Other events observed during the postmarketing evaluation of escitalopram. Although no causal relationship to escitalopram treatment has been found, the following adverse events have been reported in association with escitalopram treatment in at least three patients (unless otherwise noted) and not described elsewhere in the Adverse Reactions section (total of 1,720,000 patients estimated to have been treated with escitalopram).
Stomatitis, drug interaction NOS, feeling abnormal, hypersensitivity NOS, nonaccidental overdose, injury NOS, dysgeusia.
In addition, although no causal relationship to racemic citalopram treatment has been found, the following adverse events have been reported to be temporally associated with racemic citalopram treatment subsequent to the marketing of racemic citalopram and were not observed during the premarketing evaluation of escitalopram or citalopram: acute renal failure, akathisia, anaphylaxis, choreoathetosis, delirium, dyskinesia, epidermal necrolysis, erythema multiforme, gastrointestinal haemorrhage, haemolytic anemia, hepatic necrosis, myoclonus, neuroleptic malignant syndrome, nystagmus, pancreatitis, priapism, prolactinaemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, torsades de pointes, ventricular arrhythmia and withdrawal syndrome.
Coadministration with monoamine oxidase inhibitors (MAOIs) may cause serotonin syndrome (see Contraindications).
Coadministration with serotonergic drugs (e.g. tramadol, sumatriptan), may lead to an enhancement of serotonergic effects. Similarly, Hypericum perforatum (St John's wort) should be avoided, as adverse interactions have been reported with a range of drugs including antidepressants.
There have been reports of enhanced effects when SSRIs have been given with lithium or tryptophan and therefore concomitant use of SSRIs with these drugs should be undertaken with caution.
Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other centrally acting drugs.
Escitalopram has a low potential for clinically significant drug interactions. In vitro studies have shown that the biotransformation of escitalopram to its demethylated metabolites depends on three parallel pathways (cytochrome P450 (CYP) 2C19, 3A4 and 2D6). Escitalopram is a very weak inhibitor of isoenzymes CYP1A2, 2C9, 2C19, 2E1 and 3A, and a weak inhibitor of 2D6.
Effects of other drugs on escitalopram in vivo. The pharmacokinetics of escitalopram was not changed by coadministration with ritonavir (CYP3A4 inhibitor). Furthermore coadministration with ketoconazole (potent CYP3A4 inhibitor) did not change the pharmacokinetics of racemic citalopram.
Coadministration of racemic citalopram with cimetidine (potent CYP2D6, 3A4 and 1A2 inhibitor) resulted in increased plasma concentrations of the racemate (< 45% increase). Thus, caution should be exercised at the upper end of the dose range of escitalopram when used concomitantly with high doses of cimetidine.
Coadministration of medicinal products that inhibit CYP2C19 (e.g. omeprazole) can result in elevated plasma concentrations of escitalopram. A reduction in the dose of escitalopram may be necessary.
Effects of escitalopram on other drugs in vivo. Escitalopram is an inhibitor of the enzyme CYP2D6. Caution is recommended when escitalopram is coadministered with medicinal products that are mainly metabolised by this enzyme, and that have a narrow therapeutic index, e.g. flecainide, propafenone and metoprolol (when used in cardiac failure), or some CNS acting medicinal products that are mainly metabolised by CYP2D6, e.g. antidepressants such as desipramine, clomipramine and nortryptyline or antipsychotics like risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted.
Coadministration with desipramine (a CYP2D6 substrate) resulted in a twofold increase in plasma levels of desipramine. Therefore, caution is advised when escitalopram and desipramine are coadministered. A similar increase in plasma levels of desipramine, after administration of imipramine, was seen when given together with racemic citalopram.
Coadministration with metoprolol (a CYP2D6 substrate) resulted in a twofold increase in the plasma levels of metoprolol. However, the combination had no clinically significant effects on blood pressure and heart rate.
The pharmacokinetics of ritonavir (CYP3A4 inhibitor) was not changed by coadministration with escitalopram.
Furthermore, pharmacokinetic interaction studies with racemic citalopram have demonstrated no clinically important interactions with carbamazepine (CYP3A4 substrate), triazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), warfarin (CYP3A4 and CYP2C9 substrate), levomepromazine (CYP2D6 inhibitor), lithium and digoxin.
Alcohol. The combination of SSRIs and alcohol is not advisable.