Lamotrigine

Registered South African indications:

• Epilepsy 
• Bipolar disorder 

Contraindications 

• Hypersensitivity to the active ingredient or any of its excipients

Cautions 

South African recommendations

• Pregnancy
• Breastfeeding
• Renal impairment 
• Moderate to severe hepatic impairment (Child-Pugh Classes B & C)
• Risk factors for adverse skin reactions (See additional prescribing points)
  - Children 
  - Coadministration with valproate 
  - High initial dose 
  - Exceeding recommended dose escalation 
  - History of allergy or rash to other antiepileptic agents
• Risk factors for suicide risk
  - Bipolar disorder
  - Epilepsy
  - History of suicidal behaviour or thoughts, or a significant degree of suicidal ideation prior to treatment
  - Young adults
• Brugada syndrome
• Clinically important structural or functional heart disease
• Abrupt withdrawal
• Children with major depressive disorder and other psychiatric disorders (when used for bipolar disorder)
• Parkinson's disease
• Coadministration with sodium channel blockers
• Galactose intolerance e.g. galactosaemia
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Renal impairment
• Moderate to severe hepatic impairment (Child-Pugh Classes B & C)
• Risk factors for rash (See additional prescribing points) 
  - Children  
• - Coadministration with valproate  
  - High initial dose  
  - Exceeding recommended dose escalation  
  - History of allergy or rash to other antiepiletic agents
• Risk factors for suicide risk 
  - Bipolar disorder   
  - History of suicidal behaviour or thoughts, or a significant degree of suicidal ideation prior to treatment 
  - Young adults 
• Clinically important structural or functional heart disease 
  - Brugada syndrome
  - Other cardiac channelopathies
  - Heart failure
  - Ischaemic heart disease
  - Heart block
  - Ventricular arrhythmias
• Abrupt withdrawal
• Myoclonic seizures
• Children with typical absence seizures
• Children with major depressive disorder and other psychiatric disorders (when used for bipolar disorder)
• Parkinson's disease
• Coadministration with other preparations containing lamotrigine
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: dsp, tab

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Epilepsy
- Partial epilepsy with or without secondary generalised tonic-clonic seizures (monotherapy or adjunctive therapy)
- Primary generalised tonic-clonic seizures 
- Seizures associated with Lennox-Gastaut syndrome (adjunctive therapy)

• Oral (dsp, tab): See table below

Treatment regimen	Week 1-2	Week 3-4	Usual Maintenance dose
Monotherapy
Monotherapy	25mg, dly	50mg, dly	Maintenance: 100-200mg/day, in 1-2 divided doses; Titrate by 50-100mg every 1-2 weeks until optimal response (some patients have required 500mg/day to achieve the desired response)
Adjunctive therapy with valproate regardless of any concomitant medications
Dosing regimen with valproate with or without any other antiepileptic drugs (AEDs)	25mg, on alternate days (12.5mg/day)	25mg, dly	Maintenance: 100-200mg/day, in 1-2 divided doses; Titrate by 25-50mg every 1-2 weeks until optimal response
Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation
Dosing regimen without valproate but with phenytoin, carbamazepine, phenobarbitone, primidone, or other inducers of lamotrigine glucuronidation e.g. rifampicin, lopinavir/ ritonavir	50mg, dly	100mg/day, in 2 divided doses	Maintenance: 200-400mg/day, in 2 divided doses; Titrate by 100mg every 1-2 weeks until optimal response
Adjunctive therapy without valproate and without inducers or inhibitors of lamotrigine glucuronidation
Dosing regimen with oxcarbazepine (1200mg/day) without inducers or inhibitors of lamotrigine glucuronidation	25mg, dly	50mg, dly	Maintenance: 100-200mg/day, in 1-2 divided doses; Titrate by 50-100mg every 1-2 weeks until optimal response
For patients taking AEDs where pharmacokinetic interaction with lamotrigine is not known, the treatment regimen as recommended for lamotrigine and concurrent valproate should be used

Bipolar disorder
- Prevention of mood episodes, predominantly by preventing depressive episodes

• Oral (dsp, tab): See table below

Treatment regimen	Week 1-2	Week 3-4	Week 5	Target stabilisation dose (week 6)
Monotherapy with lamotrigine or adjunctive therapy without significant inducers or inhibitors of lamotrigine glucuronidation
Dosage regimen with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation, or monotherapy	25mg, dly	50mg/day, in 1-2 divided doses	100mg/day, in 1-2 divided doses	200mg/day, in 1-2 divided doses; Dosing range: 100-400mg/24hrs
Adjunctive therapy with inhibitors of lamotrigine glucuronidation e.g. valproate
Dosage regimen with inhibitors of lamotrigine glucuronidation e.g. valproate	25mg, on alternate days (12.5mg/day)	25mg, dly	50mg/day, in 1-2 divided doses	100mg/day, in 1-2 divided doses; Max dose: 200mg/24hrs
Adjunctive therapy with inducers of lamotrigine glucuronidation and without inhibitors e.g. valproate
Dosage regimen without valproate but with phenytoin, carbamazepine, phenobarbitone, primidone, or other inducers of lamotrigine glucuronidation e.g. rifampicin, lopinavir/ ritonavir	50mg, dly	100mg/day as 50mg, 12hrly	200mg/day as 100mg, 12hrly	300mg/day in week 6, if necessary increasing to usual target dose of 400mg/day as 200mg, 12hrly, in week 7, to achieve optimal response
In patients taking AEDs where the pharmacokinetic interaction with lamotrigine is currently not known, the dose escalation as recommended for lamotrigine with concurrent valproate, should be used

It is important to adhere to the recommended dosages especially in combination therapy with valproate where one-tenth to one-fifth of the normal dose is used

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The recommended initial dose and subsequent dose escalation should not be exceeded to minimise the risk of skin rash. Do not exceed the maximum dosage

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In epilepsy monotherapy, some patients have required 500mg/day to achieve the desired response 

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For bipolar disorder, the transition regimen involves escalating the dose of lamotrigine to a maintenance stabilisation dose over six weeks after which other psychotropic and/ or antiepileptic agents can be withdrawn, if clinically indicated. The target stabilization dose will alter depending on clinical response 

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Patients with bipolar disorder may terminate lamotrigine without a step wise reduction of dose 

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See additional prescribing points for restarting therapy, and  maintenance stabilisation total daily dose following withdrawal of concomitant psychotropic or anti-epileptic medicines

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Dispersible tablets should be dispersed in a small volume of water (at least enough to cover the whole tablet). The tablets may also be chewed, or swallowed whole with a little water, if preferred

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If a calculated dose of lamotrigine (e.g. patients with hepatic impairment) does not equate to whole tablets, the dose to be administered should be equal to the lower number of whole tablets

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When concomitant antiepileptic medicines are withdrawn to achieve lamotrigine monotherapy or other anti-epileptic drugs/medicines are added-on to treatment regimes containing lamotrigine , consideration should be given to the effect this may have on lamotrigine pharmacokinetics

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Indications and dosages registered in other jurisdictions

Epilepsy
- Partial and generalised seizures, including tonic-clonic seizures (monotherapy or adjunctive therapy)
- Seizures associated with Lennox-Gastaut syndrome (adjunctive therapy or initial antiepileptic drug)

• Oral (tab, dsp): See table below

Treatment regimen	Week 1-2	Week 3-4	Usual Maintenance dose
Monotherapy
Monotherapy	25mg, dly	50mg, dly	Maintenance dose: 100-200mg/day, in 1-2 divided doses; Titrate by 50-100mg every 1-2 weeks until optimal response (some patients have required 500mg/day to achieve the desired response)
Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation)
Dosing regimen with valproate regardless of concomitant medicinal products	25mg, on alternate days (12.5mg/day)	25mg, dly	Maintenance dose: 100-200mg/day, in 1-2 divided doses; Titrate by 25-50mg every 1-2 weeks until optimal response
Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation
Dosing regimen without valproate but with phenytoin, carbamazepine, phenobarbitone, primidone,  rifampicin, lopinavir/ ritonavir	50mg, dly	100mg/day, in 2 divided doses	Maintenance dose: 200-400mg/day, in 2 divided doses; Titrate by 100mg every 1-2 weeks until optimal response (some patients have required 700mg/day to achieve desired response)
Adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation
Dosing regimen with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	25mg, dly	50mg, dly	Maintenance dose: 100-200mg/day, in 1-2 divided doses; Titrate by 50-100mg every 1-2 weeks until optimal response
For patients taking AEDs where pharmacokinetic interaction with lamotrigine is not known, the treatment regimen as recommended for lamotrigine and concurrent valproate should be used

Bipolar disorder
- Prevention of depressive episodes in patients with bipolar I disorder who experience predominantly depressive episodes

• Oral (tab, dsp): See table below

Treatment regimen	Week 1-2	Week 3-4	Week 5	Target stabilisation dose (week 6)
Monotherapy with lamotrigine or adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation
Dosage regimen with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation, or monotherapy	25 mg, dly	50mg/day, in 1-2 divided doses	100mg/day, in 1-2 divided doses	200mg/day, in 1-2 divided doses; Dosing range: 100-400mg/24hrs
Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation)
Dosage regimen with valproate regardless of any concomitant medicinal products	25mg, on alternate days (12.5mg/day)	25mg, dly	50mg/day, in 1-2 divided doses	100mg/day, in 1-2 divided doses; Max dose: 200mg/24hrs
Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation
Dosage regimen without valproate but with phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, lopinavir/ ritonavir	50mg, dly	100mg/day as 50mg, 12hrly	200mg/day as 100mg, 12hrly	300mg/day in week 6, if necessary increasing to usual target dose of 400mg/day as 200mg, 12hrly, in week 7, to achieve optimal response
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known, the dose escalation as recommended for lamotrigine with concurrent valproate, should be used

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Not indicated for the acute treatment of manic or depressive episodes

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For bipolar disorder, the transition regimen involves escalating the dose of lamotrigine to a maintenance stabilisation dose over six weeks after which other psychotropic medicinal products and/ or antiepileptic agents can be withdrawn, if clinically indicated

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Patients with bipolar disorder may terminate lamotrigine without a step wise reduction of dose

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See additional prescribing points for restarting therapy, and  maintenance stabilisation total daily dose following withdrawal of concomitant psychotropic or anti-epileptic medicines

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Because of the risk of rash the initial dose and subsequent dose escalation should not be exceeded

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

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Tablets should be swallowed whole and not chewed or crushed

Chewable/dispersible 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. Do not attempt to administer partial quantities of the chewable/dispersible tablets

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If the calculated dose of lamotrigine (for example for 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

Paed. forms avail. in SA and covered in this monograph: dsp, tab

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Epilepsy
- Partial epilepsy with or without secondary generalised tonic-clonic seizures (monotherapy)
- Primary generalised tonic-clonic seizures 

Younger than 12 years

• Not recommended for use 

Older than 12 years

• See adult dosage

Epilepsy
- Partial epilepsy with or without secondary generalised tonic-clonic seizures, not satisfactorily controlled with other antiepileptic medicines (adjunctive therapy)
- Seizures associated with Lennox-Gastaut syndrome (adjunctive therapy)

Younger than 2 years

• Not recommended for use 

Between 2-12 years

• Oral (dsp, tab): See table below

Treatment	Week 1-2	Week 3-4	Usual maintenance dose
Adjunctive therapy with valproate regardless of any concomitant medications
Dosing regimen with valproate with or without any other antiepileptic drugs (AEDs)	0.15mg/kg, dly*	0.3mg/kg, dly	Maintenance dose: 1-5mg/kg/day, in 1-2 divided doses; Titrate by 0.3mg/kg every 1-2 weeks until optimal response; Max: 200mg/24hrs
Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation
Dosing regimen without valproate but with phenytoin, carbamazepine, phenobarbitone, primidone, or other inducers of lamotrigine glucuronidation e.g.rifampicin, lopinavir/ ritonavir	0.6mg/kg/day, in 2 divided doses	1.2mg/kg/day, in 2 divided doses	Maintenance dose: 5-15mg/kg/day, in 1-2 divided doses; Titrate by 1.2mg/kg every 1-2 weeks until optimal response; Max: 400mg/24hrs
Adjunctive therapy without valproate and without inducers or inhibitors of lamotrigine glucuronidation
Dosing regimen with oxcarbazepine without inducers or inhibitors of lamotrigine glucuronidation	0.3mg/kg/day, in 1-2 divided doses	0.6mg/kg/day, in 1-2 divided doses	Maintenance dose: 1-10mg/kg/day, in 1-2 divided doses; Titrate by 0.6mg/kg every 1-2 weeks until optimal response; Max: 200mg/24hrs
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known, the treatment regimen as recommended for lamotrigine with concurrent valproate should be used

Older than 12 years

• See adult dosage 

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To ensure a therapeutic dose is maintained, the weight of a child must be monitored and the dose reviewed as weight changes occur.  If the doses calculated for children, according to bodyweight, do not equate to whole tablets the dose to be administered should be equal to the lower number of whole tablets 

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*If the calculated daily dose in patients taking valproate is 1-2mg, then 2mg lamotrigine may be taken on alternate days for the first two weeks. If the calculated daily dose is less than 1mg, then lamotrigine should not be administered. Do not attempt to give partial quantities of the dispersible tablets

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The recommended initial dose and subsequent dose escalation should not be exceeded to minimise the risk of skin rash

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Patients aged 2-6 years may require a maintenance dose at the higher end of the recommended range

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Dispersible tablets should be dispersed in a small volume of water (at least enough to cover the whole tablet). The tablets may also be chewed, or swallowed whole with a little water, if preferred

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Not established for use in children and adolescents (<18 years) for bipolar disorder 

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Indications and dosages registered in other jurisdictions

Epilepsy
- Partial and generalized seizures, including tonic-clonic seizures (monotherapy)

Younger than 13 years

• Not established for use

Older than 13 years

• See adult dosage

Epilepsy
- Partial and generalised seizures, including tonic-clonic seizures (adjunctive treatment)
- Seizures associated with Lennox-Gastaut syndrome (adjunctive therapy or initial antiepileptic drug)
- Typical absence seizures (monotherapy)

Younger than 2 years

• Not recommended for use

Between 2-12 years

• Oral (dsp, tab): See table below

Treatment	Week 1-2	Week 3-4	Usual maintenance dose
Monotherapy of typical absence seizures	0.3mg/kg/day, in 1-2 divided doses	0.6mg/kg/day, in 1-2 divided doses	Maintenance: 1-15mg/kg/day, in 1-2 divided doses; Titrate by max. 0.6mg/kg, dly every 1-2 weeks until optimal response; Max: 200mg/24hrs
Adjunctive therapy with valproate (inhibitor of lamotrigine glucuronidation)
Dosing regimen with valproate regardless of any other concomitant medicinal products	0.15mg/kg, dly*	0.3mg/kg, dly	Maintenance: 1-5mg/kg/day, in 1-2 divided doses; Titrate by max. 0.3mg/kg every 1-2 weeks until optimal response; Max: 200mg/24hrs
Adjunctive therapy without valproate and with inducers of lamotrigine glucuronidation
Dosage regime without valproate but with phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, lopinavir/ ritonavir	0.6mg/kg/day, in 2 divided doses	1.2mg/kg/day, in 2 divided doses	Maintenance: 5-15mg/kg/day, in 1-2 divided doses; Titrate by max. 1.2mg/kg every 1-2 weeks until optimal response; Max: 400mg/24hrs
Adjunctive therapy without valproate and without inducers of lamotrigine glucuronidation
Dosage regimen with other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation	0.3mg/kg/day, in 1-2 divided doses	0.6mg/kg/day, in 1-2 divided doses	Maintenance: 1-10mg/kg/day, in 1-2 divided doses; Titrate by max. 0.6mg/kg every 1-2 weeks until optimal response; Max: 200mg/24hrs
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known, the treatment regimen as recommended for lamotrigine with concurrent valproate should be used *If the calculated daily dose in patients taking valproate is 1mg or more but less than 2mg, then lamotrigine 2mg chewable/ dispersible tablets may be taken on alternate days for the first two weeks. If the calculated daily dose in patients taking valproate is less than 1mg, then lamotrigine should not be administered

Older than 13 years

• See adult dosage

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To ensure a therapeutic dose is maintained the weight of a child must be monitored and the dose reviewed as weight changes occur

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It is likely that patients aged two to six years will require a maintenance dose at the higher end of the recommended range

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If the calculated dose of lamotrigine does not equate to whole tablets, the dose should be rounded down to the nearest whole tablet

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Tablets should be swallowed whole and not chewed or crushed

Chewable/dispersible 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. Do not attempt to administer partial quantities of the chewable/dispersible tablets 

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Not recommended for use in children <18 years for bipolar disorder 

Pregnancy

South African recommendations

• Caution; positive evidence of risk
• Safety in pregnancy has not been established
• There is some evidence of an increased risk of oral cleft malformations following exposure to lamotrigine in pregnancy. The decision to use lamotrigine during pregnancy should be taken by the physician following assessment of the benefit/risk profile
• A large amount of data on pregnant women exposed to lamotrigine monotherapy during the first trimester of pregnancy (more than 8700) do not suggest a substantial increase in the risk for major congenital malformations, including oral clefts. Animal studies have shown developmental toxicity
• If therapy with lamotrigine 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. 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

Recommendations in other jurisdictions

• Caution; positive evidence of risk in animal studies
• A large amount of epidemiological study data from more than 12,700 pregnancies exposed to lamotrigine monotherapy, including more than 9,100 pregnancies exposed during the first trimester, do not indicate that lamotrigine therapy at maintenance doses is associated with an increased risk of major congenital malformations. Studies investigating the effect of doses higher than the usual maintenance dose of 100-200mg per day on the risk of major congenital malformations have shown conflicting results. Some studies did not find evidence of a dose-response effect, however data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) showed a statistically significant increase in the rate of major congenital malformations with dose of lamotrigine ≥325mg per day, compared with doses <325mg per day (OR 1.68, 95% CI 1.01-2.80). Therefore, if therapy with lamotrigine is considered necessary during pregnancy, the lowest possible therapeutic dose is recommended
• Animal studies have shown developmental toxicity 
• 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. 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
• Specialist advice should be given to women who are of childbearing potential. The antiepileptic treatment should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, sudden discontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. Monotherapy should be preferred whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics 

Breastfeeding

South African recommendations

• Caution 
• Safety in breastfeeding has not been established
• The decision to breastfeed should be taken in by the mother in consultation with the physician. The potential benefits of breastfeeding should be weighed against the potential risk of adverse effects occurring in the infant
• 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 mothers’. Therefore, in some breastfed infants, serum concentrations of lamotrigine may reach levels at which pharmacological effects occur

Recommendations in other jurisdictions

• Caution
• 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 breastfed infants, serum concentrations of lamotrigine may reach levels at which pharmacological effects occur
• The potential benefits of breastfeeding should be weighed against the potential risk of adverse effects occurring in the infant. Should a woman decide to breastfeed while on therapy with lamotrigine, the infant should be monitored for adverse effects, such as sedation, rash and poor weight gain

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• Animal experiments did not reveal impairment of fertility by lamotrigine

Renal Impairment

• Mild to severe: Caution; no dose adjustment recommended 
• End-stage: Caution; dose adjustment recommended 
  Initial doses should be based on patient’s concomitant medicinal products; reduced maintenance doses should be used for patients with significant renal functional impairment

Hepatic Impairment

• Mild (Child-Pugh Class A): No dose adjustment recommended
• Moderate to severe (Child-Pugh Class B and C): Caution; dose adjustment recommended
  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

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Aggression
• Irritability
• Confusion
• Hallucinations
• Tics
• Nightmares
• Headache
• Somnolence
• Dizziness
• Vertigo
• Paresthesia
• Tremor
• Insomnia
• Agitation
• Ataxia
• Nystagmus
• Unsteadiness
• Aseptic meningitis
• Movement disorders
• Worsening of Parkinson's disease
• Extrapyramidal effects
• Choreoathetosis
• Increase in seizure frequency (epilepsy only)
• Tiredness

Gastrointestinal Disorders 

• Nausea and vomiting
• Diarrhoea
• Dry mouth

Hepatobiliary Disorders 

• Hepatic failure
• Hepatic dysfunction 
• Increased liver function tests

Genitourinary Disorders

• Tubulointerstitial nephritis (may occur in association with uveitis)

Musculoskeletal Disorders 

• Arthralgia
• Back pain
• Lupus-like reactions
• Decreased bone mineral density
• Osteopenia
• Osteoporosis
• Fractures

Skin and Subcutaneous Tissue Disorders 

• Skin rash
  - Maculopapular
• Alopecia
• Photosensitivity reaction
• Angioedema
• Stevens-Johnson Syndrome
• Toxic epidermal necrolysis
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Immune, Blood and Lymphatic System Disorders 

• Haematological abnormalities
  - Neutropenia
  - Leucopenia
  - Anaemia
  - Thrombocytopenia
  - Pancytopenia
  - Aplastic anaemia
  - Agranulocytosis
• Lymphadenopathy
• Haemophagocytic lymphohistiocytosis
• Hypersensitivity syndrome
  - Fever
  - Lymphadenopathy
  - Facial oedema
  - Abnormalities of the blood, liver and kidney 
  - Disseminated intravascular coagulation
  - Multi-organ failure
  - Rash
• Hypogammaglobulinaemia

Sensory Disorders 

• Diplopia
• Blurred vision
• Conjunctivitis
• Uveitis

Others

• Pain

• Glucuronidation inducers (See additional prescribing points)
• Phenytoin
• Carbamazepine
• Primidone
• Phenobarbital
• Rifampicin
• Hormonal contraceptives
• Ethinylestradiol/ levonorgestrel combination (See additional prescribing points) 
• Lopinavir/ ritonavir (See additional prescribing points) 
• Atazanavir/ ritonavir (See additional prescribing points)
• Glucuronidation inhibitors (See additional prescribing points)
• Valproate
• Strong or moderate CYP3A4 inducers
• Organic cationic transporter 2 (OCT 2) substrates with a narrow therapeutic index
• Renally excreted substrates of OCT 2
• Dofetilide
• Metformin
• Gabapentin 
• Varenicline

Other interactions

• Laboratory assay used in some rapid urine drug screens (See additional prescribing points)

• Renal function
• Hepatic function

Specific cases may require

• Electrocardiogram (ECG)
• Weight (children)  
• Serum levels of coadministered anticonvulsants 

Additional observations

• Hypersensitivity reactions, including signs and symptoms of DRESS
  - Lymphadenopathy
  - Fever
  - Rash
  - Possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems
• Signs or symptoms of aseptic meningitis
• Suicidality
• Clinical worsening (bipolar disorder)
• Signs and symptoms of blood dyscrasias
  - Fever
  - Sore throat
  - Mouth ulcers
  - Infections
  - Easy bruising
  - Petechial or purpuric hemorrhage

Skin reactions/ rash

• There have been reports of adverse skin reactions, which have predominantly occurred within the first 8 weeks after initiation of lamotrigine treatment. The majority of rashes are mild and self-limiting, however serious, potentially life-threatening skin rashes including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis have been reported especially in children and in patients (adults and children) who also used valproate. Cases have however been reported after prolonged treatment (6 months)
• Skin reactions in all clinical studies occurred in adults in approximately 10% and in children 17%. In patients on concomitant valproate, skin reactions occurred in 21% of adults and in 34% of children, of whom 12% and 17% respectively withdrew from treatment. Although the majority recover on withdrawal of lamotrigine, some patients experience irreversible scarring and there have been cases of associated death
• In adults enrolled in studies utilising 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 SJS (1 in 1000)
• The risk of serious skin rashes in children is higher than in adults. Available data suggest the incidence of rashes which needed hospitalisation in children is from 1 in 300 to 1 in 100
• In clinical trials with lamotrigine in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000
• 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 8 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
  - Concomitant use of valproate
• Caution is also required when treating patients with a history of allergy or rash to other antiepileptic agents 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
• As it cannot be predicted reliably which rashes will prove to be life-threatening, 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

Co-administration with hormonal contraceptives

• The use of an ethinyloestradiol/ levonorgestrel (30µg/ 150µg) combination increases the clearance of lamotrigine by approximately two-fold, resulting in decreased lamotrigine levels. Following titration, higher maintenance doses of lamotrigine (by as much as two-fold) may be needed to attain a maximal therapeutic response.During the pill-free week, a two-fold increase in lamotrigine levels has been observed. Dose-related adverse events cannot be excluded. Therefore, consideration should be given to using contraception without a pill-free week, as first line therapy (for example, continuous hormonal contraceptives or non-hormonal methods)
• 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. It is recommended that from the time that the hormonal contraceptive is started, the lamotrigine dose is increased by 50-100mg/day every week, according to the individual clinical response. Dose increases should not exceed this rate, unless the clinical response supports larger increases
• 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%. It is recommended to gradually decrease the daily dose of lamotrigine by 50-100mg each week (at a rate not exceeding 25% of the total daily dose per week) over a period of 3 weeks, unless the clinical response indicates otherwise 
• Starting lamotrigine in patients already taking hormonal contraceptives: Dose escalation should follow the normal dose recommendation described in the dosage section
• 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

Restarting therapy

• Prescribers should assess the need for escalation to maintenance dose when restarting lamotrigine in patients who have discontinued it for any reason, since the risk of serious rash is associated with high initial doses and exceeding the recommended dose escalation for lamotrigine. 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, 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

Co-administration with atazanavir/ ritonavir and lopinavir/ ritonavir

• No adjustments to the recommended dose escalation of lamotrigine should be necessary when lamotrigine is added to the existing 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 or lopinavir/ ritonavir is added, or decreased if discontinued 

Maintenance stabilisation total daily dose following withdrawal of concomitant psychotropic or anti-epileptic medicines in treatment of bipolar disorder

Treatment regimen	Week 1 (beginning with withdrawal)	Week 2	Week 3 onwards*
Withdrawal of inhibitors of lamotrigine glucuronidation e.g. valproate
Following withdrawal of inhibitors of lamotrigine glucuronidation e.g. valproate	Double the stabilisation dose, not exceeding an increase of more than 100mg/week i.e. 100mg/day target stabilisation dose will be increased in week 1 to 200mg/day	Maintain this dose (200mg/day) in 2 divided doses
Withdrawal of inducers of lamotrigine glucuronidation depending on original dose of lamotrigine
Dosage regimen when the following are withdrawn: phenytoin, carbamazepine, phenobarbitone, primidone, or other inducers of lamotrigine glucuronidation e.g. rifampicin, lopinavir/ ritonavir	400mg/day	300mg/day	200mg/day
	300mg/day	225mg/day	150mg/day
	200mg/day	150mg/day	100mg/day
Withdrawal of medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation
Dosage regimen when other medicinal products that do not significantly inhibit or induce lamotrigine glucuronidation are withdrawn	Maintain target dose achieved in dose escalation (200mg/day; in 2 divided doses; dose range 100-400mg/day)
In patients taking medicinal products where the pharmacokinetic interaction with lamotrigine is currently not known, 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 400mg/day as needed

Adjustment of lamotrigine daily dosing following the addition of other medicinal products in treatment of bipolar disorder

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

Interactions involving laboratory tests

• Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false positive readings, particularly for phencyclidine (PCP). A more specific alternative chemical method should be used to confirm a positive result 

In vitro studies show that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations. It inhibits human cardiac sodium channels with rapid onset and offset kinetics and strong voltage dependence, consistent with other Class IB antiarrhythmic agents. At therapeutic doses, lamotrigine did not slow ventricular conduction (widen QRS) in healthy individuals in a thorough QT study; however, in patients with clinically important structural or functional heart disease lamotrigine could potentially slow ventricular conduction (widen QRS) and induce proarrhythmia. The results of pharmacological studies suggest that lamotrigine acts at voltage-sensitive sodium channels to stabilise neuronal membranes and inhibit neurotransmitter release, principally that of glutamate, an excitatory amino acid which is thought to play a key role in the generation of epileptic seizures.

Tablet 25mg

• Aspen lamotrigine (Pharmacare)
• Austell-lamotrigine (Austell)
• Dyna-lamotrigine (Pharma Dynamics)
• Epitec (Cipla Medpro)
• Lamictin (GSK) originator
• Lamitor (Dr Reddy)
• Lamotrigine 25mg Zydus (Aurobindo Pharma)
• Lamotrigine Unichem 25mg (Unichem SA)
• Merck-lamotrigine (Mylan)
• Sandoz Lamotrigine (Sandoz)
• Serinem (Unichem SA)

Tablet 50mg

• Aspen lamotrigine (Pharmacare)
• Austell-lamotrigine (Austell)
• Dyna-lamotrigine (Pharma Dynamics)
• Epitec (Cipla Medpro)
• Girotec  (Aurobindo)
• Lamictin (GSK) originator
• Lamidus (Zydus)
• Lamitor (Dr Reddy)
• Lamorola 50 (Strides Pharma)
• Lamotrigine 50mg Zydus (Aurobindo Pharma)
• Lamotrigine Unichem 50mg (Unichem SA)
• Merck-lamotrigine (Mylan)
• Sandoz Lamotrigine (Sandoz)
• Serinem (Unichem SA)

Tablet 100mg

• Aspen lamotrigine (Pharmacare)
• Austell-lamotrigine (Austell)
• Dyna-lamotrigine (Pharma Dynamics)
• Epitec (Cipla Medpro)
• Girotec  (Aurobindo)
• Lamictin (GSK) originator
• Lamidus (Zydus)
• Lamitor (Dr Reddy)
• Lamorola 100 (Strides Pharma)
• Lamotrigine 100mg Zydus (Aurobindo Pharma)
• Lamotrigine Unichem 100mg (Unichem SA)
• Merck-lamotrigine (Mylan)
• Sandoz Lamotrigine (Sandoz)
• Serinem (Unichem SA)

Tablet 200mg

• Aspen lamotrigine (Pharmacare)
• Austell-lamotrigine (Austell)
• Dyna-lamotrigine (Pharma Dynamics)
• Epitec (Cipla Medpro)
• Girotec  (Aurobindo)
• Lamictin (GSK) originator
• Lamidus (Zydus)
• Lamitor (Dr Reddy)
• Lamotrigine 200mg Zydus (Aurobindo Pharma)
• Lamotrigine Unichem 200mg (Unichem SA)
• Merck-lamotrigine (Mylan)
• Sandoz Lamotrigine (Sandoz)
• Serinem (Unichem SA)

Tablet dispersible 2mg

• Lamictin P2 (GSK) originator

Tablet dispersible 5mg

• Lamictin P5 (GSK) originator

Tablet dispersible 25mg

• Lamictin P25 (GSK) originator

Tablet dispersible 50mg

• Lamictin P50 (GSK) originator

Tablet dispersible 100mg

• Lamictin P100 (GSK) originator (Discontinued: 03/2019) 

Tablet dispersible 200mg

• Lamictin P200 (GSK) originator (Discontinued: 03/2019)