Dolin 5 mg, 10 mg and 20 mg TABLETS

Treatment of major depressive episodes.

Adults
DOLIN should be administered as a single oral dose of 10 mg daily in otherwise healthy adults. Depending on individual patient response, the dose may be increased to a maximum of 20 mg daily. Usually 2-4 weeks are necessary for an antidepressant response.
Elderly patients (> 65 years of age)
A longer half-life and a decreased clearance have been demonstrated in the elderly. The maximum recommended dose for elderly patients is 10 mg daily.
Reduced renal function
Dosage adjustment is not necessary in patients with mild or moderate renal impairment. No information is available on the treatment of patients with severely reduced renal function (creatinine clearance < 30 ml/min).
Reduced hepatic function
Dosages should be halved to the lower end of the dose range in patients with hepatic insufficiency. The maximum recommended dose for adult patients with hepatic impairment is 10 mg daily.
DOLIN are administered as a single daily dose. DOLIN may be taken without regard to food intake.
Serotonin withdrawal
When stopping DOLIN therapy, gradual dose reduction should be considered.

Hypersensitivity to escitalopram or to any of the excipients.
Children under 18 years of age; as safety and efficacy have not been established in this population.
Patients with known QT interval prolongation or congenital long QT syndrome (see WARNINGS AND SPECIAL PRECAUTIONS and INTERACTIONS)
Medicinal products that are known to prolong QT interval (see WARNINGS AND SPECIAL PRECAUTIONS and INTERACTIONS)
Monoamine Oxidase Inhibitors:
Cases of serious reactions have been reported in patients receiving serotonin selective reuptake inhibitor (SSRI) in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued an SSRI and have been started on a MAOI (see INTERACTIONS). Some cases presented with features resembling serotonin syndrome (see SIDE EFFECTS: Class reactions). DOLIN should not be used in combination with a MAOI. DOLIN may be started 14 days after discontinuing treatment with a MAOI. At least 7 days should elapse after discontinuing DOLIN treatment before starting a MAOI.

Warnings
QT interval prolongation: DOLIN have been found to cause a dose-dependent prolongation of the QT interval. Cases of QT interval prolongation, ventricular prolongation and ventricular dysrhythmia including torsade de pointes have been reported during the post-marketing period, predominantly in patients of female gender, with hypokalaemia, or with preexisting QT interval prolongation or other cardiac diseases. Caution is advised in patients with significant bradycardia; or in patients with recent acute myocardial infarction or uncompensated heart failure. Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk of malignant dysrhythmia and should be corrected before treatment with DOLIN is started. If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started. If signs of cardiac dysrhythmia occur during treatment with [PRODUCT NAME], the treatment should be withdrawn and an ECG should be performed.
Mania u2013 DOLIN should be discontinued in any patient entering a manic phase. DOLIN should be used with caution in patients with a history of mania/hypomania.
Paradoxical anxiety u2013 Some patients with panic disorder may experience increased anxiety symptoms at the start of treatment with [PRODUCT NAME]. This paradoxical reaction usually subsides within two weeks of continued treatment. A low starting dose is advised to reduce the likelihood of a paradoxical anxiogenic effect.
Seizures - DOLIN should be discontinued in any patient who develops seizures. DOLIN should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. DOLIN should be discontinued if there is an increase in seizure frequency.
Diabetes mellitus - In patients with diabetes mellitus treatment with DOLIN may alter glycaemic control, possibly due to improvement of depressive symptoms. The doses of insulin and/or oral hypoglycaemic medications may need to be adjusted.
Suicide - As an improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for the risk of suicide.
Haemorrhage - There have been reports of cutaneous bleeding abnormalities, such as ecchymoses and purpura, with escitalopram. Caution is advised in patients taking [PRODUCT NAME], particularly in concomitant use with medicines known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin and non-steroidal anti-inflammatory medicines (NSAIDs)), as well as in patients with a history of bleeding disorders.
ECT (electroconvulsive therapy) - There is limited published clinical experience of concurrent administration of DOLIN and ECT, therefore caution is advisable.
Risk of Serotonin syndrome
Co-administration with MAO inhibitors may cause serotonin syndrome. Co-administration with other serotonergic medicines (e.g. tramadol, sumatriptan) as well as other antidepressants with serotonergic properties may lead to an enhancement of serotonin associated effects, e.g. the serotonin syndrome. There have been reports of enhanced effects when escitalopram has been given with lithium or tryptophan and therefore concomitant use of DOLIN with these medicines should be undertaken with caution.

Escitalopram has a low potential for clinically significant medicine 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 weak inhibitor of isoenzyme CYP1A2, 2C9, 2C19, 2E1, and 3A, and weak inhibitor of 2D6.
QT interval prolongation
Pharmacokinetic and pharmacodynamic studies of DOLIN combined with other medicinal products that prolong the QT interval have not been performed. An additive effect of escitalopram and these medicinal products cannot be excluded. Therefore, co-administration of DOLIN with medicinal products that prolong the QT interval, such as Class 1A and Ill antidysrhmythics (e.g. amiodarone, quinidine), antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants (e.g. desimipramine, imipramine), certain antimicrobial agents (e.g. moxifloxacin, erythromycin IV, pentamidine, anti-malarial treatment particularly halofantrine), certain antihistamines (e.g. mizolastine) and anti-retrovirals (e.g. ritonavir, saquanivir, lopinavir), is contraindicated.
Ritonavir: The pharmacokinetics of single doses of escitalopram were not changed by co-administration with a single dose of ritonavir (CYP3A4 inhibitor).
Ketoconazole: Co-administration with ketoconazole (potent CYP3A4 inhibitor) has no effect on pharmacokinetics of [PRODUCT NAME].
Cimetidine: Co-administration of racemic citalopram with cimetidine (potent CYP2D6, 3A4 and 1A2 inhibitor) resulted in increased plasma Concentrations of the racemate (43 % increase in AUC, 39 % increase in C max). Thus, caution should be exercised at the upper end of the dose range of DOLIN when used concomitantly with high doses of cimetidine.
Monoamine Oxidase inhibitors (MAOI), Sumatriptan & Tramadol: Co-administration with MAO inhibitors may cause serotonin syndrome. Co-administration with other-serotonergic medicines (e.g. tramadol, sumatriptan) as well as other antidepressants with serotonergic properties may lead to an enhancement of serotonin associated effects, e.g. the serotonin syndrome.
There have been reports of enhanced effects when escitalopram has been given with lithium or tryptophan and therefore concomitant use of DOLIN with these medicines should be undertaken with caution (see WARNINGS AND SPECIAL PRECAUTIONS).
Desipramine: Co-administration with a single dose of desipramine (a CYP2D6 substrate) resulted in a twofold increase in plasma levels of desipramine. Therefore, caution is advised when DOLIN and desipramine are co-administered. A similar increase in plasma levels of desipramine, after administration of imipramine, was seen when given together with racemic citalopram.
Metoprolol: Co-administration with a single dose of metoprolol 100 mg (a CYP2D6 substrate) resulted in a twofold increase in the C max and a 52 % increase of the AUC of metoprolol. However, the combination had no clinically significant effects on blood pressure and heart rate.
Selegiline: Racemic citalopram increased the AUC of selegiline by 29 %. Other: Pharmacokinetic interaction studies with racemic citalopram have demonstrated no clinically important interactions with carbamazepine (CYP3A4 substrate), triazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate) (single dose), warfarin (CYP3A4 and CYP2C9 substrate), levomepromazine (CYP2D6 inhibitor), lithium and digoxin. However, prothrombin time was slightly increased after a single dose of 25 mg warfarin. The International Normalised Ratio (INR) needs to be carefully monitored in patients on the combination.

The safety of DOLIN in pregnant and lactating women has not been established.

DOLIN does not impair intellectual function or psychomotor performance. Patients who are depressed and require treatment may have an impaired ability to drive or operate machinery. They should be warned of this possibility and advised to avoid such tasks if so affected.

Adverse reactions observed with DOLIN are most frequent during the first one or two weeks of treatment and may decrease in intensity and frequency with continued treatment. After prolonged administration abrupt cessation of DOLIN may produce withdrawal reactions in some patients.

Treatment
There is no specific antidote. Treatment is supportive and symptomatic. Gastric lavage should be carried out as soon as possible after oral ingestion. Cardiac and vital signs monitoring are recommended along with general symptomatic supportive measures.