Suicidal Thoughts And Behaviors In Pediatric And Young Adult Patients
In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.
Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients
|Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated|
|Increases Compared to Placebo|
|<18||14 additional patients|
|18-24||5 additional patients|
|Decreases Compared to Placebo|
|25-64||1 fewer patient|
|≥65||6 fewer patients|
It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.
Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing ZOLOFT, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including ZOLOFT, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [See , ]. Serotonin syndrome can also occur when these drugs are used alone.
Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of ZOLOFT with MAOIs is contraindicated. In addition, do not initiate ZOLOFT in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking ZOLOFT, discontinue ZOLOFT before initiating treatment with the MAOI [See , ].
Monitor all patients taking ZOLOFT for the emergence of serotonin syndrome. Discontinue treatment with ZOLOFT and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of ZOLOFT with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
Increased Risk Of Bleeding
Drugs that interfere with serotonin reuptake inhibition, including ZOLOFT, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
Inform patients of the increased risk of bleeding associated with the concomitant use of ZOLOFT and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.
Activation Of Mania Or Hypomania
In patients with bipolar disorder, treating a depressive episode with ZOLOFT or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with ZOLOFT. Prior to initiating treatment with ZOLOFT, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.
Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [See ].
ZOLOFT has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. ZOLOFT should be prescribed with caution in patients with a seizure disorder.
The pupillary dilation that occurs following use of many antidepressant drugs including ZOLOFT may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including ZOLOFT, in patients with untreated anatomically narrow angles.
Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including ZOLOFT. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
In patients with symptomatic hyponatremia, discontinue ZOLOFT and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs [See Use In Specific Populations].
False-Positive Effects On Screening Tests For Benzodiazepines
False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking ZOLOFT. This finding is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of ZOLOFT. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish ZOLOFT from benzodiazepines [See ].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling ().
Suicidal Thoughts And Behaviors
Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [See and WARNINGS AND PRECAUTIONS].
Important Administration Instructions for Oral Solution
For patients prescribed ZOLOFT oral solution, inform them that:
Disulfiram Contraindication For ZOLOFT Oral Solution
Inform patients not to take disulfiram when taking ZOLOFT oral solution. Concomitant use is contraindicated due the alcohol content of the oral solution [see ].
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of ZOLOFT with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [See WARNINGS AND PRECAUTIONS , ].
Increased Risk Of Bleeding
Inform patients about the concomitant use of ZOLOFT with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-thecounter medications that increase the risk of bleeding [See WARNINGS AND PRECAUTIONS].
Activation Of Mania/Hypomania
Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [See WARNINGS AND PRECAUTIONS].
Advise patients not to abruptly discontinue ZOLOFT and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when ZOLOFT is discontinued [See WARNINGS AND PRECAUTIONS].
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling,
or difficulty breathing [See ].
Inform pregnant women that ZOLOFT may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN) [See Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
Impairment Of Fertility
A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (3.1 times the maximum recommended human dose on a mg/m2 basis in adolescents).
Use In Specific Populations
Overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. Some studies have reported increases for specific major birth defects; however, these study results are inconclusive [See Data]. There are clinical considerations regarding neonates exposed to SSRIs and SNRIs, including ZOLOFT, during the third trimester of pregnancy [See Clinical Considerations].
Although no teratogenicity was observed in animal reproduction studies, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (MRHD) in rats and doses 3.1 times the MRHD in rabbits on a mg/m2 basis in adolescents. When sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days after birth at the MRHD [See Data].
The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise a pregnant woman of possible risks to the fetus when prescribing ZOLOFT.
ZOLOFT oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy.
Disease-associated maternal and/or embryo/fetal risk
A prospective longitudinal study followed 201 pregnant women with a history of major depression who were euthymic taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Fetal/Neonatal adverse reactions
Exposure to SSRIs and SNRIs, including ZOLOFT in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).
When treating a pregnant woman with ZOLOFT during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to ZOLOFT in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [See Data].
Third Trimester Exposure
Neonates exposed to ZOLOFT and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on post-marketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome [See WARNINGS AND PRECAUTIONS].
Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997-2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient-reported maternal use of SSRIs “in early pregnancy” and an antenatal SSRI prescription “in later pregnancy”.
First Trimester Exposure
The weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in pregnant women who were not exposed to sertraline. A meta-analysis of studies suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% CI=0.88-1.17) or cardiac malformations (summary odds ratio=0.93, 95% CI=0.70-1.23) among offspring of women with first trimester exposure to sertraline. An increased risk of congenital cardiac defects, specifically septal defects, the most common type of congenital heart defect, was observed in some published epidemiologic studies with first trimester sertraline exposure; however, most of these studies were limited by the use of comparison populations that did not allow for the control of confounders such as the underlying depression and associated conditions and behaviors, which may be factors associated with increased risk of these malformations.
Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 3.1 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m2 basis in adolescents. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.4 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (3.1 times the MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in stillborn pups and pup deaths during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg 0.8 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.4 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown.
Available data from published literature demonstrate low levels of sertraline and its metabolites in human milk [See Data]. There are no data on the effects of sertraline on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOLOFT and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.
In a published pooled analysis of 53 mother-infant pairs, exclusively human milk-fed infants had an average of 2% (range 0% to 15%) of the sertraline serum levels measured in their mothers. No adverse reactions were observed in these infants.
The safety and efficacy of ZOLOFT have been established in the treatment of OCD in pediatric patients aged 6 to 17 [See , , ]. Safety and effectiveness in pediatric patients in patients with OCD below the age of 6 have not been established. Safety and effectiveness have not been established in pediatric patients for indications other than OCD. Two placebo-controlled trials were conducted in pediatric patients with MDD, but the data were not sufficient to support an indication for use in pediatric patients.
Monitoring Pediatric Patients Treated With ZOLOFT
Monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases [See , WARNINGS AND PRECAUTIONS]. Decreased appetite and weight loss have been observed with the use of SSRIs. Monitor weight and growth in pediatric patients treated with an SSRI such as ZOLOFT.
Weight Loss In Studies In Pediatric Patients With MDD
In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for MDD (n=373), there was a difference in weight change between ZOLOFT and placebo of roughly 1 kg, for both children (ages 6-11) and adolescents (ages 12-17), in both age groups representing a slight weight loss for the ZOLOFT group compared to a slight gain for the placebo group. For children, about 7% of the ZOLOFT-treated patients had a weight loss greater than 7% of body weight compared to 0% of the placebo-treated patients; for adolescents, about 2% of ZOLOFT-treated patients had a weight loss > 7% of body weight compared to about 1% of placebo-treated patients.
A subset of patients who completed the randomized controlled trials in patients with MDD (ZOLOFT n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. Those subjects who completed 34 weeks of ZOLOFT treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. However, there are no studies that directly evaluate the long-term effects of ZOLOFT on the growth, development, and maturation in pediatric patients.
Alcohol Content In ZOLOFT Oral Solution
ZOLOFT oral solution contains 12% alcohol.
Juvenile Animal Data
A study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but there was no effect on fertility in either males or females.
In this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80 mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with 80 mg/kg/day and females treated with doses ≥10 mg/kg/day. There was no effect on male and female reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day), except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment but not at the end of the drug –free period. The highest dose of 80 mg/kg/day produced plasma levels (AUC) of sertraline 5 times those seen in pediatric patients (6 -17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day).
Of the total number of patients in clinical studies of ZOLOFT in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 797 (17%) were ≥ 65 years old, while 197 (4%) were ≥ 75 years old.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of
the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
In 354 geriatric subjects treated with ZOLOFT in MDD placebo-controlled trials, the overall profile of adverse reactions was generally similar to that shown in Table 3[See ], except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients.
SNRIs and SSRIs, including ZOLOFT, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [See WARNINGS AND PRECAUTIONS].
The recommended dosage in patients with mild hepatic impairment (Child-Pugh score 5 or 6) is half the recommended dosage due to increased exposure in this patient population. The use of ZOLOFT in patients with moderate (Child-Pugh score 7 to 10) or severe hepatic impairment (Child-Pugh score 10-15) is not recommended, because ZOLOFT is extensively metabolized, and the effects of ZOLOFT in patients with moderate and severe hepatic impairment have not been studied [See , ].
No dose adjustment is needed in patients with mild to severe renal impairment. Sertraline exposure does not appear to be affected by renal impairment [See ].
The effect of sertraline on the QTc interval was
evaluated in a randomized, double-blind, placebo- and positive-controlled
three-period crossover thorough QTc study in 54 healthy adult subjects. At
2-fold the maximum recommended daily dose (~3-fold the steady-state exposure
for sertraline and N-desmethylsertraline), the largest mean ΔΔQTc was
10 ms with upper bound of two-sided 90% confidence interval of 12 ms. The
length of the QTc interval was also positively correlated with serum
concentrations of sertraline and N- desmethylsertraline concentrations. These
concentration-based analyses, however, indicated a lesser effect on QTc at
maximally observed concentration than in the primary analysis [See WARNINGS
AND PRECAUTIONS, ADVERSE REACTIONS, DRUG INTERACTIONS, OVERDOSAGE].
Sertraline undergoes extensive first pass metabolism. The
principal initial pathway of metabolism for sertraline is N-demethylation.
N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104
hours. Both in vitro biochemical and in vivo pharmacological testing have shown
N-desmethylsertraline to be substantially less active than sertraline. Both
sertraline and N-desmethylsertraline undergo oxidative deamination and
subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of
radiolabeled sertraline involving two healthy male subjects, sertraline
accounted for less than 5% of the plasma radioactivity. About 40-45% of the
administered radioactivity was recovered in urine in 9 days. Unchanged
sertraline was not detectable in the urine. For the same period, about 40-45%
of the administered radioactivity was accounted for in feces, including 12-14%
Desmethylsertraline exhibits time-related, dose dependent
increases in AUC (0-24-hour), Cmax and Cmin, with about a 5- to 9-fold increase
in these pharmacokinetic parameters between day 1 and day 14.
Sertraline pharmacokinetics were evaluated in a group of
61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) including both
males (N=28) and females (N=33). Relative to the adults, pediatric patients
aged 6-12 years and 13-17 years showed about 22% lower AUC (0-24 hr) and Cmax
values when plasma concentration was adjusted for weight. The half-life was
similar to that in adults, and no gender-associated differences were observed [See
DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Sertraline plasma clearance in a group of 16 (8 male, 8
female) elderly patients treated with 100 mg/day of ZOLOFT for 14 days was
approximately 40% lower than in a similarly studied group of younger (25 to 32
year old) individuals. Steady-state, therefore, was achieved after 2 to 3 weeks
in older patients. The same study showed a decreased clearance of
desmethylsertraline in older males, but not in older females [See Use In Specific
Many antidepressant drugs (e.g., SSRIs, including ZOLOFT,
and most tricyclic antidepressant drugs) inhibit the biochemical activity of
the drug metabolizing isozyme CYP2D6 (debrisoquin hydroxylase), and, thus, may
increase the plasma concentrations of co-administered drugs that are
metabolized by CYP2D6. The drugs for which this potential interaction is of
greatest concern are those metabolized primarily by CYP2D6 and that have a
narrow therapeutic index (e.g., tricyclic antidepressant drugs and the Type 1C
antiarrhythmics propafenone and flecainide). The extent to which this
interaction is an important clinical problem depends on the extent of the
inhibition of CYP2D6 by the antidepressant and the therapeutic index of the
co-administered drug. There is variability among the drugs effective in the
treatment of MDD in the extent of clinically important 2D6 inhibition, and in
fact ZOLOFT at lower doses has a less prominent inhibitory effect on 2D6 than
some others in the class. Nevertheless, even ZOLOFT has the potential for
clinically important 2D6 inhibition [See DRUG INTERACTIONS].
In three separate in vivo interaction studies, ZOLOFT was
co-administered with CYP3A4 substrates, terfenadine, carbamazepine, or
cisapride under steady-state conditions. The results of these studies indicated
that ZOLOFT did not increase plasma concentrations of terfenadine,
carbamazepine, or cisapride. These data indicate that ZOLOFT’s extent of
inhibition of CYP3A4 activity is not likely to be of clinical significance.
Results of the interaction study with cisapride indicate that ZOLOFT 200 mg
(once daily) induces the metabolism of cisapride (cisapride AUC and Cmax were
reduced by about 35%) [See DRUG INTERACTIONS].
Preclinical studies have shown ZOLOFT to induce hepatic
microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic
enzymes minimally as determined by a small (5%) but statistically significant
decrease in antipyrine half-life following administration of 200 mg of ZOLOFT
per day for 21 days. This small change in antipyrine half-life reflects a
clinically insignificant change in hepatic metabolism.
The efficacy of ZOLOFT as a treatment for MDD was
established in two randomized, double-blind, placebocontrolled studies and one
double-blind, randomized-withdrawal study following an open label study in
adult (ages 18 to 65) outpatients who met the Diagnostic and Statistical Manual
of Mental Disorders (DSM-III) criteria for MDD (studies MDD-1 and MDD-2).
Overall, these studies demonstrated ZOLOFT to be superior
to placebo on the Hamilton Rating Scale for Depression (HAMD-17) and the
Clinical Global Impression Severity (CGI-S) of Illness and Global Improvement
(CGI-I) scores. Study MDD-2 was not readily interpretable regarding a dose
response relationship for effectiveness.
Analyses for gender effects on outcome did not suggest
any differential responsiveness on the basis of sex.
The effectiveness of ZOLOFT in the treatment of OCD was
demonstrated in three multicenter placebo-controlled studies of adult (age
18-65) non-depressed outpatients (Studies OCD-1, OCD-2, and OCD-3). Patients in
all three studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean
baseline ratings on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total
score ranging from 23 to 25.
The effectiveness of ZOLOFT was studied in the risk
reduction of OCD relapse. In Study OCD-4, patients ranging in age from 18-79
meeting DSM-III-R criteria for OCD who had responded during a 52-week
single-blind trial on ZOLOFT 50-200 mg/day (n=224) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of
observation for analysis of discontinuation due to relapse or insufficient
clinical response. Response during the single-blind phase was defined as a
decrease in the Y-BOCS score of ≥ 25% compared to baseline and a CGI-I of
1 (very much improved), 2 (much improved) or 3 (minimally improved).
Insufficient clinical response during the double-blind phase indicated a
worsening of the patient’s condition that resulted in study discontinuation, as
assessed by the investigator. Relapse during the double-blind phase was defined
as the following conditions being met (on three consecutive visits for 1 and 2,
and condition 3 being met at visit 3):
Patients receiving continued ZOLOFT treatment experienced
a statistically significantly lower rate of discontinuation due to relapse or
insufficient clinical response over the subsequent 28 weeks compared to those receiving
placebo. This pattern was demonstrated in male and female subjects.
The effectiveness of ZOLOFT for the treatment of OCD was
demonstrated in a 12-week, multicenter, placebocontrolled, parallel group study
in a pediatric outpatient population (ages 6-17) (Study OCD-5). ZOLOFT (N=92) was
initiated at doses of either 25 mg/day (pediatric patients ages 6-12) or 50
mg/day (adolescents, ages 13-17), and then titrated at 3 and 4 day intervals
(25 mg incremental dose for pediatric patients ages 6-12) or 1 week intervals (50
mg incremental dose adolescents ages 13-17) over the next four weeks to a
maximum dose of 200 mg/day, as tolerated. The mean dose for completers was 178
mg/day. Dosing was once a day in the morning or evening. Patients in this study
had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the
Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score of 22.
Patients receiving ZOLOFT experienced a mean reduction of approximately 7 units
on the CY-BOCS total score which was statistically significantly greater than the
3 unit reduction for placebo patients (n=95). Analyses for age and gender
effects on outcome did not suggest any differential responsiveness on the basis
of age or sex.
The effectiveness of ZOLOFT in the treatment of PD was
demonstrated in three double-blind, placebo-controlled studies (Studies PD-1,
PD-2, and PD-3) of adult outpatients who had a primary diagnosis of PD
(DSM-III-R), with or without agoraphobia.
In Study PD-4, patients meeting DSM-III-R criteria for PD
who had responded during a 52-week open trial on ZOLOFT 50-200 mg/day (n=183)
were randomized to continuation of ZOLOFT or to substitution of placebo for up to
28 weeks of observation for discontinuation due to relapse or insufficient
clinical response. Response during the open phase was defined as a CGI-I score
of 1(very much improved) or 2 (much improved). Insufficient clinical response
in the double-blind phase indicated a worsening of the patient’s condition that
resulted in study discontinuation, as assessed by the investigator. Relapse
during the double-blind phase was defined as the following conditions being met
on three consecutive visits:
Patients receiving continued ZOLOFT treatment experienced
a statistically significantly lower rate of discontinuation due to relapse or
insufficient clinical response over the subsequent 28 weeks compared to those receiving
placebo. This pattern was demonstrated in male and female subjects.
The effectiveness of ZOLOFT in the treatment of PTSD was
established in two multicenter placebo-controlled studies (Studies PSTD-1 and
PSTD-2) of adult outpatients who met DSM-III-R criteria for PTSD. The mean duration
of PTSD for these patients was 12 years (Studies PSTD-1 and PSTD-2 combined)
and 44% of patients (169 of the 385 patients treated) had secondary depressive
Studies PSTD-1 and PSTD-2 were 12-week flexible dose
studies. ZOLOFT was initiated at 25 mg/day for the first week, and titrated in
weekly increments of 50 mg per day to a maximum dose of 200 mg/day on the basis
of clinical response and tolerability. The mean ZOLOFT dose for completers was
146 mg/day and 151 mg/day, respectively, for Studies PSTD-1 and PSTD-2. Study
outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS),
which is a multi-item instrument that measures the three PTSD diagnostic
symptom clusters of reexperiencing/intrusion, avoidance/numbing, and
hyperarousal as well as the patient-rated Impact of Event Scale (IES), which
measures intrusion and avoidance symptoms. Patients receiving ZOLOFT (N=99 and
N=94, respectively) showed statistically significant improvement compared to
placebo (N=83 and N=92) on change from baseline to endpoint on the CAPS, IES,
and on the Clinical Global Impressions (CGI-S) Severity of Illness and Global
Improvement (CGI-I) scores.
In two additional placebo-controlled PTSD trials (Studies
PSTD-3 and PSTD-4), the difference in response to treatment between patients
receiving ZOLOFT and patients receiving placebo was not statistically
significant. One of these additional studies was conducted in patients similar
to those recruited for Studies PSTD-1 and PSTD-2, while the second additional
study was conducted in predominantly male veterans.
In Study PSTD-5, patients meeting DSM-III-R criteria for
PTSD who had responded during a 24-week open trial on ZOLOFT 50-200 mg/day
(n=96) were randomized to continuation of ZOLOFT or to substitution of placebo
for up to 28 weeks of observation for relapse. Response during the open phase
was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a
decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during
the double-blind phase was defined as the following conditions being met on two
Patients receiving continued ZOLOFT treatment experienced
statistically significantly lower relapse rates over the subsequent 28 weeks
compared to those receiving placebo. This pattern was demonstrated in male and
Study SAD-1 was a 12-week, flexible dose study comparing
ZOLOFT (50-200 mg/day), n=211, to placebo, n=204, in which ZOLOFT was initiated
at 25 mg/day for the first week, then titrated to the maximum tolerated dose in
50 mg increments biweekly. Study outcomes were assessed by the:
Study SAD-2 was a 20-week, flexible dose study that
compared ZOLOFT (50-200 mg/day), n=135, to placebo, n=69. ZOLOFT was titrated
to the maximum tolerated dose in 50 mg increments every 3 weeks. Study outcome
was assessed by the:
ZOLOFT was shown to be statistically significantly more
effective than placebo as measured by the BSPS total score and fear, avoidance
and physiologic factor scores, as well as the FQ-SPS total score, and to have
statistically significantly more responders than placebo as defined by the
CGI-I. Subgroup analyses did not suggest differences in treatment outcome on
the basis of gender. There was insufficient information to determine the effect
of race or age on outcome.
In Study SAD-3, patients meeting DSM-IV criteria for SAD
who had responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week
placebo-controlled trial on ZOLOFT 50-200 mg/day were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 24 weeks of
observation for relapse. Relapse was defined as ≥ 2 point increase in the
Clinical Global Impression Severity of Illness (CGI-S) score compared to
baseline or study discontinuation due to lack of efficacy. Patients receiving
ZOLOFT continuation treatment experienced a statistically significantly lower
relapse rate during this 24-week period than patients randomized to placebo substitution.
The effectiveness of ZOLOFT for the treatment of PMDD was
established in two double-blind, parallel group, placebo-controlled flexible
dose trials (Studies PMDD-1 and PMDD-2) conducted over 3 menstrual cycles in
adult female patients. The effectiveness of ZOLOFT for PMDD for more than 3
menstrual cycles has not been systematically evaluated in controlled trials.
Patients in Study PMDD-1 met DSM-III-R criteria for Late
Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity referred to as
PMDD in DSM-IV. Patients in Study PMDD-2 met DSM-IV criteria for PMDD. Study PMDD-1
utilized continuous daily dosing throughout the study, while Study PMDD-2
utilized luteal phase dosing (intermittent dosing) for the 2 weeks prior to the
onset of menses. The mean duration of PMDD symptoms was approximately 10.5
years in both studies. Patients taking oral contraceptives were excluded from
these trials; therefore, the efficacy of ZOLOFT in combination with oral
contraceptives for the treatment of PMDD is unknown.
There was insufficient information to determine the
effect of race or age on outcome in these studies.
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