Monoamine oxidase inhibitors: Concomitant use is contraindicated.
Irreversible (non-selective) MAOIs (selegiline): Sertraline should not be used in combination with irreversible (non-selective) MAOIs such as selegiline. Sertraline must not be initiated for at least 14 days after discontinuation of treatment with an irreversible (non-selective) MAOI. Sertraline must be discontinued for at least seven days before starting treatment with an irreversible (non-selective) MAOI.
Reversible, selective MAO-A inhibitor (moclobemide): Due to risk of serotonin syndrome, the combination of sertraline with a reversible and selective MAOI, such as moclobemide, is not recommended. After treatment with a reversible MAO-inhibitor, a shorter withdrawal period than 14 days may be used before initiation of sertraline treatment. It is recommended that sertraline should be discontinued for at least seven days before starting treatment with a reversible MAOI.
Reversible, non-selective MAOI (linezolid): The antibiotic linezolid is a weak reversible and non-selective MAOI and should not be given to patients treated with sertraline. Severe adverse reactions have been reported in patients who have recently been discontinued from a MAOI and started on sertraline, or have recently had sertraline therapy discontinued prior to initiation of a MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling NMS, seizures, and death.
Pimozide: Coadministration of single low dose pimozide 2 mg with sertraline was associated with a mean increase in pimozide AUC and Cmax of about 40%, but was not associated with any changes in electrocardiogram. 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 use of sertraline and pimozide is contraindicated.
CNS depressants and alcohol: The coadministration of sertraline 200 mg per day did not potentiate the effects of alcohol, carbamazepine, or haloperidol on cognitive and psychomotor performance in healthy subjects; however, the concomitant use of sertraline and alcohol is not recommended.
Chronic use of sertraline 200 mg per day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, it is recommended that plasma phenytoin concentrations be monitored after initiation of sertraline therapy, with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant drugs. Also, coadministration of phenytoin may cause a reduction of sertraline plasma levels.
Serotonergic drugs: Based on the mechanism of action of SNRIs and SSRIs, including sertraline, and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including sertraline, are coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid, lithium, tramadol, or St. John's Wort. The concomitant use of sertraline with other SSRIs, SNRIs or tryptophan is not recommended.
Triptans (sumatriptan): There have been rare post-marketing reports describing patients with weakness, hyperreflexia, incoordination, confusion, anxiety, and agitation after use of sertraline and sumatriptan. If concomitant treatment with sertraline and sumatriptan is clinically warranted, appropriate observation of the patient is advised.
Lithium: Coadministration of sertraline with lithium did not significantly alter lithium pharmacokinetic, but did result in an increase in tremor relative to placebo, indicating a possible pharmacodynamic interaction. When coadministering sertraline with lithium, which may act via serotonergic mechanisms, it is recommended that plasma lithium levels be monitored after initiation of sertraline therapy with appropriate adjustments to the lithium dose.
Protein-bound drugs: Since sertraline is tightly bound to plasma protein, the administration of sertraline to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digoxin) 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.
In a study comparing prothrombin time AUC (0-120 hour) after dosing with warfarin, before and after 21 days of dosing with either sertraline or placebo, there was a 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 this change is unknown. Thus, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped.
Medicines that interfere with hemostasis (NSAIDs, aspirin, warfarin): Serotonin release by platelets plays an important role in hemostasis. There is an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of abnormal bleeding. Concurrent use of an NSAID, aspirin or warfarin potentiates the risk. Thus, patients should be cautioned about using such drugs concurrently with sertraline.
Coadministration of sertraline with warfarin resulted in a small but statistically significant increase in prothrombin time, the clinical significance of which is unknown. Thus, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped.
Valproate: The effect of sertraline on valproate levels has not been evaluated in clinical trials. In the absence of such data, it is recommended that plasma valproate levels be monitored after initiation of sertraline therapy with appropriate adjustments to the valproate dose.
Cimetidine: Coadministration of sertraline with cimetidine caused a substantial decrease in sertraline clearance. The clinical significance of this change is unknown.
CNS-active drugs (diazepam): Coadministration of sertraline with intravenous diazepam resulted in a small, statistically significant changes in some pharmacokinetic parameters. The clinical significance of these changes is unknown.
Hypoglycemic drugs (tolbutamide, glibenclamide, biguanides): Coadministration of sertraline with tolbutamide resulted in a small, statistically significant changes in some pharmacokinetic parameters. The clinical significance of these changes is unknown.
Sertraline did not affect the pharmacokinetics of glibenclamide.
Patients receiving biguanides should monitor their blood glucose carefully when sertraline is introduced.
Drugs metabolized by cytochrome P450 (CYP) 2D6: Sertraline may act as a mild-moderate inhibitor of CYP 2D6. Chronic dosing with sertraline 50 mg per day showed moderate elevation (mean 23%-37%) of steady-state desipramine plasma levels (a marker of CYP 2D6 isozyme activity). Clinically relevant interactions may occur with other CYP 2D6 substrates with a narrow therapeutic index such as class 1C antiarrhythmics (propafenone, flecainide, tricyclic antidepressants and typical antipsychotics), particularly at higher sertraline dose levels.
Drugs metabolized by other CYP enzymes (CYP 3A4, CYP 2C9, CYP 2C19, CYP 1A2): Sertraline does not act as an inhibitor of CYP 3A4, CYP 2C9, CYP 2C19, and CYP 1A2 to a clinically significant degree. This has been confirmed by in vivo interaction studies with CYP3A4 substrates (endogenous cortisol, carbamazepine, terfenadine, alprazolam), CYP2C19 substrate diazepam, and CYP2C9 substrates tolbutamide, glibenclamide and phenytoin. In vitro studies indicate that sertraline has little or no potential to inhibit CYP 1A2.
Atenolol: Sertraline had no effect on the beta-adrenergic blocking ability of atenolol.
Digoxin: Sertraline did not change serum digoxin levels or digoxin renal clearance.
Microsomal enzyme induction: Sertraline was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life after administration of 200 mg per day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.
Other Interaction: Electroconvulsive Therapy (ECT): There are no clinical studies establishing the risks or benefits of the combined use of ECT and sertraline.