Lopresor Tablets 100 mg

1. Name Of The Medicinal Product

Lopresor Tablets 100mg

2. Qualitative And Quantitative Composition

Each tablet contains 100mg metoprolol tartrate BP

3. Pharmaceutical Form

Film coated tablet

4. Clinical Particulars

4.1 Therapeutic Indications

Hypertension and angina pectoris, cardiac arrhythmias, especially supraventricular tachyarrhythmias. Adjunct to treatment of thyrotoxicosis. Early intervention ith Lopresor in myocardial infarction reduces infarct size and the incidence of ventricular fibrillation. Pain relief may also decrease the need for opiate analgesics. Lopresor has been shown to reduce mortality when administered to patients with acute myocardial infarction. Prophylaxis of migraine.

4.2 Posology And Method Of Administration

Lopresor tablets should be administered orally and swallowed unchewed. The dose must always be adjusted to the individual requirements of the patient but should not exceed 400mg/day. The following are guidelines:

Adults

Hypertension: initially a dose of 100mg per day should be prescribed either as single or divided doses. Depending upon the response the dosage may be increased by 100mg per day at weekly intervals to 200mg daily given in single or divided doses. Over the dosage range most patients may be expected to respond rapidly and satisfactorily. A further reduction in blood pressure may be achieved if Lopresor is used in conjunction with an antihypertensive diuretic or other hypotensive agent.

Lopresor may be administered with benefit both to previously untreated patients with hypertension and to those in whom the response to previous therapy is inadequate. In the latter type of patient the previous therapy may be continued and Lopresor added into the regime with adjustment of the previous therapy if necessary.

Angina Pectoris: 50-100mg twice or three times daily

In general a significant improvement in exercise tolerance and reduction of anginal attacks may be expected with a dose of 50-100mg twice daily.

Cardiac Arrhythmias: A dosage of 50mg two or three times daily is usually sufficient. If necessary the dose can be increased up to 300mg per day administered in divided doses.

Hyperthyroidism: 50mg four times daily. The dosage should be progressively reduced as euthyroid state is slowly achieved.

Myocardial Infarction:

Early intervention: 50mg every 6 hours for 48 hours, preferably within 12 hours of the onset of chest pain.

Maintenance: the usual maintenance dose is 200mg daily given in divided doses. The treatment should be continued for at least 3 months.

Prophylaxis of Migraine: 100-200mg daily, given in divided doses (morning and evening).

Elderly

There is no evidence to suggest that dosage requirements are different in otherwise healthy elderly patients. However, caution is indicated in elderly patients as an excessively pronounced decrease in blood pressure or pulse rate may cause the blood supply to vital organs to fall to inadequate levels.

In patients with significant hepatic dysfunction the lower dosage recommendations will be more appropriate.

Children

Not recommended

4.3 Contraindications

Known hypersensitivity to metoprolol and related derivatives or to any of the excipients, severe asthma or history of severe bronchospasm, atrioventricular block of second or third degree, uncontrolled heart failure, clinically relevant sinus bradycardia, sick-sinus syndrome, severe peripheral arterial disease, cardiogenic shock, hypotension, untreated phaeochromocytoma, metabolic acidosis.

Metoprolol is also contraindicated when myocardial infarction is complicated by significant bradycardia, first degree heart block, systolic hypotension (less than 100mmHg) and/or severe heart failure.

4.4 Special Warnings And Precautions For Use

A warning stating “Do not take this medicine if you have a history of wheezing or asthma” will appear on the label.

Although cardioselective beta-blockers, including Lopresor, may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers these should be avoided in patients with reversible obstructive airway disease unless there are compelling clinical reasons for their use. Therapy with a beta₂- stimulant may become necessary or current therapy require adjustment.

Metoprolol may aggravate bradycardia and symptoms of peripheral arterial circulatory disorders. If the patient develops increasing bradycardia, (heart rate less than 50 to 55 beats/min) Lopresor should be given in lower doses or gradually withdrawn.

In addition, anaphylactic reactions precipitated by other agents may be particularly severe in patients taking β-blockers, and may be resistant to normal doses of adrenaline. Whenever possible, β-blockers, including Lopresor, should be avoided for patients who are at increased risk of anaphylaxis

Abrupt cessation of therapy with a beta-blocker should be avoided, especially in patients with ischaemic heart disease. When possible, Lopresor should be withdrawn gradually over a period of 10 days, the doses diminishing to 25mg for the last 6 days. During its withdrawal, the patient should be kept under close surveillance and replacement therapy should be initiated where required.

Beta-blockers, including Lopresor, should not be used in patients with untreated congestive heart failure ( see “Contraindications”). This condition should first be stabilised. Additional therapy should also be considered for patients with a history of heart failure or patients who are known to have a poor cardiac reserve, e.g. diuretics and/or digitalisation.

Because of their negative effect on atrioventricular conduction, beta-blockers, including Lopresor, should be given only with caution to patients with first degree atrioventricular block (see “Contraindications”)

Beta-blockers mask some of the clinical signs of thyrotoxicosis. Therefore, Lopresor should be administered with caution to patients having, or suspected of developing, thyrotoxicosis, and both thyroid and cardiac function should be monitored closely

Lopresor should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycaemic agents (see “Interactions with other medicaments and other forms of interaction”). In labile and insulin-dependent diabetes it may be necessary to adjust the hypoglycaemic therapy. Lopresor may mask some of the symptoms of hypoglycaemia by inhibition of sympathetic nerve functions and patients should be warned accordingly.

In patients with a treated phaeochromocytoma, an alpha-blocker should be given concomitantly.

In patients with significant hepatic dysfunction it may be necessary to adjust the dosage because metoprolol undergoes biotransformation in the liver.

The administration of adrenaline to patients undergoing beta-blockade can result in an increase in blood pressure and bradycardia although this is less likely to occur with beta₁-selective drugs.

Lopresor therapy should be brought to the attention of the anaesthetist prior to general anaesthesia. The benefits of continuing a treatment with a beta-blocker, including Lopresor, should be balanced against the risk of withdrawing it in each patient. When it has been decided to interrupt a beta-blockade in preparation for surgery, therapy should be discontinued for at least 24 hours. Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation. However, the risk of hypertension may be increased. If treatment is continued, caution should be observed with the use of certain anaesthetic drugs. In a patient under beta-blockade, the anaesthetic selected should be one exhibiting as little negative inotropic activity as possible (halothane/nitrous oxide). The patient may be protected against vagal reactions by intravenous administration of atropine.

Beta-blockers may increase the number and duration of angina attacks in patients with Prinzmetal's angina (variant angina pectoris). However, relatively selective beta₁-receptor blockers, such as Lopresor, can be used in such patients, but only with the utmost care

Patients with anamnestically known psoriasis should take beta-blockers only after careful consideration.

The full oculomucocutaneous syndrome, as described elsewhere with practolol, has not been reported with Lopresor. However, part of this syndrome (dry eyes either alone or, occasionally, with skin rashes) has occurred. In most cases the symptoms cleared when Lopresor treatment was withdrawn. Patients should be observed carefully for potential ocular effects. If such effects occur, discontinuation of Lopresor should be considered. (see advice about discontinuation above).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The effects of metoprolol and other antihypertensive drugs on blood pressure are usually additive, and care should be taken to avoid hypotension. However, combinations of antihypertensive drugs may often be used with benefit to improve control of hypertension.

As beta-blockers may affect the peripheral circulation, care should be exercised when drugs with similar activity, e.g. ergotamine are given concurrently.

Care should also be exercised when beta-blockers are given in combination with sympathetic ganglion blocking agents, other beta-blockers (also in the form of eye drops) or MAO inhibitors.

Prazosin

The acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta-blocker

Clonidine

If combination treatment with clonidine is to be discontinued metoprolol should be withdrawn several days before clonidine.This is because the hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment

Calcium channel blockers

Calcium channel blockers such as verapamil and diltiazem may potentiate the depressant effects of beta-blockers on blood pressure, heart rate, cardiac contractility and atrioventricular conduction. A calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients receiving Lopresor because there is a risk of cardiac arrest in this situation. Patients taking an oral calcium channel blocker of the verapamil type in combination with Lopresor should be closely monitored

CYP2D6 inhibitors

Potent inhibitors of this enzyme may increase the plasma concentration of metoprolol (see section 5.2. Pharmacokinetic properties). Caution should therefore be exercised when co-administering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.

Class I anti-arrhythmic drugs and amiodarone

Amiodarone, propafenone, and other class I anti-arrhythmic agents such as quinidine and disopyramide may potentiate the effects of beta-blockers on heart rate and atrioventricular conduction

Nitroglycerin

Nitroglycerin may enhance the hypotensive effect of Lopresor.

Digitalis glycosides

Concurrent use of digitalis glycosides may result in excessive bradycardia and/or increase in atrioventricular conduction time.

Sympathomimetics

Metoprolol will antagonise the beta₁ effects of sympathomimetic agents but should have little influence on the bronchodilator effects of beta₂-agonists at normal therapeutic doses.

Insulin and oral hypoglycaemic drugs

In diabetic patients who use insulin, beta-blocker treatment may be associated with increased or prolonged hypoglycaemia. Beta-blockers may also antagonise the hypoglycaemic effects of sulfonylureas. The risk of either effect is less with a beta₁-selective drug such as Lopresor than with a non-selective beta-blocker. However, diabetic patients receiving Lopresor should be monitored to ensure that diabetes control is maintained (see also “Special warnings and special precautions for use”).

Non-steroidal anti-inflammatory drugs

Concurrent treatment with non-steroidal anti-inflammatory drugs such as indomethacin may decrease the antihypertensive effect of metoprolol.

Lignocaine

Metoprolol may impair the elimination of lignocaine.

General anaesthetics

Some inhalation anaesthetics may enhance the cardiodepressant effect of beta-blockers (see “Special warnings and special precautions for use”)

Hepatic enzyme inducers/inhibitors

Enzyme inducing agents (e.g. rifampicin) may reduce plasma concentrations of metoprolol, whereas enzyme inhibitors (e.g. cimetidine) may increase plasma concentrations.

Alcohol

During concomitant ingestion of alcohol and metoprolol the concentration of blood alcohol may reach higher levels and may decrease more slowly.

4.6 Pregnancy And Lactation

Beta-blockers reduce placental perfusion which may result in intrauterine foetal death, immature and premature deliveries . Lopresor should not be used in pregnancy or lactation unless it is considered that the benefit outweighs the possible risk to the foetus/infant.

Metoprolol has, however, been used in pregnancy associated hypertension under close supervision after 20 weeks gestation. Although the drug crosses the placental barrier and is present in cord blood no evidence of foetal abnormalities have been reported. Animal experiments have shown neither teratogenic potential nor other adverse events on the embryo and/or foetus relevant to the safety assessment of the product.

The amount of metoprolol ingested via breast milk seems to be negligible with regard to its beta-blocking effects if the mother is treated in doses within the therapeutic range.

If Lopresor is used during pregnancy and lactation special attention should be paid to the foetus, neonate and breast-fed infant for undesirable effects of the drug's beta-blocking action (e.g. bradycardia, hypoglycaemia). The lowest possible dose should be used, and treatment should be discontinued at least 2 to 3 days before delivery to avoid increased uterine contractility and effects of beta-blockade in the newborn baby.

4.7 Effects On Ability To Drive And Use Machines

As with all beta-blockers, metoprolol may affect patients' ability to drive and operate machinery. Patients should be warned accordingly.

4.8 Undesirable Effects

Frequency estimates: very common

Blood and the lymphatic system disorders
Very rare	thrombocytopenia
Psychiatric disorders
Rare	depression, nightmares
Very rare	personality disorder, hallucinations
Nervous system disorders
Common	dizziness, headache
Rare	alertness decreased, somnolence or insomnia, paraesthesia
Eye disorders
Very rare	visual disturbance (eg. blurred vision), dry eyes and/or eye irritation
Ear and labyrinth disorders
Very rare	tinnitus, and, in doses exceeding those recommended, hearing disorders (eg. hypoacusis or deafness)
Cardiac disorders
Common	bradycardia
Rare	heart failure, cardiac arrhythmias, palpitation
Very rare	cardiac conduction disorders, precordial pain,
Vascular disorders
Common	orthostatic hypotension (occasionally with syncope)
Rare	oedema, Raynaud's phenomenon
Very rare	gangrene in patients with pre-existing severe peripheral circulatory disorders
Respiratory , thoracic and mediastinal disorders
Common	exertional dyspnoea
Rare	bronchospasm (which may occur in patients without a history of obstructive lung disease)
Very rare	rhinitis
Gastrointestinal disorders
Common	nausea and vomiting, abdominal pain
Rare	diarrhoea or constipation
Very rare	dry mouth
Not known	retroperitoneal fibrosis (relationship to Lopresor has not been definitely established)
Hepatobiliary Disorders
Not known	hepatitis
Skin and subcutaneous tissue disorders
Rare	skin rash (in the form of urticaria, psoriasiform and dystrophic skin lesions)
Very rare	photosensitivity, hyperhydrosis, alopecia, worsening of psoriasis
Musculoskeletal and connective tissue disorders
Rare	muscle cramps
Very rare	arthritis
Reproductive system and breast disorders
Very rare	disturbances of libido and potency
Not known	Peyronie's disease (relationship to Lopresor has not been definitely established)
General disorders and administration site conditions
Common	fatigue
Investigations
Very rare	weight increase, liver function test abnormal

Post Marketing Experience

The following adverse reactions have been reported during post-approval use of Lopresor: confusional state, an increase in blood triglycerides and a decrease in high density lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.

4.9 Overdose

Signs and symptoms

In more severe cases an overdosage of metoprolol may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness, coma, convulsions, nausea, vomiting, cyanosis, hypoglycaemia and occasionally hyperkalaemia.

The first manifestations of overdosage appear 20 minutes to 2 hours after ingestion of Lopresor. The effects of massive overdose may persist for several days, despite declining plasma concentrations

Treatment

Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate. Even apparently well patients who have taken a small overdose should be closely observed for signs of poisoning for at least 4 hours.

In the event of a potentially life-threatening oral overdose, use induction of vomiting or gastric lavage (if within 4 hours after ingestion of Lopresor) and/or activated charcoal to remove the drug from the gastrointestinal tract. Metoprolol can not be effectively removed by haemodialysis.

Atropine may be given intravenously to control significant bradycardia. Intravenous beta-agonists such as prenalterol or isoprenaline should be used to treat bradycardia and hypotension; very high doses may be needed to overcome the beta-blockade. Dopamine, dobutamine or noradrenaline may be given to maintain blood pressure. Glucagon has positive inotropic and chronotropic effects on the heart that are independent of beta-adrenergic receptors, and has proved effective in the treatment of resistant hypotension and heart failure associated with beta-blocker overdose.

Diazepam is the drug of choice for controlling seizures. A beta₂-agonist or aminophylline can be used to reverse bronchospasm; patients should be monitored for evidence of cardiac arrhythmias during and after administration of the bronchodilator.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group

Lopresor is a cardioselective beta-adrenergic blocking agent.

Mechanism of action

It has a relatively greater blocking effect on beta₁-receptors (i.e. those mediating adrenergic stimulation of heart rate and contractility and release of free fatty acids from fat stores) than on beta₂-receptors which are chiefly involved in broncho and vasodilation. It has no membrane-stabilising effect nor partial agonist (intrinsic sympathomimetic) activity.

The stimulant effect of catecholamines on the heart is reduced or inhibited by metoprolol. This leads to a decrease in heart rate, cardiac contractility and cardiac output.

5.2 Pharmacokinetic Properties

Absorption

Metoprolol is well absorbed after oral administration, peak plasma concentrations occurring 1.5 - 2 hours after dosing. The bioavailability of a single dose is approximately 50%, increasing to approximately 70% during repeated administration. The bioavailability also increases if metoprolol is given with food.

Distribution and Biotransformation

Approximately 10% of metoprolol in plasma is protein bound. Metoprolol crosses the placenta, and is found in breast milk (see “Pregnancy and lactation”).

Metoprolol is extensively metabolised by enzymes of the cytochrome P450 system in the liver. The oxidative metabolism of metoprolol is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolisers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Orientals are PMs.

CYP2D6 poor metabolisers exhibit several-fold higher plasma concentrations of metoprolol than extensive metabolisers with normal CYP2D6 activity. None of the metabolites of metoprolol contribute significantly to its beta-blocking effect.

Elimination

Elimination is mainly by hepatic metabolism and the average elimination half-life is 3.5 hours (range 1 to 9 hours). Rates of metabolism vary between individuals, with poor metabolisers (approximately 10%) showing higher plasma concentrations and slower elimination than extensive metabolisers. Within individuals, however, plasma concentrations are stable and reproducible.

Characteristics in Patients

Because of variation in rates of metabolism, the dose of metoprolol should always be adjusted to the individual requirements of the patient. As the therapeutic response, adverse effects and relative cardioselectivity are related to plasma concentration, poor metabolisers may require lower than normal doses. Dosage adjustment is not routinely required in the elderly or in patients with renal failure, but dosage may need to be reduced in patients with significant hepatic dysfunction when metoprolol elimination may be impaired.

5.3 Preclinical Safety Data

There are no further data of relevance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Avicel PH101, povidone, Aerosil 200, sodium starch glycollate, magnesium stearate, hydroxypropylmethylcellulose, polysorbate 80, purified special talc, dispersed blue (E132), titanium dioxide (E171).

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Protect from moisture.

6.5 Nature And Contents Of Container

56 tablets in an Al/PVC(PVdC) blister pack.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Recordati Pharmaceuticals Limited

Isis House

43 Station Road

Henley-on-Thames

Oxfordshire

RG9 1AT

UK

8. Marketing Authorisation Number(S)

PL 25046/0010

9. Date Of First Authorisation/Renewal Of The Authorisation

06 June 1997 / 22 October 2003

10. Date Of Revision Of The Text

06/10/2010

Lamotrigine 200mg Tablets

1. Name Of The Medicinal Product

LAMOTRIGINE 200mg TABLETS

2. Qualitative And Quantitative Composition

Each tablet contains 200mg Lamotrigine.

For excipients, see 6.1

3. Pharmaceutical Form

Tablet.

Light yellow, round, flat, uncoated tablets with a score line on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Epilepsy

Adults and adolescents aged 13 years and above

− Adjunctive or monotherapy treatment of partial seizures and generalised seizures, including tonic-clonic seizures.

− Seizures associated with Lennox-Gastaut syndrome. Lamotrigine Tablets is given as adjunctive therapy but may be the initial antiepileptic drug (AED) to start with in Lennox-Gastaut syndrome.

Children and adolescents aged 2 to 12 years

− Adjunctive treatment of partial seizures and generalised seizures, including tonic-clonic seizures and the seizures associated with Lennox-Gastaut syndrome.

− Monotherapy of typical absence seizures.

Bipolar disorder

Adults aged 18 years and above

− Prevention of depressive episodes in patients with bipolar I disorder who experience predominantly depressive episodes (see section 5.1).

Lamotrigine Tablets is not indicated for the acute treatment of manic or depressive episodes.

4.2 Posology And Method Of Administration

Method of Administration

Lamotrigine Tablets should be swallowed whole with a little water and should not be chewed or crushed.

Posology

Restarting therapy

Prescribers should assess the need for escalation to maintenance dose when restarting Lamotrigine Tablets in patients who have discontinued Lamotrigine Tablets for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for lamotrigine (see section 4.4). The greater the interval of time since the previous dose, the more consideration should be given to escalation to the maintenance dose. When the interval since discontinuing lamotrigine exceeds five half-lives (see section 5.2), Lamotrigine Tablets should generally be escalated to the maintenance dose according to the appropriate schedule.

It is recommended that Lamotrigine Tablets not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.

Epilepsy

The recommended dose escalation and maintenance doses for adults and adolescents aged 13 years and above (Table 1) and for children and adolescents aged 2 to 12 years (Table 2) are given below. Because of a risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).

When concomitant AEDs are withdrawn or other AEDs/medicinal products are added on to treatment regimes containing lamotrigine, consideration should be given to the effect this may have on lamotrigine pharmacokinetics (see section 4.5).

Table 1: Adults and adolescents aged 13 years and above - recommended treatment regimen in epilepsy

Treatment regimen	Weeks 1 + 2	Weeks 3 + 4	Usual maintenance dose
Monotherapy:	25mg/day (once a day)	50mg/day (once a day)	100 - 200mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50 - 100mg everyone to two weeks until optimal response is achieved 500mg/day has been required by some patients to achieve desired response
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation - see section 4.5):
This dosage regimen should be used with valproate regardless of any concomitant medicinal products	12.5mg/day (given as 25mg on alternate days)	25mg/day (once a day)	100 - 200mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 25 - 50mg every one to two weeks until optimal response is achieved
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	50mg/day (once a day)	100mg/day (two divided doses)	200 - 400mg/day (two divided doses) To achieve maintenance, doses may be increased by maximum of 100mg every one to two weeks until optimal response is achieved 700mg/day has been required by some patients to achieve desired response
Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	25mg/day (once a day)	50mg/day (once a day)	100 - 200mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50 - 100mg every one to two weeks until optimal response is achieved
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.

Table 2: Children and adolescents aged 2 to 12 years - recommended treatment regimen in epilepsy (total daily dose in mg/kg body weight/day)

Treatment regimen	Weeks 1 + 2	Weeks 3 + 4	Usual maintenance dose
Monotherapy of typical absence seizures:	0.3mg/kg/day (once a day or two divided doses)	0.6mg/kg/day (once a day or two divided doses)	1 - 10mg/kg/day, although some patients have required higher doses (up to 15mg/kg/day) to achieve desired response (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6mg/kg/day every one to two weeks until optimal response is achieved
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation - see section 4.5):
This dosage regimen should be used with valproate regardless of any other concomitant medicinal products	0.15mg/kg/day * (once a day)	0.3mg/kg/day (once a day)	1 - 5mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.3mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 200mg/day
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	0.6mg/kg/day (two divided doses)	1.2mg/kg/day (two divided doses)	5 - 15mg/kg/ day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 1.2mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 400mg/day
Adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	0.3mg/kg/day (once a day or two divided doses)	0.6mg/kg/day (once a day or two divided doses)	1 - 10mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6mg/kg every one to two weeks until optimal response is achieved, with a maximum of maintenance dose of 200mg/day
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.

To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur. It is likely that patients aged two to six years will require a maintenance dose at the higher end of the recommended range.

If epileptic control is achieved with adjunctive treatment, concomitant AEDs may be withdrawn and patients continued on Lamotrigine Tablets monotherapy.

Children below 2 years

There are limited data on the efficacy and safety of lamotrigine for adjunctive therapy of partial seizures in children aged 1 month to 2 years (see section 4.4). There are no data in children below 1 month of age. Thus Lamotrigine Tablets is not recommended for use in children below 2 years of age. If, based on clinical need, a decision to treat is nevertheless taken, see sections 4.4, 5.1 and 5.2.

Bipolar disorder

The recommended dose escalation and maintenance doses for adults of 18 years of age and above are given in the tables below. The transition regimen involves escalating the dose of lamotrigine to a maintenance stabilisation dose over six weeks (Table 3) after which other psychotropic medicinal products and/or AEDs can be withdrawn, if clinically indicated (Table 4). The dose adjustments following addition of other psychotropic medicinal products and/or AEDs are also provided below (Table 5). Because of the risk of rash the initial dose and subsequent dose escalation should not be exceeded (see section 4.4).

Table 3: Adults aged 18 years and above - recommended dose escalation to the maintenance total daily stabilisation dose in treatment of bipolar disorder

Treatment Regimen	Weeks 1 + 2	Weeks 3 + 4	Week 5	Target Stabilisation Dose (Week 6)*
Monotherapy with lamotrigine OR adjunctive therapy WITHOUT valproate and WITHOUT inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	25mg/day (once a day)	50mg/day (once a day or two divided doses	100mg/day (once a day or two divided doses)	200mg/day – usual target dose for optimal response (once a day or two divided doses) Doses In the range 100 - 400mg/day used in clinical trials
Adjunctive therapy WITH valproate (inhibitor of lamotrigine glucuronidation - see section 4.5):
This dosage regimen should be used with valproate regardless of any concomitant medicinal products	12.5mg/day (given as 25mg on alternate days)	25mg/day (once a day)	50mg/day (once a day or two divided doses)	100mg/day – usual target dose for optimal response (once a day or two divided doses) Maximum dose of 200mg/day can be used depending on clinical response
Adjunctive therapy WITHOUT valproate and WITH inducers of lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used without valproate but with: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	50mg/day (once a day)	100mg/day (two divided doses)	200mg/day (two divided doses)	300mg/day in week 6, if necessary increasing to usual target dose of 400mg/day in week 7, to achieve optimal response (two divided doses)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the dose escalation as recommended for lamotrigine with concurrent valproate, should be used.

* The Target stabilisation dose will alter depending on clinical response

Table 4: Adults aged 18 years and above - maintenance stabilsation total daily dose following withdrawal of concomitant medicinal products in treatment of bipolar disorder

Once the target daily maintenance stabilisation dose has been achieved, other medicinal products may be withdrawn as shown below.

Treatment Regimen	Current lamotrigine stabilisation dose (prior to withdrawal)	Week 1 (beginning with withdrawal)	Week 2	Week 3 onwards *
Withdrawal of valproate (inhibitor of lamotrigine glucuronidation - see section 4.5), depending on original dose of lamotrigine:
When valproate is withdrawn, double the stabilisation dose, not exceeding an increase of more than 100mg/week	100mg/day	200mg/day	Maintain this dose (200mg/day) (two divided doses)
200mg/day	300mg/day	400mg/day	Maintain this dose (400mg/day)
Withdrawal of inducers of lamotrigine glucuronidation (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when the following are withdrawn: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	400mg/day	400mg/day	300mg/day	200mg/day
300mg/day	300mg/day	225mg/day	150mg/day
200mg/day	200mg/day	150mg/day	100mg/day
Withdrawal of medicinal products that do NOT signifcantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are withdrawn	Maintain target dose achieved in dose escalation (200mg/day; two divided doses) (dose range 100 - 400mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate should be used.

* Dose may be increased to 400mg/day as needed

Table 5: Adults aged 18 years and above - adjustment of lamotrigine daily dosing following the addition of other medicinal products in treatment of bipolar disorder

There is no clinical experience in adjusting the lamotrigine daily dose following the addition of other medicinal products. However, based on interaction studies with other medicinal products, the following recommendations can be made:

Treatment Regimen	Current lamotrigine stabilisation dose (prior to addition)	Week 1 (beginning with addition)	Week 2	Week 3 onwards
Addition of valproate (inhibitor of lamotrigine glucuronidation - see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when valproate is added regardless of any concomitant medicinal products	200mg/day	100mg/day	Maintain this dose (100mg/day)
300mg/day	150mg/day	Maintain this dose (150mg/day)
400mg/day	200mg/day	Maintain this dose (200mg/day)
Addition of inducers of lamotrigine glucuronidation in patients NOT taking valproate (see section 4.5), depending on original dose of lamotrigine:
This dosage regimen should be used when the following are added without valproate: phenytoin carbamazepine phenobarbital primidone rifampicin lopinavir/ritonavir	200mg/day	200mg/day	300mg/day	400mg/day
150mg/day	150mg/day	225mg/day	300mg/day
100mg/day	100mg/day	150mg/day	200mg/day
Addition of medicinal products that do NOT significantly inhibit or induce lamotrigine glucuronidation (see section 4.5):
This dosage regimen should be used when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are added	Maintain target dose achieved in dose escalation (200mg/day; dose range 100-400mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen as recommended for lamotrigine with concurrent valproate, should be used.

Discontinuation of Lamotrigine Tablets in patients with bipolar disorder

In clinical trials, there was no increase in the incidence, severity or type of adverse reactions following abrupt termination of lamotrigine versus placebo. Therefore, patients may terminate Lamotrigine Tablets without a step-wise reduction of dose.

Children and adolescents below 18 years

Lamotrigine Tablets is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy (see section 4.4).

General dosing recommendations for Lamotrigine Tablets in special patient populations

Women taking hormonal contraceptives

The use of an ethinyloestradiol/levonorgestrel (30µg/150µg) combination increases the clearance of lamotrigine by approximately two-fold, resulting in decreased lamotrigine levels. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) may be needed to attain a maximal therapeutic response. During the pill-free week, a two-fold increase in lamotrigine levels has been observed. Dose-related adverse events cannot be excluded. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Starting hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will in most cases need to be increased by as much as two-fold (see sections 4.4 and 4.5). It is recommended that from the time that the hormonal contraceptive is started, the lamotrigine dose is increased by 50 to 100mg/day every week, according to the individual clinical response. Dose increases should not exceed this rate, unless the clinical response supports larger increases. Measurement of serum lamotrigine concentrations before and after starting hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. If necessary, the dose should be adapted. In women taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods; see sections 4.4 and 4.5).

Stopping hormonal contraceptives in patients already taking maintenance doses of lamotrigine and NOT taking inducers of lamotrigine glucuronidation

The maintenance dose of lamotrigine will in most cases need to be decreased by as much as 50% (see sections 4.4 and 4.5). It is recommended to gradually decrease the daily dose of lamotrigine by 50-100mg each week (at a rate not exceeding 25% of the total daily dose per week) over a period of 3 weeks, unless the clinical response indicates otherwise. Measurement of serum lamotrigine concentrations before and after stopping hormonal contraceptives may be considered, as confirmation that the baseline concentration of lamotrigine is being maintained. In women who wish to stop taking a hormonal contraceptive that includes one week of inactive treatment ("pill-free week"), serum lamotrigine level monitoring should be conducted during week 3 of active treatment, i.e. on days 15 to 21 of the pill cycle. Samples for assessment of lamotrigine levels after permanently stopping the contraceptive pill should not be collected during the first week after stopping the pill.

Starting lamotrigine in patients already taking hormonal contraceptives

Dose escalation should follow the normal dose recommendation described in the tables.

Starting and stopping hormonal contraceptives in patients already taking maintenancedoses of lamotrigine and TAKING inducers of lamotrigine glucuronidation

Adjustment to the recommended maintenance dose of lamotrigine may not be required.

If the doses calculated for children, according to bodyweight, do not equate to whole tablets the dose to be administered is that equal to the lower number of whole tablets.

Elderly (above 65 years)

No dosage adjustment from recommended schedule is required. The pharmacokinetics of lamotrigine in this age group do not differ significantly from a non elderly adult population (see section 5.2).

Renal impairment

Caution should be exercised when administering Lamotrigine Tablets to patients with renal failure. For patients with end-stage renal failure, initial doses of lamotrigine should be based on patients' concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment (see sections 4.4 and 5.2).

Hepatic impairment

Initial, escalation and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh grade B) and 75% in severe (Child-Pugh grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response (see section 5.2).

4.3 Contraindications

Lamotrigine is contraindicated in individuals with known hypersensitivity to lamotrigine.

Lamotrigine is cleared primarily by metabolism in the liver. No studies have been carried out in patients with significant impairment of hepatic function. Until such data become available Lamotrigine cannot be recommended in this condition.

4.4 Special Warnings And Precautions For Use

Skin rash

There have been reports of adverse skin reactions, which have generally occurred within the first 8 weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self limiting, however rarely, serious potentially life threatening skin rashes including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.8).

In adults enrolled in studies utilizing the current lamotrigine dosing recommendations the incidence of serious skin rashes is approximately 1 in 500 in epilepsy patients (see section 4.8).

The approximate incidence of serious skin rashes reported as SJS in adults and children over the age of 12 is 1 in 1000. The risk is higher in children under the age of 12 than in adults. Available data from a number of studies suggest the incidence in children under the age of 12 requiring hospitalisation due to rash ranges from 1 in 300 to 1 in 100 (see section 4.8).

In children, the initial presentation of a rash can be mistaken for an infection, physicians should consider the possibility of a drug reaction in children that develop symptoms of rash and fever during the first eight weeks of therapy.

Additionally the overall risk of rash appears to be strongly associated with:-

-	High initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see section 4.2).
-	Concomitant use of valproate, which increases the mean half life of lamotrigine nearly two fold (see section 4.2).

Approximately half of these cases have been reported as Stevens-Johnson syndrome (1 in 1000). In clinical trials in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000.

The risk of serious skin rashes in children is higher than in adults. Available data from a number of studies suggest the incidence of rashes associated with hospitalisation in epileptic children is from 1 in 300 to 1 in 100.

In children, the initial presentation of a rash can be mistaken for an infection, physicians should consider the possibility of a reaction to lamotrigine treatment in children that develop symptoms of rash and fever during the first eight weeks of therapy.

Additionally the overall risk of rash appears to be strongly associated with:

− high initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy (see section 4.2)

− concomitant use of valproate (see section 4.2).

Caution is also required when treating patients with a history of allergy or rash to other AEDs as the frequency of non-serious rash after treatment with lamotrigine was approximately three times higher in these patients than in those without such history.

All patients (adults and children) who develop a rash should be promptly evaluated and lamotrigine withdrawn immediately unless the rash is clearly not drug related to lamotrigine treatment. It is recommended that Lamotrigine Tablets not be restarted in patients who have discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefit clearly outweighs the risk.

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema and abnormalities of the blood and liver (see section 4.8). The syndrome shows a wide spectrum of clinical severity and may, rarely, lead to disseminated intravascular coagulation (DIC) and multiorgan failure. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. Patients should be warned to seek immediate medical advice if signs and symptoms develop. If such signs and symptoms are present the patient should be evaluated immediately and lamotrigine discontinued if an alternative aetiology cannot be established.

Clinical worsening and suicide risk

Suicidal ideation and behaviour have been reported in patients treated with AEDs in several indications. A meta-analysis of randomised placebo-controlled trials of AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for lamotrigine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

In patients with bipolar disorder, worsening of depressive symptoms and/or the emergence of suicidality may occur whether or not they are taking medications for bipolar disorder, including Lamotrigine Tablets. Therefore patients receiving Lamotrigine Tablets for bipolar disorder should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes. Certain patients, such as those with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Hormonal contraceptives

Effects of hormonal contraceptives on lamotrigine efficacy

The use of an ethinyloestradiol/levonorgestrel (30µg/150µg) combination increases the clearance of lamotrigine by approximately two-fold resulting in decreased lamotrigine levels (see section 4.5). A decrease in lamotrigine levels has been associated with loss of seizure control. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) will be needed in most cases to attain a maximal therapeutic response. When stopping hormonal contraceptives, the clearance of lamotrigine may be halved. Increases in lamotrigine concentrations may be associated with dose-related adverse events.

Patients should be monitored with respect to this.

In women not already taking an inducer of lamotrigine glucuronidation and taking a hormonal contraceptive that includes one week of inactive treatment (for example "pill-free week"), gradual transient increases in lamotrigine levels will occur during the week of inactive treatment (see section 4.2). Variations in lamotrigine levels of this order may be associated with adverse effects. Therefore, consideration should be given to using contraception without a pill-free week, as first-line therapy (for example, continuous hormonal contraceptives or non-hormonal methods).

The interaction between other oral contraceptive or HRT treatments and lamotrigine have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters.

Effects of lamotrigine on hormonal contraceptive efficacy

An interaction study in 16 healthy volunteers has shown that when lamotrigine and a hormonal contraceptive (ethinyloestradiol/levonorgestrel combination) are administered in combination, there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH (see section 4.5). The impact of these changes on ovarian ovulatory activity is unkown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with lamotrigine cannot be excluded. Therefore, women should have a review of their contraception when starting lamotrigine, and the use of alternative non-hormonal methods of contraception should be encouraged. A hormonal contraceptive should only be used as the sole method of contraception if there is no other alternative. If the oral contraceptive pill is chosen as the sole method of contraception, women should be advised to promptly notify their physician if they experience changes in menstrual pattern (e.g. breakthrough bleeding) while taking lamotrigine as this may be an indication of decreased contraceptive efficacy. Women taking lamotrigine should notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations.

Dihydrofolate reductase

Lamotrigine is a weak inhibitor of dihydrofolate reductase hence there is a possibility of interference with folate metabolism during long-term therapy (see section 4.6). However, during prolonged human dosing, lamotrigine did not induce significant changes in the haemoglobin concentration, mean corpuscular volume, or serum or red blood cell folate concentrations up to 1 year or red blood cell folate concentrations for up to 5 years.

Renal failure

In single dose studies in subjects with end stage renal failure, plasma concentrations of lamotrigine were not significantly altered. However, accumulation of the glucuronide metabolite is to be expected; caution should therefore be exercised in treating patients with renal failure.

Patients taking other preparations containing lamotrigine

Lamotrigine Tablets should not be administered to patients currently being treated with any other preparation containing lamotrigine without consulting a doctor.

Development in children

There are no data on the effect of lamotrigine on growth, sexual maturation and cognitive, emotional and behavioural developments in children.

Precautions relating to epilepsy

As with other AEDs, abrupt withdrawal of lamotrigine may provoke rebound seizures. Unless safety concerns (for example rash) require an abrupt withdrawal, the dose of lamotrigine should be gradually decreased over a period of 2 weeks.

There are reports in the literature that

Colifoam

1. Name Of The Medicinal Product

Colifoam. 10% w/w Rectal Foam

2. Qualitative And Quantitative Composition

Hydrocortisone Acetate 10% w/w.

For a full list of excipients see Section 6.1

3. Pharmaceutical Form

Aerosol foam.

4. Clinical Particulars

4.1 Therapeutic Indications

Ulcerative colitis, proctosigmoiditis and granular proctitis.

4.2 Posology And Method Of Administration

All ages:

One applicatorful inserted into the rectum once or twice daily for two to three weeks and every second day thereafter.

4.3 Contraindications

Local contra-indications to the use of intrarectal steroids include obstruction, abscess, perforation, peritonitis, fresh intestinal anastomoses, extensive fistulae, and tuberculous, fungal or viral infections.

4.4 Special Warnings And Precautions For Use

General precautions common to all corticosteroid therapy should be observed during treatment with Colifoam, especially in the case of young children. Treatment should be administered with caution in patients with severe ulcerative disease because of their predisposition to perforation of the bowel wall. Although uncommon at this dosage local irritation may occur.

Patients/and or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 pharmacokinetic interactions that can increase the risk of side effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Systemic and topical administration of corticosteroids to pregnant animals can cause abnormalities of foetal development. The relevance of this finding to human beings has not been established but at present steroids should not be used extensively in pregnancy, that is in large amounts or for prolonged periods.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Although uncommon at this dosage, irritation may occur.

Side effects are very unusual with Colifoam, but long term frequent use may cause problems in some people. This is particularly so if the medicine is not used as directed. Although uncommon at this dosage, the following side effects may occur; unexpected fattening of the face, neck and body, periods may stop unexpectedly and hair starts to grow on the face (in women), dusky complexion with purple markings, local irritation.

A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.

4.9 Overdose

Not applicable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The use of topically applied steroids in the treatment of ulcerative colitis, proctosigmoiditis and granular proctitis is well known.

5.2 Pharmacokinetic Properties

The topically applied steroid acts locally and so pharmacokinetics are not relevant to its activity.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene Glycol

Emulsifying Wax

Polyoxyethylene (10) Stearyl Ether

Cetyl Alcohol

Methyl Hydroxybenzoate

Propyl Hydroxybenzoate

Triethanolamine

Water Purified

Propellant HP-70

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Pressurised container containing flammable propellant. Protect from sunlight and do not expose to temperatures about 50°C. Store below 25°C. Do not refrigerate. Do not spray on naked flame or any incandescent material. Keep away from sources of ignition - no smoking. Do not pierce or burn even after use.

6.5 Nature And Contents Of Container

Aerosol canister containing 20.8g of foam, plus a plastic applicator.

6.6 Special Precautions For Disposal And Other Handling

SEE LEAFLET.

1. Shake the canister vigorously before each use.

2. Fill applicator so that the foam fills about ¼ of the applicator body. Only a short press is needed to do this.

3. Wait until foam has stopped expanding.

4. Repeat step 2 until the foam expands to just reach the “Fill” line. This normally takes 2 - 4 short press/waits.

5. Stand with one leg raised on a chair, or lie down on your left side. Insert gently into back passage and push plunger fully into the applicator.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

UK

Trading as:

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

8. Marketing Authorisation Number(S)

PL 15142/0088

9. Date Of First Authorisation/Renewal Of The Authorisation

02 Jul 2007.

10. Date Of Revision Of The Text

19^th July 2010