Citalopram 40 mg/ml Oral Drops, Solution

Each ml contains: Citalopram hydrochloride, corresponding to 40 mg citalopram. 1 drop = 2 mg citalopram; 1 ml = 20 drops = 40 mg citalopram Ethanol = 76mg/ml Methyl Parahydroxybenzoate = 1mg/ml Propyl Parahydroxybenzoate = 0.1mg/ml

Treatment of depressive illness in the initial phase and as maintenance against potential relapse/recurrence.

Citalopram is also indicated in the treatment of panic disorder with or without agoraphobia.

For oral administration after mixing with water

MAJOR DEPRESSIVE EPISODES

The recommended dose is 16mg (8 drops) daily). In general, improvement in patients starts after one week but may only become evident from the second week of therapy.

As with all antidepressant medicinal products, dosage should be reviewed and adjusted if necessary within 3 to 4 weeks of initiation of therapy and thereafter as judged clinically appropriate. Although there may be an increased potential for undesirable effects at higher doses, if after some weeks on the recommended dose insufficient response is seen, some patients may benefit from having their dose increased up to a maximum of 48mg (24 drops) a day in 16mg (8 drops) steps according to the patient's response. Dosage adjustments should be made carefully on an individual patient basis, to maintain the patient at the lowest effective dose.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.

PANIC DISORDER

Patients should be started on 8mg (4 drops)/day and the dose gradually increased in 8mg (4 drops) steps according to the patient's response up to the recommended dose. The recommended dose is 16-24mg (8 to 12 drops) daily. A low initial starting dose is recommended to minimise the potential worsening of panic symptoms, which is generally recognised to occur early in the treatment of this disorder. Although there may be an increased potential for undesirable effects at higher doses, if after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 48mg (16 drops)/day. Dosage adjustments should be made carefully on an individual patient basis, to maintain the patients at the lowest effective dose.

Patients with panic disorder should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer.

Reduced hepatic function

Dosage should be restricted to the lower end of the dose range.

Reduced renal function

Dosage adjustment is not necessary in cases of mild or moderate renal impairment. No information is available in cases of severe renal impairment (creatinine clearance <20mL/min)

Withdrawal symptoms seen on discontinuation of citalopram

Abrupt discontinuation should be avoided. When stopping treatment with citalopram the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously described dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Citalopram Oral Drops can be taken as a single daily dose, at any time of day, without regard to food intake.

Citalopram Oral Drops have approximately 25% increased bioavailability compared to tablets. The tablet corresponds to the number of drops as follows:

Children & Adolescents (<18 years)

Citalopram should not be used in the treatment of children and adolescents under the age of 18 years.

Elderly Patients (>65 years of age)

The recommended daily dose is 16mg (8 drops). Dependent on individual patient response this may be increased to a maximum of 32mg (16 drops) daily.

Hypersensitivity to citalopram.

Monoamine Oxidase Inhibitors. Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with monoamine oxidase inhibitors (MAOI), including the selective MAOI selegiline and the reversible MAOI (RIMA), moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI.

Some cases presented with features resembling serotonin syndrome. Symptoms of a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.

Citalopram should not be used in combination with a MAOI. Citalopram may be started 14 days after discontinuing treatment with an irreversible MAOI and at least one day after discontinuing treatment with the reversible MAOI (RIMA), moclobemide. At least 7 days should elapse after discontinuing citalopram treatment before starting a MAOI or RIMA.

Sumatriptan's serotonergic effects are suspected to be enhanced by SSRI's. Until further evidence is available it is advised not to use citalopram simultaneously with 5-HT agonists e.g. sumatriptan.

Concomitant treatment with pimozide

Use in children and adolescents under 18 years of age

Citalopram should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Diabetes – In patients with diabetes, treatment with an SSRI may alter glycaemic control, possibly due to improvement of depressive symptoms. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Seizures – Seizures are a potential risk with antidepressant drugs, The drug should be discontinued in any patient who develops seizures. Citalopram should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Citalopram should be discontinued if there is an increase in seizure frequency.

ECT – There is little clinical experience of concurrent administration of citalopram and ECT, therefore caution is advisable.

Mania – Citalopram should be used with caution in patients with a history of mania/hypomania. Citalopram should be discontinued in any patient entering a manic phase.

Suicide/suicidal thoughts – Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which citalopram is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder .The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. In addition, there is a possibility of an increased risk of suicidal behaviour in young adults.

Patients (and caregivers of patients) should be alerted about the need to monitor for the emergence of such events and to seek medical advice immediately if these symptoms persist.

Haemorrhage – There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura, as well as haemorrhagic manifestations e.g. gastrointestinal haemorrhage with SSRIs. The risk of gastrointestinal haemorrhage may be increased in elderly people during treatment with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs)and ticlopidine as well as in patients with a history of bleeding disorders.

Withdrawal symptoms seen on discontinuation of citalopram treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. In clinical trials, adverse events seen on treatment discontinuation occurred in approximately 40% of patients treated with citalopram and 20% of patients taking placebo.

The risk of withdrawal symptoms may be dependent on several factors including the duration and dose therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability and visual disturbances are the most commonly reported reactions.

Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more).

It is therefore advised that citalopram should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs.

Experience with citalopram has not revealed any clinically relevant interactions with neuroleptics, However, as with other SSRIs, the possibility of a pharmacodynamic interaction cannot be excluded.

Consideration should be given to factors which may affect the disposition of a minor metabolite of citalopram (didemethylcitalopram) since increased levels of this metabolite could theoretically prolong the QTc interval in susceptible individuals. However, in ECG monitoring of 2500 patients in clinical trials, including 277 patients with pre-existing cardiac conditions, no clinically significant changes were noted.

Some patients with panic disorder experience an initial anxiogenic effect when starting pharmacotherapy. A low starting dose (see Posology) reduces the likelihood of this effect.

Warnings on excipients:

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per ml.

This medicinal product also contains propyl parahydroxybenzoate (E216) and methyl parahydroxybenzoate (E218), which may cause allergic reactions (possibly delayed).

Monoamine Oxidase Inhibitors (MAOIs) should not be used in combination with SSRIs.

The metabolism of citalopram is only partly dependent on the hepatic cytochrome P450 isozyme CYP2D6 and, unlike some other SSRIs, citalopram is only a weak inhibitor of this important enzyme system which is involved in the metabolism of many drugs (including antiarrhythmics, neuroleptics, beta-blockers, TCAs and some SSRIs). Protein binding is relatively low (<80%). These properties give citalopram a low potential for clinically significant drug interactions.

Alcohol – The combination of citalopram and alcohol is not advisable. However, clinical studies have revealed no adverse pharmacodynamic interactions.

Serotonergic drugs – Co-administration with serotonergic drugs (e.g. tramadol, sumatriptan) may lead to enhancement of 5-HT associated effects.

Lithium and tryptophan – There is no pharmacokinetic interaction between lithium and citalopram. However, there have been reports of enhanced serotonergic effects when SSRIs have been given with lithium or tryptophan and therefore the concomitant use of citalopram with these drugs should be undertaken with caution. Routine monitoring of lithium levels need not be adjusted.

SSRI's increase plasma concentrations of some tricyclic antidepressants.In a pharmacokinetic study no effect was demonstrated on either citalopram or imipramine levels, although the level of desipramine, the primary metabolite of imipramine, was increased.

In animal studies cimetidine had little or no influence on citalopram kinetics.

SSRIs may increase the risk of bleeding if they are administered concomitantly with anticoagulants or drugs which have an effect on platelet functioning.

Undesirable effects may be more common during concomitant use of serotonin-reuptake inhibitors and herbal preparations containing St John's Wort (hypericum perforatum).

Pimozide – Co-administration of a single dose of pimozide 2mg to subjects treated with racemic citalopram 40mg/day for 11 days caused an increase in AUC and Cmax of pimozide, although not consistently throughout the study. The co-administration of pimozide and citalopram resulted in a mean increase in the QTc interval of approximately 10msec. Due to the interaction noted at low dose of pimozide, concomitant administration of citalopram and pimozide is contraindicated.

No pharmacodynamic interactions have been noted in clinical studies in which citalopram has been given concomitantly with benzodiazepines, neuroleptics, analgesics, lithium, alcohol, antihistamines, antihypertensive drugs, beta-blockers and other cardiovascular drugs.

Adverse effects observed with citalopram are in general mild and transient. They are most prominent during the first one or two weeks of treatment and usually attenuate as the depressive state improves.

The most commonly observed adverse events associated with the use of citalopram and not seen at an equal incidence among placebo-treated patients were: nausea, somnolence, dry mouth, increased sweating and tremor. The incidence of each in excess over placebo is low (<10%).

In comparative clinical trials with tricyclic antidepressants the incidence of adverse events occurring with citalopram was found to be lower in all cases.

Withdrawal reactions have been reported in association with selective serotonin reuptake inhibitors (SSRIs), including citalopram. Common symptoms include dizziness, paraesthesia, headache, anxiety and nausea. Abrupt discontinuation of treatment with citalopram oral drops should be avoided. The majority of symptoms experienced on withdrawal of SSRIs are non-serious and self-limiting.

Treatment emergent adverse events reported in clinical trials (N=2985):-

Frequency	Very common	Common	Uncommon	Rare	Very rare
	1/10	1/100 to <1/10	1/1,000 to <1/100	1/10,000 to <1/1,000	<1/10,000,
Metabolism and nutrition disorders			Weight decrease, weight increase
Psychiatric disorders		Somnolence, insomnia, agitation, nervousness	Sleep disorder, decreased libido, concentration impaired, abnormal dreaming, amnesia, anxiety, increased appetite, anorexia, apathy, impotence, suicide attempt, confusion, yawning	Euphoria, increased libido
Nervous system disorders		< Headache, tremor, dizziness	Paraesthesia, migraine	Extrapyramidal disorder, convulsions, psychomotor restlessness /akathisia
Eye disorders		Abnormal accommodation	Abnormal vision
Ear and labyrinth disorders				Tinnitus
Cardiac Disorders		Palpitation	Postural hypotension, tachycardia
Respiratory, thoracic and mediastinal disorders			Rhinitis	Coughing
Gastro-intestinal disorders		Nausea, dry mouth, constipation, diarrhoea	Dyspepsia, vomiting, abdominal pain, flatulence, increased saliva, taste perversion
Skin and subcutaneous disorders		Increased sweating	Rash, pruritus
Renal and urinary disorders			Micturition disorder, polyuria
Reproductive system and breast disorders			Ejaculation failure, anorgasmia female.
Musculoskeletal, connective tissue and bone disorders				Myalgia
General Disorders /td>		Asthenia	Fatigue	Malaise

Suicidal thoughts/behaviour (frequency unknown): Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation.

Post Marketing

The following side effects apply to the therapeutic class of SSRIs:

Metabolism and Nutrition Disorders: Rare cases of hyponatraemia and inappropriate ADH secretion have been reported and appear to be reversible on discontinuation. The majority of the reports were associated with older patients.

Psychiatric disorders: Hallucinations, mania, depersonalisation, panic attacks (these symptoms may be due to the underlying disease)

Nervous System Disorders: Serotonin Syndrome.

Cardiac Disorders: Treatment with SSRIs has occasionally been associated with symptoms suggestive of postural hypotension, hypotension, hypertension and tachycardia. There have also been very rare reports of supraventricular and ventricular arrhythmias. To date causality has not been established.

Gastro-intestinal disorders: Gastro-intestinal bleeding

Hepato-biliary disorders: Abnormal LFT's

Skin and subcutaneous tissue disorders: Angioedema, ecchymoses. Photosensitivity reactions have been reported very rarely.

Musculoskeletal disorders: Arthralgia

Reproductive disorders: Galactorrhoea

General disorders: Anaphylactoid reactions

Withdrawal symptoms seen on discontinuation of citalopram treatment

Discontinuation of citalopram (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability and visual disturbances are the most commonly reported reactions. Generally these events are mild to moderate and are self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when citalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out.

Rosemont Pharmaceuticals Limited

POM

17 November 2009