: frequent adverse events are defined as those occurring
on one or more occasions in at least 1/100 patients; infrequent adverse events
are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring
in less than 1/1,000 patients.
Body as a Whole--Frequent: chest pain and chills; Infrequent:
chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide
attempt; Rare: abdominal syndrome acute, hypothermia, intentional injury, neuroleptic
malignant syndrome, photosensitivity reaction.
Cardiovascular System--Frequent: hemorrhage, hypertension;
Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension,
migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular
headache; Rare: atrial fibrillation, bradycardia, cerebral embolism, cerebral
ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block,
pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis,
vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation.
Digestive System--Frequent: increased appetite, nausea
and vomiting; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia,
eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage,
hyperchlorhydria, increased salivation, liver function tests abnormal, melena,
mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst;
Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis,
esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis,
hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit,
pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach
ulcer hemorrhage, tongue edema.
Endocrine System--Infrequent: hypothyroidism; Rare:
diabetic acidosis, diabetes mellitus.
Hemic and Lymphatic System--Infrequent: anemia, ecchymosis;
Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis,
petechia, purpura, thrombocythemia, thrombocytopenia.
Metabolic and Nutritional--Frequent: weight gain; Infrequent:
dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia,
peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased,
BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia,
hypocalcemia, iron deficiency anemia, SGPT increased.
Musculoskeletal System--Infrequent: arthritis, bone
pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy,
myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis.
Nervous System--Frequent: agitation, amnesia, confusion,
emotional lability, paresthesia, and sleep disorder; Infrequent: abnormal gait,
acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS
depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility,
hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus,
neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder†,
psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction,
circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal
syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased,
reflexes increased, stupor.
Respiratory System--Infrequent: asthma, epistaxis, hiccup,
hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis,
hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor.
Skin and Appendages--Infrequent: acne, alopecia, contact
dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous
rash; Rare: furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis,
purpuric rash, pustular rash, seborrhea.
Special Senses--Frequent: ear pain, taste perversion,
tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare:
blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis,
iritis, parosmia, scleritis, strabismus, taste loss, visual field defect.
Urogenital System--Infrequent: abortion*, albuminuria,
amenorrhea*, anorgasmia, breast enlargement, breast pain, cystitis, dysuria,
female lactation*, fibrocystic breast*, hematuria, leukorrhea*, menorrhagia*,
metrorrhagia*, nocturia, polyuria, urinary incontinence, urinary retention,
urinary urgency, vaginal hemorrhage*; Rare: breast engorgement, glycosuria,
hypomenorrhea*, kidney pain, oliguria, uterine hemorrhage*, uterine fibroids
enlarged*.
† Personality disorder is the COSTART term for designating
non-aggressive objectionable behavior. * Adjusted for gender Postintroduction
Reports--Voluntary reports of adverse events temporally associated with fluoxetine
that have been received since market introduction of fluoxetine and that may
have no causal relationship with the drug include the following: aplastic anemia,
atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice,
confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory
syndrome with involuntary tongue protrusion reported to develop in a 77-year-old
female after 5 weeks of fluoxetine therapy and which completely resolved over
the next few months following drug discontinuation), eosinophilic pneumonia,
epidermal necrolysis, erythema nodosum, exfoliative dermatitis, gynecomastia,
heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related
hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing
in patients with risk factors including drugs associated with such events and
worsening of preexisting movement disorders, neuroleptic malignant syndrome-like
events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism,
pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, sudden unexpected
death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal
bleeding after drug withdrawal, ventricular tachycardia (including torsades
de pointes-type arrhythmias), and violent behaviors.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class--Fluoxetine is not a controlled
substance.
Physical and Psychological Dependence--Fluoxetine has not been
systematically studied, in animals or humans, for its potential for abuse, tolerance,
or physical dependence. While the premarketing clinical experience with fluoxetine
did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior,
these observations were not systematic and it is not possible to predict on
the basis of this limited experience the extent to which a CNS active drug will
be misused, diverted, and/or abused once marketed. Consequently, physicians
should carefully evaluate patients for history of drug abuse and follow such
patients closely, observing them for signs of misuse or abuse of fluoxetine
(e.g., development of tolerance, incrementation of dose, drug-seeking behavior).
DRUG INTERACTIONS
As with all drugs, the potential for interaction by a variety
of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement,
etc.) is a possibility (see Accumulation and Slow Elimination under CLINICAL
PHARMACOLOGY).
Drugs Metabolized by P450IID6--Approximately 7% of the
normal population has a genetic defect that leads to reduced levels of activity
of the cytochrome P450 isoenzyme P450IID6. Such individuals have been referred
to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and
TCAs. Many drugs, including fluoxetine and other selective uptake inhibitors
of serotonin, are metabolized by this isoenzyme; thus, both the pharmacokinetic
properties and relative proportion of metabolites are altered in poor metabolizers.
However, for fluoxetine and its metabolite, the sum of the plasma concentrations
of the four active enantiomers is comparable between poor and extensive metabolizers
(see Variability in Metabolism under CLINICAL PHARMACOLOGY).
Fluoxetine, like other agents that are metabolized by P450IID6,
inhibits the activity of this isoenzyme, and thus may make normal metabolizers
resemble "poor metabolizers." Therapy with medications that are predominantly
metabolized by the P450IID6 system and that have a relatively narrow therapeutic
index (see list below), should be initiated at the low end of the dose range
if a patient is receiving fluoxetine concurrently or has taken
it in the previous 5 weeks. Thus, her dosing requirements
resemble those of "poor metabolizers." If fluoxetine is added to the treatment
regimen of a patient already receiving a drug metabolized by P450IID6,
the need for decreased dose of the original medication should be considered.
Drugs with a narrow therapeutic index represent the greatest concern (e.g.,
flecainide, vinblastine, and TCAs). Due to the risk of serious ventricular
arrhythmias and sudden death potentially associated with elevated plasma
levels of thioridazine, thioridazine should not be administered with fluoxetine
or within a minimum of 5 weeks after fluoxetine has been discontinued
(see CONTRAINDICATIONS and WARNINGS).
Drugs Metabolized by Cytochrome P450IIIA4--In an in vivo interaction
study involving co-administration of fluoxetine with single doses of terfenadine
(a cytochrome P450IIIA4 substrate), no increase in plasma terfenadine concentrations
occurred with concomitant fluoxetine. In addition, in vitro studies have shown
ketoconazole, a potent inhibitor of P450IIIA4 activity, to be at least 100 times
more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism
of several substrates for this enzyme, including astemizole, cisapride, and
midazolam. These data indicate that fluoxetine’s extent of inhibition of cytochrome
P450IIIA4 activity is not likely to be of clinical significance.
CNS Active Drugs--The risk of using fluoxetine in combination
with other CNS active drugs has not been systematically evaluated. Nonetheless,
caution is advised if the concomitant administration of fluoxetine and such
drugs is required. In evaluating individual cases, consideration should be given
to using lower initial doses of the concomitantly administered drugs, using
conservative titration schedules, and monitoring of clinical status (see Accumulation
and Slow Elimination under CLINICAL PHARMACOLOGY).
Anticonvulsants--Patients on stable doses of phenytoin and
carbamazepine have developed elevated plasma anticonvulsant concentrations and
clinical anticonvulsant toxicity following initiation of concomitant fluoxetine
treatment.
Antipsychotics--Some clinical data suggests a possible pharmacodynamic
and/or pharmacokinetic interaction between serotonin specific reuptake inhibitors
(SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and clozapine
has been observed in patients receiving concomitant fluoxetine. A single case
report has suggested possible additive effects of pimozide and fluoxetine leading
to bradycardia. For thioridazine, see CONTRAINDICATIONS
and WARNINGS.
Benzodiazepines--The half-life of concurrently administered
diazepam may be prolonged in some patients (see Accumulation and Slow Elimination
under CLINICAL PHARMACOLOGY). Co-administration
of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations
and in further psychomotor performance decrement due to increased alprazolam
levels.
Lithium--There have been reports of both increased and decreased
lithium levels when lithium was used concomitantly with fluoxetine. Cases of
lithium toxicity and increased serotonergic effects have been reported. Lithium
levels should be monitored when these drugs are administered concomitantly.
Tryptophan--Five patients receiving fluoxetine in combination
with tryptophan experienced adverse reactions, including agitation, restlessness,
and gastrointestinal distress.
Monoamine Oxidase Inhibitors--See CONTRAINDICATIONS.
Antidepressants--In two studies, previously stable plasma levels
of imipramine and desipramine have increased greater than 2- to 10-fold when
fluoxetine has been administered in combination. This influence may persist
for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA
may need to be reduced and plasma TCA concentrations may need to be monitored
temporarily when fluoxetine is co-administered or has been recently discontinued
(see Accumulation and Slow Elimination under CLINICAL
PHARMACOLOGY, and Drugs Metabolized by P450IID6 under Drug
Interactions).
Sumatriptan—There have been rare postmarketing reports describing
patients with weakness, hyperreflexia, and incoordination following the use
of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant
treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine,
sertraline, or citalopram) is clinically warranted, appropriate observation
of the patient is advised.
Potential Effects of Co-administration of Drugs Tightly Bound
to Plasma Proteins--Because fluoxetine is tightly bound to plasma protein, the
administration of fluoxetine to a patient taking another drug that is tightly
bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations
potentially resulting in an adverse effect.
Conversely, adverse effects may result from displacement of
protein-bound fluoxetine by other tightly bound drugs (see Accumulation and
Slow Elimination under CLINICAL PHARMACOLOGY).
Warfarin--Altered anti-coagulant effects, including increased
bleeding, have been reported when fluoxetine is co-administered with warfarin.
Patients receiving warfarin therapy should receive careful coagulation monitoring
when fluoxetine is initiated or stopped.
Electroconvulsive Therapy--There are no clinical studies establishing
the benefit of the combined use of ECT and fluoxetine. There have been rare
reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.
Carcinogenesis, Mutagenesis, Impairment of Fertility--There
is no evidence of carcinogenicity, mutagenicity, or impairment of fertility
with fluoxetine.
Carcinogenicity--The dietary administration of fluoxetine to
rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively
(approximately 1.2 and 0.7 times, respectively, the maximum recommended human
dose [MRHD] of 80 mg on a mg/m2 basis), produced no evidence of carcinogenicity.
Mutagenicity--Fluoxetine and norfluoxetine have been shown
to have no genotoxic effects based on the following assays: bacterial mutation
assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and
in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.
Impairment of Fertility--Two fertility studies conducted in
rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times
the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse
effects on fertility.
Pregnancy--Pregnancy Category C: In embryo-fetal development
studies in rats and rabbits, there was no evidence of teratogenicity following
administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times,
respectively, the MRHD of 80 mg on a mg/m2 basis), throughout organogenesis.
However, in rat reproduction studies, an increase in stillborn pups, a decrease
in pup weight, and an increase in pup deaths during the first 7 days postpartum
occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on
a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD
on a mg/m2 basis) during gestation and lactation. There was no evidence
of developmental neurotoxicity in the surviving offspring of rats treated with
12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was
5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Fluoxetine should
be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Labor and Delivery--The effect of fluoxetine on labor and delivery
in humans is unknown. However, because fluoxetine crosses the placenta and because
of the possibility that fluoxetine may have adverse effects on the newborn,
fluoxetine should be used during labor and delivery only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers--Because fluoxetine is excreted in human milk,
nursing while on fluoxetine is not recommended. In one breast milk sample, the
concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration
in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were
reported. In another case, an infant nursed by a mother on fluoxetine developed
crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma
drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the
second day of feeding.
Pediatric Use--Safety and effectiveness in pediatric patients
have not been established. Geriatric Use--The diagnosis of PMDD is not applicable
to postmenopausal women. Hyponatremia--Several cases of hyponatremia (some with
serum sodium lower than 110 mmol/L) have been reported. The hyponatremia appeared
to be reversible when fluoxetine was discontinued. Although these cases were
complex with varying possible etiologies, some were possibly due to the syndrome
of inappropriate antidiuretic hormone secretion (SIADH). The majority of these
occurrences have been in older patients and in patients taking diuretics or
who were otherwise volume depleted. In a placebo-controlled, double-blind trial,
10 of 313 fluoxetine patients and 6 of 320 placebo recipients had a lowering
of serum sodium below the reference range; this difference was not statistically
significant. The lowest observed concentration was 129 mmol/L. The observed
decreases were not clinically significant.
Platelet Function--There have been rare reports of altered
platelet function and/or abnormal results from laboratory studies in patients
taking fluoxetine. While there have been reports of abnormal bleeding in several
patients taking fluoxetine, it is unclear whether fluoxetine had a causative
role.
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