Date of approval.
Date of revision.
Lamotrigine Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings: Severe rash
This product may cause a severe rash requiring hospitalization and interruption of therapy. The incidence of rash, including Stevens-Johnson syndrome, was approximately 0.8% (8/1,000) in pediatric patients (2 to 16 years of age) receiving this product as adjunctive therapy for epilepsy and 0.3% (3/1,000) in adult patients receiving adjunctive therapy for epilepsy, respectively. In clinical trials of bipolar disorder and other mood disorders, the incidence of severe rash was 0.08% (0.8/1,000) in adult patients receiving initial monotherapy with this product and 0.13% (1.3/1,000) in adult patients receiving adjuvant therapy with this product, respectively. One rash-related death occurred in a prospective cohort study of 1,983 pediatric epilepsy patients (2 to 16 years of age) taking this product for adjuvant therapy. Rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients in post-marketing experience worldwide, but their numbers are too small to accurately estimate their incidence.
No known factors other than age have been identified to predict the risk or severity of rash caused by this product. It has been suggested, but not proven, that the following increase the risk of rash: (1) combining this product with valproate, (2) exceeding the recommended initial dose of this product, or (3) exceeding the recommended incremental dose of this product. However, cases have been reported in the absence of these factors.
Almost all life-threatening rashes caused by this product appeared within 2 to 8 weeks of initial treatment. However, there have been isolated cases that have occurred after extended treatment (e.g., 6 months). Therefore, the potential risk of the first rash cannot be predicted based on the duration of treatment.
Although this product also causes a harmless rash, it is not possible to predict which rashes will be severe or life-threatening. Therefore, this product should usually be discontinued at the first sign of a rash unless the rash can be diagnosed as unrelated to this drug. Interruption of treatment may also fail to prevent the rash from progressing to a life-threatening or permanent loss of function or scarring [see PRECAUTIONS [Severe Rash]].
Drug name].
Generic Name: Lamotrigine Tablets
English Name: Lamotrigine Tablets
Hanyu Pinyin: Lamosanqin Pian
Ingredients
The active ingredient is: Lamotrigine
Chemical name: 3,5-diamino-6-(2,3-dichlorophenyl)- 1,2,4-triazine
Chemical structure formula.
Molecular formula: C9H7N5Cl2
Molecular weight: 256.09
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
Epilepsy.
Monotherapy for children over 12 years of age and adults with.
1. simple partial seizures
2. Complex partial seizures
3. Secondary generalized tonic-clonic seizures
4. primary generalized tonic-clonic seizures
Monotherapy in children under 12 years of age is not recommended at this time because data from controlled trials in this specific target population are not yet available.
Add-on therapy for children over 2 years of age and adults.
1. simple partial-onset seizures
2. complex partial seizures
3. Secondary generalized tonic-clonic seizures
4. Primary generalized tonic-clonic seizures
This product can also be used to treat seizures in combination with Lennox-Gastaut syndrome.
Specification
(1) 50mg (2) 100mg
Dosage and Administration
Dosing method.
To ensure maintenance of the therapeutic dose, patient’s weight needs to be monitored and the dose should be verified in case of weight change.
If the calculated dose of this product (for children and patients with impaired liver function) is not the full number of tablets, the dose used should be the lower limit of the full number of tablets.
The effect of these changes on the pharmacokinetics of this drug should be considered when other co-administered antiepileptic drugs are discontinued for monotherapy with this drug or when other antiepileptic drugs are added to the addition of this drug to the regimen (see [Drug Interactions]).
Restarting Treatment
When a patient needs to restart treatment after discontinuing this product for any reason, the prescriber should evaluate the need for a gradual increase from the starting dose to the maintenance dose because of the risk of severe rash with starting high doses and increasing doses above the recommended dose (see [Precautions]). The longer the interval from the previous dose, the more important it is to consider tapering from the starting dose to the maintenance dose. If lamotrigine is discontinued for more than 5 half-lives (see [Pharmacokinetics]), the recommended lamotrigine escalation regimen should usually be followed to gradually increase from the starting dose to the maintenance dose.
Retreatment with this product is not recommended for patients who discontinued it due to rash during prior therapy, unless the anticipated benefits clearly outweigh the potential risks.
-Monotherapy dose.
Adults and children 12 years of age and older.
The initial dose of this product for monotherapy is 25 mg once daily for two weeks; followed by 50 mg once daily for two weeks. Thereafter, the dose is increased every 1-2 weeks with a maximum increase of 50-100 mg until optimal efficacy is achieved. The usual maintenance dose to achieve optimal efficacy is 100-200 mg/day given once daily or in two divided doses. However, some patients may require 500 mg of this product daily to achieve the desired efficacy.
The recommended dose escalation for monotherapy in adults and children over 12 years of age is shown in the table.
1 + 2 weeks 3 + 4 weeks Usual maintenance 25mg
(once daily) 50mg
(once daily) 100-200mg
(once daily or in two oral doses)
To achieve maintenance dose, daily dose may be increased by 50-100mg every 1-2 weeks To reduce the risk of rash development, the initial dose and subsequent dose increments should not exceed the table above (see [Caution]).
-Dose for add-on therapy.
Adults and children over 12 years of age.
For patients co-administered with sodium valproate, regardless of whether they are taking other antiepileptic drugs, the initial dose of this product is 25 mg every other day for two weeks and 25 mg once daily for the next two weeks. thereafter, the dose should be increased every 1-2 weeks by a maximum of 25-50 mg until optimal efficacy is achieved. The usual maintenance dose for optimal efficacy is 100-200 mg once daily or in two divided doses.
For patients on enzyme-inducing antiepileptic drugs, with or without other antiepileptic drugs (except sodium valproate), the initial dose is 50 mg once daily for 2 weeks, followed by 100 mg twice daily for 2 weeks. Thereafter, the dose is increased by a maximum of 100 mg every 1-2 weeks until optimal efficacy is achieved. The usual maintenance dose for optimal efficacy is 200-400 mg per day in two divided doses. Some patients require 700 mg of this product daily to achieve the desired efficacy.
In patients on other drugs that do not significantly inhibit or induce glucuronidation (see [Drug Interactions]), the initial dose is 25 mg once daily for two weeks and 50 mg once daily for the next two weeks. Thereafter, the dose level is increased every 1-2 weeks by 50-100 mg/day, and the subsequent dose should be increased until optimal efficacy is achieved. The usual maintenance dose to achieve optimal efficacy is 100-200 mg/day once daily or in two divided doses.
The recommended dose escalation for combination drug therapy in adults and children over 12 years of age is shown in Table
Combination medications 1 + 2 weeks 3 + 4 weeks Usual maintenance dose Valproate with/without other antiepileptic drugs 12.5 mg
(25mg, every other day) 25mg
(once daily) 100-200mg
(once daily or in two divided doses)
To achieve maintenance dose may be increased by 25-50mg every 1-2 weeks enzyme induced antiepileptic* with/without other antiepileptic drugs (except sodium valproate) 50mg
(once daily) 100mg
(divided into two doses) 200-400mg
(divided into two doses)
To achieve maintenance dose may be increased by 100mg every 1-2 weeks therapeutic dose escalation regimen of other drugs that do not significantly inhibit or induce glucuronidation of this product (see [Dosage]) 25mg
(once daily) 50mg
(once daily) 100-200mg
(once daily or in two divided doses)
To achieve maintenance dose may be increased by 50-100mg every 1-2 weeks* e.g. phenytoin, carbamazepine, phenobarbital and paroxetine Note: If the patient is taking an antiepileptic drug with which the pharmacokinetics of this product are currently unknown, the recommended dose of this product in combination with sodium valproate should be used, followed by a gradual increase in dose until The dose should be increased gradually to achieve optimal efficacy. To reduce the risk of rash, the initial dose and subsequent dose increments should not exceed the table above (see [Precautions]).
Children (2-12 years).
In patients taking sodium valproate with/without any other antiepileptic drug, the initial dose of this product is 0.15 mg/kg/day once daily for 2 weeks and 0.3 mg/kg once daily for the next 2 weeks. thereafter, the dose should be increased every 1-2 weeks up to a maximum increase of 0.3 mg/kg until optimal efficacy is achieved. The usual maintenance dose to achieve optimal efficacy is 1-5 mg/kg/day in a single dose or in two divided doses, with a maximum daily dose of 200 mg.
The initial dose of this product is 0.6 mg/kg/day in two divided doses for two weeks in patients who are co-administered with antiepileptic drugs (AEDs) or other drugs that induce glucuronidation of this product (see [Drug Interactions]), with or without other antiepileptic drugs (except sodium valproate), and 1.2 mg/kg/day in two divided doses for the next two weeks. Thereafter, the dose should be increased every 1-2 weeks up to a maximum of 1.2 mg/kg until optimal efficacy is achieved. The usual maintenance dose to achieve optimal efficacy is 5-15 mg/kg/day in two divided doses, with a maximum daily dose of 400 mg.
To obtain an effective maintenance dose, the child’s weight must be monitored and the dose reassessed based on changes in weight.
In patients on other drugs that do not significantly inhibit or induce glucuronidation of this product (see [Drug Interactions]), the initial dose of this product is 0.3 mg/kg/day once or in two divided doses for two weeks, followed by 0.6 mg/kg/day once or in two divided doses for two weeks. Thereafter, the dose is increased every 1-2 weeks to a maximum of 0.6 mg/kg/day until optimal efficacy is achieved. The usual maintenance dose for optimal efficacy is 1-10 mg/kg/day once or twice daily, with a maximum dose of 200 mg/day.
The recommended dose escalation method (total daily mg/kg/day) for drug combination therapy in children (2-12 years) is shown in the table below.
Combination medications 1 + 2 weeks 3 + 4 weeks Usual maintenance dose of sodium valproate with/without other antiepileptic drugs 0.15 mg/kg**
(once daily) 0.3mg/kg
(once daily) may be increased by 0.3mg/kg every 1-2 weeks to reach maintenance dose of 1-5mg/kg (once daily or in two divided doses) enzyme-induced antiepileptic* with/without other antiepileptic drugs (except sodium valproate) 0.6mg/kg
(divided into two doses) 1.2mg/kg
(divided into two doses) May be increased by 1.2 mg/kg for 1-2 weeks to achieve a maintenance dose of 5-15 mg/kg (divided into two doses) Dosing regimen for other drugs that do not significantly inhibit or induce glucuronidation of this product (see [Dosage]) 0.3 mg/kg
(once or in two doses) 0.6mg/kg
(once or in two divided doses) To achieve a maintenance dose of 1-10mg/kg increase by 0.6mg/kg every 1-2 weeks (once or in two divided doses daily) Maximum daily dose is 200mg
*E.g. phenytoin, carbamazepine, phenobarbital and paroxetine Note: If the patient is taking an antiepileptic drug with which the pharmacokinetics of this product interact is currently unknown, the recommended dose of this product in combination with sodium valproate should be used, followed by a gradual increase in dose until optimal efficacy is achieved. **Note: If the calculated daily dose is 1-2 mg, 2 mg of this product should be taken every other day for the first two weeks. If the calculated dose is less than 1mg, the product should not be taken.
To reduce the risk of rash, do not exceed the above table for both the initial dose and subsequent incremental doses (see [Precautions]).
Patients 2-6 years of age.
The required maintenance dose may be at the high end of the recommended dose range.
Children less than 2 years of age.
There is insufficient information on the use of this product in children younger than 2 years of age; therefore, this product is not recommended for use in children younger than 2 years of age.
General dosing recommendations for this product in special patient populations
Women taking hormonal contraceptives
(a) Initiation of this product in women already taking hormonal contraceptives.
Although oral contraceptives can increase the clearance of this product (see [Precautions] and [Drug Interactions]), the recommended dose escalation guidelines for this product do not need to be adjusted based solely on the patient’s use of hormonal contraceptives. Dose escalation should be based on whether the product is combined with sodium valproate (an enzyme inhibitor of the product); or whether the product is combined with an enzyme inducer of the product; or whether the product is added in the absence of sodium valproate or a glucuronidating agent of the product, following the guidelines for dose escalation (see Table 1 for patients with epilepsy).
(b) Initiation of hormonal contraceptives in patients already on a maintenance dose of this product but not on a glucuronidation-inducing agent of this product.
The maintenance dose of this product will need to be increased in most cases, possibly by up to 2-fold (see [Precautions] and [Drug Interactions]). It is recommended that the dose of this product be increased at a rate of 50-100 mg/day per week, depending on the individual clinical response, when starting hormonal contraceptives. The dose should not be increased beyond this rate unless the clinical response supports a higher dose increase.
(c) Discontinuation of hormonal contraceptives in patients already taking maintenance doses of this product but not taking a glucuronidation-inducing agent of this product.
The maintenance dose of this product will need to be reduced by up to possibly 50% in most cases (see [Precautions] and [Drug Interactions]). It is recommended that the daily dose of this product be reduced gradually (at a rate of no more than 25% of the total daily dose per week) at 50-100 mg/week for more than 3 weeks, unless clinical response indicates otherwise.
Combination with atazanavir/ritonavir
Although atazanavir/ritonavir has been shown to reduce plasma concentrations of this product (see [Drug Interactions]), no adjustment to the recommended dose escalation guidelines for lamotrigine is required based on patient use of atazanavir/ritonavir. Dose escalation should be based on whether the product is added to sodium valproate (an enzyme inhibitor of the product); or whether the product is added in the absence of sodium valproate or an inducer of glucuronidation of the product, and follow the guidelines for dose escalation.
In patients already taking maintenance doses of this product and not receiving glucuronidation-inducing agents, an increase in the dose of this product is required if atazanavir/ritonavir is added, and a decrease in the dose of this product is required if atazanavir/ritonavir therapy is discontinued.
Dosing in patients with hepatic impairment.
The initial, escalating and maintenance doses of this product should usually be reduced by approximately 50% and 75% in patients with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment, respectively. Incremental and maintenance doses should be adjusted according to clinical efficacy.
Dosing in patients with impaired renal function.
Caution should be exercised in the administration of this product in patients with impaired renal function. In patients with advanced renal failure, the initial dose of this product should follow the dosing regimen used in combination with other antiepileptic drugs, with a reduced maintenance dose for patients with significantly impaired renal function (see [Precautions]). For more information on pharmacokinetics, see [Pharmacokinetics].
Adverse reactions
Adverse reactions identified from clinical trial data in epilepsy or bipolar disorder are divided into indication-specific sections. Adverse reactions identified through postmarketing surveillance for these two indications are included in a new postmarketing adverse reactions section. All three sections should be consulted simultaneously when considering the overall safety profile of lamotrigine.
Classification of adverse reactions.
Very common (³1/10).
Common (³1/100 to <1/10).
Uncommon (³1/1,000 to <1/100).
Rare (³1/10,000 to<1/1000),
Very rare (<1/10000).
Epilepsy
The following adverse reactions were all identified in clinical trials in epilepsy. These adverse reactions, as well as those identified in clinical trials and postmarketing surveillance for bipolar disorder, need to be considered when considering the overall safety profile of lamotrigine.
Skin and Subcutaneous Tissue Lesions
Very common: rash
Rare: Stevens-Johnson syndrome
Very rare: toxic epidermolysis bullosa
In double-blind, add-on clinical trials in adults, the incidence of rash was as high as 10% in patients taking this product and 5% in patients taking placebo. 2% of patients had a rash that led to discontinuation of this product. This rash, which is generally maculopapular in appearance, usually appears during the first 8 weeks of treatment and disappears after discontinuation of the product (see [Precautions]).
Rare, severe, potentially life-threatening rashes have been reported, including Stevens-Johnson syndrome (SJS) and toxic epidermolysis bullosa (Lyell syndrome). Although most patients recover after discontinuation of the drug, some patients experience irreversible maculopapularity and there have been rare cases associated with death (see [Precautions]).
Severe rashes have been reported, for example, in adults and children over 12 years of age at an incidence of approximately 1:1000. children under 12 years of age are at higher risk than adults. Some studies have shown that the incidence of rash in children under 12 years of age requiring hospitalization is 1:300 to 1:100 (see [Precautions]).
The initial onset of rash in children may be mistaken for an infection; physicians should consider the possibility of a drug reaction if children develop a rash and fever during the first 8 weeks of treatment with this product.
In addition, the overall risk of developing a rash is strongly associated with the following factors.
-High starting doses of this product and subsequent increases in dose above the recommended escalating dose (see [Dosage]).
-Concurrent application of sodium valproate (see [Dosage]).
Rash has also been reported as part of an allergic syndrome with multiple forms of systemic symptoms (see Immune System Abnormalities)
Hematologic and lymphatic system abnormalities
Extremely rare: hematologic abnormalities (including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and very rare aplastic anemia and granulocyte deficiency), lymphadenopathy
Hematologic abnormalities and lymphadenopathy may or may not be associated with allergic syndromes (see Immune System Abnormalities).
Immune system abnormalities
Extremely rare: allergy syndrome** (includes symptoms such as fever, lymphadenopathy, facial edema, abnormalities of blood and liver function, rare diffuse intravascular coagulation (DIC), and multiorgan failure)
**: The rash has also been reported as part of an allergic syndrome with multiple forms of systemic symptoms including fever, lymphadenopathy, facial edema, and abnormalities of blood and liver function. The severity of the clinical reactions caused by this syndrome varies widely; in very rare cases it can cause diffuse intravascular coagulation (DIC) and multi-organ failure. It is important to be aware of early manifestations of allergic reactions (e.g., fever, lymphadenopathy), even if the rash is not obvious. If signs and symptoms appear, the patient should be informed to seek immediate medical attention. If signs and symptoms of early reactions appear, the patient should be evaluated immediately; if another cause cannot be determined, the product should be discontinued.
Psychiatric abnormalities
Common: aggressive behavior, irritability
Very rare: unsteadiness, hallucinations, confusion
Neurological abnormalities
Very common: headache
Common: drowsiness, insomnia, dizziness, tremors
Uncommon: ataxia
Rare: nystagmus
Ocular abnormalities
Uncommon: diplopia, blurred vision
Gastrointestinal abnormalities
Common: nausea, vomiting, diarrhea
Hepatobiliary abnormalities
Very rare: elevated liver function tests, liver function abnormalities, liver failure
The presence of liver function abnormalities is usually associated with allergic reactions, but isolated cases without obvious signs of allergy have been reported.
Muscle, bone and connective tissue abnormalities
Very rare: lupus-like reactions
Systemic symptoms and administration site reactions
Common: fatigue
Bipolar disorder.
The following adverse reactions were identified in clinical trials in bipolar disorder. These adverse reactions, as well as those identified in epilepsy clinical trials and post-marketing surveillance, need to be considered when considering the overall safety profile of lamotrigine.
Skin and subcutaneous tissue lesions
Very common: rash
Rare: Stevens-Johnson syndrome
When all studies of bipolar disorder receiving lamotrigine (control and non-control) were considered, the incidence of rash among patients treated with lamotrigine was 12%. However, in controlled clinical trials of patients with bipolar disorder, the incidence of rash was 8% in patients receiving lamotrigine and 6% in patients receiving placebo.
Neurological abnormalities
Very common: headache
Common: Agitation, drowsiness, dizziness
Muscle, bone and connective tissue abnormalities
Common: arthralgia
Systemic symptoms and administration site reactions
Common: pain, back pain
Post-marketing surveillance.
The adverse reactions included in this section were identified during postmarketing surveillance for these two indications. These adverse reactions, as well as those identified in clinical trials for epilepsy and bipolar disorder, need to be considered when considering the overall safety profile of lamotrigine.
Skin and subcutaneous tissue lesions
Rare: alopecia areata
Mental system abnormalities
Extremely rare: nightmares
Neurological abnormalities
Very common: drowsiness, ataxia, headache, dizziness
Common: nystagmus, tremor, insomnia
Rare: aseptic meningitis (see [caution])
Very rare: agitation, swaying, dyskinesia, worsening Parkinson’s disease, extrapyramidal reactions, choreoathetoid tardive dyskinesia
Lamotrigine has been reported to potentially worsen Parkinson’s symptoms in patients with existing Parkinson’s disease, and isolated cases of extrapyramidal reactions and choreoathetosis have been reported in patients without this underlying disease.
Ophthalmic abnormalities
Very common: diplopia, blurred vision
Rare: conjunctivitis
Gastrointestinal abnormalities
Very common: nausea, vomiting
Common: diarrhea
Only seen in epilepsy
Neurological abnormalities
Very rare: increased seizure frequency
Withdrawal seizures
See [Caution] 14.
Persistent status epilepticus
See [Precautions] 15.
Unexplained sudden death in patients with epilepsy
See [Precautions] 16.
Contraindications
Contraindicated in patients with known hypersensitivity to this product and any of the ingredients in this product.
Precautions
1. Severe skin rash
Pediatric patients: A prospective cohort study showed that the incidence of severe rash associated with discontinuation of this product and hospitalization was approximately 0.8% (16/1983) in pediatric epilepsy patients (2 to 16 years of age) receiving adjunctive therapy. 3 dermatologists reviewed 14 of these cases and disagreed on the severity of the rash. For example, one expert did not believe that Stevens-Johnson syndrome was present in any of these cases; another believed that Stevens-Johnson syndrome was present in 7 of them. There was 1 rash-related death among these 1983 patients. In addition, toxic epidermolysis bullosa with or without permanent sequelae and/or death is rare in postmarketing experience in the United States and other countries.
There is evidence that co-administration of valproate in multidrug regimens for pediatric patients increases the risk of severe, life-threatening rash. The incidence of severe rash was 1.2% (6/482) in pediatric patients who were co-administered valproate compared to 0.6% (6/952) in those who were not co-administered valproate.
Adult patients: The incidence of severe rash associated with discontinuation and hospitalization was 0.3% (11/3,348) in adult patients treated with this product in pre-marketing epilepsy clinical trials. In clinical trials of bipolar and other mood disorders, the incidence of severe rash in adult patients treated with this product as initial monotherapy was 0.08% (1/1,233), while the incidence of severe rash in adult patients treated with this product as adjunctive therapy was 0.13% (2/1,538). There were no deaths in these subjects. However, rare cases of rash-related deaths have been reported in post-marketing experience worldwide, but their number is too small to accurately estimate their incidence.
Among the rashes that have resulted in hospitalization are Stevens-Johnson syndrome, toxic epidermolysis bullosa, angioedema, and rashes with multiple forms of systemic symptoms: fever, lymphadenopathy, facial edema, and abnormal blood and liver function.
There is evidence that the combination of valproate in a multidrug regimen in adult patients increases the risk of severe, life-threatening rash. In a clinical trial of 584 patients with epilepsy who combined this product and valproate, 6 (1%) were hospitalized for rash; conversely 4 (0.16%) of 2398 patients and volunteers who used this product without valproate were hospitalized.
Patients with a history of allergy or rash to other antiepileptic drugs (AEDs): exceeding the recommended initial dose and/or dose escalation rate, and patients with a history of allergy or rash to other AEDs may be at increased risk of non-severe rash.
2. Rash
Adverse skin reactions have been reported and generally occur within the first 8 weeks of initiation of treatment with this tablet. Most rashes are mild and self-limiting. However, serious rashes requiring hospitalization and discontinuation of the product have been reported, including Stevens-Johnson syndrome and toxic epidermolysis bullosa (TEN) (see [Adverse Reactions]).
The initial onset of rash in children may be mistaken for an infection; physicians should consider the possibility of a drug reaction if children develop rash and fever during the first 8 weeks of treatment with this product.
In addition, the overall risk of developing a rash is strongly associated with the following factors.
-The initial dose of this product is too high and subsequent increases in dose above the recommended dose (see [Dosage]).
-Concomitant application of sodium valproate (see [Dosage]).
Patients with a history of allergy or rash to other antiepileptic drugs should also be aware that they are approximately 3 times more likely to develop a non-severe rash after treatment with this drug than patients without such a history.
All patients (adults and children) who develop a rash should be evaluated promptly and the drug discontinued immediately unless the rash can be diagnosed as unrelated to the drug. In patients who have discontinued this product due to rash during prior therapy, reintroduction of treatment with this product is not recommended unless the anticipated benefit outweighs the potential risk.
3. Allergic reactions
Allergic reactions, some of which are fatal or life-threatening, have also occurred. Some of these reactions cause clinical multi-organ failure/disorders, including abnormal liver function and signs of diffuse intravascular coagulation. It is important to be aware of the prevention of early manifestations of allergic reactions (e.g., fever, lymphadenopathy), even if the rash is not obvious. If signs and symptoms of early reactions occur, the patient should be evaluated immediately; if another cause cannot be determined, the product should be discontinued.
Patients should be informed of signs or symptoms of rash or other allergic reactions (e.g., fever, lymphadenopathy) that may indicate a serious medical event prior to initial treatment with this product, and any of these symptoms should be reported to the physician immediately.
4. Acute Multi-Organ Failure
Multi-organ failure has been observed in patients receiving this drug, and in some cases has been fatal or irreversible. In clinical trials of patients with epilepsy receiving this product, the rates of death and varying degrees of hepatic failure due to multiorgan failure reported in adult and pediatric patients were 2/3,796 and 4/2,435, respectively. no such deaths were reported in clinical trials of patients with bipolar disorder. Rare deaths due to multiorgan failure have also been reported in charity and post-marketing use. Most deaths occurred in conjunction with other medical events, including persistent epilepsy, very severe sepsis, and hantavirus, making it difficult to identify the initial cause of death.
In addition, three patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl) developed multiorgan dysfunction and diffuse intravascular coagulation 9 to 14 days after the addition of this product to the AED regimen. All patients developed rash and 2 patients developed rhabdomyolysis. 2 pediatric patients were co-treated with valproate, while adult patients were co-treated with carbamazepine and clonazepam. All patients recovered with supportive therapy after discontinuation of this product.
5. Renal failure
In single-dose studies in patients with advanced renal failure, plasma concentrations of this product were not significantly altered. However, accumulation of glucuronide metabolites can be expected; therefore, it should be used with caution in patients with renal failure.
6. Hepatic Failure
In patients with severe hepatic impairment (Child-Pugh class C), the initial and maintenance dose should be reduced by 75%. The drug should be used with caution in patients with severe hepatic impairment.
7. Hematologic system dysfunction
Hematologic dysfunction has been reported that may or may not be related to the allergic syndrome, including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia and, rarely, aplastic anemia and simple red blood cell aplastic anemia.
8. Suicidal behavior and ideation
Patients taking AEDs for any indication, including this product, are at increased risk of suicidal ideation or behavior. Patients treated with AEDs for any indication should be monitored for the emergence or worsening of depression, suicidal ideation or behavior, and/or any abnormal changes in mood or behavior.
A pooled analysis of 199 placebo-controlled clinical trials of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk of developing suicidal ideation or behavior than patients randomized to placebo (corrected relative risk 1.8, 95% CI:1.2, 2.7). In these trials, the mean duration of treatment was 12 weeks, and the incidence of suicidal behavior or ideation was 0.43% in 27,863 AED-treated patients compared with 0.24% in 16,029 placebo-treated patients, or approximately 1 additional case of suicidal ideation or behavior per 530 patients. Four drug-treated patients in the trial committed suicide, while no placebo-treated patients developed suicide, but the number of events was too small to draw any conclusions about the effect of drugs on suicide.
Increases in suicidal ideation or behavior were observed as early as 1 week after initiation of treatment with AEDs and continued to increase over the treatment period evaluated. Because most trials in the analysis did not exceed 24 weeks, the risk of suicidal ideation or behavior after 24 weeks could not be assessed.
Data from the analyses showed a generally consistent risk of suicidal ideation or behavior between drugs. The increased risk of suicidal ideation or behavior for AEDs with different mechanisms of action and for different indication ranges suggests that this risk applies to all AEDs used for any indication. in the clinical trials analyzed, the risk did not vary significantly by age (5 to 100 years).
The table below lists the absolute and relative risks according to indication for all AEDs evaluated.
Risks summarized according to indication of the antiepileptic drugs in the pooled analysis
Indication Placebo-treated patients with events per 1000 patients Medication-treated patients with events per 1000 patients Relative risk: incidence in medication-treated patients/incidence in placebo-treated patients Risk difference: additional medication-treated patients with events per 1000 patients Epilepsy 1.03.43.52.4 Psychiatric disorders 5.78.51.52.9 Other 1.01.81.90.9 Total 2.44.31.81.9
The relative risk of suicidal ideation or behavior was higher in clinical trials for epilepsy than for psychosis or other, but the difference in absolute risk was similar for epilepsy and psychiatric indications.
Anyone considering prescribing this or other AEDs must weigh the risk of suicidal ideation or behavior against the risk of untreated disease. Epilepsy and many other disorders for which AEDs are prescribed are themselves associated with increased morbidity and mortality and risk of suicidal ideation and behavior. If suicidal ideation or behavior occurs during treatment, prescribers should consider whether the presence of these symptoms is related to the patient’s own illness.
Patients, their caregivers, and family members should be informed of the increased risk of suicidal ideation and behavior with AEDs and advised to monitor for the onset or worsening of signs and symptoms of depression, any abnormal changes in mood or behavior, or the onset of suicidal ideation, behavior, or self-harming ideation. The appearance of relevant behaviors should be reported immediately to the health care provider.
9. Medication for patients with bipolar disorder
Risk of clinical deterioration and suicide associated with bipolar disorder: Patients with bipolar disorder may experience worsening of depressive symptoms and/or suicidal ideation and behavior (suicide) regardless of whether or not they are taking medication for bipolar disorder. Patients receiving this product for bipolar disorder should be monitored closely for clinical deterioration (including the development of new symptoms) and suicidal behavior, especially at the beginning of a course of treatment or at dose changes.
In addition, patients with a history of suicidal behavior or suicidal ideation, as well as those who exhibit significant suicidal ideation prior to the initiation of treatment are at increased risk of developing suicidal ideation or attempting suicide and should be carefully monitored during treatment [see [Precautions] Suicidal Behavior and Ideation].
A change in treatment regimen, including possible interruption of dosing, should be considered for patients who develop clinical deterioration (including the development of new symptoms) and/or suicidal ideation/behavior, especially if the symptoms are more severe, emergent, or not part of the chief complaint.
To reduce the risk of overdose, this product should be prescribed in a minimum amount of tablets consistent with that used in patients with better disease control. Overdoses of this product have been reported, some of which have been fatal [see [Drug Overdose]].
10. Nonbacterial Meningitis
Treatment with this product increases the risk of non-bacterial meningitis. Because untreated meningitis from other causes may have serious consequences, patients should be evaluated for other causes of meningitis and treated appropriately.
Post-marketing cases of non-bacterial meningitis have been reported in pediatric and adult patients taking this product for different indications. Pre-appearance symptoms include headache, fever, nausea, vomiting, and neck stiffness. Rash, photophobia, myalgia, chills, confusion, and drowsiness have also been reported in some cases. Symptoms were reported between the onset of 1 day and the start of treatment 1.5 months later. In most cases, symptoms were reported to subside after discontinuation of the product. Re-exposure resulted in the rapid onset of symptoms that are usually more severe (from within 30 minutes to 1 day after restarting treatment). Some of the patients who developed non-bacterial meningitis on this treatment may have underlying systemic lupus erythematosus or other autoimmune diseases.
The cerebrospinal fluid (CSF) analyzed at the onset of clinical symptoms in the reported cases was characterized by mild to moderate increases in CSF cells, normal glucose levels, and mild to moderate increases in protein. poor CSF white blood cell counts showed significant increases in neutrophils in most cases, although significant increases in lymphocytes were reported in approximately one-third of cases. Some patients also reported new signs and symptoms involving other organs (the vast majority involving the liver and kidneys), which may indicate that the nonbacterial meningitis observed in these cases was part of an allergic reaction [see [Caution]].
11. Potential Medication Errors
Medication errors with this product have occurred. In particular, the name of this product or this product may be confused with the names of other commonly used drugs. It is also possible that a medication error may occur between different dosage forms of this product. To reduce the possibility of medication errors, the product should be written and presented clearly. The properties of the tablets are described in the medication guide accompanying the product, which highlights the distinctive markings, color, and properties of the formulation to help identify different drug package sizes and therefore may help reduce the risk of medication errors. To avoid using the wrong drug or dosage form, patients are strongly advised to visually inspect the tablets they are taking each time they fill their prescription records to confirm that the drug being taken is the product and is in the correct dosage form.
12. Combined use with oral contraceptives
Some estrogen-containing oral contraceptives reduce the serum concentration of this product [see [Pharmacokinetics]]. For most patients taking this product, it is necessary to adjust the dose of this product when starting or stopping estrogen-containing oral contraceptives [see [DOSAGE AND ADMINISTRATION] for general dosing recommendations for this product in special patient populations]. Levels of this product are expected to increase during the week of inactivity (the “no-dose period”) and to double at the end of that week. Increased plasma levels of this product can cause additional adverse effects such as dizziness, ataxia, and diplopia.
13. Hormonal contraceptives
13.1 Effect of hormonal contraceptives on the efficacy of the tablets.
Studies have shown that the ethinylestradiol/levonorgestrel (30 μg/150 μg) combination can increase the clearance of this product by approximately 2-fold, resulting in a decrease in the level of this product (see [Drug Interactions]). After gradual dose increases, maintenance of maximum efficacy requires an increase in the maintenance dose of this product (up to 2-fold) in most cases. In women who are not taking this glucuronidation inducer but are taking a hormonal contraceptive (including a 1-week inactivation period, i.e., a “no-dose period”), the level of this drug increases temporarily and gradually during the no-dose week. The increase was greater when the dose was increased before or during the week of inactivity. For dosing instructions, see “General Dosing Regimen Recommendations, Dosage and Administration in Specific Patients.”
Clinicians should appropriately manage women who initiate or discontinue hormonal contraceptives during treatment with this drug and should adjust the dose of this drug in most cases if necessary.
Other oral contraceptives and hormone replacement therapy (HRT) have not been studied, but these drugs may have similar effects on the pharmacokinetic parameters of this product.
13.2 Effect of Benadryl tablets on the efficacy of hormonal contraceptives.
A drug interaction study in 16 healthy volunteers demonstrated a moderate increase in levonorgestrel clearance and changes in serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) when this product was administered concomitantly with a hormonal contraceptive (ethinylestradiol/levonorgestrel) (see [Drug Interactions]). The effect of these changes on ovarian ovulatory activity is unknown. However, the possibility that these changes result in reduced contraceptive efficacy in some patients taking both hormonal drugs and this tablet cannot be ruled out. Therefore, patients should be advised to report to their physician at the earliest possible time if they experience altered menstrual cycle conditions, such as sudden bleeding.
14. Withdrawal episodes
As with other AEDs, this product should not be discontinued abruptly. In patients with epilepsy there is a risk of increased seizure frequency. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt discontinuation of this product. However, these 2 patients with bipolar disorder had other confounding factors that contributed to the seizures. Discontinuation of this product should be tapered to discontinuation (approximately 50% per week) over a period of not less than 2 weeks, unless safety considerations require faster discontinuation [see [DOSAGE AND ADMINISTRATION] for general dosing recommendations for this product in special patient populations].
15. Persistent status epilepticus
It is difficult to effectively assess the incidence of treatment-induced status epilepticus in patients treated with this drug because participants in clinical trials did not use consistent criteria to identify cases. 2,343 adult patients had at least 7 definite reports of status epilepticus. In addition, a range of different seizure exacerbations (e.g., continuous seizures, sudden seizures, etc.) were reported.
16. Sudden Unexpected Death in Epilepsy (SUDEP)
Twenty cases of sudden death of unknown cause were reported in a cohort study of 4,700 patients with epilepsy (5,747 exposed patient-years) in post-marketing studies of this product.
Some of these cases could be interpreted as epilepsy-related deaths, but seizures that did not occur at night were not observed. This represents a per patient-year incidence of death of 0.0035. Although this rate exceeds that expected in an age- and sex-matched healthy population, it is within the range of estimates of the incidence of sudden unexplained death in patients with epilepsy not taking this product (from 0.0005 in the general epilepsy patient population to 0.004 in the recent clinical trial population (similar to the clinical development program for this product) to 0.005 in refractory epilepsy (0.005 in patients). Therefore, whether these numbers indicate confidence in the drug or suggest problems depends on the comparability of the reporting population to the population receiving the product and the accuracy of the estimates. It is likely that the most plausible result is that patients receiving this drug have similar SUDEP estimation rates to patients receiving other AEDs that have been clinically examined in similar populations that show no chemical correlation. Importantly, there was no chemical correlation between the drug and this product. This evidence suggests that the higher SUDEP rate reflects the rate of the population rather than the effect of the drug, although this evidence has not been definitively demonstrated.
17. Adding this product to a polypharmacy regimen that includes valproate
Because valproate reduces the clearance of this product, the dose of this product is reduced by half when valproate is included compared to when valproate is not present.
18. Binding to eyes and other melanin-containing tissues
Since this product binds to melanin, it accumulates over time in melanin-rich tissues. This increases the likelihood of toxicity in these tissues after long-term use. Although an ophthalmic examination was performed in a clinical trial, the examination was not sufficient to rule out subtle effects or damage after prolonged exposure. Furthermore, the effectiveness of available tests to detect potential adverse effects of this product in combination with melanin is not known. Therefore, although there are no specific recommendations for periodic ophthalmic monitoring, the prescribing physician should be aware of the potential for long-term effects on the eye.
19. Laboratory Tests
The significance of monitoring plasma concentrations of this product has not been determined in patients treated with this product. Because of possible pharmacokinetic interactions with other drugs, including AEDs (see [Drug Interactions] Table: Effects of other drugs on glucuronidation of this product), indications may arise for the need to monitor plasma levels of this product and co-administered drugs, particularly during dose adjustments. In general, clinical judgment should be made based on monitored plasma levels of this product and other drugs, and a determination should be made as to whether dose adjustment is necessary.
20. Effect of this product on organic cation transporter 2 (OCT 2) substrates
This product is an inhibitor of renal tubular secretion, which is achieved by inhibition of OCT 2 protein (see Interactions). This may result in increased plasma levels of certain drugs that are primarily excreted via renal tubular secretion. It is not recommended to be used in combination with OCT 2 substrates with a narrow therapeutic index such as dofetilide.
21. Dihydrofolate reductase
This product is a weak inhibitor of dihydrofolate reductase and therefore may interfere with the metabolism of folic acid during long-term treatment.
22. Patients taking other preparations containing this product
This product should not be used in patients who are taking other preparations containing this product for treatment without consulting a physician.
23. Effects on the ability to drive and operate machinery
Two studies with volunteers demonstrated that the effects of this product on coordination of fine visual movements, eye movements, body oscillations and subjective sedative effects were not different from those of placebo.
Neurological adverse events such as dizziness and diplopia have been reported in clinical trials with this product. Therefore, patients should understand the possible effects of this product on them before driving and operating machinery.
For Pregnant and Lactating Women
Pregnancy
Risk Overview
Data from several prospective pregnancy exposure registry studies and epidemiological studies in pregnant women did not reveal an increased frequency of major malformations or a change in the pattern of malformations in women exposed to lamotrigine compared to the general population. Data on lamotrigine pregnancy exposure are primarily from patients with epilepsy. In animal studies, developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) resulted when lamotrigine was given at doses lower than the clinically administered dose during pregnancy.
Lamotrigine decreased fetal folate concentrations in rats, an effect associated with adverse pregnancy outcomes in animals and humans.
The background risk of major birth defects and miscarriage could not be estimated in the respective populations, and in the general US population the background risk of major birth defects and miscarriage in pregnancy is estimated to be 2%-4% and 15%-20%, respectively.
Clinical considerations
As with other antiepileptic drugs, physiologic changes during pregnancy may affect lamotrigine concentrations and treatment effects. Lamotrigine concentrations have been reported to decline during pregnancy and return to pre-pregnancy concentrations after delivery. Dose adjustments may be necessary to maintain clinical efficacy.
Human data
Data from several international pregnancy registries do not show an overall risk of malformation growth. The International Lamotrigine Pregnancy Registry reported 2.2% (95% CI: 1.6%, 3.1%) of 1558 infants treated with lamotrigine monotherapy in the first trimester had congenital malformations.The NAAED Pregnancy Registry reported 2.0% of 1562 infants treated with lamotrigine monotherapy in the first trimester had significant congenital malformations.EURAP, a large North American international pregnancy registry outside of North America, reported 2.9% (95% CI: 2.3%, 3.7%) of 2,514 birth defects reported in first-trimester lamotrigine monotherapy neonates. The incidence of major congenital malformations was similar to that estimated for the general population.
An increased risk of isolated cleft lip was observed in the NAAED Pregnancy Registry, where 2200 infants exposed to lamotrigine in early gestation had a risk of 3.2 (95% CI: 1.4, 6.3) per 1000, a 3-fold increase compared to unexposed healthy controls. This finding has not been observed in other large international pregnancy registries. In addition, case-control studies based on 21 congenital anomaly registries covering more than 10 million births in Europe reported an adjusted ratio of 1.45 (95% CI: 0.8, 2.63) for exposure to lamotrigine isolated cleft lip.
Several meta-analyses reported comparing the disease group exposed to lamotrigine during pregnancy compared to healthy subjects without an increased risk of major congenital malformations. No pattern of specific malformation types was observed.
The same meta-analysis assessed the risk of additional maternal and infant outcomes, including fetal death, stillbirth, preterm birth, small for gestational age, and neurodevelopmental delay. Although there are no data suggesting that lamotrigine monotherapy exposure increases the risk of these outcomes, differences in outcome definitions, study methodology, and control groups make it difficult to draw conclusions.
Breastfeeding
Risk Overview
Lamotrigine is present in the breast milk of lactating women taking lamotrigine. If the dose of lamotrigine is increased during pregnancy but not reduced to the pre-pregnancy dose after delivery, the mother’s serum and milk levels are elevated to high levels postpartum and therefore the newborn and small infant are at risk for high serum levels. The drug requires glucuronidation for clearance. The ability to glucuronidate is immature in infants, and this may also affect the level of lamotrigine exposure. Rash, apnea, lethargy, poor sucking and adverse weight gain (requiring hospitalization in some cases) have been reported in children breastfed by mothers taking lamotrigine. Whether these events were caused by lamotrigine is unknown. There are no data on the effects of this drug on lactation.
The developmental and health benefits of breastfeeding should be considered along with the clinical need for lamotrigine in mothers, the potential adverse effects of lamotrigine on breastfed infants.
Clinical considerations
Breastfed infants should be closely monitored for adverse events due to lamotrigine. Infant lamotrigine serum levels should be measured to rule out toxicity problems that occur at elevated concentrations. Breastfeeding should be discontinued in infants who develop lamotrigine toxicity.
Data
Data from several small studies have reported that lamotrigine blood levels in nursing infants can reach up to 50% of the mother’s blood levels.
[Pediatric Dosage].
See [Dosage] for monotherapy and add-on therapy for children 12 years of age and older
Children 2 to 12 years of age.
Because data from appropriate studies in children are insufficient, it is not possible to recommend doses for monotherapy in children under 12 years of age.
See [Dosage] for add-on therapy.
Safety and efficacy have not been established in children under 2 years of age, and dosing in children under 2 years of age is not recommended.
Geriatric Use]
The pharmacokinetics of this product in the elderly is not significantly different from that of young adults, and therefore no dose adjustment to the recommended regimen is required.
Drug Interactions]
UDP-glucuronosyltransferase has been identified as the enzyme responsible for the metabolism of this product. There is no evidence that this product produces clinically meaningful induction or inhibition of hepatic oxidative drug metabolizing enzymes, and no interaction between this product and drugs metabolized by cytochrome P450 enzymes is likely to occur. This product may induce auto-metabolism, but this effect is limited and not clinically significant.
Table: Effect of other drugs on glucuronidation of this product
Drugs that significantly inhibit the glucuronidation of this product Drugs that significantly induce the glucuronidation of this product Drugs that do not significantly inhibit or induce the glucuronidation of this product Valproate Carbamazepine Lithium Phenytoin Butalbital Phenylpropiophenone Paracetamol Olanzapine Phenobarbital Oxcarbazepine Rifampin Felbamate Lopinavir/Ritonavir Gabapentin
Atazanavir/ritonavir* Levetiracetam Ethinylestradiol/levonorgestrel combination** Pregabalin Topiramate Zonisamide Aripiprazole* Dosing guidelines can be found in [Dosage] – General dosing recommendations for this product in special patient populations
**Other oral contraceptives and HRT treatments have not been studied, although the effects of these drugs on the pharmacokinetic parameters of this product may be similar. See [DOSAGE AND ADMINISTRATION] – General recommendations for use in special patient populations (women taking hormonal contraceptives) and [PRECAUTIONS] – Hormonal contraceptives
Interactions with AEDs (see [Dosage])
Certain antiepileptic drugs that induce hepatic drug metabolizing enzymes (e.g., phenytoin, carbamazepine, phenobarbital, and paromidone) induce glucuronidation and thus enhance the metabolism of this product.
Inhibition of glucuronidation by sodium valproate decreases the metabolism of this product, and the mean half-life of this product increases nearly twofold (see [Precautions] and [Dosage]).
Central nervous system reactions, including nausea, blurred vision, dizziness, diplopia, and ataxia, have been reported in patients taking carbamazepine following administration of this product. These reactions usually resolve with a reduction in the dose of carbamazepine. In studies of this product and oxcarbazepine in healthy adult volunteers, the results were similar, but dose reductions were not studied.
In a study in healthy volunteers, concomitant administration of felbamate (1,200 mg twice daily) with the tablets (100 mg twice daily for 10 days) did not appear to have a clinically relevant effect on the pharmacokinetics of this product.
Based on a retrospective analysis of plasma levels in patients receiving this product, gabapentin did not alter the apparent clearance of this product with or without gabapentin.
Potential drug-drug interactions between levetiracetam and this product were assessed in placebo-controlled clinical trials by evaluating serum concentrations. These data suggest that this product did not affect the pharmacokinetics of levetiracetam, and that levetiracetam did not affect the pharmacokinetics of this product.
The steady-state trough serum concentrations of this product were not affected by concomitant pregabalin (200 mg 3 times daily). There were no pharmacokinetic interactions between this product and pregabalin.
Topiramate did not result in changes in plasma concentrations of this product. Administration of this product resulted in a 15% increase in topiramate concentrations.
In studies in patients with epilepsy, concomitant administration of zonisamide (200 to 400 mg/day) along with tablets (150 to 500 mg/day) had no significant effect on the pharmacokinetics of this product.
Although changes in plasma concentrations of other antiepileptic drugs have been reported, controlled studies have shown no evidence that this product affects the plasma concentrations of concomitantly administered antiepileptic drugs. Evidence from in vitro studies suggests that this product does not displace other antiepileptic drugs from their protein binding sites.
In a study in healthy adult volunteers administered 200 mg of this product and 1200 mg of oxcarbazepine, oxcarbazepine did not alter the metabolism of this product and this product did not cause metabolism of oxcarbazepine.
Interactions with other psychotropic drugs (see [Dosage])
There was no effect on lithium salt pharmacokinetics in 20 healthy subjects receiving 100 mg/this product in combination with 2 g of anhydrous glucose lithium salt twice daily for 6 days.
Multiple oral doses of bupropion in 12 subjects had no significant effect on the pharmacokinetics of a single oral dose of this product tablet, but there was a slight increase in the AUC of this product glucuronide.
In a steady-state pharmacokinetic interaction study in healthy adult volunteers, a daily dose of olanzapine, 15 mg, reduced the AUC and Cmax of 200 mg of this product per day by an average of 24% and 20%, respectively. Effects of this magnitude are generally not considered clinically significant. There was no effect of 200 mg of this product per day on the pharmacokinetics of olanzapine.
In 14 healthy adult volunteers, multiple oral doses of 400 mg of this product per day had no clinically significant effect on the pharmacokinetics of a single dose of 2 mg of risperidone. 12 of 14 volunteers reported drowsiness after concomitant administration of 2 mg of risperidone and this product, compared to only 1 of 20 subjects who reported drowsiness when risperidone was administered alone, and when this product tablet None reported it when administered alone.
In a study of 18 adult patients with bipolar I disorder using an established dosing regimen of this product (>/=100 mg/day), the dose of aripiprazole was increased from 10 mg/day to a target dose of 30 mg/day for 7 days and then administered once daily for an additional 7 days. As a result, a mean reduction in Cmax and AUC of approximately 10% was observed for this product. The magnitude of this change resulted in an effect that was not expected to be clinically significant.
In vitro experiments have shown that the major metabolite of this product is 2-N-glucuronide, which can be inhibited when incubated concomitantly with sodium valproate, butalbital, clonazepam, amitriptyline, haloperidol and lorazepam. Sodium valproate is known to decrease the clearance of this product in vivo, and in these experiments, the effect of co-administration of butalbital acetone on the clearance of this product was observed to be second only to that of sodium valproate; however, multiple oral doses of butalbital acetone to 12 healthy volunteers did not have a statistically significant effect on the pharmacokinetics of a single administration of this product at low doses (100 mg) and caused only a mild increased. These phenomena suggest that the risk of clinical interaction with amitriptyline, clonazepam, haloperidol, or lorazepam is almost impossible. In vitro experiments similarly suggest that clozapine, phenelzine, risperidone, sertraline, triazolone, or fluoxetine do not affect clearance of this product. The human hepatic mitochondrial metabolism profile of butofuranolol suggests that it does not reduce clearance of drugs that are primarily metabolized by the CYP2D6 enzyme.
Interaction with hormonal contraceptives
Effect of hormonal contraceptives on the pharmacokinetics of this product
In a study of 16 female volunteers, combined oral contraceptive tablets consisting of 30 μg ethinylestradiol and 150 μg levonorgestrel increased the clearance of this product by approximately 2-fold when administered orally, resulting in an average decrease in AUC and Cmax of 52% and 39%, respectively. Serum concentrations of this product increased gradually during the 1 week of inactivity (e.g., the 1 week of “no contraceptive use”) and were on average approximately 2-fold higher during the 1 week interval of inactivity until the next dose (see [DOSAGE AND ADMINISTRATION]). Precautions] – Hormonal contraceptives.
Effect of this product on the pharmacokinetics of hormonal contraceptives
In a study involving 16 female volunteers, the steady-state dose of 300 mg of this product had no effect on the pharmacokinetics of the ethinylestradiol component of the combined oral contraceptive tablets. A moderate increase in clearance of the levonorgestrel component by oral administration was observed, with a mean decrease in AUC and Cmax of levonorgestrel of 19% and 12%, respectively. Measurements of serum FSH, LH and estradiol during the study period showed a loss of inhibition of ovarian hormonal activity in some women, but serum progesterone measurements showed no evidence of hormonal aspects of ovulation in any of the 16 subjects. The effect of moderately elevated clearance of levonorgestrel and altered serum FSH and LH on ovarian ovulatory activity is unknown (see [Precautions]). The effects of this product at doses above 300 mg/day have not been studied, nor have they been studied with other estrogenic products.
Interactions with Other Drugs
In a study with 10 male volunteers, rifampicin increased the clearance of this product and shortened the half-life of this product due to the induction of hepatic enzymes responsible for glucuronidation. Patients treated concomitantly with rifampicin should be treated with the recommended regimen of this product in combination with an inducer of glucuronidation (see [DOSAGE]).
In a study with healthy volunteers, lopinavir/ritonavir approximately halved the plasma concentration of this product, likely due to the induction of glucuronidation. In patients receiving concomitant therapy with lopinavir/ritonavir, the recommended regimen of this product in combination with a glucuronidation-inducing agent should be used (see [DOSAGE]).
In a study in healthy adult volunteers, atazanavir/ritonavir (300 mg/100 mg) decreased the plasma AUC and Cmax of this product (100 mg, single dose) by a mean of 32% and 6%, respectively (see “DOSAGE AND ADMINISTRATION – General Dosing Recommendations for This Product in Special Patient Populations”).
In vitro data evaluating the effect of this product on OCT 2 confirm that this product, but not the N(2)-glucuronide metabolizing substrate, has an inhibitory effect on OCT 2 activity at potentially clinically relevant concentrations. These data confirm that this product is an OCT 2 inhibitor with an IC50 value of 53.8 µM (see [Precautions]).
Interactions in Laboratory Tests
Interference with the assay in some rapid urine drug screens has been reported, leading to false positive results, particularly with phencyclidine. Positive results should be confirmed using other more specific chemical methods.
[Drug Overdose].
Acute ingestions exceeding 10-20 times the maximum therapeutic dose have been reported, including fatal events. Drug overdose can cause symptoms such as nystagmus, ataxia, impaired consciousness, grand mal seizures, and coma. Prolongation of the QRS interval (intraventricular block) has also been observed in patients with drug overdose.
In case of overdose, the patient should be hospitalized and given appropriate supportive therapy; if needed, gastric lavage should be performed.
Pharmacology and Toxicology
Pharmacological effects
The exact mechanism of the anticonvulsant effect of lamotrigine is not known. In animal models tested for anticonvulsant activity, lamotrigine was effective in suppressing the development of convulsions in the maximal electroshock seizure (MES) and pentylenetetrazol tests, and in the visual and electrically evoked antiepileptic discharge (EEAD) tests for anticonvulsant activity. Lamotrigine inhibited both ignition onset and complete ignition states in a rat ignition model. However, the relevance of these models to human epilepsy is unclear.
One of the proposed mechanisms of action of lamotrigine is the effect on sodium channels, but its relevance has yet to be determined in humans. In vitro assays have shown that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing nerve cell membranes, which in turn regulates presynaptic transmitter release of presynaptic excitatory amino acids (e.g., glutamate and aspartate).
Lamotrigine does not inhibit N-methyl-D-aspartate (NMDA)-induced depolarization of rat cortex or NMDA-induced cGMP formation in immature rat cerebellum, nor does it substitute for compounds (CNQX, CGS, TCHP) that compete or are not competitive with the ligands of this glutamate receptor complex. The IC50 of lamotrigine for NMDA-induced currents in cultured hippocampal neurons (in the presence of 3 μM glycine) exceeds 100 μM.
Toxicological studies
Genotoxicity
The results of the lamotrigine Ames test, the in vitro mouse lymphoma test, the in vitro human lymphocyte chromosome aberration test and the in vivo rat bone marrow micronucleus test were all negative.
Reproductive toxicity
Oral administration of lamotrigine to mice up to 20 mg/kg/day (in mg/ m2, lower than the human dose of 400 mg/day) showed no effect on fertility.
In mice, rats, and rabbits, oral administration of lamotrigine at doses up to 125, 25, and 30 mg/kg during the organogenesis period resulted in reduced fetal weight and increased incidence of fetal skeletal variation at doses with maternal toxicity in mice and rats, respectively, and a no-effect dose of 75, 6.25, and 30 mg/kg for embryo/fetal developmental toxicity in mice, rats, and rabbits, respectively, approximating (mice and rabbit) or lower (rat) than the human dose of 400 mg/day (in mg/m2), respectively.
Postnatal assessment of the offspring of pregnant rats given lamotrigine 5 and 25 mg/kg orally during organogenesis showed neurobehavioral abnormalities in both dose groups; the lowest effect dose for developmental neurotoxicity in rats was lower than the human dose of 400 mg/day (in mg/m2); maternal toxicity was observed in rats in the high dose group.
In pregnant rats, oral administration of lamotrigine at 5, 10 and 20 mg/kg during late gestation and throughout lactation resulted in increased offspring mortality (including stillbirth) in all dose groups; the lowest effect dose for perinatal developmental toxicity in rats was lower than the human dose of 400 mg/day (in mg/m2); maternal toxicity was observed in rats in the high and medium dose groups.
Fetal folate concentrations were reduced in pregnant rats given lamotrigine at doses greater than or equal to 5 mg/kg/day (at mg/ m2 , lower than the human dose of 400 mg/day).
Carcinogenicity
No carcinogenicity was observed in mice or rats given lamotrigine orally for up to 2 years at doses up to 30 mg/kg/day and 10-15 mg/kg/day, respectively, and the highest dose tested was below the human dose of 400 mg/day (in mg/m2).
Toxicity in young animals
In a juvenile animal study, lamotrigine was administered orally to young rats at 5, 15, and 30 mg/kg from 7 to 62 days of age, with reduced viability and growth at high doses and long-term neurobehavioral abnormalities seen at high and moderate doses (animals were tested as adults and reduced voluntary activity, increased reactivity, and learning deficits were observed). No effect on the development of young animals at doses lower than the human dose of 400 mg/day (in mg/m2).
Pharmacokinetics]
The product is rapidly and completely absorbed in the intestinal tract, with no significant first-pass metabolism. Peak plasma concentration is reached about 2.5 hours after oral administration. The peak time after eating is slightly delayed, but the degree of absorption is not affected. Experiments have shown that the pharmacokinetic profile remains linear at the highest single administered dose of 450 mg. The maximum blood concentration at steady state varied considerably between individuals, but in the same individual, the difference in concentration was minimal.
The plasma protein binding rate is approximately 55%; the potential for toxicity from plasma protein replacement is extremely low, with a volume of distribution of 0.92-1.22 L/kg.
In healthy adults, the mean steady-state clearance is 39±14 ml/min. Clearance of this drug is primarily metabolized to glucuronide conjugates, which are then excreted in the urine. Less than 10% of the prodrug is excreted in the urine. Only about 2% of the drug-related material is eliminated in the feces. Clearance and half-life are independent of dose. The mean elimination half-life in healthy adults is 24-35 h. UDP-glucuronosyltransferase has been shown to be the metabolizing enzyme for this product. In a study of subjects with Gilbert’s syndrome, the mean apparent clearance was 32% lower than that of normal controls, but the ratio remained within the range of the general population.
The mild induction of auto-metabolism by this product is dose dependent. However, there is no evidence that this product affects the pharmacokinetics of other antiepileptic drugs. Interactions between this product and drugs metabolized by cytochrome P450 enzymes are also unlikely to occur.
The half-life of this product is significantly affected by the combination of drugs, with the mean half-life shortened to about 14 hours when combined with glucuronidation inducers such as carbamazepine and phenytoin and increased by nearly 70 hours when combined with sodium valproate alone (see [DOSAGE AND ADMINISTRATION] and [DRUG INTERACTIONS]).
Clearance is adjusted for body weight and is higher in children less than or equal to 12 years of age than in adults, with the highest values in children less than 5 years of age. The half-life of this product is generally shorter in children than in adults, with mean values approaching 7 hours when combined with enzyme inducers such as carbamazepine and phenytoin, and increasing to 45-50 hours when combined with sodium valproate alone (see [DOSAGE AND ADMINISTRATION]).
Pharmacokinetic studies of this product in 12 healthy elderly volunteers aged 65-76 years and 12 younger volunteers aged 26-38 years showed that after a single dose of 150 mg, mean plasma clearance was approximately 37% lower in the elderly than in the young. However, the mean clearance in the elderly (0.39 ml/min/kg) was within the range of the mean clearance (0.31-0.65 ml/min/kg) obtained in nine studies of young people taking 30-450 mg of the drug in a single dose. Population pharmacokinetic analyses of young and old people (including 12 elderly volunteers who underwent pharmacokinetic studies and 13 elderly patients with epilepsy enrolled in clinical trials of monotherapy) showed no clinically meaningful differences in clearance of this product. After a single dose, the apparent clearance decreased by 12% from 35 ml/min at age 20 to 31 ml/min at age 70. After 48 weeks of treatment, the apparent clearance decreased from 41 ml/min in younger adults to 37 ml/min in older adults, a 10% reduction. To date, there are no pharmacokinetic studies of this product specifically in elderly patients with epilepsy.
There is no experience with the administration of this product in patients with renal failure. In subjects with renal failure, single-dose pharmacokinetic studies showed that the pharmacokinetics of this product were not greatly affected; however, the concentration of the major glucuronide metabolite in plasma increased almost eightfold due to decreased renal clearance.
Single-dose pharmacokinetic studies were performed in 24 patients with varying degrees of hepatic impairment and 12 healthy subjects as controls. The mean apparent clearance of this product was 0.31, 0.24 and 0.10 ml/min/kg in patients with impaired hepatic function (Child-Pugh classification) grades A, B and C, respectively, and 0.34 ml/min/kg in healthy controls. doses should normally be reduced in patients with impaired hepatic function grades B and C (see [Dosage]).
Storage】Seal and store in a dry place.
Package
50mg: aluminum-plastic packaging. 10 tablets/plate, 2 plates/box; 10 tablets/plate, 3 plates/box; 10 tablets/plate, 4 plates/box.
100mg: aluminum-plastic packaging. 10 tablets/plate, 1 plate/box; 10 tablets/plate, 2 plates/box; 10 tablets/plate, 3 plates/box.
【Validity】 24 months
【Execution Standard】
【Approval number】
【Marketing license holder
Company name: Zhejiang Huahai Pharmaceutical Co.
Registered Address: Flood Bridge, Linhai City, Zhejiang Province
Manufacturer
Company name: Zhejiang Huahai Pharmaceutical Co.
Production Address: Flood Bridge, Linhai City, Zhejiang Province
Postal code: 317024
Telephone number: 0576-85010288
Fax number: 0576-85016013
Web address: www.huahaipharm.com