INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo CITRAZ 5 (film-coated tablets)
CITRAZ 10 (film-coated tablets)
CITRAZ 20 (film-coated tablets)

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

CITRAZ 5 (film-coated tablets)
CITRAZ 10 (film-coated tablets)
CITRAZ 20 (film-coated tablets)

COMPOSITION
CITRAZ 5:
Each film-coated tablet contains escitalopram oxalate equivalent to
escitalopram 5 mg
CITRAZ 10: Each film-coated tablet contains escitalopram oxalate equivalent to escitalopram 10 mg
CITRAZ 20: Each film-coated tablet contains escitalopram oxalate equivalent to escitalopram 20 mg

PHARMACOLOGICAL CLASSIFICATION
A 1.2 Psychoanaleptics (antidepressants)

PHARMACOLOGICAL ACTION
Mechanism of action
Escitalopram is a selective inhibitor of serotonin (5-HT)-uptake.
Escitalopram has minimal effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake.
Escitalopram has no or very low affinity for a series of receptors including 5-HT
1A, 5-HT2, DA, D1 and D2 receptors, alpha1-, alpha2-, beta-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine and opioid receptors.
Pharmacokinetic properties
Absorption
Absorption is independent of food intake (mean T
maxis 4 hours after multiple dosing).
Distribution
The apparent volume of distribution (V
d, â/F) after oral administration is about 12 to 26 L/kg. The plasma protein binding of escitalopram is approximately 55%.
Biotransformation
Escitalopram is metabolised in the liver to the demethylated and didemethylated metabolites. Alternatively, the nitrogen may be oxidised to form the N-oxide metabolite. Both parent substance and metabolites are partly excreted as glucuronides. Unchanged escitalopram is the predominant compound in plasma. After multiple dosing the mean concentrations of the demethyl- and didemethyl metabolites are usually 28 - 31% and <5% of the escitalopram concentration, respectively. Biotransformation of escitalopram to the demethylated metabolite is mediated by a combination of CYP2C19, CYP3A4 and CYP2D6.
Elimination
The elimination half-life (t
l/2beta) after multiple dosing is about 30 hours and the oral plasma clearance (Cloral) is about 0,6 L/min. Escitalopram and major metabolites are - like racemic citalopram - assumed to be eliminated both by the hepatic (metabolic) and the renal routes with the major part of the dose excreted as metabolites in urine. Hepatic clearance is mainly by the P450 enzyme system. CYP2C19 is the primary isoenzyme involved in the demethylation of escitalopram, followed by CYP3A4 and CYP2D6.
There are linear pharmacokinetics. Steady state plasma levels are achieved in about 1 week. Average steady state concentrations of 50 nmol/L (range 20 to 125 nmol/L) are achieved at a daily dose of 10 mg.
Elderly patients (>65 years of age)
A longer half-life (about 50%) and decreased clearance values, due to a reduced rate of metabolism, have been demonstrated in the elderly.
Reduced hepatic function
Escitalopram is eliminated more slowly in patients with reduced hepatic function. The half-life of escitalopram is twice as long in patients with hepatic impairment and steady state escitalopram concentrations at a given dose will be approximately twice as high as in patients with normal liver function.
Reduced renal function
Escitalopram is eliminated more slowly in patients with mild to moderate reduction of renal function with no major impact on the escitalopram concentrations in serum. At present no information is available for the treatment of patients with severely reduced renal function (creatinine clearance <30 mL/min).
Polymorphism
Based on in vitro results with escitalopram and in vivo results with the racemic citalopram, genetic polymorphism with respect to CYP2D6 is not known. With respect to CYP2C19, it may be of clinical relevance, as shown in limited numbers.

INDICATIONS
Treatment of major depressive episodes.

CONTRAINDICATIONS
Hypersensitivity to CITRAZ or any of the excipients.
Children, as safety and efficacy have not been established in this population.
Monoamine Oxidase Inhibitors- Cases of serious reactions have been reported in patients receiving an SSRI such as CITRAZ in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued an SSRI and have been started on an MAOI (see INTERACTIONS).
Some cases presented with features resembling serotonin syndrome (see SIDE-EFFECTS AND SPECIAL PRECAUTIONS).
CITRAZ should not be used in combination with a MAOI. CITRAZ may be started 14 days after discontinuing treatment with a MAOI. At least 7 days should elapse after discontinuing CITRAZ treatment before starting a MAOI.

WARNINGS
Mania - CITRAZ should be discontinued in any patient entering a manic phase. CITRAZ should be used with caution in patients with a history of mania/hypomania.
Paradoxical anxiety - Some patients with panic disorder may experience increased anxiety symptoms at the start of treatment with antidepressants. This paradoxical reaction usually subsides within two weeks during continued treatment. A low starting dose is advised to reduce the likelihood of a paradoxical anxiogenic effect.
Seizures - CITRAZ should be discontinued in any patient who develops seizures. CITRAZ should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. CITRAZ should be discontinued if there is an increase in seizure frequency.
Diabetes mellitus - In patients with diabetes mellitus, treatment with CITRAZ may alter glycaemic control, possibly due to improvement of depressive symptoms. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.
Suicide - As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored during this period. The possibility of a suicide attempt is inherent in depression and may persist until significant therapeutic effect is achieved.
Haemorrhage - There have been reports of cutaneous bleeding abnormalities, such as ecchymoses and purpura with CITRAZ. Caution is advised in patients taking CITRAZ, particularly in concomitant use with medicines known to affect platelet function (e.g. atypical anti-psychotics 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 CITRAZ and ECT, therefore caution is advisable.

Effects on ability to drive and use machines
CITRAZ
does not impair intellectual function or psychomotor performance. Nevertheless, patients who are depressed and require treatment may have an impaired ability to drive or operate machinery. They should be warned of the possibility and advised to avoid such tasks if so affected.
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 (see INTERACTIONS).

INTERACTIONS
CITRAZ
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). CITRAZ is a very weak inhibitor of isoenzyme CYP1A2, 2C9, 2C19, 2E1 and 3A and weak inhibitor of 2D6.
Effects of other medicinal products on escitalopram in vivo
The pharmacokinetics of single doses of CITRAZ were not changed by co-administration with a single dose of ritonavir (CYP3A4 inhibitor). Furthermore co-administration with ketoconazole (potent CYP3A4 inhibitor) did not change the pharmacokinetics of racemic citalopram.
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 CITRAZ when used concomitantly with high doses of cimetidine.

Other studies:
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 (see WARNINGS). There have been reports of enhanced effects when CITRAZ has been given with lithium or tryptophan and therefore concomitant use of CITRAZ with these medicines should be undertaken with caution (see WARNINGS).

Effects of escitalopram on other medicinal products in vivo
Co-administration with a single dose of desipramine (a CYP2D6 substrate) resulted in a two fold increase in plasma levels of desipramine. Therefore, caution is advised when CITRAZ 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.
Co-administration with a single dose of metoprolol 100 mg (a CYP2D6 substrate) resulted in a two fold 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.
The pharmacokinetics of ritonavir (CYP3A4 inhibitor) were not changed by co-administration with CITRAZ.
Racemic citalopram increased the AUC of selegiline by 29%.
Furthermore, 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.

PREGNANCY AND LACTATION
The safety of CITRAZ in pregnant and lactating women has not been established.

DOSAGE AND DIRECTIONS FOR USE
Adults
Major depressive episodes:
CITRAZ 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.
Panic disorder:
A single oral dose of 5 mg is recommended for the first week before increasing the dose to 10 mg daily. The dose may be further increased, up to a maximum of 20 mg daily, dependent on individual patient response.

Elderly patients (>65 years of age)
A longer half-life and a decreased clearance have been demonstrated in the elderly, therefore a lower initial and maximum dose should be considered.
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.
When stopping CITRAZ therapy, gradual dose reduction should be considered.
CITRAZ is administered as a single daily dose. CITRAZ may be taken without regard to food intake.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Very common (>1/10), Common (> 1/100 and <1/10), Uncommon (> 1/1000 and < 1/100), Rare (> 1/10 000 and < 1/1000), Very rare (< 1/10 000)
Adverse reactions observed with CITRAZ 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 CITRAZ may produce withdrawal reactions in some patients.
Cardiovascular disorders:
Uncommon: Postural hypotension
Metabolic and nutritional disorders:
Common: Decreased appetite
Incidence unknown: Hyponatraemia, inappropriate ADH secretion
Psychiatric disorders:
Incidence unknown: Hallucinations, mania, confusion, agitation, anxiety, depersonalisation, panic attacks, nervousness
Neurological disorders:
Common : Insomnia, somnolence, dizziness, fatigue, drowsiness
Uncommon: Sleep disorder, taste disorder
Incidence unknown: Seizures, tremor, movement disorders, serotonin syndrome (typically characterised by a rapid onset of changes in mental state with confusion, mania, agitation, hyperactivity, shivering, fever, tremor, ocular movements, myoclonus, hyperreflexia and incoordination)
Respiratory, thoracic and mediastinal disorders:
Common: Sinusitis, yawning
Gastrointestinal disorders:
Common: Nausea, vomiting, diarrhoea, constipation, anorexia
Incidence unknown: Dry mouth
Hepato-biliary disorders:
Incidence unknown: Abnormal liver function tests
Skin and subcutaneous tissue disorders:
Common: Increased sweating
Incidence unknown: Rash, pruritus, ecchymoses, angioedema
Musculoskeletal, connective tissue and bone disorders:
Incidence unknown: Arthralgia, myalgia
Renal and urinary disorders:
Incidence unknown: Urinary retention
Reproductive system and breast disorders:
Common: Decreased libido (men and women), ejaculation disorder and impotence (male), anorgasmia (female), galactorrhoea
Eye disorders:
Uncommon: Abnormal vision
General disorders:
Common: Pyrexia
Incidence unknown: Anaphylactic reactions

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Symptoms
Doses of 190 mg have been taken without any symptoms being reported.
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.

IDENTIFICATION
CITRAZ 5:
White, round, biconvex, film-coated tablets embossed ‘RDY’on one side and ‘462’on the other side
CITRAZ 10: White, round, biconvex, film-coated tablets embossed ‘RDY 463’on one side and break-line on the other side
CITRAZ 20: White, round, biconvex, film-coated tablets embossed ‘RDY 464’on one side and break-line on the other side

PRESENTATION
CITRAZ 5:
30 film-coated tablets packed in white HDPE bottles
CITRAZ 10: 30 film-coated tablets packed in white HDPE bottles
CITRAZ 20: 30 film-coated tablets packed in white HDPE bottles

STORAGE INSTRUCTIONS
Store below 25ºC.
Keep tablets in the original container.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
CITRAZ 5:
41/1.2/0843
CITRAZ 10: 41/1.2/0844
CITRAZ 20: 41/1.2/0845

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Dr Reddy’s Laboratories (Pty) Limited
381 Rossouw Street
Murrayfield
Pretoria
0184

DATE OF PUBLICATION OF THE PACKAGE INSERT
August 2008

New addition to this site: March 2010
Source: Pharmaceutical Industry

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