Citalopram 10mg Tablets (Sandoz Limited )

1. Name Of The Medicinal Product

Citalopram 10mg Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 10mg citalopram (as citalopram hydrobromide).

each film-coated tablet contains 11.5 mg lactose monohydrate

For excipients, see 6.1

3. Pharmaceutical Form

Film-coated tablet

White round film-coated tablet without score line

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depressive episodes.

Treatment of panic disorder with or without agoraphobia

4.2 Posology And Method Of Administration

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 to avoid paradox reactions (i.e. e. panic, anxiety) (see section 4.4); after this the dose may be increased to 20mg per day. The first therapeutic effects usually appear after 2 – 4 weeks. The dose may continue to be increased to 60mg per day depending on individual patient response. Full therapeutic response may take up to 3 months to develop. It may be necessary to continue treatment for several months. Documentation from clinical efficacy studies exceeding 6 months is insufficient.

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 30 mg 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:

Patients 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. 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.

Poor metabolisers regarding CYP2C19:

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).

For the different dosage regimens suitable strengths should be prescribed.

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 sections 4.4 and 4.8). 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.

4.3 Contraindications

Hypersensitivity to citalopram or to any of the excipients.

Citalopram should not be given to patients receiving Monoamine Oxidase Inhibitors (MAOIs) including selegiline in daily doses exceeding 10 mg/day. Citalopram should not be given for fourteen days after discontinuation of an irreversible MAOI or for the time specified after discontinuation of a reversible MAOI (RIMA) as stated in the prescribing text of the RIMA. MAOIs should not be introduced for seven days after discontinuation of citalopram (see Section 4.5 Interactions with other medicinal products and other forms of interaction).

Concommitant treatment with pimozide (see also section 4.5).

Citalopram is contraindicated in the combination with linezolid unless there are facilities for close observation and monitoring of blood pressure (see section 4.5).

4.4 Special Warnings And Precautions For Use

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.

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.

Akathisia/psychomotor restlessness:

The use of citalopram 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.

Paradoxical anxiety reactions

Some patients with panic disorder may experience increased anxiety symptoms at the beginning 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 an anxiogenic effect (see section 4.2).

Withdrawal symptoms seen on discontinuation of SSRI treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8).

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).

Citalopram should be prescribed in the smallest quantity of tablets in order to reduce the risk of overdose.

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

In patients with diabetes, treatment with an SSRI may alter glycaemic control . Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Citalopram 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.

There is little clinical experience of concurrent administration of citalopram and electro-convulsive therapy, therefore caution is advisable.

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.

There have been reports of prolonged bleeding time and/or bleeding abnormalities such as ecchymosis, gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings with SSRIs (see Section 4.8 Undesirable effects). Caution is advised in patients taking SSRIs, particularly in concomitant use with active substances known to affect platelet function or other active substances that can increase the risk of haemorrhage as well as in patients with a history of bleeding disorders (see Section 4.5 Interactions with other medicinal products and other forms of interaction).

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.

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

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.

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 with other medicinal products and other forms of interaction).

At the beginning of the treatment, insomnia and agitation can occur. A dose titration may be helpful.

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, in patients with suspected congenital long QT-syndrome or in patients with hypokalaemia/hypomagnesaemia. ECG monitoring of 2500 patients in clinical trials, including 277 patients with pre-existing cardiac conditions, did not reveal clinically significant changes. However, ECG monitoring may be advisable in case of overdose or conditions of altered metabolism with increased peak levels, e.g. liver impairment.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Pharmacodynamic interactions

Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAOI selegiline and the reversible MAOIs linezolid (non-selective) and moclobemide (selective for type A and in patients who have recently discontinued an SSRI and have been started on a MAOI.

Concomitant use of citalopram and pimozide is contra-indicated (see section 4.3). Concomitant administration of a single dose of 2 mg pimozide to healthy volunteers, who were treated with citalopram 40 mg/day for 11 days, caused only a minor increase in the AUC and Cmax of pimozide of approximately 10%, not being statistically significant. Despite the minor increase in plasma pimozide levels, the QTc interval was more prolonged after concomitant administration of citalopram and pimozide (on average 10 ms) as compared to administration of a single dose of pimozide alone (on average 2 ms). Since this interaction was already observed after administration of a single dose of pimozide, concomitant treatment with citalopram and pimozide is contra-indicated.

Some cases presented with features resembling serotonin syndrome. Symptoms of serotonergic syndrome: hyperthermia, diaphoresis, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital functions confusion, irritability and agitation. If progressing without intervention the condition can be fatal due to rhabdomyolysis, central hyperthermia with multi organ acute impairment, delirium and coma.(see Section 4.3 Contraindications).

The serotonergic effect of sumatriptan may be potentiated by selective serotonin re-uptake inhibitors (SSRIs). Until further information is available, the simultaneous use of citalopram and 5-HT agonists, such as sumatriptan and other triptans, is not recommended (see Section 4.4 Special warnings and precautions for use).

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

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.

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).

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.

Undesirable effects may be more common during concomitant use of citalopram and herbal preparations containing St John's wort (Hypericum perforatum) (see Section 4.4 Special warnings and precautions for use).

No pharmacodynamic or pharmacokinetic interactions have been demonstrated between citalopram and alcohol. However, the combination of citalopram and alcohol is not advisable.

Pharmacokinetic interactions

Escitalopram (the active enantiomer of citalopram) is an inhibitor of the enzyme CYP2D6. Caution is recommended when citalopram is co-administered with medicinal products that are mainly metabolised by this enzyme, and that have a narrow therapeutic index, e.g. flecainide, propafenone and metoprolol (when used in cardiac failure), or some CNS acting medicinal products that are mainly metabolised by CYP2D6, e.g. antidepressants such as desipramine, clomipramine and nortryptyline or antipsychotics like risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted. Co-administration with metoprolol resulted in a two-fold increase in the plasma levels of metoprolol.

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

Cimetidine, a known enzyme-inhibitor, caused a 40 % 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.

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 escitalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.

There is no pharmacokinetic interaction between lithium and citalopram. However, there have been reports of enhanced serotonergic effects when SSRIs were administered in combination with lithium or tryptophan. Caution is advised during simultaneous use of citalopram with these active substances. Routine monitoring of lithium levels should be continued as usual.

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.

No pharmacokinetic interaction was observed between citalopram and levomepromazine, digoxin or carbamazepine and its metabolite carbamazepine-epoxide.

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

4.6 Pregnancy And Lactation

Pregnancy:

There are no adequate data from the use of citalopram in pregnant women. Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans is unknown. Citalopram should not be used during pregnancy unless clearly necessary.

Cases of withdrawal symptoms in newborns have been described after the use of SSRI at the end of pregnancy. Newborn 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.

Lactation:

Citalopram is excreted in milk in small quantities. The advantages of breastfeeding should outweigh the potential adverse effects for the child.

4.7 Effects On Ability To Drive And Use Machines

Citalopram has minor or moderate influence on the ability to drive and use machines.

Psychoactive medicinal products can reduce the ability to make judgements and to react to emergencies. Patients should be informed of these effects and be warned that their ability to drive a car or operate machinery could be affected.

4.8 Undesirable Effects

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

Treatment emergent adverse events reported in clinical trials:

Psychiatric disorders

very common (> 1/10): somnolence, insomnia, agitation, nervousness

common (> 1/100, < 1/10): sleep disorders, impaired concentration, abnormal dreaming, amnesia, anxiety, decreased libido, increased appetite, anorexia, apathy, confusion

uncommon (> 1/1,000, < 1/100): euphoria, increased libido

Frequency not known (cannot be estimated from the available data): Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section 4.4)

Other events reported since authorisation of citalopram: hallucinations, mania, depersonalisation, panic attack

Nervous system disorders

very common (> 1/10): headache, tremor, dizziness

common (> 1/100, < 1/10): migraine, paraesthesia

uncommon (> 1/1,000, < 1/100): extrapyramidal disorder, convulsions

rare (> 1/10,000, < 1/1,000): psychomotor restlessness/akathisia (see section 4.4)

Cardiac disorders

very common (> 1/10): palpitations

common (> 1/100, < 1/10): tachycardia

uncommon (> 1/1,000, < 1/100): bradycardia

Other events reported since authorisation of citalopram: supraventricular and ventricular arrhythmias

Vascular disorders

common (> 1/100, < 1/10): postural hypotension, hypotension, hypertension

Gastrointestinal disorders

very common (> 1/10): nausea, dry mouth, constipation, diarrhoea

common (> 1/100, < 1/10): dyspepsia, vomiting, abdominal pain, flatulence, increased salivation

Renal and urinary disorders

common (> 1/100, < 1/10): micturition disorder, polyuria

Metabolism and nutrition disorders

common (> 1/100, < 1/10): weight decrease, weight increase

Hepato-biliary disorders

uncommon (> 1/1,000, < 1/100): increased liver enzyme values

Respiratory disorders

common (> 1/100, < 1/10): rhinitis, sinusitis

uncommon (> 1/1,000, < 1/100): coughing

Reproductive system disorders

common (> 1/100, < 1/10): ejaculation failure, female anorgasmia, dysmenorrhoea, impotence

Other events reported since authorisation of citalopram: galactorrhoea

Skin disorders

very common (> 1/10): increased sweating

common (> 1/100, < 1/10): rash, pruritus

uncommon (> 1/1,000, < 1/100): photosensitivity

Other events reported since authorisation of citalopram: angiodema

Eye disorders

very common (> 1/10): abnormal accommodation

common (> 1/100, < 1/10): abnormalities of vision

Special senses disorders

common (> 1/100, < 1/10): taste abnormalities

Ear and labyrinth disorders

uncommon (> 1/1,000, < 1/100): tinnitus

Musculoskeletal disorders

uncommon (> 1/1,000, < 1/100): myalgia

Other events reported since authorisation of citalopram: arthralgia

General disorders

very common (> 1/10): asthenia

common (> 1/100, < 1/10): fatigue, yawning

uncommon (> 1/1,000, < 1/100): allergic reactions, syncope, malaise

Other events reported since authorisation of citalopram: anaphylactoid reactions

rare (> 1/10,000, < 1/1,000)

Haemorrhage (for example, gynaecological haemorrhage, gastrointestinal haemorrhage, ecchymosis and other forms of skin haemorrhage or bleeding in the mucous membranes) can occur on rare occasions.

In rare cases a serotonin syndrome has been reported in patients using SSRIs. Hyponatriaemia and the syndrome of inappropriate anti-diuretic hormone secretion (SIADH) has been reported rarely, predominantly in the elderly (see Section 4.4 “Special warnings and precautions for use”).

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 sections 4.2 and 4.4).

4.9 Overdose

Fatal dose not known. Patients have survived ingestion of up to 2 g citalopram. The effects will be potentiated by alcohol taken at the same time. Potential interaction with tricyclic antidepressants and MAOIs.

Symptoms

Nausea, vomiting, sweating, tachycardia, drowsiness, coma, dystonia, convulsions, hyperventilation and hyperpyrexia have been reported. Cardiac features that have been observed include nodal rhythm, prolonged QT intervals and wide QRS complexes. 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.

Management

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.

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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group

Selective Serotonin Re-uptake Inhibitors.

ATC code: N06A B04

Citalopram is an antidepressant with a strong and selective inhibitory action on the uptake of 5-hydroxytryptamine (5-HT, serotonin).

Mechanism of action and pharmacodynamic effects

Tolerance to the inhibitory effect of citalopram on 5-HT uptake does not occur during long-term treatment.

The antidepressant effect is probably connected with the specific inhibition of serotonin uptake in the brain neurons.

Citalopram has almost no effect on the neuronal uptake of noradrenaline, dopamine and gamma-aminobutyric acid. Citalopram shows no affinity, or only very little, for cholinergic, histaminergic and a variety of adrenergic, serotonergic and dopaminergic receptors.

Citalopram is a bi-cyclic isobenzophurane-derivative that is chemically not related to tricyclic and tetracyclic antidepressants or other available antidepressants. The main metabolites of citalopram are also selective serotonin uptake inhibitors, though to a lesser degree. The metabolites are not reported to contribute to the overall antidepressant effect.

5.2 Pharmacokinetic Properties

General characteristics of the active substance

Absorption

Citalopram is rapidly absorbed following oral administration: the maximum plasma concentration is reached on average after 4 (1-7) hours. Absorption is independent of food intake. Oral bioavailability is approximately 80%.

Distribution:

The apparent distribution volume is 12-17 l/kg. The plasma-protein binding of citalopram and its metabolites is below 80%.

Bio-transformation:

Citalopram is metabolised into demethylcitalopram, didemethylcitalopram, citalopram-N-oxide and the deaminated propionic acid-derivative. The propionic acid-derivative is pharmacologically inactive. Demethylcitalopram, didemethylcitalopram and citalopram-N-oxide are selective serotonin uptake inhibitors, although weaker than the parent compound.

In vivo research has demonstrated that the plasma levels of citalopram and its metabolites depend on the sparteine/debrisoquine phenotype and the mephenytoin phenotype. However, it is not necessary to dose individually according to these phenotypes.

Elimination:

The plasma half-life is approximately 1½ days. After systemic administration, the plasma clearance is approximately 0.3-0.4 l/min and after oral administration the plasma clearance is approximately 0.4 l/min.

Citalopram is mainly eliminated via the liver (85%), but also partly (15%) via the kidneys. Of the quantity of citalopram administered, 12-23 % is eliminated unaltered via the urine. Hepatic clearance is approximately 0.3 l/min and renal clearance is 0.05-0.08 l/min.

Steady-state concentrations are reached after 1-2 weeks. A linear relationship has been demonstrated between the steady-state plasma level and the dose administered. At a dose of 40 mg per day, an average plasma concentration of approximately 300 nmol/l is reached. There is no clear relationship between citalopram plasma levels and therapeutic response or side effects.

Characteristics relating to patients

Longer plasma half-life values and a smaller clearance have been found in older patients due to a reduced metabolism.

The elimination of citalopram progresses more slowly in patients with reduced liver function. The plasma half-life of citalopram is approximately twice as long and the steady-state plasma concentration approximately twice as high in comparison with patients with a normal liver function.

The elimination of citalopram progresses more slowly in patients with a mild to moderate renal function disorder, without any major impact on the pharmacokinetics of citalopram. No information is available on treatment of patients with severe renal impairment (creatinine clearance less than 20 ml/min).

5.3 Preclinical Safety Data

Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential. Phospholipidosis has been observed in several organs following multiple administration in rats. The effect was reversible at discontinuation. Accumulation of phospholipids has been observed in long term animal studies with many cation-amphophilic drugs. The clinical relevance of these results is not clear.

Reproduction toxicity studies in rats have demonstrated skeletal anomalies in the offspring, but no increased frequency of malformations. The effects may be related to the pharmacological activity or may be a consequence of maternal toxicity. Peri- and postnatal studies have revealed reduced survival in offspring during the lactation period. The potential risk for humans is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core:

Cellulose, microcrystalline

Glycerol 85 %

Magnesium stearate

Maize starch

Lactose monohydrate

Copovidone

Sodium starch glycollate (type A)

Coating:

Macrogol 6000

Hypromellose

Talc

Titanium dioxide (colouring agent E 171)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

The film-coated tablets are packed in

-PVDC-PVC / aluminium blisters and inserted into a carton.

-HDPE-bottle

10, 14, 20, 28, 30, 50, 56, 60, 98, 100 film-coated tablets in blister; 100 and 250 film-coated tablets in HDPE-bottle intended for dose-dispensing and hospitals.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Sandoz Limited

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Marketing Authorisation Number(S)

PL 4416/0913

9. Date Of First Authorisation/Renewal Of The Authorisation

24^th March 2005

10. Date Of Revision Of The Text

November 2010

Chlorphenamine Elixir BP

1. Name Of The Medicinal Product

Chlorphenamine Elixir BP

Rhino-Syrup Allergy

Pollenase Allergy Syrup

Lloyds Pharmacy Allergy Relief Syrup

2. Qualitative And Quantitative Composition

Each 5ml contains Chlorphenamine Maleate BP 2.0mg

3. Pharmaceutical Form

Sugar free syrup in bottles of 150ml

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of symptoms caused by allergic conditions such as hayfever, allergic rhinitis, perennial rhinitis, vasomotor rhinitis, urticaria and skin rashes, angioneurotic oedema, drug and serum reactions, food allergy, insect bites etc, which are responsive to antihistamines.

4.2 Posology And Method Of Administration

Adults and children over 12 years:		2 spoonfuls (10ml) every 4-6 hours. Daily maximum should be 24mg i.e. 60ml.
Elderly:		As for adults. Elderly patients are more likely to experience confusional psychosis and other neurological anticholinergic side effects.
Children:	Up to1 year	Not Recommended
	1-2year	½ spoonful (2.5ml) twice a day
	2-5 years	½ spoonful (2.5ml) every 4 – 6 hours. Daily maximum should be 6mg i.e.15ml.
	6-12 years	1 spoonful (5ml) every 4 –6 hours. Daily maximum should be 12mg i.e. 30ml.

4.3 Contraindications

Chlorphenamine is contraindicated in patients who are hypersensitive to antihistamines or any other ingredients in the syrup.

Chlorphenamine is contraindicated in patients who have had treatment with Monoamine Oxidase Inhibitors (MAOI's) within the last 14 days as the anticholinergic properties of chlorphenamine are intensified by MAOI's.

4.4 Special Warnings And Precautions For Use

Chlorphenamine produces anticholinergic effects such as drowsiness, dizziness, blurred vision and psychomotor impairment. This may cause serious problems when the patient is driving or using machinery.

Due to the anticholinergic effect of the drug caution is advised in patients who have epilepsy, raised intra-ocular pressure including glaucoma, prostatic hypertrophy, severe hypertension or cardiovascular disease, bronchitis, bronchiectasis and asthma, hepatic disease and thyrotoxicosis. The neurological anticholinergic effects are more likely in the elderly and children.

The effects of alcohol are likely to be increased.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Alcoholic drinks and certain other central nervous system depressants such as anxiolytics or hypnotics can potentiate the sedative effects of chlorphenamine.

Phenytoin metabolism is inhibited by chlorphenamine and this can cause phenytoin toxicity.

The anticholinergic effects of chlorphenamine are intensified by the use of other anticholinergic drugs such as atropine, tricyclic antidepressants and MAOI's (see contraindications).

4.6 Pregnancy And Lactation

Safety in pregnancy has not been established. The use of chlorphenamine in pregnancy should be assessed and only used when the possible benefits outweigh the possible risks to the foetus. Effects on the neonate have been seen when chlorphenamine is used in the third trimester of pregnancy.

There may be some inhibition of lactation by chlorphenamine and some of the drug may be secreted into the breast milk. Therefore the risk to the mother and child should be assessed against the possible benefits of using chlorphenamine when breast feeding.

4.7 Effects On Ability To Drive And Use Machines

As with all antihistamines, dizziness and drowsiness may occur. Extreme caution should be advised when driving or operating machinery.

4.8 Undesirable Effects

Undesirable effects include sedation, which varies from slight drowsiness to deep sleep.

There have been occasional reports of the following: lassitude, inability to concentrate, blurred vision, hepatitis including jaundice, urinary retention, headaches, dry mouth, dizziness, palpitations, tachycardia, arrhythmias, hypotension, chest tightness, thickening of the bronchial secretions, haemolytic anaemia and other blood dyscrasias, tinnitus, depression, irritability, nightmares, twitching, muscular weakness and incoordination.

Gastrointestinal disturbances have been reported occasionally including, nausea, vomiting, diarrhoea, dyspepsia, abdominal pain and anorexia.

Allergic reactions have been observed and include exfoliative dermatitis, photosensitivity and urticaria.

Paradoxical excitation in children and confusional psychosis in the elderly can occur.

4.9 Overdose

The estimated lethal dose of Chlorphenamine Maleate is 25-50mg per kg bodyweight. Symptoms of overdose include sedation, paradoxical stimulation of the CNS, toxic psychosis, seizures, apnoea, convulsions, anticholinergic effects, dystonic reactions and cardiovascular collapse including arrhythmias.

Treatment should include gastric lavage for massive overdosage or induced emesis using syrup of Ipecacuanha. Following this activated charcoal and cathartics may be administered to minimise absorption.

Symptomatic and supportive measures should be given, with particular attention paid to the cardiac, respiratory, renal and hepatic functions and fluid and electrolyte balance. Hypotension and arrhythmias should be treated vigorously. If convulsions occur sedate with intramuscular paraldehyde, or i.v. diazepam or phenytoin Haemoperfusion may be used in severe cases.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Chlorphenamine is a potent H₁– blocking drug. It antagonises the pharmacological actions of histamine released by antigen-antibody reaction in allergic diseases, thus providing symptomatic relief.

Chlorphenamine alone is less effective when pollen counts are high, allergen exposure is prolonged and nasal congestion has become prominent.

5.2 Pharmacokinetic Properties

Chlorphenamine Elixir is an immediate release liquid containing the well established active ingredient Chlorphenamine Maleate.

Chlorphenamine maleate is absorbed relatively slowly from the gastrointestinal tract and peak plasma concentrations occur between 2.5 and 6 hours after oral administration. It is reported that only 25 to 50% of an oral dose is absorbed as it appears that chlorphenamine undergoes considerable first pass metabolism. Metabolites include desmethyl- and didesmethylchlorphenamine. Chlorphenamine distributes widely in the body and penetrates into the CNS. In the circulation, about 70% of chlorphenamine is bound to plasma proteins.

Excretion of unchanged drug and metabolites is mainly via the urine and is dependent on urinary pH and flow rate. The elimination half-life is widely variable and has been reported to range from 2 to 43 hours. However, the duration of action is only 4-6 hours which is shorter than might be predicted.

It is reported that in children, absorption is faster and more extensive, and there is a quicker clearance with a shorter half-life.

5.3 Preclinical Safety Data

None provided.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maltitol Solution USP

Citric Acid Monohydrate Ph. Eur

Sodium Citrate Ph. Eur

Sodium Benzoate Ph. Eur

Carmellose Sodium Ph. Eur

Strawberry Flavour C9987

Purified Water Ph. Eur

6.2 Incompatibilities

None Stated

6.3 Shelf Life

The shelf-life of this product is 36 months

6.4 Special Precautions For Storage

Store below 25°C. Protected from light

6.5 Nature And Contents Of Container

Amber glass or PET bottles with HDPE, EPE wadded, tamper evident child resistant closure.

6.6 Special Precautions For Disposal And Other Handling

None Stated

ADMINISTRATIVE DATA

7. Marketing Authorisation Holder

Sandoz Ltd

Woolmer Way

Bordon

Hampshire GU35 9QE

United Kingdom

8. Marketing Authorisation Number(S)

PL 4416/0368

9. Date Of First Authorisation/Renewal Of The Authorisation

7^th March 2000

10. Date Of Revision Of The Text

July 2004

Cetraben Emollient Cream

1. Name Of The Medicinal Product

Cetraben Emollient Cream

2. Qualitative And Quantitative Composition

White Soft Paraffin 13.2% w/w

Light Liquid Paraffin 10.5% w/w

For excipients see section 6.1.

3. Pharmaceutical Form

Cream.

A thick white cream with the characteristic odour of paraffin oil.

4. Clinical Particulars

4.1 Therapeutic Indications

Cetraben Emollient Cream is an emollient, moisturising and protective cream for the symptomatic relief of red, inflamed, damaged, dry or chapped skin, especially when associated with endogenous or exogenous eczema.

4.2 Posology And Method Of Administration

Cetraben Cream should be applied to the dry skin areas as often as required and rubbed in.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

None known.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

No special precautions are required.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

Very rarely, mild allergic skin reactions including rash and erythema have been observed, in which case use of the product should be discontinued.

4.9 Overdose

None reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: D02A X (Other Emollients and Protectives)

The ingredients of Cetraben Cream have an emollient, moisturising and protective properties.

5.2 Pharmacokinetic Properties

Cetraben cream acts only on the skin.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Emulsifying wax

Cetyl stearyl Alcohol

Glycerin

Butylparaben

Methylparaben

Ethylparaben

Propylparaben

Phenoxetol

Citric Acid

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Polypropylene jars with a pump dispenser of 1050g, 500g, 150g and 50g, polyethylene screw capped jars* or tubes of 125g, polyethylene tubes of 50g and polyethylene tubes of 20g.

* not currently marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Genus Pharmaceuticals

Park View House

65 London Road

Newbury

Berkshire

RG14 1JN

United Kingdom

8. Marketing Authorisation Number(S)

PL 06831/0259

9. Date Of First Authorisation/Renewal Of The Authorisation

21/09/2006

10. Date Of Revision Of The Text

7 July 2011

Cisplatin 50mg Freeze Dried Powder for Injection

1. Name Of The Medicinal Product

Cisplatin 50.

2. Qualitative And Quantitative Composition

Cisplatin 50.0mg.

3. Pharmaceutical Form

Yellowish-white, freeze-dried cake in vials containing 50 mg cisplatin.

4. Clinical Particulars

4.1 Therapeutic Indications

Cisplatin has antitumour activity either as a single agent or in combination chemotherapy particularly in the treatment of testicular and metastatic ovarian tumours, also cervical tumours, lung carcinoma and bladder cancer.

4.2 Posology And Method Of Administration

Route of administration: Intravenous infusion.

Cisplatin should be dissolved in water for injections such that the reconstituted solution contains 1 mg/ml of Cisplatin. This solution should then be diluted in 2 litres of 0.9% saline or a dextrose/saline solution (to which 37.5 g of mannitol may be added) and administration should be over a 6-8 hour period.

Adults and children

Single agent therapy:

The usual dose regimen given as a single agent is 50 - 120 mg/m² by infusion once every 3 - 4 weeks or 15 - 20 mg/m² by infusion daily for 5 consecutive days, every 3 - 4 weeks.

Combination chemotherapy:

Dosage may be adjusted if the drug is used in combination with other antitumour chemotherapy.

With multiple drug treatment schedules Cisplatin is usually given in doses 20 mg/m² upwards every 3 - 4 weeks.

Dosage should be reduced for patients with renal impairment or depressed bone marrow function.

Pre-treatment hydration with 1 - 2 litres of fluid infused for 8 - 12 hours prior to the Cisplatin will initiate diuresis. Adequate subsequent hydration should maintain diuresis during the 24 hours following administration.

Aluminium containing equipment should not be used for administration of Cisplatin as it may interact with metal aluminium to form a black precipitate of platinum.

4.3 Contraindications

Cisplatin is contra-indicated in patients who have previous allergic reactions to Cisplatin or other platinum compounds as anaphylactic-like reactions have been reported. Relative contra-indications are pre-existing renal impairment, hearing disorders and depressed bone marrow function which may increase toxicity.

4.4 Special Warnings And Precautions For Use

This agent should only be administered under the direction of physicians experienced in cancer chemotherapy.

Renal function: Cisplatin produces cumulative nephrotoxicity. Renal function and serum electrolyte (magnesium, sodium, potassium and calcium) should be evaluated prior to initiating cisplatin treatment and prior to each subsequent course of therapy.

To maintain urine output and reduce renal toxixity it is recommended that Cisplatin be administered as an intravenous infusion over 6-8 hours, as indicated in section 4.2 'Posology and method of administration'. Moreover, pre-treatment intravenous hydration with 1-2 litres of fluid over 8-12 hours followed by adequate hydration for the next 24 hours is recommended.

Repeat courses of Cisplatin should not be given unless levels of serum creatinine are below 1.5 mg/100 ml (100 mcmol/l) or blood urea below 55 mg/100 ml (9 mmol/l) and circulating blood elements are at an acceptable level.

Special care has to be taken when cisplatin-treated patients are given concomitant therapies with other potentially nephrotoxic drugs (See also section 4.5 'Interaction with other medicinal products and other forms of Interaction').

In addition, adequate post-treatment hydration and urinary output should be monitored. Concomitant use of nephrotoxic drugs may seriously impair kidney function.

Bone marrow function: Peripheral blood counts should be monitored frequently in patients receiving Cisplatin. Although the haematologic toxicity is usually moderate and reversible, severe thrombocytopenia and leucopenia may occur. In patients who develop thrombocytopenia special precautions are recommended: care in performing invasive procedures; search for signs of bleeding or bruising; test of urine, stools and emesis for occult blood, avoiding aspirin and other NSAIDs. Patients who develop leucopenia should be observed carefully for signs of infection and might require antibiotic support and blood product transfusions.

Hearing function: Cisplatin may produce cumulative ototoxicity, which is more likely to occur with high-dose regimens. Audiometry should be performed prior to initiating therapy, and repeated audiograms should be performed when auditory symptoms occur or clinical hearing changes become apparent. Clinically important deterioration of auditive function may require dosage modifications or discontinuation of therapy.

CNS functions: Cisplatin is known to induce neurotoxicity; therefore, neurologic examination is warranted in patients receiving a cisplatin-containing treatment. Since neurotoxicity may result in irreversible damage, it is recommended to discontinue therapy with Cisplatin when neurologic toxic signs or symptoms become apparent.

Anaphylactic-like reactions to Cisplatin have been observed. These reactions can be controlled by administration of antihistamines, adrenaline and/or glucocorticoids.

Neurotoxicity secondary to Cisplatin administration has been reported and therefore neurological examinations are recommended. Cisplatin has been shown to be mutagenic. It may also have an anti-fertility effect. Other anti-neoplastic substances have been shown to be carcinogenic and this possibility should be borne in mind in long term use of Cisplatin.

Liver function should also be monitored periodically.

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cisplatin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving cisplatin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Cisplatin is mostly used in combination with antineoplastic drugs having similar cytotoxic effects. In these circumstances additive toxicity is likely to occur.

Nephrotoxic drugs: Aminoglycoside antibiotics, when given concurrently or within 1-2 weeks after cisplatin administration, may potentiate its nephrotoxic effects. Concomitant use of other potentially nephrotoxic drugs (e.g. amphotericin B) is not recommended during Cisplatin therapy.

Ototoxic drugs: Concurrent and/or sequential administration of ototoxic drugs such as aminoglycoside antibiotics or loop diuretics may increase the potential of Cisplatin to cause ototoxicity, especially in the presence of renal impairment.

Renally excreted drugs: Literature data suggest that Cisplatin may alter the renal elimination of bleomycin and methotrexate (possibly as a result of cisplatin-induced nephrotoxicity) and enhance their toxicity.

Anticonvulsant agents: In patients receiving Cisplatin and phenytoin, serum concentrations of the latter may be decreased, possibly as a result of decreased absorption and/or increased metabolism. In these patients, serum levels of phenytoin should be monitored and dosage adjustments made as necessary.

Antigout agents: Cisplatin may raise the concentration of blood uric acid. Thus, in patients concurrently receiving antigout agents such as allopurinol, colchicine, probenecid or sulfinpyrazone, dosage adjustment of these drugs may be necessary to control hyperuricemia and gout.

4.6 Pregnancy And Lactation

Cisplatin has been shown to be teratogenic and embryotoxic in animals. The use of the drug should be avoided in pregnant of nursing women if possible.

4.7 Effects On Ability To Drive And Use Machines

There are no known effects of Cisplatin on the ability to drive or operate machinery. However, the profile of undesirable effects (central nervous system and special sense) may reduce the patient's driving skills and abilities to operate machinery.

4.8 Undesirable Effects

Nephrotoxicity: Acute renal toxicity, which was highly frequent in the past and represented the major dose-limiting toxicity of Cisplatin, has been greatly reduced by the use of 6 to 8-hour infusions as well as by concomitant intravenous hydration and forced diuresis. Cumulative toxicity, however, remains a problem and may be severe. Renal impairment, which is associated with tubular damage, may be first noted during the second week after a dose and is manifested by an increase in serum creatinine, blood urea nitrogen, serum uric acid and/or a decrease in creatinine clearance. Renal insufficiency is generally mild to moderate and reversible at the usual doses of the drug (recovery occurring as a rule within 2-4 weeks); however, high or repeated Cisplatin doses can increase the severity and duration of renal impairment and may produce irreversible renal insufficiency (sometimes fatal). Renal failure has been reported also following intraperitoneal instillation of the drug.

Cisplatin may also cause serious electrolyte disturbances, mainly represented by hypomagnesemia, hypocalcemia, and hypokalemia, and associated with renal tubular dysfunction. Hypomagnesemia and/or hypocalcemia may become symptomatic, with muscle irritability or cramps, clonus, tremor, carpopedal spasm, and/or tetany.

Gastrointestinal toxicity: Nausea and vomiting occur in the majority of Cisplatin-treated patients, usually starting within 1 hour of treatment and lasting up to 24 hours or longer. These side effects are only partially relieved by standard antiemetics. The severity of these systems may be reduced by dividing the total dose per cycle into smaller doses given once daily for five days.

Haematologic toxicity: Myelosuppression often occurs during Cisplatin therapy, but is mostly mild to moderate and reversible at the usual doses. Leucopenia is dose- related, possibly cumulative, and usually reversible. The onset of leucopenia occurs usually between days 6 and 26 and the time of recovery ranges from 21 to 45 days. Thrombocytopenia is also a dose-limiting effect of Cisplatin but is usually reversible. The onset of thrombocytopenia is usually from days 10 to 26 and the time of recovery ranges from about 28 to 45 days.

The incidence of Cisplatin-induced anaemia (haemoglobin drop of 2 g/100 ml) ranges from 9% to 40%, although this is a difficult toxic effect to assess because it may have a complex aetiology in cancer patients.

There have been rare reports of acute myelogenous leukemias and myelodysplastic syndromes arising in patients who have been treated with Cisplatin, mostly when given in combination with other potentially leukomogenic agents.

Ototoxicity: Unilateral or bilateral tinnitus, with or without hearing loss, occurs in about 10% of Cisplatin-treated patients and is usually reversible. The damage to the hearing system appears to be dose-related and cumulative, and it is reported more frequently in very young and very old patients.

The overall incidence of audiogram abnormalities is 24%, but large variations exist. These abnormalities usually appear within 4 days after drug administration and consist of at least a 15 decibel loss in pure tone threshold.The audiogram abnormalities are most common in the 4000-8000 Hz frequencies.

Neurotoxicity: Peripheral neuropathies occur infrequently with usual doses of the drug. These are generally sensory in nature (e.g. paresthesia of the upper and lower extremities) but can also include motor difficulties, reduced reflexes and leg weakness. Autonomic neuropathy, seizures, slurred speech, loss of taste and memory loss have also been reported. These neuropathies usually appear after prolonged therapy, but have also developed after a single drug dose. Peripheral neuropathy may be irreversible in some patients; however, it has been partially or completely reversible in others following discontinuance of Cisplatin therapy.

Hypersensitivity: Anaphylactic and anaphylactic-like reactions, such as flushing, facial oedema, wheezing, tachycardia and hypotension, have been occasionally reported. These reactions may occur within a few minutes after intravenous administration. Antihistamine, adrenaline and/or glucocorticoids control all these reactions. Rarely, urticarial or maculopapular skin rashes have also been observed.

Ocular toxicity: Optic neuritis, papilloedema, and cortical blindness have been reported rarely in patients receiving Cisplatin. These events are usually reversible after drug withdrawal.

Hepatotoxicity: Mild and transient elevations of serum AST and ALT levels may occur infrequently.

Other toxicities: Other reported toxicities are:

cardiovascular abnormalities (coronary artery disease, congestive heart failure, arrhythmias, postural hypotension, thrombotic microangiopathy, etc), hyponatremia / syndrome of inappropriate antidiuretic hormone (SIADH)), mild alopecia, myalgia, pyrexia and gingival platinum line. Pulmonary toxicity has been reported in patients treated with Cisplatin in combination with bleomycin or 5-fluorouracil.

Hyperuricaemia: Hyperuricaemia occurring with Cisplatin is more pronounced with doses greater than 50 mg/m². Allopurinol effectively reduces uric acid levels.

Hypomagnesemia: Asymptomatic hypomagnesemia has been documented in a certain number of patients treated with Cisplatin, symptomatic hypomagnesemia has been observed in a limited number of cases.

Convulsions: Seizures have also been reported with the use of this product.

Cardiotoxicity: Isolated cases of tachycardia and arrhythmia have been reported with Cisplatin chemotherapy.

Thromboembolism: Cancer patients are generally at an increased risk for thromboembolic events. Cerebrovascular accidents (e.g. haemorrhagic and ischaemic stroke, amaurosis fugax, sagittal sinus thrombosis) have been observed in patients receiving Cisplatin therapy.

Local effects such as phlebitis, cellulitis and skin necrosis (following extravasation of the drug) may also occur.

Cisplatin can affect male fertility. Impairment of spermatogenesis and azoospermia have been reported. Although the impairment of spermatogenesis can be reversible, males undergoing Cisplatin treatment should be warned about the possible adverse effects on male fertility.

4.9 Overdose

There are no special instructions.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: L01XA01

In vitro studies indicate that DNA is the principal target molecule of cis-platinum.

The basis for the selectivity of the cis-isomer may reside in its ability to react in a specifically defined configuration with DNA.

Modification of the DNA template results in the selective inhibition of DNA synthesis.

The drug is cell cycle non-specific.

5.2 Pharmacokinetic Properties

A biphasic plasma-decay pattern occurs in man after bolus administration. The initial plasma half-life in man is 25 - 49 minutes and the terminal half-life 3 - 4 days. In addition, a third excretory phase with a longer half-life may be postulated from the high plasma platinum concentration found after 21 days. During the terminal phase more than 90% of the drug is bound to plasma proteins.

The urinary elimination of the drug is incomplete: the 5-day recovery of platinum in the urine being only 27 to 45%.

Studies in man measuring free platinum species have shown a mean terminal half-life of 48 minutes after bolus injection, which probably corresponds to the initial half-life (25 - 49 minutes) seen when total platinum is monitored and reflects the distribution of the drug. Urinary excretion of filterable platinum was greater after 6 hours infusion (75%) than after a 15 minute injection (40%) of the same dose of cis-platinum.

Diuresis induced by high-volume hydration or mannitol infusion was associated with a reduction in the concentration of platinum excreted in the urine. The reduced concentration of platinum caused by the high urine volume may play a role in renal protection.

5.3 Preclinical Safety Data

No further preclinical safety data are available.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Mannitol

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

The unopened vials should be stored at room temperature, protected from light.

The reconstituted solution must not be cooled or refrigerated, as cooling may result in precipitation. It should be kept at room temperature and protected from light, also during intravenous infusion. Any unused solution should be discarded.

Keep out of the reach and sight of children.

6.5 Nature And Contents Of Container

Colourless glass vials (Type II) with bromobutyl rubber stoppers and aluminium snap-caps.

6.6 Special Precautions For Disposal And Other Handling

Cisplatin powder should be dissolved in sterile Water for Injections such that the reconstituted solution contains 1mg/ml of Cisplatin. The reconstituted solution should be diluted in 2 litres of 0.9% saline or a dextrose/saline solution (to which 37.5g of mannitol may be added).

Personnel should be trained in good technique for reconstitution and handling. Pregnant staff should be excluded from working with Cisplatin.

Care should be taken to prevent inhaling particles and exposing the skin to Cisplatin. Adequate protective clothing should be worn, such as PVC gloves, safety glasses, disposable gowns and masks.

In the event of contact with eyes, wash with water or saline. If the skin comes into contact with the drug wash thoroughly with water and in both cases seek medical advice. Seek immediate medical attention if the drug is ingested or inhaled.

All used materials, needles, syringes, vials and other items which have come into contact with cytotoxic drugs should be incinerated. Contaminated surfaces should be washed with copious amounts of water.

Administrative Data

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

CT13 9NJ

UK

8. Marketing Authorisation Number(S)

PL 0032/0334

9. Date Of First Authorisation/Renewal Of The Authorisation

25 March 2002 / 22 February 2006

10. Date Of Revision Of The Text

February 2010

Ref CS5_0

Chirocaine 0.625mg / ml or 1.25mg / ml solution for infusion

Chirocaine

0.625 mg/ml or 1.25 mg/ml solution for infusion

For Epidural use only

Levobupivacaine

Read all of this leaflet carefully before you start taking this medicine

• Keep this leaflet. You may need to read it again.


• If you have any further questions, please ask your doctor or nurse.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.

In this leaflet:

1. What Chirocaine is and what it is used for

2. Before you are given Chirocaine

3. How you will be given Chirocaine

4. Possible side effects

5. How to store Chirocaine

6. Further information

What Chirocaine Is And What It Is Used For

Chirocaine belongs to a group of medicines called local anaesthetics. This type of medicine is used to make an area of the body numb or free from pain.

Chirocaine Solution for Infusion is for adult use only.

Chirocaine is used for pain relief:

• after major surgery


• during childbirth.

Before You Are Given Chirocaine

Do not use Chirocaine:

• if you are allergic (hypersensitive) to levobupivacaine, to any similar local anaesthetics or to any of the other ingredients in Chirocaine (see Section 6)


• if you have very low blood pressure


• as a type of pain relief given by injection into the area around the neck of the womb (the cervix) during the early stage of labour (paracervical block)


• to numb an area by injecting Chirocaine into a vein.

Take special care with Chirocaine:

Tell your doctor before you are given Chirocaine if you have any of the diseases or conditions below. You may need to be checked more closely or given a smaller dose.

• if you suffer from diseases of the nervous system


• if you are weak or ill


• if you are elderly


• if you have liver disease.

Taking other medicines

Please, tell your doctor or nurse if you are taking or have recently taken any other medicines, including medicines you have obtained without a prescription. In particular, tell them if you are taking medicines for:

• irregular heart beats (such as mexiletine)


• fungal infections (such as ketoconazole) since this may affect how long Chirocaine stays in your body


• asthma (such as theophylline) since this may affect how long Chirocaine stays in your body.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, think you may be pregnant or are breast-feeding.

Chirocaine must not be a given for pain relief by injection into the area around the neck of the womb or cervix during childbirth (paracervical block).

The effect of Chirocaine on the child during the early stage of pregnancy is not known. Therefore, Chirocaine should not be used during the first three months of your pregnancy, unless your doctor thinks it is necessary.

It is not known if levobupivacaine passes into breast milk. However from the experience with a similar drug, only small amounts of levobupivacaine are expected to pass into breast milk. Breast-feeding is therefore possible after having a local anaesthesic.

Driving and using machines

The use of Chirocaine can have a considerable effect on the ability to drive or use machines. You must not drive or operate machinery until all the effects of Chirocaine and the immediate effects of surgery have worn off. Make sure you get advice about this matter from the doctor or nurse who is treating you, before leaving hospital.

Important information about some of the ingredients of Chirocaine

This medicinal product contains 3.6 mg/ml sodium in the bag or ampoule solution to be taken into consideration by patients on a controlled sodium diet.

How You Will Be Given Chirocaine

Your doctor will give you Chirocaine through a small tube in your back (epidural). Your doctor and nurse will watch you carefully while you are being given Chirocaine.

Dosage

Adults:

The amount of Chirocaine you will be given and how often it is given will depend on why it is being used and also on your health, age and weight. The smallest dose that can produce numbness in the required area will be used. The dose will be carefully worked out by your doctor.

When Chirocaine is used for pain relief during childbirth the dose used should be particularly carefully controlled.

Children:

Not recommended.

If you get more Chirocaine than you should

If you get more Chirocaine than you should, you may have numbness of the tongue, dizziness, blurred vision, muscle twitching, severe breathing difficulties (including stopping breathing) and even fits (convulsions). If you notice any of these symptoms, tell your doctor immediately. Sometimes too much Chirocaine may also cause low blood pressure, fast or slow heartbeats and changes in your heart rhythm. Your doctor may need to give you other medicines to help stop these symptoms.

Possible Side Effects

Like all medicines, Chirocaine can cause side effects, although not everybody gets them.

Tell your doctor or nurse immediately if you notice any of the following side effects. Some side effects with Chirocaine can be serious.

very common: affects more than 1 user in 10

common: affects 1 to 10 users in 100

uncommon: affects 1 to 10 users in 1,000

rare: affects 1 to 10 users in 10,000

very rare: affects less than 1 user in 10,000

not known: frequency cannot be estimated from the available data

Very common side effects are:

• feeling tired or weak, short of breath, looking pale (these are all signs of anaemia)


• low blood pressure


• nausea.

Common side effects are:

• dizziness


• headache


• vomiting


• problems (distress) for an unborn child


• back pain


• high body temperature (fever)


• pain after surgery.

Other side effects (frequency not known) are:

• serious allergic (hypersensitive) reactions which cause severe breathing difficulties, difficulty in swallowing, hives and very low blood pressure


• allergic (hypersensitive) reactions recognised by red itchy skin, sneezing, sweating a lot, rapid heartbeat, fainting or swelling of the face, lips, mouth, tongue or throat


• loss of consciousness


• drowsiness


• blurred vision


• breathing stopping


• localised tingling


• numbness of the tongue


• muscle weakness or twitching


• loss of bladder or bowel control


• paralysis


• fits (convulsions).

Fast, slow or irregular heartbeats, and heart rhythm changes that can be seen on an ECG, have also been reported as side effects.

Rarely, some side effects may be permanent.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse right away.

How To Store Chirocaine

• Keep out of the reach and sight of children.


• Do not use Chirocaine after the expiry date shown on the label. The expiry date refers to the last day of that month.


• Your doctor will store this medicine for you.


• The solution should be used immediately after opening.


• The solution should not be used if there are visible particles in it.

Medicines should not be disposed of through wastewater or household waste. These measures will help to protect the environment.

Further Information

What Chirocaine contains

The active ingredient is levobupivacaine (as hydrochloride).

Chirocaine 0.625  mg/ml solution for infusion: One ml contains 0.625  mg levobupivacaine (as the hydrochloride).

Chirocaine 1.25  mg/ml solution for infusion: One ml contains 1.25  mg levobupivacaine (as the hydrochloride).

The other ingredients are water for injections, sodium chloride, sodium hydroxide and a small quantity of hydrochloric acid.

What Chirocaine looks like and contents of the pack

Chirocaine is a clear, colourless solution, in a flexible polyester bag with an aluminium over pouch. Each bag contains 100 ml or 200 ml solution. It is supplied in packs of 5 bags of the 100 ml or 200 ml solution or 24 or 60 bags of the 100 ml solution and 12 or 32 bags of the 200  ml solution. (Not all pack sizes may be marketed.)

Marketing Authorisation Holder

In the UK:

Abbott Laboratories Ltd

Abbott House

Vanwall Business Park

Vanwall road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

Manufacturer

Baxter Healthcare S.A.

Moneen Road

Castlebar

Ireland

This medicinal product is authorised in the Member States of the EEA under the following names:

Chirocaine: Norway, Italy, Sweden, Portugal, Switzerland, Latvia, Netherlands, Poland, France, UK, Ireland, Finland, Greece, Slovenia, Austria, Belgium, Hungary, Bulgaria, Czech Republic, Luxembourg.

Chirocane: Spain

This leaflet was last approved in May 2010

CB-30-01-600

Celectol 200 Tablets

1. Name Of The Medicinal Product

Celectol 200 Tablets

2. Qualitative And Quantitative Composition

Celiprolol Hydrochloride 200mg.

For excipients, see section 6.1

3. Pharmaceutical Form

White film coated biconvex heart shaped tablets engraved with 200 and a breakline on one face and the Celectol logo on the other face.

4. Clinical Particulars

4.1 Therapeutic Indications

The management of mild to moderate hypertension.

4.2 Posology And Method Of Administration

Route of Administration: Oral

Adults:

The initial dose is 200mg orally taken once daily with a glass of water. Celectol should preferably be taken first thing in the morning, 30 minutes before food or 2 hours after a meal. If response is inadequate, the dose may be increased to 400 mg once daily according to the therapeutic response.

In hypertensive patients additional treatment with other anti-hypertensive agents is possible, in particular with diuretics. When a combination is initiated an increased monitoring the blood pressure is recommended.

Elderly patients:

Dosage as for adults.

However close monitoring of elderly patients should be exercised, as renal and hepatic functions may be decreased in this population.

Children:

Not recommended.

Patients with renal insufficiency.

Dosage may require adjustment. See section 4.4 (precautions).

4.3 Contraindications

As with other beta-adrenoceptor antagonists, celiprolol should not be used in cases of cardiogenic shock, uncontrolled heart failure, sick-sinus syndrome, (including sino-atrial block), second or third degree heart block, severe bradycardia (<45-50 beats per minute), severe renal impairment with creatinine clearance less than 15ml per minute, acute episodes of asthma, untreated phaeochromocytoma, metabolic acidosis, hypotension, hypersensitivity to the active substance or any of the excipients, or severe peripheral arterial circulatory disturbances.

Celectol tablets should not be prescribed for patients being treated with theophylline.

4.4 Special Warnings And Precautions For Use

Although cardio selective beta blockers may have less effect on lung function than non selective beta blockers, as with all beta blockers these should be avoided in patients with chronic obstructive airways disease, and in patients with a history of bronchospasm or bronchial asthma, unless there are compelling clinical reasons for their use. Where such reasons exist, celiprolol may be used but with the utmost caution under specialist supervision. The label will carry the following warning: If you have a history of asthma or wheezing, please ask your doctor before taking this medicine.

Celectol may be used in patients with mild to moderate degrees of reduced renal function as celiprolol is cleared by both renal and non-renal excretory pathways. A reduction in dosage by half may be appropriate in patients with creatinine clearances in the range of 15 to 40ml per minute. However, careful surveillance of such patients is recommended until steady state blood levels are achieved which typically would be within one week. Celectol is not recommended for patients with creatinine clearance less than 15ml per minute. Patients with hepatic impairment should also be carefully monitored after commencing therapy and a reduced dosage should be considered.

In patients with coronary insufficiency, treatment should not be discontinued abruptly.

Sudden withdrawal of beta-adrenoceptor blocking agents in patients with ischaemic heart disease may result in the appearance of anginal attacks of increased frequency or severity or deterioration in cardiac state. Although no adverse effects due to abrupt cessation of Celectol have been seen in clinical trials, therapy should be gradually reduced over 1-2 weeks, at the same time, if necessary, initiating replacement therapy to prevent exacerbation of angina pectoris.

Celectol therapy must be reported to the anaesthetist prior to general anaesthesia. If it is decided to withdraw the drug before surgery, 48 hours should be allowed to elapse between the last dose and anaesthesia. Continuation of beta blockade reduces the risk of arrhythmias during induction and intubation, although reflex tachycardia may be attenuated and the risk of hypotension may be increased (see “Interactions”). In the event of continuation of Celectol treatment special care should be exercised when using anaesthetic agents such as ether, cyclopropane or trichloroethylene. The patient may be protected against vagal reactions by the intravenous administration of atropine.

Celectol should only be used with caution in patients with well-controlled congestive cardiac failure under strict medical surveillance. Evidence of decompensation should be regarded as a signal to discontinue therapy.

In patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), beta blockers should be used with great caution as aggravation of these disorders may occur. Close monitoring is advisable.

Celiprolol may induce bradycardia. If the pulse rate decreases to less than 50-55 beats per minute at rest and the patient experiences symptoms related to the bradycardia, the dosage should be reduced.

Due to its negative effect on conduction time, celiprolol should only be given with caution to patients with first degree heart block.

Beta blockers may increase the number and the duration of anginal attacks in patients with Prinzmetal's angina, due to unopposed alpha-receptor mediated coronary artery vasoconstriction. The use of beta-1 selective adrenoceptor blocking drugs such as celiprolol may be considered in these patients, but the utmost care should be exercised.

Beta blockers have been reported to exacerbate psoriasis, and patients with a history of psoriasis should take celiprolol only after careful consideration.

Celiprolol should be used with caution in patients with treated phaeochromocytoma and must not be adminstered until after alpha-blockade has been established. Close monitoring is advisable.

In patients with a history of anaphylactic reactions, beta blockers may increase the sensitivity to allergens and the seriousness of the reactions.

aution should be observed in patients with Diabetes Mellitus as beta blockers may mask the symptoms of hypoglycaemia (in particular, tachycardia).

Beta blockers may mask the symptoms of thyrotoxicosis.

Celiprolol may give a positive reaction when drug-screening tests are conducted in competitive sport since beta-blockers may be restricted in certain sports. Competitors should check with the appropriate sports authorities.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Associations not recommended:

It has been shown that the bioavailability of celiprolol is impaired when it is given with food. Co-administration of chlorthalidone and hydrochlorothiazide also reduces the bioavailability of celiprolol.

Calcium channel antagonists such as verapamil (and to a lesser extent diltiazem) and beta blockers both slow A-V conduction and depress myocardial contractility through different mechanisms. When changing from verapamil to celiprolol and vice versa, a period between stopping one and starting the other is recommended. Concomitant administration of both drugs is not recommended and should only be initiated with both clinical signs and ECG monitored carefully. Patients with pre existing conduction abnormalities should not be given the two drugs together.

In case of shock or hypotension due to floctafenine, beta-blockers may reduce the effectiveness of drugs used to compensate these symptoms.

Digitalis glycosides, in association with beta-adrenoceptor blocking drugs, may increase A-V conduction time.

Beta blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-adrenoceptor blocking drug should be withdrawn several days before discontinuing clonidine. There is a theoretical risk that concurrent administration of monoamine oxidase inhibitors and high doses of beta-adrenoceptor blockers, even if they are cardio selective, can producehypotension and is therefore not recommended.

Precautions for use

Care should be taken in prescribing beta-adrenoceptor blockers with Class I antiarrhythmic agents (e.g. disopyramide, quinidine) and amiodarone, since these agents may potentiate the negative effects on A-V conduction and myocardial contractility. Clinical and ECG monitoring must be performed.

Beta blockers may intensify the blood sugar lowering effects of insulin and oral antidiabetic drugs, and the dosage of antidiabetics may therefore require adjustment. In addition, beta-adrenoceptor blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia (in particular, tachycardia).

Therapy with beta-adrenoceptor blockers must be reported to the anaesthetist prior to general anaesthesia as they may attenuate the reflex tachycardia and increase the risk of hypotension (see section 4.4 “Special warnings and special precautions for use”).

Take into account

Concomitant therapy with dihydropyridine calcium channel antagonists, such as nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent or uncontrolled cardiac insufficiency. Blood pressure should be closely monitored in case of co-administration of celiprolol and dihydropyridine derivatives especially when therapy is initiated.

Drugs inhibiting prostaglandin synthetase, such as ibuprofen or indomethacin, may decrease the hypotensive effects of beta-adrenoceptor blocking drugs.

Sympathomimetic agents, such as adrenaline, may counteract the effects of beta blockers.

Concomitant use of other antihypertensive agents, or of tricyclic antidepressants, barbiturates or phenothiazines, may potentiate the orthostatic hypotensive effects of beta blockers.

Concomitant therapy with mefloquine may cause bradycardia.

4.6 Pregnancy And Lactation

The safety of this medicinal product for use in human pregnancy has not been established. An evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to reproduction, development of the embryo or foetus, the course of gestation and peri- and post-natal development.

However, beta-adrenoceptor blocking drugs in general have been associated with reduced placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. Celiprolol should therefore not be used during pregnancy unless there is no safer alternative.

In the newborn of treated mothers, beta-blocking activity persists for several days after birth and this may result in an increased risk of cardiac and pulmonary complications in the neonate in the post natal period. In addition, adverse effects (especially hypoglycaemia, bradycardia and respiratory distress) may occur in foetus and neonate.. Therefore close monitoring of the neonate is recommended for the first 3 to 5 days of life.

Most beta blockers will pass into breast milk, although to variable extents. The use of Celectol is therefore not recommended in breast-feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

It has been shown that driving ability is unlikely to be impaired in patients taking Celectol. However, it should be taken into account that occasional dizziness or fatigue may occur as well as the potential for tremor, headaches or impaired vision. If affected, patients should be advised not to drive or operate machines.

4.8 Undesirable Effects

Beta-adrenoceptor blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia (in particular, tachycardia).

Occasional side effects, which are usually mild and transient have occurred. These include headache, hot flushes, asthenia, dizziness, fatigue, somnolence and insomnia (sleep disturbances). Additional side effects associated with beta-2 agonist activity, tremor and palpitations, have been reported. These effects usually do not require withdrawal of therapy. Depression and hypersensitivity pneumonitis have been reported rarely.

Bronchospasm, skin rashes and/or visual disturbances have been reported in association with the use of beta blockers. Celectol should be discontinued if these effects occur.

In addition, the following undesirable effects, listed by body system, are generally attributable to the pharmacological activity of beta-adrenergic blockers:

Cardiovascular: bradycardia, slowed A-V conduction, hypotension, heart failure, cold and cyanotic extremities. In susceptible patients: precipitation of existing A-V block, exacerbation of intermittent claudication, Raynaud's disease or syndrome.

CNS: confusion, hallucinations, psychoses, nightmares.

Neurological: paraesthesia.

Respiratory: bronchospasm may occur in patients with bronchial asthma or with a history of bronchial complaints. Dyspnoea and interstitial pneumonitis have also been rarely reported.

Gastro-intestinal: vomiting, diarrhoea, nausea and gastralgia.

Integumentary: skin disorders (cutaneous effects including psoriasiform rash), dry eyes.

Reproductive system: Libido decrease, male impotency.

Eye: Visual disturbances have been reported including xerophthalamias.

Hepatobiliary: Increase in transaminases.

Metabolism and Nutritional: Hypoglycaemia, hyperglycemia.

Collagen disorders: Antinuclear antibodies have been observed, exceptional and reversible lupus syndrome.

Others: An increase in ANA (antinuclear antibodies) has been reported, although its clinical relevance is not clear.

4.9 Overdose

No data are available regarding celiprolol overdose in humans.

The most common symptoms to be expected following overdosage with a beta-adrenoceptor blocking drug are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.

General treatment should be symptomatic and supportive and be conducted under close supervision, with the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastro-intestinal tract. Haemodialysis or haemoperfusion may be considered.

Bradycardia or extensive vagal reactions should be treated with intravenous atropine, 1-2mg. Cardiac pacing should be considered in refractory bradycardia and heart block. Hypotension should be treated with plasma or plasma substitutes and, if necessary, intravenous catecholamines including dopamine and dobutamine.

Glucagon is the treatment of choice for severe hypotension, heart failure or cardiogenic shock. A bolus of 2-10mg IV in adults (50-150 micrograms/kg in a child) should be followed by an infusion of 1-5mg/hour (50 micrograms/kg/hour), titrated to clinical response. Note vials normally contain 1mg = 1 unit and other treatments may be more convenient to use. Some patients do not respond to glucagon and if vomiting occurs without any improvement in blood pressure, further glucagon is unlikely to be of benefit. Adverse effects of glucagon administration include vomiting, hyperglycaemia, hypokalaemia and hypocalcaemia.

If glucagon is not available or if there is severe bradycardia and hypotension, which is not improved by glucagon, use isoprenaline starting at an infusion rate of 5-10 micrograms/minute (0.02 micrograms/kg/min in children increasing to a maximum of 0.5 micrograms/kg/min) and increased as necessary depending on clinical response. Large doses (up to 800 micrograms/min) have been reported to be necessary on some occassions. Isoprenaline may be ineffective at improving blood pressure despite increasing heart rate.

In severe hypotension additional inotropic support may be necessary with a beta agonist such as dobutamine 2.5-40 micrograms/kg/min (adults and children). Other inotropes such as dopamine, adrenaline (epinephrine) or noradrenaline (norepinephrine) may occassionally be of benefit or consider the use of an intra-aortic balloon pump to sustain an adequate cardiac output. Management of cases of severe hypotension and cardiogenic shock should be discussed with your local poisons service in the UK NPIS 0844 892 0111.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Celiprolol is a vasoactive beta-l selective adrenoceptor antagonist with partial beta-2 agonist activity indicated in mild to moderate hypertension. The beta-2 agonist activity is thought to account for its mild vasodilating properties. It lowers blood pressure in hypertensive patients at rest and on exercise. The effects on heart rate and cardiac output are dependant on the pre-existing background level of sympathetic tone.

Under conditions of stress such as exercise celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. However, at rest minimal impairment of cardiac function is seen.

Celectol therapy has not been shown to adversely effect plasma lipid profiles.

5.2 Pharmacokinetic Properties

Celiprolol is a hydrophilic compound that is incompletely absorbed from the gastrointestinal tract. Plasma half-life is approximately 5-6 hours and pharmacodynamic effects are present for at least 24 hours. After once daily administration celiprolol is only slightly metabolised before excretion in the bile and urine in almost equal quantities.

It has been shown that the bioavailability of celiprolol is impaired when it is given with food. Co-administration of chlorthalidone, hydrochlorothiazide and theophylline also reduces the bioavailability of celiprolol.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol BP

Microcrystalline Cellulose BP

Croscarmellose Sodium NF

Magnesium Stearate BP

Film coating:

Opadry YS-l-7006 (clear) contains E464 and polyethylene glycol.

Opadry Y-1-7000 (white) contains E171, E464 and polyethylene glycol.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Container	Pack size
1. Securitainers.	100
2. HDPE (High Density Polyethylene Bottles).	100
3. Blister packs 250μ clear opaque rigid UPVC with 20μ hard temper aluminium foil	56, 28, 10, 7, 5, 4 or 3
4. Blister packs 250μ opaque rigid UPVC with 20μ hard temper aluminium foil.	56, 28, 10, 7, 5, 4 or 3

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

8. Marketing Authorisation Number(S)

PL 17780/0429

9. Date Of First Authorisation/Renewal Of The Authorisation

28/01/2009

10. Date Of Revision Of The Text

19/01/2010

LEGAL CATEGORY

POM