Brands, Medical Use, Clinical Data
- Selective Serotonin Reuptake Inhibitors (SSRIs)
Brands / Synonyms
Apo-Sertraline; Lustral; Sertralina [Spanish]; Sertraline Hydrochloride; Sertralinum [Latin]; Sultamicillin Tosylate; Zoloft; Zoloft
For the treatment of posttraumatic stress disorder, depression, obsessive-compulsive disorder and panic disorder
Sertraline, an antidepressant drug similar to citalopram, fluoxetine, and paroxetine, is of the selective serotonin reuptake inhibitor (SSRI) type. Sertraline has one active metabolite and is used to treat depression, obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder.
Mechanism of Action
It is believed that sertraline inhibits reuptake of serotonin at the neuronal membrane. SSRIs have less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs because of decreased binding to histamine, acetylcholine, and norepinephrine receptors.
The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.
Symptoms of toxicity include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome.
Biotrnasformation / Drug Metabolism
All Dosage Forms of ZOLOFT:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. Concomitant use in
patients taking pimozide is contraindicated.
ZOLOFT is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive ingredients in
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content of the
Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins
Because sertraline is tightly bound to plasma protein, the administration of ZOLOFT® (sertraline hydrochloride) to a patient
taking another drug which 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 ZOLOFT
by other tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of
dosing with either ZOLOFT (50-200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline
for ZOLOFT compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the ZOLOFT group was delayed
compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be
carefully monitored when ZOLOFT therapy is initiated or stopped.
In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there
were significant increases in ZOLOFT mean AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical
significance of these changes is unknown.
CNS Active Drugs
In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either ZOLOFT
(50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the ZOLOFT
group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in Tmax for
desmethyldiazepam in the ZOLOFT group compared to a 20% decrease in the placebo group (p<0.03). The clinical significance of these
changes is unknown.
In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT did not significantly alter steady-
state lithium levels or the renal clearance of lithium.
Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of ZOLOFT therapy with
appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated
with a mean increase in pimozide AUC and Cmax of about 40%, but was not associated with any changes in EKG. Since the highest
recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters
at doses higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to the narrow therapeutic
index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of ZOLOFT and pimozide should
be contraindicated (see CONTRAINDICATIONS).
The risk of using ZOLOFT in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is
advised if the concomitant administration of ZOLOFT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major
depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and
social anxiety disorder to ZOLOFT. Care and prudent medical judgment should be exercised when switching, particularly from long-acting
agents. The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake
inhibitor (SSRI) to another has not been established.
Monoamine Oxidase Inhibitors
See CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4
In three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine,
carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that sertraline did not increase
plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline’s extent of inhibition of P450
3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that sertraline
200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6
Many drugs effective in the treatment of major depressive disorder, e.g., the SSRIs, including sertraline, and most tricyclic
antidepressant drugs effective in the treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that
are metabolized by P450 2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by
2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive
disorder 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 P450 2D6 by the antidepressant and the therapeutic index of the co-administered drug.
There is variability among the drugs effective in the treatment of major depressive disorder in the extent of clinically important 2D6
inhibition, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class.
Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition. Consequently, concomitant use of a drug
metabolized by P450 2D6 with ZOLOFT may require lower doses than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may be required
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., citalopram,
fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs)
The extent to which SSRI–TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of
the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with ZOLOFT, because sertraline may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is co-administered
In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 22 days (including 200 mg/day for the final 13 days)
caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose.
ZOLOFT administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide,
suggesting that the decreased clearance was due to a change in the metabolism of the drug. The clinical significance of this decrease in
tolbutamide clearance is unknown.
ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.
In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 17 days (including 200 mg/day for the last 10 days) did
not change serum digoxin levels or digoxin renal clearance.
Microsomal Enzyme Induction
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/day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.) Serotonin release by platelets plays an important
role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between the use
of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that
concurrent use of a non-selective NSAID (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or aspirin potentiated
the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with ZOLOFT.
There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and ZOLOFT.
Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant
use of ZOLOFT and alcohol is not recommended.