OverdoseSymptoms and Treatment:
Human Experience:
There have been 3 cases of sertraline overdosage (approximately 4 to 10 times the maximum recommended daily dose). These 3 patients recovered completely without the need for specific therapy.
Management of Overdoses:
Establish and maintain an airway, insure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdose.
Cardiac and vital signs monitoring are recommended along with general symptomatic and supportive measures.
There are no specific antidotes for sertraline.
Due to the large volume of distribution of sertraline, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.
In managing overdose, the possibility of multiple drug involvement must be considered.
Dosage
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The administration should be initiated at 50 mg daily and increased gradually if needed, noting carefully the clinical response and any evidence of intolerance. It should be kept in mind that there may be a lag in therapeutic response. Increasing the dosage rapidly does not normally shorten this latent period and may increase the incidence of side effects.
Initial Treatment:
As no clear dose-response relationship has been demonstrated, a dose of 50 mg/day is recommended as the initial dose. A gradual increase in dosage may be considered if no clinical improvement is observed. Based on pharmacokinetic parameters, steady-state sertraline plasma levels are achieved after approximately 1 week of once daily dosing; accordingly, dose changes, if necessary, should be made at intervals of at least 1 week. Doses should not exceed a maximum of 200 mg/day.
As with other antidepressants, the full antidepressant effect may be delayed until 4 weeks of treatment or longer.
Sertraline should be administered with food once daily preferably with the evening meal, or, if administration in the morining is desired, with breakfast.
As with many other medications, sertraline should be used with caution in patients with renal and/or hepatic impairment (see Precautions).
Maintenance:
When a satisfactory clinical response has been obtained, the dosage should be reduced (within the 50 to 200 mg range) to the minimum that will maintain relief of symptoms.
Supplied
50 mg:
Each white and yellow capsule contains: Sertraline HCl 50 mg. Nonmedicinal ingredients: Cornstarch; lactose, anhydrous; magnesium stearate; sodium lauryl sulfate. Capsule shells contain gelatin, silicon dioxide, sodium lauryl sulfate, methyl and propylparabens, titanium dioxide, dye D & C Yellow #10, and dye FD & C Yellow #6. Tartrazine-free. White high density polyethylene botles of 100 and 250.
100 mg:
Each orange capsule contains: Sertraline HCl 100 mg. Nonmedicinal ingredients: Cornstarch; lactose, anhydrous; magnesium stearate; sodium lauryl sulfate. Capsule shells contain gelatin, silicon dioxide, sodium lauryl sulfate, methyl- and propylparabens, titanium dioxide, dye D&C Yellow #10 and dye FD&C Red #40. Tartrazine-free. White high density polyethylene bottles of 100.
Store at controlled room temperature between 15 and 30°C.
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Adverse effects
According to the manufacturer of Zoloft brand of sertraline Pfizer, sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or pimozide (Orap). The alcohol-containing sertraline concentrate is contraindicated with disulfiram (Antabuse). The prescribing information recommends that the treatment of the elderly and patients with liver impairment “must be approached with caution”. Due to the slower elimination of sertraline in these groups, their exposure to sertraline may be as high as three times the average exposure for the same dose.
Among the common adverse effects associated with sertraline and listed in the prescribing information, the effects with the greatest difference from placebo are nausea (25% vs 11% for placebo), ejaculation failure (14% vs 1% for placebo), insomnia (21% vs 11% for placebo), diarrhea (20% vs 10% for placebo), dry mouth (14% vs 8% for placebo), somnolence (13% vs 7% for placebo), dizziness (12% vs 7% for placebo), tremor (8% vs 2% for placebo) and decreased libido (6% vs 1% for placebo). Those that most often resulted in interruption of the treatment were nausea (3%), diarrhea (2%) and insomnia (2%). Sertraline appears to be associated with microscopic colitis, a rare condition of unknown etiology.
Akathisia, that is “inner tension, restlessness, and the inability to stay still”, caused by sertraline was observed in 16% of patients in a case series. This and other reports note that akathisia begins soon after the initiation of treatment or increase of the dose, often, several hours after taking the medication. Akathisia usually disappears within several days after sertraline is stopped or its dose is decreased. In some cases, clinicians confused akathisia with anxiety, and increased the dose of sertraline causing further worsening of the patients’ symptoms. The experts note that because of the possible link of akathisia with suicide and the distress it causes to the patient, “it is of vital importance to increase awareness amongst staff and patients of the symptoms this relatively common condition”.
Over more than six months of sertraline therapy for depression, patients showed an insignificant weight increase of 0.1%. Similarly, a 30 months-long treatment with sertraline for OCD, resulted in a mean weight gain of 1.5% (1 kg).Although the difference did not reach statistical significance, the weight gain was lower for fluoxetine (Prozac) (1%) but higher for citalopram (Celexa), fluvoxamine (Luvox) and paroxetine (Paxil) (2.5%). Only 4.5% of the sertraline group gained a large amount of weight (defined as more than 7% gain). This result compares favorably with placebo, where, according to the literature, 3–6% of patients gained more than 7% of their initial weight. The large weight gain was observed only among female members of the sertraline group; the significance of this finding is unclear because of the small size of the group.
Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency and did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, and psychomotor coordination. In spite of lower subjective rating, no clinically relevant differences were observed in the objective cognitive performance in a group of people treated for depression with sertraline for 1.5 year as compared to healthy controls.
Birth defects and effects on breast-fed infants
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The studies comparing the levels of sertraline and its principal metabolite, desmethylsertraline, in mother’s blood to their concentration in umbilical cord blood at delivery indicated that the fetus’s exposure to sertraline and its metabolite is approximately a third of the maternal exposure. The use of sertraline during the first trimester of pregnancy was associated with the increased odds of the following birth defects: omphalocele—six-fold, septal defects—two-fold, anal atresia and limb reduction defects—four-fold. Concentration of sertraline and desmethylsertraline in the breast milk is highly variable and, on average, is of the same order of magnitude as their concentration in the blood plasma of the mother. As a result, more than half of the breast-fed babies receive less than 2 mg/day of sertraline and desmethylsertraline combined, and in most cases these substances are undetectable in their blood. No changes in the serotonin uptake by the platelets of breast-fed infants were found, as measured by their blood serotonin levels before and after their mothers began sertraline treatment.
Sexual side effects
The observed frequency of the sexual side effects depends greatly on whether they are reported by patients spontaneously, as in the manufacturer’s trials, or actively solicited by the physicians. There have been several double-blind studies of the sexual side effects comparing sertraline with placebo or other antidepressants. While nefazodone (Serzone) and bupropion did not have negative effect on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties vs. 18% before the treatment (or 61% vs 0% according to another paper). Similarly, in a group of women who initially had not have difficulties achieving orgasm, 41% acquired this problem during treatment with sertraline. The 40% rate of orgasm dysfunction (vs 9% for placebo) on sertraline was observed in a mixed group in another study. Sexual arousal disorder defined as “inadequate lubrication and swelling for women and erectile difficulties for men” occurred in 12% of sertraline patients as compared with 1% of patients on placebo. At the same time, sexual desire and overall satisfaction with sex stayed the same, as in the beginning of the sertraline treatment, and slightly below the placebo.
Suicidality
The FDA requires all antidepressants, including sertraline, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the FDA experts that found a 2-fold increase of the suicidal ideation and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group.
Suicidality in adults
Suicidal ideation and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, sertraline use in adults decreased the odds of suicidality with a marginal statistical significance by 37% or 50% depending of the statistical technique used. The authors of the FDA analysis note that “given the large number of comparisons made in this review, chance is a very plausible explanation for this difference”. The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidality. Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the patients on sertraline as compared to the ones on placebo.
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Discontinuation syndrome
Main article: SSRI discontinuation syndrome
Abrupt interruption of sertraline may result in withdrawal or discontinuation syndrome. This syndrome occurred in 60% of the sertraline subjects in a blind discontinuation study, as compared to 14% of fluoxetine and 66% of paroxetine subjects. During the 5-8 days of the sertraline discontinuation, the most frequent symptoms reported by more than a quarter of patients were irritability, agitation, dizziness, headache, nervousness, crying, emotional lability, bad dreaming and anger. Approximately one third of the subjects experienced mood worsening to the level generally associated with a major depressive episode.
During its premarketing assessment, multiple doses of sertraline hydrochloride were administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to sertraline hydrochloride varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for multiple indications, including major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
Untoward events associated with this exposure were recorded by clinical investigators using 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 untoward events into a smaller number of standardized event categories.
In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of sertraline hydrochloride who experienced a treatment-emergent adverse event of the type cited on at least one occasion while receiving sertraline hydrochloride. 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.
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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.