Cipramil^® Drops 40 mg/ml

Oral drops 40 mg/ml (44.48 mg citalopram hydrochloride corresponding to 40 mg citalopram base per ml).

Oral drops, solution.

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

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

Posology

MAJOR DEPRESSIVE EPISODES

The recommended dose is 16 mg (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 48 mg (24 drops) a day in 16 mg (8 drops) steps according to the patient's response (see section 5.1). 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 8 mg (4 drops)/day and the dose gradually increased in 8 mg (4 drops) steps according to the patient's response up to the recommended dose. The recommended dose is 16-24 mg (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 48 mg (16 drops) /day (see section 5.1). 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.

Elderly patients > 65 years of age)

Children (< 18 years of age)

Citalopram should not be used in the treatment of children and adolescents under the age of 18 years (see section 4.4).

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 <20 mL / 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 (see section 4.4 Special Warnings and Special Precautions for Use and section 4.8 Undesirable Effects). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Method of administration

For oral administration after mixing with water, orange juice or apple juice.

Cipramil 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:

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 inhibitor (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.

Concomitant treatment with pimozide (see section 4.5).

Suicide/suicidal thoughts or clinical worsening

Other psychiatric conditions for which Cipramil 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, or 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. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Use in children and adolescents under 18 years of age

Serotonin syndrome

Hyponatraemia

Diabetes

Seizures

ECT

Mania

Haemorrhage

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.

Glaucoma

Akathisia/psychomotor restlessness

Withdrawal symptoms seen on discontinuation of SSRI treatment

The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache 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 (see “Withdrawal symptoms seen on discontinuation of citalopram”, Section 4.2 Posology and Method of Administration).

Monoamine Oxidase Inhibitors (MAOIs) should not be used in combination with SSRIs (see 4.3 Contraindications).

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 between citalopram and alcohol.

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

Lithium & 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.

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.

Dynamic interactions between citalopram and herbal remedy St John's Wort (Hypericum perforatum) can occur, resulting in an increase in undesirable effects.

A pharmacokinetic/pharmacodynamic interaction study in healthy volunteers with concomitant administration of citalopram and metoprolol (a CYP2D6 substrate) showed a twofold increase in metoprolol concentrations, but no statistically significant increase in the effect of metoprolol on blood pressure and heart rate.

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.

Pimozide

Co administration of a single dose of pimozide 2 mg to subjects treated with racemic citalopram 40 mg/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 10 msec. Due to the interaction noted at a low dose of pimozide, concomitant administration of citalopram and pimozide is contraindicated.

Pregnancy

Animal studies did not provide any evidence of teratogenicity, however the safety of citalopram during human pregnancy has not been established. As with all drugs citalopram should only be used in pregnancy if the potential benefits of treatment to the mother outweigh the possible risks to the developing foetus.

Neonates should be observed if maternal use of citalopram continues into the later stages of pregnancy, particularly in the third trimester. Abrupt discontinuation should be avoided during pregnancy.

The following symptoms may occur in the neonates after maternal SSRI/SNRI use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either serotonergic effects or discontinuation symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.

Lactation

Citalopram is known to be excreted in breast milk. Its effects on the nursing infant have not been established. If treatment with citalopram is considered necessary, discontinuation of breast feeding should be considered.

Citalopram does not impair intellectual function and psychomotor performance. However, patients who are prescribed psychotropic medication may be expected to have some impairment of general attention and concentration either due to the illness itself, the medication or both and should be cautioned about their ability to drive a car and operate machinery.

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 Cipramil 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):

Frequent ( 5 - 20%)

Increased sweating, headache, tremor, dizziness, abnormal accommodation, somnolence, insomnia, agitation, nervousness, nausea, dry mouth, constipation, diarrhoea, palpitation, asthenia.

Less frequent (1 - <5%)

Rash, pruritus, paraesthesia, migraine, abnormal vision, taste perversion, sleep disorder, decreased libido, impaired concentration, abnormal dreaming, amnesia, anxiety, increased appetite, anorexia, apathy, impotence, suicide attempt, confusion, dyspepsia, vomiting, abdominal pain, flatulence, increased salivation, weight decrease, weight increase, postural hypotension, tachycardia, rhinitis, micturition disorder, polyuria, ejaculation failure, female anorgasmia, fatigue, eye disorders (visual disturbance, mydriasis (which may lead to acute narrow angle glaucoma), see section 4.4 Special warnings and precautions for use).

Rare (<1%)

Myalgia, movement disorders, convulsions, tinnitus, euphoria, increased libido, coughing, malaise. Psychomotor restlessness/akathisia (see section 4.4 Special Warnings and Special Precautions for Use)

Post Marketing- The following adverse reactions apply to the therapeutic class of SSRIs

Skin Disorders: Angiodema; ecchymoses. Photosensitivity reactions have been reported very rarely.

Disorders of metabolism and nutrition: 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 the older patients.

Gastrointestinal disorders : Gastrointestinal bleeding.

General disorders: Anaphylactoid reactions.

Hepato-billiary disorders: Abnormal LFT's.

Musculoskeletal disorders: Arthralgia.

Neurological disorders: Serotonin syndrome.

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

Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section 4.4).

Reproductive disorders: Galactorrhoea.

Withdrawal symptoms seen on discontinuation of SSRI treatment

Discontinuation of citalopram (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache 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 (see section 4.2 Posology and Method of Administration and section 4.4 Special Warnings and Special Precautions for use).

Fatal dose is not known. Patients have survived ingestion of more than 2 g citalopram.

The effects may be potentiated by alcohol taken at the same time.

Potential interaction with TCAs, MAOIs and other SSRIs.

Symptoms

Nausea, dizziness, tachycardia, tremor, drowsiness and somnolence may occur. At higher doses convulsions may occur within a few hours after ingestion. Hyperventilation, hyperpyrexia and coma have been reported.

ECG changes including nodal rhythm, prolonged QT intervals and wide QRS complexes may occur and rarely rhabdomolysis. Fatalities have been reported.

Prolonged bradycardia with severe hypotension and syncope has also been reported.

Rarely, features of the "serotonin syndrome" may occur in severe poisoning. This includes alteration of mental status, neuromuscular hyperactivity and autonomic instability. There may be hyperpyrexia and elevation of serum creatine kinase. Rhabdomyolysis is rare.

Treatment

There is no specific antidote.

An ECG should be taken.

Consider oral activated charcoal in adults and children who have ingested more than 5 mg/kg body weight within 1 hour. Activated charcoal given ½ hour after ingestion of citalopram has been shown to reduce absorption by 50%.

Control convulsions with intravenous diazepam if they are frequent or prolonged

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable.

ATC-code: N 06 AB 04

Biochemical and behavioural studies have shown that citalopram is a potent inhibitor of the serotonin (5-HT)-uptake. Tolerance to the inhibition of 5-HT-uptake is not induced by long-term treatment with citalopram.

Citalopram is the most Selective Serotonin Reuptake Inhibitor (SSRI) yet described, with no, or minimal, effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake.

In contrast to many tricyclic antidepressants and some of the newer SSRI's, citalopram has not or very low affinity for a series of receptors including 5-HT _1A, 5-HT₂, DA D₁ and D₂ receptors, α₁-, α₂-, β-adrenoceptors, histamine H₁, muscarine cholinergic, benzodiazepine, and opioid receptors. A series of functional in vitro tests in isolated organs as well as functional in vivo tests have confirmed the lack of receptor affinity. This absence of effects on receptors could explain why citalopram produces fewer of the traditional side effects such as dry mouth, bladder and gut disturbance, blurred vision, sedation, cardiotoxicity and orthostatic hypotension.

Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. Like tricyclic antidepressants, other SSRI's and MAO inhibitors, citalopram suppresses REM-sleep and increases deep slow-wave sleep.

Although citalopram does not bind to opioid receptors it potentiates the anti-nociceptive effect of commonly used opioid analgesics. There was potentiation of d-amphetamine-induced hyperactivity following administration of citalopram.

The main metabolites of citalopram are all SSRIs although their potency and selectivity ratios are lower than those of citalopram. However, the selectivity ratios of the metabolites are higher than those of many of the newer SSRIs. The metabolites do not contribute to the overall antidepressant effect.

In humans citalopram does not impair cognitive (intellectual function) and psychomotor performance and has no or minimal sedative properties, either alone or in combination with alcohol.

Citalopram did not reduce saliva flow in a single dose study in human volunteers and in none of the studies in healthy volunteers did citalopram have significant influence on cardiovascular parameters. Citalopram has no effect on the serum levels of prolactin and growth hormone.

Dose response

Absorption

Distribution

Biotransformation

Elimination

Citalopram is excreted mainly via the liver (85%) and the remainder (15%) via the kidneys. About 12% of the daily dose is excreted in urine as unchanged citalopram. Hepatic (residual) clearance is about 0.35 L/min and renal clearance about 0.068 L/min.

The kinetics are linear. Steady state plasma levels are achieved in 1-2 weeks. Average concentrations of 250 nmol/L (100-500 nmol/L) are achieved at a daily dose of 40 mg. There is no clear relationship between citalopram plasma levels and therapeutic response or side effects.

Elderly patients ( 65 years)

Longer half-lives and decreased clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients.

Reduced hepatic function

Reduced renal function

Citalopram has low acute toxicity. In chronic toxicity studies there were no findings of concern for the therapeutic use of citalopram. Based on data from reproduction toxicity studies (segment I, II and III) there is no reason to have special concern for the use of citalopram in women of child-bearing potential. Citalopram has no mutagenic or carcinogenic potential.

Methyl-parahydroxybenzoate, propyl-parahydroxybenzoate, ethyl alcohol 9% v/v, hydroxyethylcellulose, purified water.

Cipramil Drops should only be mixed with water, orange juice or apple juice.

24 months (there is a “use by” date on the label).

A bottle may be used for 16 weeks after first use, if stored below 25°.

None

Brown glass bottle containing 15 ml with screw cap and polyethylene dropper. One bottle per carton.

None.

PL 0458/0071

4 August 1998

18/09/09

Legal category: POM