Lamictal 200mg chewable/dispersible tablets

Update section 3 on how to take Lamictal.

- Section 4.2: Addition of a statement that partial dosing should not be performed when using the dispersible/chewable tablets (applicable to all dispersible/chewable tablet strengths).
- Section 4.2: Update the SmPC concerning posology and administration in children co-administered with valproate where the 2 mg dispersible/chewable tablets are the lowest marketed strength.

Updates to the SmPC:
• SmPC section 4.2 – Addition of method of administration: For oral use.
• SmPC Section 4.5 - Interaction with other medicinal products and other forms of interaction. Addition of a drug interaction with paracetamol.
• SmPC section 5.3 – Minor correction of existing non-clinical information.
QRD updates across the SPC

Section 6.5:
Addition of or child resistant PVC/PVdC/aluminium foil/paper blister.
25 mg Dispersible/Chewable Tablets: removal of 21 and 42 tablets Starter Packs
50 mg Dispersible/Chewable Tablets: removal of 21 tablets Starter Packs

Section 4.4: Addition of photosensitivity reaction warning
Section 4.8: Addition of photosensitivity reaction undesirable effect to the skin and subcutaneous tissue disorders under frequency uncommon
 

Section 4.4. Update the wording on hypersensitivity syndrome.
Section 4.8 Removal of duplicate Hypersensitivity syndrome symptoms from the adverse event table
Section 4.8 Minor update – aseptic meningitis under nervous system disorders was moved from the bottom to the middle paragraph.
Section 4.8 Addition of the ADR Tubulointerstitial nephritis (TIN) that may occur in association with uveitis and involvement of the kidney as part of DRESS.
Section 4.8 Update to description of selected adverse reactions: Haematological abnormalities and lymphadenopathy and Rash.
Section 4.8 removal of duplicate statement regarding rash reported as part of hypersensitivity syndrome.
Section 4.8 Update to reporting of side effects details.

Section 4.4 - addition of warning for sodium

To update SmPC Section 4.4, 4.6, 4.8, PIL Section 2 & Section 4 in line with CMDh adopted PRAC recommendation. Inclusion of Brugada syndrome and haemophagocytic lymphohistiocytosis in take special care. Also a note to woman that are breastfeeding to observe if any symptoms are observed in the baby.

• Update to SmPC Section 4.5 - Interaction with other medicinal products and other forms of interaction – Update wording on Lamictal and Locosomide/Perampanel interaction in the SmPC.
• Update to SmPC Section 4.6 - Pregnancy and lactation – typographical mistake, removal of the word ‘therefore’

Section 4.5 Interaction with other medicinal products and other forms of interaction - Update wording on OCT-2 inhibition in the SMPC.

Please note that the combined SPC for Lamictal chewable/dispersible Tablets will no longer be used. The SPC for Lamictal chewable/dispersibleTablets will now be individual SPC documents for each strength - SPC for 2mg, SPC for 5mg, SPC for 25mg, SPC for 50mg, SPC for 100mg and SPC for 200mg (6 individual SPCs in total).

The history of the Combined Lamictal chewable/dispersible tablet SPC is attached to the Lamictal chewable/dispersible 200mg Tablets, so the trail of changes remains intact for future perusal. The SPC for 2mg, SPC for 5mg, SPC for 25mg, SPC for 50mg, and SPC for 100mg will be added to Medicines.IE as 'new' documents.

Section 4.6 – minor text deletion

Section 4.8 – addition of alopecia as a uncommon side effect. Addition of  drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported.

Description of change to SPC:

·         4.2          Posology and method of administration – explanation of why Lamictal is not recommended for use in children below 18 years of age because a randomised withdrawal study demonstrated no significant efficacy and showed increased reporting of suicidality (see section 4.4 and 5.1).

·         4.4          Special warnings and precautions for use– skin rash section updated to remove ‘epileptic’ children. Also minor typographical changes have been made to the tables.

·         5.1 Pharmacodynamic properties – addition of study for Children (10-12 years of age) and Adolescents (13-17 years of age)

Section 4.6 - amendments to the wording in the Pregnancy section for lamictal following completion of a case control study to monitor specific birth defects following in utero exposure to lamotrigine conducted through the European Network of Congenital Anomaly and Twin Registers (EUROCAT) - WWE113038/WEUKBRE3885 (voluntary PASS ) .

Introduction of 5 mg bottle pack

Section 4.8 - Undesirable effects – addition of nightmares with the frequency unknown

4.9 Overdose

Under the subheading ‘Symptoms and signs’, updated as follows:

Acute ingestion of doses in excess of 10 to 20 times the maximum therapeutic dose has been reported, including fatal cases.  Overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness, grand mal convulsion and coma. QRS broadening (intraventricular conduction delay) has also been observed in overdose patients. Broadening of QRS duration to more than 100 msec may be associated with more severe toxicity.

4.2     Posology and method of administration

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

4.4     Special warnings and precautions for use

All patients (adults and children) who develop a rash should be promptly evaluated and Lamictal withdrawn immediately unless the rash is clearly not related to lamotrigine treatment. It is recommended that Lamictal 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. If the patient has developed SJS or TEN with the use of lamotrigine, treatment with lamotrigine must not be re-started in this patient at any time.

4.8         Undesirable effects

The undesirable effects have been divided intofor epilepsy and bipolar disorder indications specific sectionsare based on the data currently available. However, both sectionsThe table below should be consulted when considering the overall safety profile of lamotrigine.

Adverse reactions identified from epilepsy monotherapy clinical trials (identified by a dagger ^†), from bipolar disorder clinical trials (identified by a section mark ^§) and during other clinical experience are listed in the table below by their incidence in clinical trials.

The following convention has been utilised for the classification of undesirable effects:-  Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Epilepsy

⁵In double‑blind, adjunctive clinical trials in adults, skin rashes occurred in up to 10% of patients taking lamotrigine and in 5% of patients taking placebo. The skin rashes led to the withdrawal of lamotrigine treatment in 2% of patients. The rash, usually maculopapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of Lamictal (see section 4.4).

⁵In clinical trials in adults, skin rashes occurred in up to 8-12% of patients taking lamotrigine and in 5-6% of patients taking placebo. The skin rashes led to the withdrawal of lamotrigine treatment in 2% of patients. The rash, usually maculopapular in appearance, generally appears within eight weeks of starting treatment and resolves on withdrawal of Lamictal (see section 4.4).

Bipolar Disorder

The undesirable effects below should be considered alongside those seen in epilepsy for an overall safety profile of lamotrigine.  Adverse events included in the table were identified during bipolar disorder clinical trials.

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with lamotrigine. The mechanism by which lamotrigine affects bone metabolism has not been identified.

¹ When all bipolar disorder studies (controlled and uncontrolled) conducted with lamotrigine are considered, skin rashes occurred in 12% of patients on lamotrigine. Whereas, in controlled clinical trials with bipolar disorder patients, skin rashes occurred in 8% of patients taking lamotrigine and in 6% of patients taking placebo.

4.4     Special warnings and precautions for use

Skin rash

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver and aseptic meningitis (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 Lamictal discontinued if an alternative aetiology cannot be established.

Aseptic meningitis was reversible on withdrawal of the drug in most cases, but recurred in a number of cases on re-exposure to lamotrigine. Re-exposure resulted in a rapid return of symptoms that were frequently more severe. Lamotrigine should not be restarted in patients who have discontinued due to aseptic meningitis associated with prior treatment of lamotrigine.

4.5     Interaction with other medicinal products and other forms of interaction

Table 6: Effects of other medicinal products on glucuronidation of lamotrigine

In a study of 18 adult patients with bipolar I disorder, receiving an established regimen of lamotrigine (100-400 mg/day), doses of aripiprazole were increased from 10 mg/day to a target of 30 mg/day over a 7 day period and continued once daily for a further 7 days.  An average reduction of approximately 10% in C_max and AUC of lamotrigine was observed. An effect of this magnitude is not expected to be of clinical consequence.

Data from in vitro assessment demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of Organic Transporter 2 (OCT 2) at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is a more potent in vitro inhibitor of OCT 2 than cimetidine, with IC50 values of 53.8 μM and 186 μM, respectively. Co-administration of lamotrigine with renally excreted medicinal products which are substrates of OCT2 (e.g. metformin, gabapentin and varenicline) may result in increased plasma levels of these medicinal products.

The clinical significance of this has not been clearly defined, however care should be taken in patients co‑administered with these medicinal products.

4.8         Undesirable effects

The undesirable effects have been divided into epilepsy and bipolar specific sections based on the data currently available. However, both sections should be consulted when considering the overall safety profile of lamotrigine.

Adverse reactions identified from monotherapy clinical trials (identified by a dagger ^†) and during other clinical experience are listed in the table below by their incidence in clinical trials.

The following convention has been utilised for the classification of undesirable effects:-  Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Epilepsy

Description of selected adverse reactions

¹ Haematological abnormalities and lymphadenopathy may or may not be associated with the hypersensitivity syndrome (see Immune system disorders²).

² 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. 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 Lamictal discontinued if an alternative aetiology cannot be established.

³ These effects have been reported during other clinical experience. There have been reports that lamotrigine may worsen parkinsonian symptoms in patients with pre‑existing Parkinson’s disease, and isolated reports of extrapyramidal effects and choreoathetosis in patients without this underlying condition.

⁴ Hepatic dysfunction usually occurs in association with hypersensitivity reactions but isolated cases have been reported without overt signs of hypersensitivity.

⁵

Rash has also been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms (see Immune system disorders²).

Bipolar Disorder

The undesirable effects below should be considered alongside those seen in epilepsy for an overall safety profile of lamotrigine.  Adverse events included in the table were identified during bipolar disorder clinical trials.

¹ When all bipolar disorder studies (controlled and uncontrolled) conducted with lamotrigine are considered, skin rashes occurred in 12% of patients on lamotrigine. Whereas, in controlled clinical trials with bipolar disorder patients, skin rashes occurred in 8% of patients taking lamotrigine and in 6% of patients taking placebo.

10.     DATE OF REVISION OF THE TEXT

20 July 2011

SUMMARY OF PRODUCT CHARACTERISTICS

1.       NAME OF THE MEDICINAL PRODUCT

Lamictal 2 mg dispersible/chewable tablets.

4.2     Posology and method of administration

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.

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

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4.2     Posology and method of administration

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