Lamotrigine 5 mg dispersible / chewable tablets

1. Name Of The Medicinal Product

Lamotrigine 5 mg dispersible/ chewable tablets

2. Qualitative And Quantitative Composition

Each Lamotrigine 5 mg dispersible/ chewable tablet contains 5 mg lamotrigine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Dispersible/ chewable tablet

White to off-white, capsule shaped uncoated tablets debossed with 'H' on one side and '81' on other 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 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 is not indicated for the acute treatment of manic or depressive episodes.

4.2 Posology And Method Of Administration

Lamotrigine dispersible/ chewable tablets may be chewed, dispersed in a small volume of water (at least enough to cover the whole tablet) or swallowed whole with a little water.

If the calculated dose of lamotrigine (for example for treatment of children with epilepsy or patients with hepatic impairment) does not equate to whole tablets, the dose to be administered is that equal to the lower number of whole tablets.

Restarting therapy

Prescribers should assess the need for escalation to maintenance dose when restarting Lamotrigine in patients who have discontinued Lamotrigine 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 should generally be escalated to the maintenance dose according to the appropriate schedule.

It is recommended that Lamotrigine 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:	25 mg/day (once a day)	50 mg/day (once a day)	100-200 mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50-100 mg every one to two weeks until optimal response is achieved. 500 mg/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	12.5 mg/day (given as 25 mg on alternate days)	25 mg/day (once a day)	100-200 mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 25-50 mg 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 phenobarbitone primidone rifampicin lopinavir/ritonavir	50 mg/day (once a day)	100 mg/day (two divided doses)	200-400 mg/day (two divided doses) To achieve maintenance, doses may be increased by maximum of 100 mg every one to two weeks until optimal response is achieved 700 mg/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	25 mg/day (once a day)	50 mg/day (once a day)	100-200 mg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 50-100 mg 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:	0.3 mg/kg/day (once a day or two divided doses)	0.6 mg/kg/day (once a day or two divided doses)	1-10 mg/kg/day, although some patients have required higher doses (up to 15 mg/kg/day) to achieve desired response (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6 mg/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	0.15 mg/kg/day* (once a day)	0.3 mg/kg/day (once a day)	1-5 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.3 mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 200 mg/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 phenobarbitone primidone rifampicin lopinavir/ritonavir	0.6 mg/kg/day (two divided doses)	1.2 mg/kg/day (two divided doses)	5-15 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 1.2 mg/kg every one to two weeks until optimal response is achieved, with a maximum maintenance dose of 400 mg/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	0.3 mg/kg/day (once a day or two divided doses)	0.6 mg/kg/day (once a day or two divided doses)	1-10 mg/kg/day (once a day or two divided doses) To achieve maintenance, doses may be increased by maximum of 0.6 mg/kg every one to two weeks until optimal response is achieved, with a maximum of maintenance dose of 200 mg/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.
If the calculated daily dose in patients taking valproate is 2.5 mg or more but less than 5 mg, then Lamotrigine 5 mg dispersible/chewable tablets may be taken on alternate days for the first two weeks. If the calculated daily dose in patients taking valproate is less than 2.5 mg, then Lamotrigine should not be administered

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 monotherapy.

It should be noted that with the currently available Lamotrigine 5 mg dispersible/ chewable tablet strength, it is not possible to accurately initiate lamotrigine therapy using the recommended dosing guidelines in paediatric patients weighing less than 17 kg.

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 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	25 mg/day (once a day)	50 mg/day (once a day or two divided doses)	100 mg/day (once a day or two divided doses)	200 mg/day – usual target dose for optimal response (once a day or two divided doses). Doses in the range 100 – 400 mg/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	12.5 mg/day (given as 25 mg on alternate days)	25 mg/day (once a day)	50 mg/day (once a day or two divided doses)	100 mg/day – usual target dose for optimal response (once day or two divided doses) Maximum dose of 200 mg/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 phenobarbitone primidone rifampicin lopinavir/ritonavir	50 mg/day (once a day)	100 mg/day (two divided doses)	200 mg/day (two divided doses)	300 mg/day in week 6, if necessary increasing to usual target dose of 400 mg/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 stabilisation 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 100 mg/week	100 mg/day	200 mg/day	Maintain this dose (200 mg/day) (two divided doses)
200 mg/day	300 mg/day	400 mg/day	Maintain this dose (400 mg/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 phenobarbitone primidone rifampicin lopinavir/ritonavir	400 mg/day	400 mg/day	300 mg/day	200 mg/day
300 mg/day	300 mg/day	225 mg/day	150 mg/day
200 mg/day	200 mg/day	150 mg/day	100 mg/day
Withdrawal 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 withdrawn	Maintain target dose achieved in dose escalation (200 mg/day; two divided doses) (dose range 100 – 400 mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known (see section 4.5), the treatment regimen recommended for lamotrigine is to initially maintain the current dose and adjust the lamotrigine treatment based on clinical response.
* Dose may be increased to 400 mg/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	200 mg/day	100 mg/day	Maintain this dose (100 mg/day)
300 mg/day	150 mg/day	Maintain this dose (150 mg/day)
400 mg/day	200 mg/day	Maintain this dose (200 mg/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 phenobarbitone primidone rifampicin lopinavir/ritonavir	200 mg/day	200 mg/day	300 mg/day	400 mg/day
150 mg/day	150 mg/day	225 mg/day	300 mg/day
100 mg/day	100 mg/day	150 mg/day	200 mg/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 (200 mg/day; dose range 100 – 400 mg/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 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 without a step-wise reduction of dose.

Children and adolescents below 18 years

Lamotrigine 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 in special patient populations

Women taking hormonal contraceptives

The use of an ethinyloestradiol/levonorgestrel (30 µg/150 µg) 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 100 mg/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- 100 mg 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 maintenance doses of lamotrigine and TAKING inducers of lamotrigine glucuronidation

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

Use with atazanavir/ritonavir

No adjustments to the recommended dose escalation of lamotrigine should be necessary when lamotrigine is added to the existing atazanavir/ritonavir therapy.

In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be conducted before and during 2 weeks after starting or stopping atazanavir/ritonavir, in order to see if lamotrigine dose adjustment is needed (see section 4.5).

Use with lopinavir/ritonavir

No adjustments to the recommended dose escalation of lamotrigine should be necessary when lamotrigine is added to the existing lopinavir/ritonavir therapy.

In patients already taking maintenance doses of lamotrigine and not taking glucuronidation inducers, the lamotrigine dose may need to be increased if lopinavir/ritonavir is added, or decreased if lopinavir/ritonavir is discontinued. Plasma lamotrigine monitoring should be conducted before and during 2 weeks after starting or stopping lopinavir/ritonavir, in order to see if lamotrigine dose adjustment is needed (see section 4.5).

Elderly (above 65 years):

No dosage adjustment from the 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 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

Hypersensitivity to the active substance or to any of the excipients.

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 eight weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self-limiting, however serious rashes requiring hospitalisation and discontinuation of lamotrigine have also been reported. These have included potentially life threatening rashes such as Stevens-Johnson syndrome and toxic epidermal necrolysis (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. 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 related to lamotrigine treatment. It is recommended that lamotrigine 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 and multiorgan failure. It is important to note that early manifestations of hypersensitivity (for example fever, lymphadenopathy) may be present even though rash is not evident. 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. Therefore patients receiving lamotrigine 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 (30 µg/150 µg) 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 unknown. However, the possibility of these changes resulting in decreased contraceptive efficacy in some patients taking hormonal preparations with lamotrigine cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern, i.e. breakthrough bleeding.

Dihydrofolate reductase

Lamotrigine has a slight inhibitory effect on dihydrofolic acid 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.

Trisenox 1mg / ml concentrate for solution for infusion

TRISENOX 1 mg/ml, concentrate for solution for infusion

Arsenic trioxide

Read all of this leaflet carefully before you start using this medicine.

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


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


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• 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 your pharmacist.

In this leaflet:

• 1. What TRISENOX is and what it is used for


• 2. Before you use TRISENOX


• 3. How to use TRISENOX


• 4. Possible side effects


• 5. How to store TRISENOX


• 6. Further information

What Trisenox Is And What It Is Used For

TRISENOX is used in patients with acute promyelocytic leukaemia (APL) whose disease has not responded to other therapies. APL is a unique type of myeloid leukaemia, a disease in which abnormal white blood cells and abnormal bleeding and bruising occur.

Before You Use Trisenox

TRISENOX must be injected under the supervision of a physician experienced in the treatment of acute leukaemias.

Do not use TRISENOX

if you are hypersensitive (allergic) to arsenic trioxide or any of the other ingredients of TRISENOX.

Take special care with TRISENOX

• Please tell your doctor immediately if you have any of the following symptoms: shortness of breath, fever, sudden weight gain, fainting, water retention or palpitations (strong heartbeat you can feel in your chest).

Your doctor must check your blood to be sure that you do not have low amounts of potassium or magnesium before your first dose of TRISENOX. You should also have a 12-lead electrocardiogram performed before your first dose. Blood tests should be repeated twice weekly while you are receiving TRISENOX. In addition, you will receive electrocardiograms twice weekly. If you are at risk for a certain type of abnormal heart rhythm (e.g. torsade de pointes or QTc prolongation) your heart will be monitored continuously. You must tell your doctor if you have impaired kidney or liver function.

Using other medicines

Please tell your doctor if you are taking any of various types of medicines which could cause a change in the rhythm of your heartbeat.

These include:

• some types of antiarrhythmics (drugs used to correct irregular heart beats, e.g. quinidine, amiodarone, sotalol, dofetilide)


• antipsychotics (e.g. thioridazine)


• antidepressants (e.g. amitriptyline)


• some types of antibiotics (e.g. erythromycin and sparfloxacin)


• some antihistamines (e.g. terfenadine and astemizole)


• any medicines that cause a decrease in magnesium or potassium in your blood (e.g. amphotericin B)


• cisapride (a medicine used to relieve certain stomach problems).

The effect of these medicines on your heartbeat can be made worse by TRISENOX. You must be sure to tell your doctor about all medicines you are taking.

Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without prescription.

Using TRISENOX with food and drink

• no restrictions on your food or drink are needed while you are receiving TRISENOX.

Pregnancy

Ask your doctor or pharmacist for advice before taking any medicine. TRISENOX may cause harm to the foetus when used by pregnant women. If you are able to become pregnant, you must use effective birth control during treatment with TRISENOX. If you are pregnant or you become pregnant during the treatment with TRISENOX, you must ask your doctor for advice.

Men should also use effective contraception during treatment with TRISENOX.

Breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine. Arsenic will be present in the milk of TRISENOX patients who are breast-feeding. Because of the potential for serious side-effects in nursing infants from TRISENOX, do not breast-feed while on TRISENOX.

Driving and using machines

The effect of TRISENOX on your ability to drive is not known. If you experience discomfort or if you feel unwell after a TRISENOX injection, you should wait until the symptoms go away before driving or using machines.

Important information about some of the ingredients of TRISENOX

Trisenox contains less than 1 mmol sodium (23 mg) per dose i.e. essentially ‘sodium-free’.

How To Use Trisenox

Your doctor will dilute TRISENOX with 100 to 250 ml of glucose 50 mg/ml (5%) injection, or sodium chloride 9 mg/ml (0.9%) injection.

Your doctor will infuse TRISENOX through a tube into a blood vessel over 1-2 hours, but the infusion may last longer if side-effects like flushing and dizziness occur.

Your doctor will give you TRISENOX once every day as a single infusion each day. In your first treatment cycle, you may be treated every day up to 50 days at most, or until your doctor determines that your disease is better. If your disease responds to TRISENOX, you will be given a second treatment cycle of 25 doses, one infusion every weekday for
5 weeks. Your doctor will decide exactly how long you must continue on therapy with TRISENOX.

Each TRISENOX ampoule must be used only once and does not contain any preservatives. Unused portions of each ampoule must be discarded properly.

Do not save any unused portions for later use.

TRISENOX must not be mixed with, or infused through the same tube with other medicinal products.

If your doctor gives you more TRISENOX than he/she should

You may experience convulsions, muscle weakness and confusion. If this happens, treatment with TRISENOX must be stopped immediately and your doctor will treat the arsenic overdose.

Possible Side Effects

Like all medicines, TRISENOX can have side effects.

While on treatment with TRISENOX, you may experience some of the following reactions:

common side effects (greater than or equal to 1 in 100 but less than 1 in 10): fatigue (weariness), increased blood sugar, shortness of breath, cough, headache.

uncommon side effects (greater than or equal to 1 in 1000 but less than 1 in 100): increased white blood cell count, Herpes zoster, pneumonia, sepsis, anaemia, dehydration, confusion, blurry vision, cardiac failure, hypotension, pneumonitis, chills, renal failure, increased weight, nausea, vomiting, diarrhoea, stomach ache, oedema (water retention), rash or itching, change in your heart rhythm or dizziness.

Frequency unkown: decreased blood cell counts, a syndrome including fever, together with difficulty in breathing, coughing and chest pain. If you experience these symptoms, you should inform your doctor immediately.

Other side effects not mentioned above may also occur in some patients.

Tell your doctor immediately if you experience shortness of breath, fever, sudden weight gain, water retention, fainting or palpitations (strong heartbeat you can feel in your chest).

If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

How To Store Trisenox

Keep out of the reach and sight of children

Do not use after the expiry date stated on the ampoule label.

Do not freeze

After dilution, if not used immediately, in-use storage times and conditions before use are the responsibility of your doctor and would normally not be longer than 24 hours at 2°C – 8°C, unless dilution has taken place in a sterile environment.

Do not use TRISENOX if you notice foreign particulate matter or if discolouration is present.

Further Information

What TRISENOX contains

• The active substance is arsenic trioxide 1 mg/ml


• The other ingredients are sodium hydroxide, hydrochloric acid and water for injections

What TRISENOX looks like and contents of the pack

• TRISENOX is a concentrate for solution for infusion. TRISENOX is supplied in glass ampoules as a concentrated, sterile, clear, colourless, aqueous solution that is prepared and diluted at the hospital and given as an infusion into a blood vessel. Each carton contains 10 single-use glass ampoules. Each ampoule contains 10 mg of arsenic trioxide.

Marketing Authorisation Holder and Manufacturer

• Marketing Authorisation Holder:

Cephalon Europe

5 Rue Charles Martigny

94700 Maisons Alfort

FRANCE

• Manufacturer:

Almac Pharma Services Limited

Almac House

20 Seagoe Industrial Estate

Craigavon

BT63 5QD

United Kingdom

This leaflet was last approved in 04/2009

This medicine has been authorised under “Exceptional Circumstances”. This means that because of the rarity of this disease, it has been impossible to get complete information on this medicine. The European Medicines Agency (EMEA) will review any new information on the medicine every year and this leaflet will be updated as necessary.

Detailed information on this medicine is available on the EMEA web site:http://www.emea.europa.eu

There are also links to other websites about rare diseases and treatments.

0834/2

PX443/4

Vertab SR

VERTAB SR 240 Tablets

VERAPAMIL HYDROCHLORIDE

Please read this leaflet carefully before you start taking your tablets.

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


• This leaflet provides some useful information for you about your medicine.


• If you have any questions or are not sure about anything ask your doctor or pharmacist.

REMEMBER: This medicine has been prescribed for you. Do not pass it to others. It may harm, them, even if their symptoms are the same as yours.

In this leaflet:

• 1. What Vertab SR 240 Tablets are and what they are used for


• 2. Before you take Vertab SR 240 Tablets


• 3. How to take Vertab SR 240 Tablets


• 4. Possible side effects


• 5. How to store Vertab SR 240 Tablets


• 6. Further information

What Vertab Sr 240 Tablets Are And What They Are Used For

The name of your medicine is: Vertab SR 240 Tablets

Vertab SR 240 Tablets belong to a group of medicines called calcium channel blockers. Calcium channel blockers change the amount of calcium getting into the muscle cell in your heart and blood vessels. This can change the strength and speed with which your heart beats. It also opens up the blood vessels so blood can be pumped around the body more easily. This helps more oxygen to get to your heart muscle and can lower your blood pressure.

Vertab SR 240 Tablets are indicated for the treatment of mild to moderate hypertension (high blood pressure) and the treatment and prevention of angina pectoris (chest pain).

Before You Take Vertab Sr 240 Tablets

If you are unsure if any of the lists applies to you, ask your doctor before you start to take your tablets.

Do not take Vertab SR 240 Tablets:

• If you have hypersensitivity to Verapamil Hydrochloride or to any of the other ingredients of Vertab SR 240 Tablets (listed in section 6 - Further information).


• If you are having a cardiogenic shock (a sudden and rapid fall in blood pressure).


• If you are having or have recently had a heart attack particularly if a slow heart beat, low blood pressure or left ventricular failure of the heart are involved.


• If you have second or third degree atrioventricular block or sino-atrial block (a disorder where parts of the heart may beat at the wrong time causing the heart not to pump blood around the body very well).


• If you have sick sinus syndrome (a heart beat disorder).


• If you have heart failure that is not currently being treated.


• If you have severe bradycardia (a condition where the heart beats at less than 50 beats per minute).


• If you have low blood pressure where the higher blood pressure reading is below 90.


• This medicine is for adults only. It should not be given to children under the age of 12.

Take special care with Vertab SR 240 Tablets:

Consult your doctor or pharmacist if:

• You suffer or you have ever suffered in the past from low blood pressure, from a condition known as "heart failure", an abnormally slow or irregular heart beat, or any other cardiac problem including Wolff-Parkinson-White syndrome.


• You suffer or you have ever suffered in the past from kidney or liver disorders. These above mentioned medical conditions may mean that your doctor will need to monitor you more closely.


• You are planning to have medical or dental surgery. This medicine may affect the anaesthetics or other treatments used.

Taking other medicines:

Please inform your doctor or pharmacist if you are taking or have recently taken any of the following medicines, even those not prescribed:

• Digoxin (used to treat certain heart conditions, such as heart failure)


• Beta-blockers or any other treatment for heart diseases and high blood pressure


• Anti-arrhythmic agents (used to steady an irregular heart beat)


• Carbamazepine, Phenytoin, Phenobarbital (usually used in epilepsy)


• Ciclosporin (normally used following organ transplants to help prevent rejection)


• Theophylline (used for breathing difficulties e.g. asthma)


• Rifampicin (antibiotic action for treatment of various infections such as tuberculosis (TB))


• Lithium (used for psychiatric conditions)


• Cimetidine (used for stomach disorders e.g. ulcers)

Taking Vertab SR 240 Tablets with food and drink:

Vertab SR 240 Tablets will increase the time your body takes to get rid of alcohol. This means that you may not have to drink as much for your blood alcohol level to be above the legal limit to drive. It will also take you longer to sober up.

Do not drink products containing grapefruit juice at the same time as you take this medicine.

Pregnancy and breast-feeding:

Consult your doctor or pharmacist if you are pregnant, trying to become pregnant, or breast-feeding.

Driving and using machines:

Vertab SR 240 Tablets can make some people feel dizzy especially when first starting to take the tablets. Do not drive, operate machinery or do anything that requires you to be alert, until you know how the tablets affect you.

Important information about some of the ingredients of Vertab SR 240 Tablets:

This medicinal product contains 36 mg sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

How To Take Vertab Sr 240 Tablets

Always take Vertab SR 240 Tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

The tablets should not be chewed. They should be swallowed whole with a glass of water.

• 
  For treatment of hypertension: The usual dosage is one tablet per day. Some patients may need to take two tablets per day (one in the morning and one in the evening with about 12 hours between doses). Do not take more than two tablets per day.


• 
  For the treatment and prevention of angina pectoris: The usual dose is one tablet twice daily.

If you take more Vertab SR 240 Tablets than you should

In case of an overdose, contact your nearest hospital casualty department or tell your doctor immediately.

If you forget to take Vertab SR 240 Tablets

If you forget to take a dose, take it as soon as you remember, unless it is almost time for your next dose. If it is, do not take the missed dose at all. Never double-up on a dose to make up for the one you have missed.

If you have trouble remembering to take your tablets, tell your doctor or your pharmacist. If you take too many tablets by mistake, any side effects (see below) may be worse than usual; in this case see your doctor.

If you stop taking Vertab SR 240 Tablets

It is important that you continue taking the tablets until your doctor tells you to stop. Do not stop because you feel better. If you stop taking the tablets too soon your condition may get worse.

Vertab SR Side Effects

Vertab SR 240 is generally well tolerated. Side effects are usually mild and transient.

In rare cases people may have an allergic reaction to Verapamil Hydrochloride.

You should tell your doctor immediately if you have any unexpected wheezing or difficulty in breathing, if you have a Quincke's oedema (swelling of the face with itching), swelling of the mouth, lips, or tongue, or if you develop a skin rash, pruritus (itching), or severe skin rash with blistering and peeling of the skin.

If you experience the following side effects you should tell your doctor immediately:

• If you develop yellowing of the skin or eyes, a fever or tenderness around the middle.


• If you have bradycardia (slow heart beats), arrhythmia (irregular heart rhythm), palpitations (awareness of an irregular or rapid heart beat), chest pains for the first time or chest pains that become more frequent, dizziness, weakness or confusion, swollen ankles, feeling faint or breathless or a burning sensation in the feet, which may become hot and throbbing.


• Hypotension (abnormally low blood pressure)

Do not stop taking the tablets, but tell your doctor if you get any of the following:

Digestive effects such as constipation, nausea (feeling sick) or vomiting, headache, flushing, fatigue, pins and needles, muscle and joint pain.

Swelling of the breasts (gynaecomastia), which is usually seen in elderly male patients, and spreading of the gums over the teeth can occur with long term treatment. These effects are very rare and resolve on stopping treatment. You should tell your doctor if these side effects appear.

If you think your medicine may be causing any problems, even if they are not described in this leaflet, tell your doctor or pharmacist.

How To Store Vertab Sr 240 Tablets

Keep out of the reach and sight of children.

Check the expiry date on the label. Do not use the tablets if the date has passed.

You should store the tablets at or below 25°C.

In case of visible signs of deterioration, you should discard the package.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Vertab SR 240 Tablets contain:

The active substance is: Verapamil Hydrochloride 240mg.

The other ingredients are: Core: Sodium alginate, Microcrystalline cellulose, Povidone, Hypromellose, Colloidal anhydrous silica, Magnesium stearate. Coating: Hypromellose, Titanium dioxide, Macrogol, Yellow Lake E-104, Blue Lake E-132 and Carnauba wax.

What Vertab SR 240 Tablets look like and content of the pack:

This medicine can be identified as modified release, light-green film-coated, capsule-shaped, scored tablets.

Vertab SR 240 Tablets are supplied in packs of 28 tablets.

The Manufacturer/Holder of Marketing Authorisation is:

Dexcel - Pharma Ltd

1 Cottesbrooke Park

Heartlands Business Park

Daventry

Northamptonshire

NN11 8YL

England

Distributed by:

Chiesi Limited

Cheadle Royal Business Park

Highfield

Cheadle

SK8 3GY

United Kingdom

Date upon which the leaflet was last revised:


February 2009

CP0032/1

1290360114-E

Cuprofen Maximum Strength Tablets

1. Name Of The Medicinal Product

Cuprofen Tablets 400 mg

Ibuprofen Tablets BP 400 mg

Cuprofen Maximum Strength Tablets

Own label: UniChem Extra Strength Ibuprofen 400mg Tablets

2. Qualitative And Quantitative Composition

Ibuprofen BP 400 mg

3. Pharmaceutical Form

Coated tablets

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of rheumatic, muscular, dental and period pains and pain in backache, neuralgia, migraine and headache, and for the symptomatic relief of colds, flu and feverishness.

4.2 Posology And Method Of Administration

For oral administration and short-term use only.

Adults, the elderly and children over 12 years:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms. The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

One tablet up to three times as day as required.

Leave at least four hours between doses and do not take more than 3 tablets in any 24 hour period.

To be taken preferably after food.

Children under 12 years:

Not to be given to children under 12 years of age.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the excipients in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other non steroidal anti-inflammatory drugs.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of gastrointestinal bleeding or perforation, relating to previous NSAIDs therapy.

Severe heart failure, renal failure or hepatic failure (see section 4.4).

Last trimester of pregnancy (see section 4.6).

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.

Other NSAIDs:

The use of Cuprofen Maximum Strength Tablets with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8)

Renal:

Renal impairment as renal function may further deteriorate (see sections 4.3 and 4.8)

Hepatic:

Hepatic dysfunction (see sections 4.3 and 4.8)

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility:

There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDSs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Cuprofen Maximum Strength Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The label will include:

Read the enclosed leaflet before taking this product.

Do not take if you:

• have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding

• are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers

• are taking other NSAID painkillers, or aspirin with a daily dose above 75mg

Speak to a pharmacist or your doctor before taking if you:

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems

• are a smoker

• are pregnant

If symptoms persist or worsen, consult your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ibuprofen should be avoided in combination with:

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.4). ). Experimental data suggests that ibuprofen may inhibit the effect of low does aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex-vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other NSAIDS including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDS may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4)

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: There is evidence for potential increases in plasma levels of lithium.

Methotrexate: There is a potential for an increase in plasma methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

4.6 Pregnancy And Lactation

Whilst no teratogenic effects have been demonstrated in animal studies, the use of Cuprofen Maximum Strength Tablets should be avoided during the first 6 months of pregnancy.

During the 3^rd trimester, ibuprofen is contraindicated as there is there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and duration of labour increased with an increased bleeding tendency in both the mother and child. (see section 4.3).

In limited studies, ibuprofen appears in the breast milk in very low concentrations and is unlikely to affect the breast-fed infant adversely.

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended doses and duration of therapy.

4.8 Undesirable Effects

Hypersensitivity reactions have been reported and these may consist of:

(a) non-specific allergic reactions and anaphylaxis

(b) respiratory tract reactivity, eg asthma, aggravated asthma, bronchospasm, dyspnoea

(c) various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Hypersensitivity reactions:

Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

Gastrointestinal:

The most commonly-observed adverse events are gastrointestinal in nature.

Uncommon: abdominal pain, nausea, dyspepsia.

Rare: diarrhoea, flatulence, constipation and vomiting

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis.

Exacerbation of colitis and Crohn's disease (see section 4.4).

Nervous System:

Uncommon: Headache

Very rare: Aseptic meningitis – single cases have been reported very rarely.

Renal:

Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

Hepatic:

Very rare: liver disorders.

Haematological:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Dermatological:

Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur.

Immune System:

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see section 4.4).

Cardiovascular and Cerebrovascular:

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke), (see section 4.4).

4.9 Overdose

In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

Experimental data suggests that ibuprofen may inhibit the effect of low does aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single does of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be like for occasional ibuprofen use.

5.2 Pharmacokinetic Properties

Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.

The half-life of ibuprofen is about 2 hours.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose BP

Ac-di-sol

Methyl cellulose (Celacol M450) BP

Magnesium stearate

Water

IMS

Polyethylene glycol

Methyl cellulose (Methocel E15)

Sepisperse Rose AP 5002 OR

Mastercote Pink FA0430

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store at or below 25°C.

6.5 Nature And Contents Of Container

a. Polypropylene containers with a low density polythene tamper evident lid (21, 100, 250, 500, 1000 tablets).

b. Polythene bags free from additives, inside a cardboard outer (5,000, 10,000 tablets).

c. Blister packs comprised of 250.i plain white rigid UPVC and 20p~ hard temper aluminium foil (12, 24, 36, 48, 96 tablets).

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Cupal Limited

Venus

1 Old Park Lane

Trafford Park

Manchester

M41 7HA

8. Marketing Authorisation Number(S)

PL 0338/0085

9. Date Of First Authorisation/Renewal Of The Authorisation

17/06/2010

10. Date Of Revision Of The Text

16/07/2010