ZOLOFT (sertraline) Drug Interactions

Medical Information

In order to provide you with relevant and meaningful content we need to know more about you.

Please choose the category that best describes you.

This content is intended for Canadian Healthcare Professionals. Would you like to proceed?

CNS Active Drugs:

ZOLOFT (200 mg daily) did not potentiate the effects of carbamazepine, haloperidol or phenytoin on cognitive and psychomotor performance in healthy subjects, however 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.


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%. Although these increases were not identified in the trial as being associated with clinically important effects on QT intervals, the trial design was not optimal for the investigation of pharmacodynamic effects in the clinical setting. For ethical considerations, a trial with higher doses could not be done. Since the highest recommended pimozide dose (12 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 is contraindicated (see CONTRAINDICATIONS and PART III: CONSUMER INFORMATION).

Serotonergic Drugs:

There is limited controlled experience regarding the optimal timing of switching from other antidepressants and antipanic agents to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) or Tricyclic Antidepressants (TCAs) etc. to another has not been established.

Co-administration with tryptophan, TCAs and other antidepressants may lead to a higher incidence of serotonin-associated side effects.

Rare postmarketing reports describe patients with weakness, hyperreflexia, and incoordination following the combined use of a selective serotonin reuptake inhibitor (SSRI) and 5-HT1 agonists (triptans). If concomitant treatment with ZOLOFT® and a triptan (e.g., almotriptan, sumatriptan, rizatriptan, naratriptan, zolmitriptan), tricyclic antidepressants, or other drugs with serotonergic activity including but not limited to amphetamines, fentanyl (and its analogues, dextromethorphan, tramadol, tapentadol, meperidine, methadone and pentazocine), fenfluramine and tryptophan is clinically warranted, appropriate observation of the patient for acute and long-term adverse events is advised.

QTc-Prolonging Drugs:

Pharmacokinetic and pharmacodynamic studies of sertraline combined with other medicinal products that prolong the QT interval have not been performed. An additive effect of sertraline and these medicinal products cannot be excluded. Therefore, co‑administration of sertraline with medicinal products that have a clear QT interval prolonging effect is discouraged. Drugs that have been associated with QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QTc prolongation and/or torsade de pointes:

  • Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide);
  • Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone);
  • Class IC antiarrhythmics (e.g., flecainide, propafenone);
  • antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone);
  • antidepressants (e.g. citalopram, fluoxetine, venlafaxine, tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine, maprotiline);
  • opioids (e.g., methadone);
  • macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, telithromycin, tacrolimus);
  • quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin);
  • antimalarials (e.g., quinine, chloroquine);
  • azole antifungals (e.g., ketoconazole, fluconazole, voriconazole);
  • domperidone;
  • 5-HT3 receptor antagonists (e.g., dolasetron, ondansetron);
  • tyrosine kinase inhibitors (e.g., vandetanib, sunitinib, nilotinib, lapatinib);
  • histone deacetylase inhibitors (e.g., vorinostat);
  • beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).

Drugs that Affect Electrolytes:

The concomitant use of ZOLOFT with drugs that can disrupt electrolyte levels is discouraged. Drugs that decrease electrolyte levels include, but are not limited to, the following: loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; high dose corticosteroids.

The above lists of potentially interacting drugs are not comprehensive. (see PRECAUTIONS, Cardiovascular).

St. John’s Wort:

In common with other SSRI’s, pharmacodynamic interactions between ZOLOFT and the herbal remedy St. John’s Wort may occur and may result in an increase in undesirable effects.


In placebo-controlled trials in normal volunteers, the co-administration of sertraline with lithium did not significantly alter lithium pharmacokinetics, but did result in an increase in tremor relative to placebo, indicating a possible pharmacodynamic interaction. When co-administering sertraline with medications, such as lithium, which may act via serotonergic mechanisms, patients should be appropriately monitored.


It is recommended that plasma phenytoin concentrations be monitored following initiations of sertraline therapy, with appropriate adjustments to the phenytoin dose. The pharmacokinetic and pharmacodynamic effects have not been adequately characterized.

Monoamine Oxidase Inhibitors:


Drugs Metabolized by P450 System:

Drugs Metabolized by P450 3A4:

In two separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine or carbamazepine, under steady-state conditions. The results of these studies demonstrated that sertraline co-administration did not increase plasma concentrations of terfenadine or carbamazepine. These data suggest that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical significance.

Drugs Metabolized by P450 2D6:

Many antidepressants, e.g., the SSRIs, including sertraline and most tricyclic antidepressants, inhibit the biochemical activity of the drug metabolizing isozyme, cytochrome P450 2D6 (debrisoquin hydroxylase), and thus may increase the plasma concentration of co-administered drugs that are metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressants and the type Ic antiarrhythmics, propafenone and flecainide. There is variability among the antidepressants in the extent of clinically important P450 2D6 inhibition. In two drug interaction clinical trials using desipramine and the recommended starting SSRI doses in normal volunteers, the effect of ZOLOFT was compared to two other SSRIs. In the first study, mean desipramine steady state AUC (24) increased by 23% and 380% during coadministration with ZOLOFT and the comparative SSRI, respectively. In a second study using a different comparative SSRI, mean desipramine steady state AUC (24) increased by 37% and 421% during coadministration with ZOLOFT and the comparative SSRI, respectively. These trial results indicate that the effect of ZOLOFT was significantly less pronounced than that of the two comparative SSRIs. Nevertheless, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT, may require lower doses than are 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.


Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol in depressed, panic disorder or OCD patients has not been studied and is not recommended.

Hypoglycemic Drugs:

There are no controlled clinical trials with ZOLOFT in diabetic patients treated with insulin or oral hypoglycemic drugs.

In a placebo-controlled trial in normal volunteers, the administration of ZOLOFT for 22 days (dose of ZOLOFT was 200 mg/day for the final 13 days), caused a statistically significant 16% decrease in the clearance of tolbutamide following an I.V. dose of 1000 mg. In a placebo-controlled study in normal volunteers, glibenclamide (5 mg) was given before and after administration of sertraline (200 mg/day final dose) to steady state or placebo. No significant changes were observed in the total plasma concentration of glibenclamide. Hypoglycemia requiring dextrose infusion was observed in one patient treated with ZOLOFT, glibenclamide, haloperidol, bisacodyl, acetylsalicylic acid and flucloxacillin. The causal relationship to ZOLOFT treatment was not firmly established. Nevertheless, close monitoring of glycemia in patients treated with ZOLOFT and oral hypoglycemic drugs or insulin is recommended since their dosage of insulin and/or concomitant oral hypoglycemia drug may need to be adjusted (see PRECAUTIONS, Diabetes/Loss of Glycemic Control).


In a parallel placebo controlled trial in normal volunteers (10 subjects per group), the administration of ZOLOFT for 17 days (dose of ZOLOFT: 200 mg for the last 10 days) did not cause changes in the total plasma concentrations of digoxin except a decrease of Tmax as compared to baseline.

Beta Blockers:

There is no experience with the use of ZOLOFT in hypertensive patients controlled by beta-blockers. In a placebo-controlled crossover study in normal volunteers, the effect of ZOLOFT on the β-adrenergic blocking activity of atenolol was assessed. The mean CD25's (the doses of isoproterenol required to increase heart rate by 25 bpm, the chronotropic dose 25 or CD25) and the average decreases in heart rate seen with atenolol during exercise test were not statistically different in the ZOLOFT versus the placebo group. These data suggest that ZOLOFT does not alter the β-blocking action of atenolol.


In a placebo-controlled crossover study in normal volunteers, the potential of cimetidine to alter the disposition of a single 100 mg dose of ZOLOFT was assessed. The mean sertraline Cmax and AUC were significantly higher in the cimetidine-treated group, as were the mean desmethylsertraline Tmax and AUC. These data suggest that concomitant administration of cimetidine may inhibit the metabolism of sertraline and its metabolite, desmethylsertraline, and may result in a decrease in the clearance and first pass metabolism of sertraline, with a possible increase in drug-related side effects.


In a normal volunteer, double-blind, placebo-controlled study comparing the disposition of intravenously administered diazepam before and after administration of sertraline (200 mg/day final dose) to steady state or placebo, there was a statistically significant 13% decrease relative to baseline in diazepam clearance for the sertraline group over that of the placebo group. These changes are of unknown clinical significance.

Drugs Affecting Platelet Function (e.g. NSAIDS, ASA and other anticoagulants)

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 use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, ASA or other anticoagulants may potentiate the risk of bleeding.

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when ZOLOFT is initiated or discontinued - see PRECAUTIONS, Abnormal Bleeding).


Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Zoloft is initiated or discontinued.

In a placebo-controlled study in healthy men comparing prothrombin time AUC (0-120 hr) following single dosing with warfarin (0.75 mg/kg) before and after dosing to steady state with either sertraline (200 mg/day final dose) or placebo, there was a statistically significant mean increase in prothrombin time of 8% relative to baseline for sertraline compared to a 1% decrease for placebo. The normalization of prothrombin time for the sertraline group was delayed compared to the placebo group. The clinical significance of these changes are unknown. Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped in patients receiving warfarin (see PRECAUTIONS, Abnormal bleeding).

Because sertraline is highly bound to plasma protein, the administration of ZOLOFT to a patient taking another drug which is tightly bound to protein may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely adverse effects may result from displacement of protein bound sertraline by other tightly bound drugs.