Lamictal 25mg tablets

Add adverse reaction - Erythema multiforme

Add adverse reaction - Erythema multiforme

Updates to the SmPC:
• SmPC section 4.2 – Addition of method of administration: For oral use.
• SmPC section 4.4 – Lamictal Tablets only: minor correction to the lactose warning to align the wording to the EU excipients guideline.
• 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 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 content

Section 6.5 - addition of Child Resistant blister description.

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 4.6 – 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.

Please note that this update is to replace the SPC approved on 12 Jan 2016.  This is due to a pregnancy variation that was submitted after the bipolar variation but approved before the HPRA approved the bipolar disorder on 12/01/2016.

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)

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 ) .

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

1.       NAME OF THE MEDICINAL PRODUCT

Lamictal 25 mg tablets.

Lamictal 50 mg tablets.

Lamictal 100 mg tablets.

Lamictal 200 mg 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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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 of 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 Lamictal 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).

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4.5     Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

UDP‑glucuronyl transferases have been identified as the enzymes responsible for metabolism of lamotrigine.  There is no evidence that lamotrigine causes clinically significant induction or inhibition of hepatic oxidative drug‑metabolising enzymes, and interactions between lamotrigine and medicinal products metabolised by cytochrome P450 enzymes are unlikely to occur. Lamotrigine may induce its own metabolism but the effect is modest and unlikely to have significant clinical consequences.

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

* For dosing guidance (see section 4.2)

** Other oral contraceptive and HRT treatments have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters (see sections 4.2 and 4.4).

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Interactions involving other medicinal products

In a study in 10 male volunteers, rifampicin increased lamotrigine clearance and decreased lamotrigine half‑life due to induction of the hepatic enzymes responsible for glucuronidation.  In patients receiving concomitant therapy with rifampicin, the appropriate treatment regimen should be used (see section 4.2).

In a study in healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentrations of lamotrigine, probably by induction of glucuronidation. In patients receiving concomitant therapy with lopinavir/ritonavir, the appropriate treatment regimen should be used (see section 4.2).

In a study in healthy adult volunteers, atazanavir/ritonavir (300 mg/100 mg) administered for 9 days reduced the plasma AUC and C_max of lamotrigine (single 100 mg dose) by an average of 32% and 6% respectively. In patients receiving concomitant therapy with atazanavir/ritonavir, the appropriate treatment regimen should be used (see section 4.2).

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4.6     Pregnancy and lactation

Risk related to antiepileptic drugs in general

Specialist advice should be given to women who are of childbearing potential. The need for treatment with AEDs should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, sudden discontinuation of AED therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child.

The risk of congenital malformations is increased by a factor of 2 to 3 in the offspring of mothers treated with AEDs compared with the expected incidence in the general population of approximately 3%. The most frequently reported defects are cleft lip, cardiovascular malformations and neural tube defects.  Therapy with multiple AEDs is associated with a higher risk of congenital malformations than monotherapy and therefore monotherapy should be used whenever possible.

Risk related to lamotrigine

Pregnancy

Epidemiological studies involving in total approximately 2000 women exposed to lamotrigine monotherapy during pregnancy cannot exclude an increased risk for congenital malformations. One registry has reported an increased incidence of facial clefts. Other data sets have not confirmed this finding. Postmarketing data from several prospective pregnancy registries have documented outcomes in over 2000 women exposed to lamotrigine monotherapy during the first trimester of pregnancy. Overall, these data do not suggest a substantial increase in the risk for major congenital malformations, although data are still too limited to exclude a moderate increase in the risk of oral clefts. Animal studies have shown developmental toxicity (see section 5.3).

If therapy with Lamictal is considered necessary during pregnancy, the lowest possible therapeutic dose is recommended.

Lamotrigine has a slight inhibitory effect on dihydrofolic acid reductase and could therefore theoretically lead to an increased risk of embryofoetal damage by reducing folic acid levels (see section 4.4). Intake of folic acid when planning pregnancy and during early pregnancy may be considered.

Physiological changes during pregnancy may affect lamotrigine levels and/or therapeutic effect. There have been reports of decreased lamotrigine plasma levels during pregnancy with a potential risk of loss of seizure control. After birth lamotrigine levels may increase rapidly with a risk of dose‑related adverse events. Therefore lamotrigine serum concentrations should be monitored before, during and after pregnancy, as well as shortly after birth. If necessary, the dose should be adapted to maintain the lamotrigine serum concentration at the same level as before pregnancy, or adapted according to clinical response. In addition, dose‑related undesirable effects should be monitored after birth.

Lactation

Data indicate that lamotrigine passes into breast milk.  In some breast‑fed infants, the serum concentrations of lamotrigine reached levels at which pharmacological effects may occur. Lamotrigine has been reported to pass into breast milk in highly variable concentrations, resulting in total lamotrigine levels in infants of up to approximately 50% of the mother’s. Therefore, in some breast-fed infants, serum concentrations of lamotrigine may reach levels at which pharmacological effects occur. Among a limited group of exposed infants, no adverse effects were observed.

The potential benefits of breast‑feeding should be weighed against the potential risk of adverse effects occurring in the infant.  Should a woman decide to breast‑feed while on therapy with lamotrigine, the infant should be monitored for adverse effects.

Fertility

Animal experiments did not reveal impairment of fertility by lamotrigine (see section 5.3).

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4.9     Overdose

Symptoms and signs

Acute ingestion of doses in excess of 10 to 20 times the maximum therapeutic dose has been reported.  Overdose has resulted in symptoms including nystagmus, ataxia, impaired consciousness and coma.

Treatment

SPC updates due to NL/H/1540/001-004/IA/001-004, Type IA #41a1 variation to register additional pack sizes

Lamictal 25 mg tablets (PA 1077/61/1)

Lamictal 50 mg tablets (PA 1077/61/2)

Lamictal 100 mg tablets (PA 1077/61/3)

Lamictal 200 mg tablets (PA 1077/61/4)

Changes to the section 6.5 (Nature and contents of container) of the SPCs and combined SPC only as per the annotations below:

Lamictal 25 mg tablets (PA 1077/61/1)

Added pack of 28 tablets.

Lamictal 50 mg tablets (PA 1077/61/2)

Added packs of 28 and 98 tablets.

Lamictal 100 mg tablets (PA 1077/61/3)

Added packs of 28, 42 and 98 tablets.

Lamictal 200 mg tablets (PA 1077/61/4)

Added packs of 28 and 42 tablets.

Change to section 10

Updated to June 2009