Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: CIPLA MEDPRO (PTY) LTD., Building 9, Parc du Cap, Mispel Street, Bellville, 7530, Customer care number: 080 222 6662
EPITEC is contraindicated in individuals with known hypersensitivity to lamotrigine or to any of the inactive ingredients in EPITEC.
In children younger than 2 years, safety and efficacy have not been demonstrated.
Severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multi-organ dysfunction and disseminated intravascular coagulation, usually with fatal outcome. Similar cases have occurred in association with the use of EPITEC. It is recommended that the medical practitioner closely monitor hepatic, renal and clotting parameters who acutely develop any combination of unexplained rash, fever, flu-like symptoms, drowsiness or worsening of seizure control, especially within the first month of starting treatment with EPITEC.
Patients should be warned to see their doctor immediately if rashes or influenza-like symptoms associated with hypersensitivity develop. Withdrawal of EPITEC should be considered if any combination of unexplained rash, fever, flu-like symptoms, drowsiness or worsening of seizure control occurs within the first 8 weeks of treatment. Available data suggest that exceeding the recommended dose at the initiation of EPITEC therapy may be associated with an increased incidence of serious skin reactions requiring withdrawal of therapy.
Abrupt withdrawal of EPITEC may provoke rebound seizures, in patients with epilepsy. Unless safety concerns (e.g. rash) require an abrupt withdrawal, the dose of EPITEC should be gradually decreased over a period of two weeks.
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 is that equal to the lower number of whole tablets (see section 4.2).
There have been reports of adverse skin reactions, which have generally presented within the first 8 weeks after initiation of EPITEC treatment. Although the majority of rashes are mild and self-limiting, serious and potentially life-threatening skin rashes, including toxic epidermal necrolysis and Stevens-Johnson syndrome (SJS), have been reported, especially in children and in patients (adults and children) who used valproate concomitantly (see section 4.8 and 4.4). Isolated cases of skin reactions have occurred after prolonged treatment (6 months).
All clinical studies have reported skin reactions in approximately 10% of adults and 17% of children. Skin reactions occurred in 21% of adults and in 34% of children, who are on concomitant valproate. Of these, 12% of adults and 17% of children discontinued treatment.
Although the majority recover on withdrawal of EPITEC, some patients experience irreversible scarring and there have been cases of associated death. In adults enrolled in studies utilising the current EPITEC 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 is higher in children 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 EPITEC in patients with bipolar disorder, the incidence of serious rash is approximately 1 in 1000. To minimise the risk of developing serious skin reactions, dosage recommendations should not be exceeded. Children's body weight should be monitored and the dose reviewed if necessary.
The initial presentation of a rash can be mistaken for an infection in children; medical practitioners should therefore consider the possibility of a medicine reaction in children that develop symptoms of fever and rash during the first eight weeks of EPITEC therapy.
Furthermore, the overall risk of skin reactions appears to be strongly associated with:
• High doses of EPITEC at the initiation of therapy and exceeding the recommended dose increases (see section 4.2).
• Concomitant valproate use, due to the fact that it increases the mean half-life of lamotrigine, as contained in EPITEC, nearly two-fold (see section 5.2 and 4.2).
Caution is also required when treating patients with a history of allergy or rash to other antiepileptic medicines, as the frequency of non-serious rash after treatment with EPITEC 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 EPITEC withdrawn immediately unless the rash is clearly not related to EPITEC treatment. It is recommended that EPITEC not be restarted in patients who have discontinued due to rash associated with prior treatment with EPITEC.
Rash has also been reported as part of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); also known as hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, pruritis, facial oedema, abnormalities of the blood, liver, and kidney aseptic meningitis and thrombocytopenia. The syndrome shows a wide spectrum of clinical severity and may lead to disseminated intravascular coagulation and multi-organ failure. It is important to note that early manifestations of hypersensitivity (e.g. 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 EPITEC discontinued if an alternative aetiology cannot be immediately established.
Aseptic meningitis was reversible on withdrawal of the EPITEC in most cases but recurred in a number of cases on re-exposure to EPITEC. Re-exposure resulted in a rapid return of symptoms that were frequently more severe. EPITEC should not be restarted in patients who have discontinued due to aseptic meningitis associated with treatment of EPITEC.
Caution is also required when treating patients with a history of allergy or rash to other AEMs 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.
HLA-B*1502 allele in individuals of Asian (primarily Han Chinese and Thai) origin has been shown to be associated with the risk of developing SJS/TEN when treated with lamotrigine. If these patients are known to be positive for HLA-B*1502, use of lamotrigine should be carefully considered.
HLH has occurred in patients taking EPITEC (see section 4.8). HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of fever, rash, neurological symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, high serum ferritin, hypertriglyceridaemia and abnormalities of liver function and coagulation. Symptoms occur generally within 4 weeks of treatment initiation.
Immediately evaluate patients who develop these signs and symptoms and consider a diagnosis of HLH. EPITEC should be discontinued unless an alternative aetiology can be established.
There is evidence that patients with bipolar disorder and with epilepsy, have an elevated risk for suicidality. This risk may continue during treatment.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicines (AEMs), including EPITEC in several indications, including epilepsy and bipolar disorder. A meta-analysis of randomised placebo-controlled trials of AEMs (including EPITEC) has also shown an increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known.
Therefore, patients should be monitored for signs of suicidal ideation and behaviours. Patients (and caregivers of patients) should be advised to seek medical advice, should signs of suicidal ideation or behaviour emerge.
Patients receiving EPITEC 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.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing EPITEC, 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.
An ethinyloestradiol/levonorgestrel (30 μg/150 μg) combination has been demonstrated to increase the clearance of EPITEC by approximately two-fold resulting in decreased EPITEC levels (see section 4.5). Following titration, higher maintenance doses of EPITEC (by as much as two-fold) will be needed in most cases to attain an optimum therapeutic response. In women taking a combined hormonal contraceptive that includes a "pill-free week" (one week of inactive treatment) and not already taking an inducer of lamotrigine glucuronidation, gradual temporary increases in lamotrigine levels occurs during the week of inactive medicine.
When EPITEC dose increases are made before or during the week of inactive contraceptive medicine, increases in lamotrigine levels will be greater. Cases of breakthrough convulsions in women also using combined hormonal contraceptives, have been reported. For dosing instructions see "General dosing recommendations in special patient populations", in section 4.2.
Women starting or stopping combined hormonal contraceptives during EPITEC therapy, should clinically be managed appropriately. Adjustments in EPITEC dosing may be needed. Other oral contraceptive and hormone replacement therapy (HRT) treatments have not been studied, though lamotrigine pharmacokinetic parameters may similarly be affected.
Studies have shown that there is a modest increase in levonorgestrel clearance and changes in serum FSH and LH when lamotrigine, as in EPITEC, and a hormonal contraceptive (ethinyloestradiol/levonorgestrel combination) are administered in combination (see section 4.5). The impact of these changes on ovarian ovulatory activity is unknown, however these changes may result in decreased contraceptive efficacy in patients taking combined hormonal contraceptive preparations. There have been reports of cases of unplanned pregnancy, metro/menorrhagia, breakthrough bleeding and amenorrhoea. Therefore, patients should be advised to report changes in their menstrual pattern, i.e. breakthrough bleeding.
Lamotrigine is an inhibitor of renal tubular secretion via OCT 2 proteins (see section 4.5). This may result in increased plasma levels of certain medicines that are substantially excreted via this route. Co-administration of EPITEC with OCT 2 substrates with a narrow therapeutic index e.g. dofetilide is not recommended.
Lamotrigine is an inhibitor of renal tubular secretion via OCT 2 proteins (see section 4.5). This may result in increased plasma levels of certain medicines that are substantially excreted via this route. Co-administration of EPITEC with OCT 2 substrates with a narrow therapeutic index e.g. dofetilide is not recommended.
There is a possibility of interference with folate metabolism during long-term therapy due to the fact that EPITEC is a weak inhibitor of dihydrofolate reductase. However, during prolonged human dosing of up to 1 year, EPITEC did not induce significant changes in haemoglobin concentration, mean corpuscular volume, serum or red blood cell folate concentrations.
In single dose studies in subjects with end stage renal failure, plasma concentrations of lamotrigine were not significantly altered. Caution should be exercised in treating patients with renal failure because there is accumulation of the glucuronide metabolite (see section 5.2: Special populations and section 4.2).
A very rare association with Brugada-type ECG has been observed, although a causal relationship has not been established. Therefore, careful consideration should be given before using lamotrigine in patients with Brugada syndrome.
In vitro testing showed that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations. Based on these in vitro findings, lamotrigine could potentially slow ventricular conduction (widen QRS) and induce proarrhythmia in patients with clinically important structural or functional heart disease. Therefore, any expected or observed benefit of lamotrigine for those patients must be carefully weighed against the potential risks for serious or fatal cardiac events. Concomitant use of other sodium channel blockers may further increase the risk of proarrhythmia (see section 5.1).
Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders. EPITEC should not be used in children and adolescents with bipolar disorder.
In clinical trials with EPITEC adverse events of a neurological character such as dizziness and diplopia have been reported. Therefore, patients should see how EPITEC therapy affects them before driving or operating machinery.
EPITEC tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption should not take EPITEC tablets (see section 2).
Uridine 5'-diphospho (UDP)-glucuronyl transferases (UGTs) have been identified as the enzymes responsible for metabolism of lamotrigine. Medicines that induce or inhibit glucuronidation may, therefore, affect the apparent clearance of lamotrigine. Strong or moderate inducers of the cytochrome P450 3A4 (CYP3A4) enzyme, which are also known to induce UGTs, may also enhance the metabolism of lamotrigine. There is no evidence that lamotrigine causes clinically significant induction or inhibition of cytochrome P450 enzymes. Lamotrigine may induce its own metabolism, but the effect is modest and unlikely to have significant clinical consequences.
Those medicines that have been demonstrated to have a clinically relevant impact on lamotrigine concentration are outlined in Table below. Specific dosing guidance for these medicines is provided in section 4.2. In addition, this table lists those medicines which have been shown to have little or no effect on the concentration of lamotrigine. Coadministration of such medicines would generally not be expected to result in any clinical impact. However, consideration should be given to patients whose epilepsy is especially sensitive to fluctuations in concentrations of lamotrigine.
Effects of medicines on the concentration of lamotrigine):
| Medicines that increase the concentration of lamotrigine (doubling of lamotrigine half-life) | Medicines that decrease the concentration of lamotrigine (halving lamotrigine half-life) | Medicines have little or no that effect on the concentration of lamotrigine |
|---|---|---|
| Valproate | Atazanavir/ritonavir* Carbamazepine Ethinyloestradiol/levonorgestrel combination** Phenytoin Phenobarbitone Phenytoin Primidone Rifampicin | Aripiprazole Bupropion Felbamate Gabapentin Oxcarbazepine Lacosamide Levetiracetam Lithium Olanzapine Oxcarbazepine Paracetamol Perampanel Topiramate Pregabalin Zonisamide |
* For dosing guidance, see section 4.2 - General Dosing Recommendations for EPITEC in Special Patient Populations, plus for women taking hormonal contraceptives also see section 4.4 – Hormonal Contraceptives.
Valproate, which inhibits the glucuronidation of lamotrigine, significantly reduces the metabolism of lamotrigine and increases the mean half-life of lamotrigine nearly two-fold.
Certain AEMs (such as phenytoin, carbamazepine, phenobarbitone and primidone) which induce cytochrome P450 enzymes also induce UGTs and, therefore, significantly enhance the metabolism of lamotrigine leading to a halving of the elimination half-life of EPITEC.
Central nervous system events, including dizziness, ataxia, diplopia, blurred vision, and nausea, have been reported in patients who received carbamazepine following the introduction of EPITEC. Reducing the dose of carbamazepine usually leads to resolution of these adverse events.
In a study in healthy adult volunteers using doses of 200 mg lamotrigine and 1 200 mg oxcarbazepine, oxcarbazepine did not alter the metabolism of lamotrigine and lamotrigine did not alter the metabolism of oxcarbazepine. However, other doses of either medicine have not been studied, while carbamazepine halves the EPITEC half-life (see above).
In a study of health volunteers, the co-administration of felbamate (1200 mg twice daily) with lamotrigine, as in EPITEC (100 mg twice daily for 10 days), appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
The apparent clearance of lamotrigine by gabapentin appears to be unchanged after analysis of plasma levels in patients who received lamotrigine, as in EPITEC, both with and without gabapentin.
Clinical trials evaluated serum concentrations of levetiracetam and lamotrigine, assessing potential interactions between levetiracetam and lamotrigine, as in EPITEC. Data indicates that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
There are no pharmacokinetic interactions between lamotrigine and pregabalin. Steady-state trough plasma concentrations of lamotrigine, as in EPITEC, were not affected by concomitant administration of pregabalin (200 mg, 3 times daily). Plasma concentrations of lamotrigine were unaffected by topiramate, however, administration of lamotrigine, as in EPITEC, resulted in a 15% increase in topiramate concentrations.
In a study of patients with epilepsy, co-administration of zonisamide (200 to 400 mg/day) with EPITEC (150 to 500 mg/day) for 35 days had no significant effect on the pharmacokinetics of lamotrigine.
Plasma concentrations of lamotrigine were not affected by concomitant lacosamide (200, 400, or 600 mg/day) in placebo-controlled clinical trials in patients with partial-onset seizures.
In a pooled analysis of data from three placebo-controlled clinical trials investigating adjunctive perampanel in patients with partial-onset and primary generalised tonic-clonic seizures, the highest perampanel dose evaluated (12 mg/day) increased lamotrigine clearance by less than 10%.
Although increases in the plasma concentrations of other antiepileptic medicines have been reported, controlled studies have shown no evidence that lamotrigine affects the plasma concentrations of concomitant antiepileptic medicines. Evidence from in vitro studies indicates that lamotrigine does not displace other antiepileptic medicines from protein binding sites.
Co-administration of 100 mg/day EPITEC with lithium at a dose of 2 g of anhydrous lithium gluconate given twice daily for six days did not alter the pharmacokinetics of lithium.
Multiple oral doses of bupropion cause only a slight increase in the AUC of lamotrigine glucuronide and does not significantly affect the single dose pharmacokinetics of lamotrigine, as contained in EPITEC.
In a study in healthy adult volunteers, 15 mg olanzapine reduced the AUC and Cmax of lamotrigine by an average of 24% and 20%, respectively. EPITEC at 200 mg did not affect the pharmacokinetics of olanzapine.
Multiple oral doses of EPITEC 400 mg daily had no clinically significant effect on the single dose pharmacokinetics of 2 mg risperidone in 14 healthy adult volunteers. Following the co-administration of risperidone 2 mg with EPITEC, 12 out of the 14 volunteers reported somnolence compared to 1 out of 20 when risperidone was given alone and none when EPITEC was administered alone.
In a study of 18 adult patients with bipolar I disorder, receiving an established regimen of lamotrigine (100 to 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 Cmax and AUC of lamotrigine was observed.
Multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single dose pharmacokinetics of 2 mg risperidone in 14 healthy adult volunteers. Following the co-administration of risperidone 2 mg with lamotrigine, 12 out of the 14 volunteers reported somnolence compared to 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone.
In a study of 18 adult patients with bipolar I disorder, receiving an established regimen of EPITEC (≥100 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 Cmax and AUC of lamotrigine was observed.
In vitro inhibition experiments indicated that the formation of lamotrigine's primary metabolite, the 2-N-glucuronide, was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol, or lorazepam. Bufuralo metabolism data from human liver microsome suggested that lamotrigine does not reduce the clearance of medicines eliminated predominantly by CYP2D6. Results of in vitro experiments also suggest that clearance of lamotrigine is unlikely to be affected by clozapine, phenelzine, risperidone, sertraline or trazodone.
The use of an ethinyloestradiol/levonorgestrel (30 mcg/150 mcg) combination causes an increase in the clearance of lamotrigine of approximately two-fold, which results in reduced lamotrigine levels. After titration, it may be necessary to use higher maintenance doses of EPITEC (by as much as two-fold) to achieve maximal therapeutic response. A two-fold increase in EPITEC levels has been observed during the pill-free week and it is not possible to exclude dose-related adverse events. Contraception without a pill-free week should therefore be considered as first-line therapy (for example continuous hormonal contraceptives or non-hormonal methods) (see section 4.2). General Dosing Recommendations for EPITEC in Special Patient Populations (for dosing instructions for women taking hormonal contraceptives) and Special warnings and precautions for use).
Breakthrough seizures have been reported in women using contraceptives.
Clinical trial results have shown that lamotrigine, as contained in EPITEC, did not influence plasma concentrations of the ethinyloestradiol component following the administration of the combined oral contraceptive pill. A modest increase in oral clearance of the levonorgestrel component was observed, resulting in an average 19% and 12% reduction in levonorgestrel AUC and Cmax , respectively. Measurement of serum FSH, LH and oestradiol during the study indicated some loss of suppression of ovarian hormonal activity in some women, although measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 subjects. The impact of the modest increase in levonorgestrel clearance, and the changes in serum FSH and LH, on ovarian ovulatory activity is unknown (see section 4.4). The effects of doses of lamotrigine other than 300 mg/day have not been studied and studies with other female hormonal preparations have not been conducted. Cases of unplanned pregnancy, menstrual disorders and amenorrhoea have been reported. Patients should be advised to report any change in menstrual bleeding pattern to their medical practitioner.
Studies have shown that due to induction of the hepatic enzymes responsible for glucuronidation, rifampicin increased lamotrigine clearance and decreased lamotrigine half-life. In patients receiving concomitant therapy with rifampicin, the treatment regimen recommended for EPITEC and concurrent glucuronidation inducers should be used (see section 4.2).
Plasma concentrations of lamotrigine, as in EPITEC, were approximately halved by lopinavir/ritonavir, most likely by means of induction of glucuronidation. In patients receiving concomitant therapy with lopinavir/ritonavir, the appropriate treatment regimen should be used (see section 4.2).
Atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC of lamotrigine, as in EPITEC, on average by 32% and Cmax by an average of 6%, respectively (single 100 mg dose of lamotrigine). In patients receiving concomitant therapy with atazanavir/ritonavir, the appropriate treatment regimen should be used (see section 4.2 - General Dosing Recommendations for EPITEC in Special Patient Populations).
In a study in healthy adult volunteers, paracetamol 1g (four times daily) reduced the plasma AUC and Cmin of lamotrigine by an average of 20% and 25%, respectively.
In a study in healthy adult volunteers, paracetamol 1g (four times daily) reduced the plasma AUC and Cmin of lamotrigine by an average of 20% and 25%, respectively. Data from in vitro assessment of the effect of lamotrigine at OCT 2 demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT 2 at potentially clinically relevant concentrations. These data demonstrate that lamotrigine is an inhibitor of OCT 2, with IC50 values of 53,8 μM (see section 4.4).
Lamotrigine, as in EPITEC, 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.
Safety of EPITEC in pregnancy and lactation has not been established.
There is some evidence of an increased risk of oral cleft malformations following exposure to EPITEC in pregnancy.
The decision to use EPITEC 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 EPITEC 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 (see section 5.3).
If therapy with EPITEC 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.
The decision to breastfeed should be taken 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.
Animal experiments did not reveal impairment of fertility by lamotrigine, as in EPITEC.
EPITEC may cause adverse events of a neurological character, such as dizziness and diplopia. Patients should therefore be advised to see how EPITEC affects them before they drive or operate machinery.
Frequent: Skin rash
Less Frequent: Stevens-Johnson syndrome
Frequency unknown: Toxic epidermal necrolysis
As reported in clinical trials, skin rashes occurred in up to 10% of patients taking EPITEC and in 5% of patients taking placebo. The skin rashes led to the withdrawal of EPITEC treatment in 2% of patients. The rash, usually maculopapular in appearance, generally appears within 8 weeks of starting treatment and resolves on withdrawal of lamotrigine (see section 4.4).
Serious, potentially life-threatening skin rashes, including angioedema, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Although the majority recover on withdrawal, some patients experience irreversible scarring and there have been rare cases of associated death (see section 4.4). The overall risk of rash appears to be strongly associated with high initial doses of EPITEC and exceeding the recommended dose escalation of EPITEC therapy (see section 4.2).
Rash has also been reported as part of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); also known as hypersensitivity syndrome associated with a variable pattern of systemic symptoms (see section 4.4).
Frequent: Blood dyscrasia.
Less frequent: Haematological abnormalities, including anaemia, neutropenia, leucopenia, thrombocytopenia, pancytopenia, aplastic anaemia, agranulocytosis, lymphadenopathy. Haematological abnormalities may or may not be associated with a DRESS/hypersensitivity syndrome (see section 4.4).
Frequency Unkown: Pseudolymphoma.
Less frequent: DRESS/Hypersensitivity syndrome* including such symptoms as fever, lymphadenopathy, facial oedema, abnormailities of the blood, liver, and kidney. *Rash has also been reported as part of a hypersensitivity syndrome which shows a wide spectrum of clinical severity and in rare cases may cause disseminated intravascular coagulation and multi-organ failure. It is important to note that early hypersensitivity manifestations (such as fever, lymphadenopathy) may be present even though rash is not evident. If the patient demonstrates such signs and symptoms, he/she should be evaluated immediately and EPITEC discontinued if an alternative aetiology cannot be established (see section 4.4).
Frequent: Aggression, irritability
Less frequent: Aggression, Tics (motor and/or phonic tics), hallucinations, confusion
Very common: Headache
Common: Dizziness, somnolence, tiredness, tremor, vertigo, paraesthesia, insomnia
Uncommon: Ataxia
Rare: Nystagmus
Uncommon: Diplopia, blurred vision
Common: Nausea, vomiting. diarrhoea
Very rare: Increased liver function tests, hepatic dysfunction, hepatic failure
Hepatic dysfunction usually occurs in association with hypersensitivity reactions but isolated cases have been reported without overt signs of hypersensitivity.
Very rare: Lupus-like reactions
Common: Tiredness
For an overall safety profile of EPITEC the following adverse events should be considered alongside those seen in patients with epilepsy:
Very common: Skin rash
Rare: Stevens-Johnson syndrome
When all bipolar disorder studies (controlled and uncontrolled) conducted with EPITEC are considered, skin rashes occurred in 12% of patients on EPITEC. Whereas, in controlled clinical trials with bipolar disorder patients, skin rashes occurred in 8% of patients taking EPITEC and in 6% of patients taking placebo.
Very common: Headache
Common: Agitation, somnolence, dizziness
Common: Arthralgia
Common: Pain, back pain
Blood and lymphatic system disorders: Haemophagocytic lymphohistiocytosis (see section 4.4)
Immune system disorders: Hypogammaglobulinaemia
Skin and subcutaneous disorders: Alopecia
Psychiatric disorders: Nightmares
Nervous system disorders: Somnolence, headache, ataxia, dizziness, nystagmus, tremor, insomnia, aseptic meningitis (see section 4.4), agitation, unsteadiness, worsening of Parkinson's disease, extrapyramidal effects, choreoathetosis, and in epilepsy only, increase in seizure frequency.
EPITEC may worsen Parkinsonian symptoms in patients with pre-existing Parkinson's disease and reports of extrapyramidal effects and choreoathetosis in patients without this underlying condition.
Eye disorders: Conjunctivitis
Renal and Urinary disorders: Tubulointerstitial nephritis*
* may occur in association with uveitis
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the "Adverse drug reaction and quality problem reporting form", found online under SAHPRA's publications: https://www.sahpra.org.za/document/adverse-drug-reactions-and-quality-problem-reporting-form/ or to Cipla Medpro (Pty) Ltd. by email: drugsafetysa@cipla.com or telephone: 080 222 6662 (toll free).
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.