Gerard Laboratories

Ciprager 10mg Film Coated Tablets

Ciprager 20mg Film Coated Tablets

10mg:

Each tablet contains citalopram hydrobromide equivalent to 10mg of citalopram.

Excipient(s):

Lactose Monohydrate 26.64 mg

20mg:

Each tablet contains citalopram hydrobromide equivalent to 20mg of citalopram.

Excipient(s):

Lactose Monohydrate 53.28 mg

For a full list of excipients, see section 6.1

Film-coated tablet

10mg:

White, round, normal, convex, film-coated tablets debossed “CM over10” on one side and “G” on the other.

20mg:

White, oval, film-coated tablets marked with “CM scoreline 20” on one side and “G” on the other. The tablet can be divided into equal halves.

Treatment of major depressive episodes.

Treatment of panic disorder with or without agoraphobia.

Citalopram should be administered as a single oral dose, either in the morning or in the evening. The tablets can be taken with or without food, but with fluid.

• Adults:

- For treatment of major depressive episodes

The usual dose is 20mg citalopram once daily, with a maximum recommended dose of 60mg per day; the dose will be dependent on the response of the individual patient.

Following treatment initiation, an antidepressant effect should not be expected for at least two weeks. Treatment should continue until the patient has been free of symptoms for 4-6 months to give adequate protection against the possibility of a relapse.

- For treatment of panic disorder

A single dose of 10mg per day for the first week is recommended; after this the dose may be increased to 20mg per day. The dose may continue to be increased to 60mg per day depending on individual patient response. Maximum effectiveness is reached after 3 months. It may be necessary to continue treatment for several months.

• Elderly:

- Treatment of major depressive episodes:

The recommended daily dose is 10mg once daily. The dose may be increased to maximal 30mg per day depending on individual response.

- Treatment of panic disorder:

The recommended daily dose is 10mg once daily. The dose may be increased to maximal 40mg per day depending on individual response.

• Children and adolescents under the age of 18:

Citalopram should not be used in the treatment of children and adolescents under the age of 18 years (See section 4.4 Special Warnings and Special Precautions for Use).

• Reduced hepatic function:

Patient with hepatic impairment should receive a starting dose of 10 mg/day. The dose should not exceed 30 mg for patients with hepatic impairment. These patients should be clinically monitored.

• Reduced renal function:

Dosage adjustment is not necessary for patients with mild to moderate renal dysfunction. No information is available for case of severe impairment of renal function (creatinine clearance <20mL/minute).

• Poor CYP2C19 metabolisers:

For known poor CYP2C19 metabolisers an initial dose of 10 mg daily the first two weeks of treatment is recommended. Depending on the outcome of the treatment the dose can thereafter be increased to 20 mg (see section 5.2).

• Withdrawal symptoms seen on discontinuation:

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.

• Hypersensitivity to citalopram or to any of the excipients.

• Monoamine Oxidase Inhibitors:

Citalopram should not be used in combination with a MAOI. Citalopram should not be given for fourteen days after discontinuing treatment with an irreversible MAOI or for the time specified after discontinuing treatment with a reversible MAOI (RIMA) as stated in the prescribing text of the RIMA. At least 7 days should elapse after discontinuing citalopram treatment before starting any MAOI (see also section 4.5 Interactions).

• 5-HT agonists:

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

Use in children & 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 attempts 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. 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 or clinical worsening – 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, 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.

Psychosis – Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.

Haemorrhage – There have been reports of bleeding abnormalities such as ecchymosis, purpura, gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings with SSRIs. Caution is advised in patients taking citalopram, particularly in concomitant use with oral anticoagulants, active substances known to affect platelet function or other active substances that may increase the risk of haemorrhage (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs), Ticlopidine and Dipyridamol) as well as in patients with a history of bleeding disorders.

Serotonin syndrome – In rare cases a serotonin syndrome has been reported in patients using SSRIs. A combination of symptoms, such as agitation, tremor, myoclonus and hyperthermia may indicate the development of this condition. Treatment with citalopram should be discontinued immediately and symptomatic treatment initiated.

Citalopram should not be used concomitantly with medicinal products with serotonergic effects such as tramadol, tryptophan, oxitriptan, sumatriptan or other triptans.

Hyponatraemia – Hyponatraemia and the syndrome of inappropriate anti-diuretic hormone secretion (SIADH) has been reported rarely, predominantly in the elderly, and generally reverses on discontinuation of therapy.

St. John's wort – Undesirable effects may be more common during concomitant use of citalopram and herbal preparations containing St. John's wort (Hypericum perforatum). Therefore citalopram and St. John's wort preparations should not be taken concomitantly (see Section 4.5 Interactions).

Akathisia/psychomotor restlessness - The use of SSRIs/SNRIs has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Withdrawal symptoms seen on discontinuation- Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8 Undesirable effects).

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 and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances have been reported following discontinuation of SSRIs/SNRIs. 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", Section 4.2 Posology and Method of Administration).

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.

The use of citalopram in patients with severe renal impairment (creatinine clearance less than 20ml/min.) is not recommended as no information is available on use in these patients. (see Section 4.2 Posology and method of administration).

In cases of impaired hepatic function dose reduction is recommended (see section 4.2 Posology and method of administration) and liver function has to be closely monitored.

The tablets contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Monoamine Oxidase Inhibitors (MAOIs) - Cases of serious reactions, sometimes fatal, have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the selective irreversible MAOI, selegiline, and the selective reversible MAOI, moclobemide (RIMA). Some cases presented with features resembling serotonin syndrome, the symptoms of which 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. Therefore, citalopram should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an irreversible MAOI or for the time specified after discontinuing treatment with a reversible MAOI (RIMA) as stated in the prescribing text of the RIMA. Similarly, at least 7 days should elapse after discontinuing citalopram treatment before starting any MAOI (see section 4.3).

Linezolid, an antibiotic with reversible and non-selective MAOI properties, should neither be coadministered. When the use of linezolid is however urgent and the wash-out period of one weeks of citalopram could not be awaited, linezolid therapy may start preliminary under strict medical supervision of cardiac function and other symptoms of serotonin syndrome.

The metabolism of citalopram is only partly dependent on the hepatic cytochrome P450 isozyme CYP2 D6 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, tryptophan, oxitryptan, sumatriptan and other triptans) may lead to serotonin syndrome. In combination with triptans, there is a potential risk of coronary vasoconstriction and hypertension too. Therefore, the simultaneous use of citalopram and these active substances is not recommended (see Section 4.4 Special warnings and special precautions for use).

Lithium – There is no pharmacokinetic interaction between lithium and citalopram. However there have been reports of serotonin syndrome when SSRIs have been given with lithium and therefore the concomitant use of citalopram with lithium should be undertaken with caution and closer and more frequent clinical monitoring is required.

Co-administration of citalopram and metoprolol (CYP2D6 substrate) resulted in a two-fold increase in the plasma levels of metoprolol. No clinically significant effects on blood pressure or heart rate were observed.

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. When desipramine is combined with citalopram, an increase of the desipramine plasma concentration has been observed. A reduction of the desipramine dose may be needed.

Cimetidine, a known enzyme-inhibitor, caused a slight rise in the average steady-state citalopram levels. Caution is therefore recommended when administering high doses of citalopram in combination with high doses of cimetidine.

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

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

Caution is warranted for patients who are being treated simultaneously with anticoagulants, active substances known to affect platelet function, or other medicines that can increase the risk of haemorrhage (e.g. NSAIDs, acetylsalicylic acid, dipyridamol, ticlopidine, atypical antipsychotics, phenothiazines, most tricyclic depressants) (see Section 4.4 Special warnings and special precautions for use).

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.

The absorption and other pharmacokinetic properties of citalopram have not been reported to be affected by food.

QT prolongation - Caution is warranted for concomitant use of other QT interval prolonging medicines or hypokalaemia/hypomagnesaemia inducing drugs as they, like Citalopram, also prolong the QT interval.

Seizures - SSRIs can lower the seizure threshold. Caution is advised when concomitantly using other medicinal products capable of lowering the seizure threshold (e.g. antidepressants (tricyclics, SSRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquin, bupropion and tramadol).

Escitalopram - The metabolism of escitalopram is mainly mediated by CYP2C19. CYP3A4 and CYP2D6 may also contribute to the metabolism although to a smaller extent. The metabolism of the major metabolite S-DCT (demethylated escitalopram) seems to be partly catalysed by CYP2D6.

Co-administration of escitalopram with omeprazole 30 mg once daily (a CYP2C19 inhibitor) resulted in moderate (approximately 50%) increase in the plasma concentrations of escitalopram.

Thus, caution should be exercised when used concomitantly with CYP2C19 inhibitors (e.g. omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine) or cimetidine. A reduction in the dose of citalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.

Pregnancy – There are limited data from the use of citalopram in pregnant women. Studies in rats have shown teratogenic effects at high doses which caused maternal toxicity (see section 5.3). The potential risk for humans is unknown. Citalopram should only be used in pregnancy if considered clearly necessary.

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

The following symptoms may occur in the new-born infant 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 withdrawal symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particular in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

Lactation – Citalopram is excreted in milk in small quantities. The advantages of breastfeeding should outweigh the potential undesirable

effects for the child.

Patients prescribed psychotropic medication may have some impairment of concentration due to the illness, the medication, or both. Patients should be cautioned about their ability to drive a car and operate machinery. Citalopram itself does not cause any impairment to intellectual function or psychomotor performance.

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.

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

Withdrawal symptoms seen on discontinuation:

Discontinuation of SSRIs/SNRIs (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitaions, emotional instability, irritability, and visual disturbances have been reported. 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).

Citalopram is given to patients at potential risk of suicide and some reports of attempted suicide have been received. Detail is often lacking regarding precise dose or combination with other drugs and/or alcohol.

Symptoms:

Somnolence, coma, stupor, seizures, ECG changes (e.g. prolonged QT interval), atrial and ventricular arrhythmia, nausea, vomiting, transpiration, cyanosis, hyperventilation. Features of serotonin syndrome may occur, particularly when other substances are co-ingested.

Treatment:

There is no known specific antidote to citalopram. Treatment should be symptomatic and supportive. Activated charcoal, osmotically working laxative (such as sodium sulphate) and stomach evacuation should be considered. If consciousness is impaired the patient should be intubated. ECG and vital signs should be monitored.

Pharmacotherapeutic group: selective serotonin reuptake inhibitors

ATC code: N 06A B04.

Citalopram has been demonstrated to be a potent inhibitor of serotonin (5-HT)-uptake. Long-term treatment with citalopram does not induce tolerance to the inhibition of 5-HT–uptake.

Citalopram is the most Selective Serotonin Reuptake Inhibitor (SSRI) yet described, with minimal effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake. Citalopram has no or very low affinity for a series of receptors including 5-HT_1A, 5-HT₂, dopamine D₁ and D₂ receptors, alpha1-, alpha2- and beta-adrenoceptors, histamine H₁, muscarine cholinergic, benzodiazepine, and opioid receptors. This is in contrast to many tricyclic antidepressants and some of the other SSRI's. Lack of receptor affinity has been confirmed using a series of functional in vitro tests in isolated organs as well as functional in vivo tests. 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.

Like tricyclic antidepressants, other SSRI's and MAO inhibitors, citalopram suppresses REM –sleep and increases deep slow-wave sleep. Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. 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 for Citalopram are higher than many of the other SSRIs. The metabolites do not contribute to the overall antidepressant effect.

Absorption: Absorption is almost complete and independent of food intake (T_max average/mean 3.8 hours). Oral bioavailability is about 80%.

Distribution: The apparent volume of distribution (V_d)_ß is about 12.3 L/kg. The plasma protein binding is below 80% for citalopram and its main metabolites.

Biotransformation: Citalopram is metabolised to the active demethylcitalopram, didemethylcitalopram, citalopram-N-oxide and an inactive deaminated proprionic acid derivative. All the active metabolites are also SSRIs, although weaker than the parent compound. Unchanged citalopram is the predominant compound in plasma. The main metabolising enzyme is CYP2C19. Some contribution from CYP3A4 and CYP2D6 is possible.

Elimination: The elimination half-life (T_{1/2 ß}) is about 1.5 days and the systemic citalopram plasma clearance (CI_s) is about 0.33 L/min, and oral plasma clearance (CI_oral) is about 0.41 L/min.

Citalopram is excreted mainly via the liver (85%) and the remainder (15%) via the kidneys. About 12% - 23% 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 is 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: Citalopram is eliminated more slowly for patients with reduced hepatic function. The half life of citalopram is about twice as long and steady state citalopram concentrations at a given dose will be about twice as high as in patients with normal liver function.

Reduced renal function: Citalopram is eliminated more slowly in patients with mild to moderate reduction of renal function, without any major impact on the pharmacokinetics of citalopram. At present no information is available for treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min).

In laboratory animals no evidence for a special hazard for humans was found. This is based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Phospholipidosis in several organs was observed in repeated dose toxicity studies in rats. This reversible effect is known for several lipophilic amines and was not connected with morphological and functional effects. The clinical relevance is not clear.

Embryotoxicity studies in rats have shown skeletal anomalites at maternal toxic doses. The effects may be related to the pharmacological activity or could be an indirect effect due to maternal toxicity. Peri- and postnatal studies have revealed reduced survival in offspring during the lactation period. The potential risk for humans is unknown.

Tablet Core

Lactose monohydrate

Maize Starch

Microcrystalline Cellulose

Povidone

Crospovidone

Magnesium Stearate

Tablet Coat

Titanium Dioxide (E171)

Lactose monohydrate

Macrogol 4000

Hypromellose (E464)

Not applicable.

2 years.

This medicinal product does not require any special storage conditions.

PVC/PVdC blisters sealed with aluminium foil. Pack sizes of 14, 20, 28, 50, 98 or 100 tablets.

PVC/PVdC blisters sealed with aluminium foil. Calendar pack size of 28 tablets.

High Density Polyethylene (HDPE) tablet containers with polypropylene (PP) caps. Pack sizes of 14, 20, 28, 50, 100 or 250 tablets.

Polypropylene tablet containers with polyethylene caps. Pack sizes of 14, 20, 28, 50, 100 or 250 tablets.

Not all pack sizes may be marketed.

No special requirements.

McDermott Laboratories Ltd t/a Gerard Laboratories

35/36 Baldoyle Industrial Estate

Grange Road

Dublin 13

Ireland

PA 577/47/1

PA 577/47/2

Date of first authorisation: 3 June 2002

Date of last renewal: 9 January 2007

July 2010