SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Haloperidol Tablets 20 mg.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20 mg of Haloperidol.

3. PHARMACEUTICAL FORM

Tablets.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Haloperidol is a neuroleptic butyrophenone drug indicated for the following conditions:

Adults

1.    Schizophrenia; treatment of symptoms and prevention of relapse.

2.    Other psychoses, especially    paranoia.

3.    Mania and hypomania.

4.    Mental or behavioural problems such as aggression, hyperactivity and self-mutilation in the mentally retarded and in patients with organic brain damage.

5.    As an adjunct to short term management of moderate to severe psychomotor agitation, excitement, violent or dangerously impulsive behaviour.

6.    Intractable hiccup.

7.    Restlessness and agitation    in the elderly.

8.    Gilles De La Tourette syndrome and severe tics.

Children

1.    Childhood behavioural disorders especially when associated with hyperactivity and aggression.

2.    Gilles De La Tourette syndrome.

3.    Childhood schizophrenia.

4.2 Posology and method of administration

For oral administration.

Dosage for all indications should be determined individually and is best initiated and titrated under close clinical supervision. To determine the initial dosage, consideration should be given to the patients age, severity of symptoms and previous response to other neuroleptics.

Patients who are elderly or debilitated or those with previously reported adverse reactions to neuroleptic drugs may require less haloperidol. Half the recommended adult starting dose should be sufficient. The optimal response in such patients is achieved with gradual titration.

Haloperidol should be used at the minimum dose that is clinically effective.

Adults: Schizophrenia, psychoses, mania and hypomania, mental or behavioural problems, psychomotor agitation, excitement, violent or dangerously impulsive behaviour, organic brain damage:

Initial dosage:

Moderate symptomatology: 1.5 - 3.0 mg two to three times daily.

Severe symptomatology/Resistant patients: 3.0 - 5.0 mg two to three times daily.

In resistant schizophrenics, a maximum daily dosage of up to 30 mg may be necessary to achieve an optimal response.

The same starting doses may be employed in adolescents, who may, in certain cases require up to 30 mg/day.

Maintenance dosage: Once satisfactory control of symptoms has been achieved, dosage should be gradually reduced to the lowest effective maintenance dose, often as low as 5 mg or 10 mg per day.

Too rapid a dosage reduction should be avoided.

Restlessness or agitation in the elderly: Initial dose 1.5 - 3.0 mg, two to three times daily, titrated as required to attain an effective maintenance dose (1.5 -30 mg daily).

Gilles De La Tourette Syndrome, severe tics, intractable hiccup:

Starting dose: 1.5 mg three times daily adjusted according to response.

A daily maintenance dose of 10 mg may be required for Gilles De La Tourette syndrome.

Children:

Childhood behavioural disorders/schizophrenia:

The total maintenance dose: 0.025 - 0.05 mg per kg per day. Half the total dose should be given in the morning and the other half in the evening, up to a maximum of 10 mg daily.

Gilles De La Tourette Syndrome: oral maintenance doses up to 10 mg per day in most patients.

4.3    Contraindications

Comatose states, CNS depression, patients with parkinson’s disease, sensitivity to haloperidol or any of the other ingredients, lesions of basal ganglia. Use during breast feeding.

In common with other neuroleptics, haloperidol has the potential to cause rare prolongation of the QT interval. Use of haloperidol is therefore contraindicated in patients with clinically significant cardiac disorders e.g. recent acute myocardial infarction, uncompensated heart failure, arrhythmias treated with class IA and III anti-arrhythmic medicinal products, QTc interval prolongation, history of ventricular arrhythmia or torsades de pointes, clinically significant bradycardia, second or third degree heart block and uncorrected hypokalaemia.

Haloperidol should not be used concomitantly with other QT prolonging drugs (see section 4.5, Interaction with other medicinal products and other forms of interaction).

4.4    Special warnings and precautions for use

Cases of sudden and unexplained death have been reported in psychiatric patients receiving antipsychotic drugs including haloperidol. The nature of the evidence makes it impossible to determine the contributory role, if any, of the drug.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Haloperidol is not licensed for the treatment of dementia-related behavioural disturbances.

Cardiovascular effects

Very rare reports of QT prolongation and/or ventricular arrhythmias, in addition to rare reports of sudden death, have been reported with haloperidol. They may occur more frequently with high doses and in predisposed patients.

The risk-benefit of haloperidol treatment should be fully assessed before treatment is commenced and patients with risk factors for ventricular arrhythmias such as cardiac disease, family history of sudden death and/or QT prolongation; uncorrected electrolyte disturbances, subarachnoid haemorrhage, starvation or alcohol abuse should be monitored carefully (ECGs and potassium levels), particularly during the initial phase of treatment, to obtain steady plasma levels. The risk of QT prolongation and/or ventricular arrhythmias may be increased with higher doses (see Sections 4.8 and 4.9) or with parenteral use, particularly intravenous administration. ECG monitoring should be performed for QT interval prolongation and for serious cardiac dysrhythmias if haloperidol is administered intravenously.

Haloperidol should be used with caution in patients known to be slow metabolisers of CYP2D6, and during use of cytochrome P450 inhibitors. Concomitant use of antipsychotics should be avoided. (See Section 4.5).

Baseline ECG is recommended prior to treatment in all patients, especially in the elderly and patients with a positive personal or family history of cardiac disease or abnormal findings on cardiac clinical examination. During therapy, the need for ECG monitoring (e.g. at dose escalation) should be assessed on an individual basis. Whilst on therapy, the dose should be reduced if QT is prolonged, and haloperidol should be discontinued if the QTc exceeds 500 ms.

Periodic electrolyte monitoring is recommended, especially for patients taking diuretics, or during intercurrent illness.

An approximately 3-fold increase risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Haloperidol should be used with caution in patients with risk factors for stroke.

Neuroleptic malignant syndrome

In common with other antipsychotic drugs, haloperidol has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterised by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

Tardive dyskinesia

As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or after drug discontinuation. The syndrome is mainly characterised by rhythmic involuntary movements of the tongue, face, mouth or jaw.

The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dosage is increased or when a switch is made to a different antipsychotic drug. Treatment should be discontinued as soon as possible.

Extrapyramidal symptoms

In common with all neuroleptics, extrapyramidal symptoms may occur, e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia.

Antiparkinson drugs of the anticholinergic type may be prescribed as required, but should not be prescribed routinely as a preventive measure.

If concomitant anti-parkinson medication is required, it may have to be continued after stopping haloperidol if its excretion is faster than that of haloperidol in order to avoid the development or aggravation of extrapyramidal symptoms. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including anti-parkinson agents, are administered concomitantly with haloperidol.

Seizures/Convulsions

It has been reported that seizures can be triggered by haloperidol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to convulsions (e.g. alcohol withdrawal and brain damage).

Hepato-biliary concerns

As haloperidol is metabolised by the liver, caution is advised in patients with liver disease. Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported.

Endocrine system concerns

Thyroxin may facilitate haloperidol toxicity. Antipsychotic therapy in patients with hyperthyroidism should be used only with great caution and must always be accompanied by therapy to achieve a euthyroid state.

Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligo- or amenorrhoea. Very rare cases of hypoglycaemia and of Syndrome of Inappropriate ADH Secretion have been reported.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Haloperidol and preventive measures undertaken.

Additional considerations

In schizophrenia, the response to antipsychotic drug treatment may be delayed. Also, if drugs are withdrawn, recurrence of symptoms may not become apparent for several weeks or months. Acute withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Relapse may also occur and gradual withdrawal is advisable.

As with all antipsychotic agents, haloperidol should not be used alone where depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis co-exist.

Caution is advised in the use of this drug in patients with renal failure, phaeochromocytoma, depressive illness, severe cardiovascular disease.

Paediatric population

Available safety data in the paediatric population indicate a risk of extrapyramidal symptoms, including tardive dyskinesia, and sedation. No long-term safety data are available.

4.5 Interaction with other medicinal products and other forms of interactions

Concomitant use of haloperidol with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Therefore concomitant use of these products is not recommended (see section 4.3-Contraindications).

Examples include certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and class III (such as amiodarone, sotalol and dofetilide), certain antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), other neuroleptics (e.g. phenothiazines, pimozide and sertindole), certain antihistamines (such as terfenadine), cisapride, bretylium and certain anti-malarials such as quinine and mefloquine. This list is not comprehensive.

Concurrent use of drugs causing electrolyte imbalance may increase the risk of ventricular arrhythmias and is not recommended (see section 4.4-Special Warnings and Precautions for Use). Diuretics, in particular those causing hypokalaemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.

Haloperidol is metabolised by several routes, including glucuronidation and the cytochrome P450 enzyme system (particularly CYP 3A4 or CYP 2D6). Inhibition of these routes of metabolism by another drug or a decrease in CYP 2D6 enzyme activity may result in increased haloperidol concentrations and an increased risk of adverse events, including QT-prolongation. In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterised as substrates or inhibitors of CYP 3A4 or CYP 2D6 isozymes, such as, itraconazole, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine. A decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations. Increases in QTc and extrapyramidal symptoms have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day).

It may be necessary to reduce the haloperidol dosage.

Effect of Other Drugs on Haloperidol

When prolonged treatment with enzyme-inducing drugs such as carbamazepine, phenobarbital, rifampicin is added to haloperidol therapy, this results in a significant reduction of haloperidol plasma levels. Therefore, during combination treatment, the haloperidol dose should be adjusted, when necessary. After stopping such drugs, it may be necessary to reduce the dosage of haloperidol.

Sodium valproate, a drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.

Effect of haloperidol on other drugs

In common with all neuroleptics, haloperidol can increase the central nervous system depression produced by other CNS depressant drugs including alcohol, hypnotics, sedatives or strong analgesics. An enhanced CNS effect has been reported with the combined use of methyldopa and haloperidol.

Haloperidol may antagonise the action of adrenaline and other sympathomimetic agents and reverse the blood pressure lowering effects of adrenergic-blocking agents such as guanethidine.

The antiparkinson effects of levodopa may be impaired by haloperidol. The dosage of anticonvulsants may need to be increased to take account of the lowered seizure threshold.

Haloperidol is an inhibitor of CYP 2D6. Haloperidol inhibits the metabolism of tricyclic antidepressants, thereby increasing plasma levels of these drugs.

Other Forms of Interaction

The combined use of lithium and haloperidol has been reported to cause neurotoxic reactions, although there is no known mechanism for this effect. In rare cases, an encephalopathy-like syndrome has been reported in combination with lithium and haloperidol. It remains controversial whether these cases represent a distinct clinical entity or whether they are in fact cases of NMS and/or lithium toxicity. Signs of encephalopathy-like syndrome include confusion, disorientation, headache, disturbances of balance and drowsiness.

A One report showing symptomless EEG (Electro-Encephalogram) abnormalities on such combined therapy has suggested that EEG monitoring might be advisable. It is recommended that lithium levels should always be maintained below 1 mmol/l when combined with haloperidol and haloperidol should be given in the lowest effective dose. If symptoms of encephalopathylike syndrome or if unexplained pyrexia occurs in the presence of extrapyramidal side effects, treatment with both lithium and haloperidol should be stopped immediately.

Antagonism of the effect of the anticoagulant phenindione has been reported.

4.6 Fertility, pregnancy and lactation

The safety of haloperidol in pregnancy has not been established. There is some evidence of harmful effects in some but not all animal studies. There have been a number of reports of birth defects following foetal exposure to haloperidol for which a causal role for haloperidol cannot be excluded. Neonates exposed to antipsychotics (including haloperidol) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. It should be used in pregnancy or in women likely to become pregnant only if the benefit clearly justifies the possible hazards to the mother and foetus and the administered dose and duration of treatment should be as low and as short as possible.

Haloperidol is excreted in breast milk. There have been isolated cases of extrapyramidal symptoms in breast-fed children. If the use of haloperidol is considered essential, the benefits of breast feeding should be balanced against its potential risks.

4.7 Effects on ability to drive and use machines

Haloperidol may cause some degree of sedation or impair alertness particularly with higher doses and at the start of treatment and may be potentiated by alcohol or other CNS depressants. Patients should be advised not to drive or operate machinery during treatment until their individual susceptibility is known.

4.8 Undesirable effects

The following ADRs have been observed from clinical trials and postmarketing experiences reported with the use of haloperidol and haloperidol decanoate. Frequencies displayed use the following convention:

Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated form the available data).

Blood and lymphatic system disorders:

Uncommon: Leucopenia.

Not known: Agranulocytosis, neutropenia, pancytopenia, thrombocytopenia.

Immune system disorders:

Uncommon: Hypersensitivity.

Not known: Anaphylactic reaction.

Endocrine disorders:

Rare: Hyperprolactinaemia.

Not known: Inappropriate antidiuretic hormone secretion.

Metabolic and nutritional disorders:

Not known: Hypoglycaemia.

Psychiatric disorders:

Very common: Agitation, insomnia.

Common: Depression, psychotic disorder.

Uncommon: Confusional state, libido decreased, loss of libido, restlessness. Not known: Feelings of being mentally dulled or slowed down, excitement.

Nervous system disorders:

Very common: Extrapyramidal disorder, hyperkinesias, headache.

Common: Tardive dyskinesia, oculogyric crisis, dystonia, dyskinesia, akathisia, bradykinesia, hypokinesia, hypertonia, somnolence, masked facies, tremor, dizziness.

Uncommon: Convulsions, Parkinsonism, akinesia, Cogwheel rigidity, sedation, muscle contractions involuntary.

Rare: Motor dysfunction, neuroleptic malignant syndrome, nystagmus.

Not known: Laryngeal dystonia, autonomic instability, epileptic fits.

Eye disorders:

Common: Visual disturbance.

Uncommon: Vision blurred.

Cardiac disorders:

Uncommon: Tachycardia.

Not known: Ventricular fibrillation, Torsade de pointes, ventricular tachycardia, extrasystoles, labile arterial pressure, ventricular arrhythmias.

Vascular disorders:

Common: Orthostatic hypotension, hypotension.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Dyspnoea.

Rare: Bronchospasm.

Not known: Laryngeal oedema, laryngospasm.

Gastrointestinal disorders:

Common: Constipation, dry mouth, salivary hypersecretion, nausea, vomiting. Not known: Loss of appetite, dyspepsia.

Hepatobiliary disorders:

Common: Liver function test abnormal

Uncommon: Hepatitis, jaundice.

Not known: Acute hepatic failure, cholestasis.

Skin and subcutaneous tissue disorders:

Common: Rash.

Uncommon: Photosensitivity reaction, urticaria, pruritis, hyperhydrosis.

Not known: Leukocytoclastic vasculitis, dermatitis exfoliative, erythema multiforme.

Musculoskeletal and connective tissue disorders:

Uncommon: Torticollis, muscle rigidity, muscle spasms, musculoskeletal stiffness.

Rare: Trismus, muscle twitching.

Renal and urinary disorders:

Common: Urinary retention.

Pregnancy, puerperium and perinatal conditions:

Not known: Drug withdrawal syndrome neonatal (see 4.6)

Reproductive system and breast disorders:

Common: Erectile dysfunction.

Uncommon: Amenorrhoea, dysmenorrhoea, galactorrhoea, breast discomfort, breast pain.

Rare: Menorrhagia, menstrual disorder, sexual dysfunction.

Not known: Gynaecomastia, priapism.

General disorders and administration site conditions:

Uncommon: Gait disturbance, hyperthermia, oedema.

Not known: Sudden death, face oedema, hypothermia.

Investigations:

Common: Weight increased, weight decreased.

Rare: Electrocardiogram QT prolonged.

Not known: Elevated creatine phosphokinase.

Additional Information

Cardiac effects such as QT-interval prolongation, torsade de pointes, ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia), and cardiac arrest have been reported. These effects may occur more frequently with high doses, and in predisposed patients.

Toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported in patients taking haloperidol. The true incidence of these reports is not known.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs - Frequency unknown.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

In general, the signs and symptoms of overdose may be an exaggeration of Down pharmacological effects, the most prominent of which would be severe extrapyrimidal symptoms, hypotension and psychic indifference with a transition to sleep. The risk of ventricular arrhythmias possibly associated with QT prolongation should be considered. The patient may appear comatose with respiratory depression and hypotension severe enough to produce a shock-like state. Paradoxically hypertension rather than hypotension may occur. Convulsions may also occur.

Treatment

There is no specific antidote to haloperidol. Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration are advised. In view of isolated reports of arrhythmia, electrocardiographic monitoring should be immediately commenced and continued for as long as clinically indicated.

Hypotension and circulatory collapse should be treated by plasma volume expansion and other appropriate measures. Adrenaline should not be used. The patient should be monitored carefully for 24 hours or longer, body temperature and adequate fluid intake should be maintained.

In cases of severe extrapyrimidal symptoms, appropriate anti-Parkinson medication should be administered.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

The mechanism of therapeutic effect of haloperidol is complex and is not clearly established. Haloperidol produces a selective effect on the CNS by competitive blockade of post synaptic dopamine receptors in the mesolimbic dopaminergic system and increased turn over of brain dopamine to produce the antipsychotic action.

Blockade of dopamine receptors also take place in the nigrostriatal dopamine pathway producing the extrapyramidal motor reactions. Blockade of the dopamine receptors in the tuberoinfundibular system decreases growth hormone release and increases prolactin release by the pituitary. There is also some blockade of alpha-adrenergic receptors of the autonomic system.

5.2. Pharmacokinetic Properties

Haloperidol is readily absorbed from the gastrointestinal tract. Approximately 70 % of the oral dose is absorbed. Haloperidol is extensively bound to protein and metabolised in the liver via oxidative N-dealkylation.. Due to the first pass effect of metabolism in the liver, plasma concentration following oral administration are lower than those following oral administration are lower than those following intramuscular administration.

There is also a wide interindividual variation in plasma concentration of haloperidol but in practice there is no simple correlation between the plasma concentration and the therapeutic effect.

The reported plasma half-life of haloperidol ranges from 13 to almost 40 hours. It is widely distributed in the body and crosses the blood brain barrier.

Approximately 40% of the single oral dose is excreted in the urine within 5 days, 1% of which is the unchanged drug. About 15 % is excreted via the bile in faeces. There is evidence of enterohepatic recycling of the drug.

5.3 Preclinical safety data

Only limited data are available, however these show no specific hazards apart from decreased fertility, limited teratogenicity as well as embryo-toxic effects in rodents.

Haloperidol has been shown to block the cardiac hERG channel in several published studies in vitro. In a number of in vivo studies intravenous administration of haloperidol in some animal models has caused significant QTc prolongation, at doses around 0.3 mg/kg i.v., giving C_max plasma levels 3 to 7 times higher than the effective human plasma concentrations of 4 to 20 ng/ml. These intravenous doses which prolonged QTc did not cause arrhythmias. In some studies higher intravenous doses of 1 to 5 mg/kg haloperidol i.v. caused QTc prolongation and/or ventricular arrhythmias at Cmax plasma levels 19 to 68 times higher than the effective human plasma concentrations.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate Povidone Maize starch Magnesium stearate Stearic acid

6.2. Incompatibilities

None reported.

6.3    Shelf life

Opaque plastic containers: 36 months.

Blister packing: 24 months.

6.4    Special precautions for storage

Store below 25 °C. Protect from light and moisture.

6.5    Nature and contents of container

Haloperidol tablets are packed in the following containers and closures.

1.    Opaque plastic containers composed of polypropylene tubes and polyethylene made tamper-evident closures in pack sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100, 112, 250, 500 and 1000.

2.    Opaque plastic containers composed of either high density polypropylene or high density polyethylene with tamper evident or child resistant tamper evident closure composed of high density polyethylene for all pack sizes (28, 30, 42, 50, 56, 60, 84, 90, 100, 112, 250, 500 and 1000) with a packing inclusion of standard polyether foam or polyethylene or polypropylene filler.

3.    Blister packs of aluminium/opaque PVC. It is subsequently packed in printed boxboard cartons in pack sizes of 28, 30, 42, 56, 60, 84, 90 and 112.

Not all packs may be marketed.

6.6 Special precautions for disposal

None stated.

7. MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited.

Units 3 and 4

Quidhampton Business Units Polhampton Lane Overton

Hants RG25 3ED, UK

8. MARKETING AUTHORISATION NUMBER(S)

PL 20416/0085

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/06/2010

10    DATE OF REVISION OF THE TEXT

14/07/2015