Interactions : אינטראקציות

4.5      Interaction with other medicinal products and other forms of interaction

Contraindicated
Monoamine Oxidase Inhibitors
Irreversible MAOIs (e.g. selegiline)
Sertraline must not be used in combination with irreversible MAOIs such as selegiline.
Sertraline must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI. Sertraline must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see section 4.3).

Reversible, selective MAO-A inhibitor (moclobemide)
Due to the risk of serotonin syndrome, the combination of sertraline with a reversible and selective MAOI, such as moclobemide, should not be given. Following 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 14 days before starting treatment with a reversible MAOI (see section 4.3).

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 (see section 4.3).

Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI (e.g. methylene blue) and started on sertraline, or have recently had sertraline therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.

Pimozide
Increased pimozide levels of approximately 35% have been demonstrated in a study of a single low dose pimozide (2 mg). These increased levels were not associated with any changes in EKG. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide, concomitant administration of sertraline and pimozide is contraindicated (see section 4.3).

Co-administration with sertraline is not recommended

CNS depressants and alcohol
The co-administration of sertraline 200 mg daily did not potentiate the effects of alcohol, carbamazepine, haloperidol, or phenytoin on cognitive and psychomotor performance in healthy subjects; however, the concomitant use of sertraline and alcohol is not recommended.

Other serotonergic drugs
         See section 4.4.

Caution is also advised with opioids [e.g. fentanyl (used in general anaesthesia or in the treatment of chronic pain)], and other serotonergic drugs (including other serotonergic antidepressants, amphetamines, triptans).

Special Precautions

Drugs that Prolong the QT Interval
The risk of QTc prolongation and/or ventricular arrhythmias (e.g. TdP) may be increased with concomitant use of other drugs which prolong the QTc interval (e.g. some antipsychotics and antibiotics) (see sections 4.4 and 5.1).

Lithium
In a placebo-controlled trial 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 lithium, patients should be appropriately monitored.

Phenytoin
A placebo-controlled trial in normal volunteers suggests that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, as some case reports have emerged of high phenytoin exposure in patients using sertraline, it is recommended that plasma phenytoin concentrations be monitored following initiation of sertraline therapy, with appropriate adjustments to the phenytoin dose.
In addition, co-administration of phenytoin a known CYP3A4 inducer, may cause a reduction of sertraline plasma levels.

Metamizole
Co-administration of sertraline with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4, may cause a reduction in plasma concentrations of sertraline with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and sertraline are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.

Triptans
There have been rare post-marketing reports describing patients with weakness, hyperreflexia, incoordination, confusion, anxiety and agitation following the use of sertraline and sumatriptan. Symptoms of serotonergic syndrome may also occur with other products of the same class (triptans). If concomitant treatment with sertraline and triptans is clinically warranted, appropriate observation of the patient is advised (see section 4.4).

Warfarin
Co-administration of sertraline 200 mg daily with warfarin resulted in a small but statistically significant increase in prothrombin time, which may in some rare cases unbalance the INR value.
Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped.

Other drug interactions, digoxin, atenolol, cimetidine

Co-administration with cimetidine caused a substantial decrease in sertraline clearance. The clinical significance of these changes is unknown. Sertraline had no effect on the beta- adrenergic blocking ability of atenolol. No interaction of sertraline 200 mg daily was observed with digoxin.

Drugs affecting platelet function
The risk of bleeding may be increased when medicines acting on platelet function (e.g.
NSAIDs, acetylsalicylic acid and ticlopidine) or other medicines that might increase bleeding risk are concomitantly administered with SSRIs, including sertraline (see section 4.4).

Neuromuscular Blockers
SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium or other neuromuscular blockers.

Drugs Metabolized by Cytochrome P450
Sertraline may act as a mild-moderate inhibitor of CYP 2D6. Chronic dosing with sertraline 50 mg daily showed moderate elevation (mean 23%-37%) of steady-state desipramine plasma levels (a marker of CYP 2D6 isozyme activity). Clinical relevant interactions may occur with other CYP 2D6 substrates with a narrow therapeutic index like class 1C antiarrhythmics such as propafenone and flecainide, TCAs and typical antipsychotics, especially at higher sertraline dose levels.

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.

Intake of three glasses of grapefruit juice daily increased the sertraline plasma levels by approximately 100% in a cross-over study in eight Japanese healthy subjects. Therefore, the intake of grapefruit juice should be avoided during treatment with sertraline (see section 4.4).

Based on the interaction study with grapefruit juice, it cannot be excluded that the concomitant administration of sertraline and potent CYP3A4 inhibitors, e.g. protease inhibitors, ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin and nefazodone, would result in even larger increases in exposure of sertraline. This also concerns moderate CYP3A4 inhibitors, e.g. aprepitant, erythromycin, fluconazole, verapamil and diltiazem. The intake of potent CYP3A4 inhibitors should be avoided during treatment with sertraline.

It cannot be excluded that CYP3A4 inducers, e.g. phenobarbital, carbamazepine, St. John´s Wort and rifampicin, may cause a reduction of sertraline plasma levels.

Sertraline plasma levels are enhanced by about 50% in poor metabolizers of CYP2C19 compared to rapid metabolizers (see section 5.2). Interaction with strong inhibitors of CYP2C19, e.g. omeprazole, lansoprazole, pantoprazole, rabeprazole, fluoxetine, fluvoxamine cannot be excluded.