Date of approval.
Date of revision.
Levetiracetam Tablets Instructions
Please read the instructions carefully and use under the guidance of a doctor
Drug Name]
Generic Name: Levetiracetam Tablets
Hanyu Pinyin: Zuoyilaxitan Pian
English Name: Levetiracetam Tablets
Ingredients
The active ingredient of this product is Levetiracetam, whose chemical name is (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide.
Chemical structure formula.
Molecular formula: C8H14N2O2
Molecular weight: 170.21
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
It is used for the additional treatment of partial seizures in adults and children over 4 years old.
Specification
0.25g
Dosage and Administration
Route of administration: Oral. It needs to be swallowed with an appropriate amount of water, and the administration is not affected by eating.
Administration method and dosage
Adults (≥18 years old) and adolescents (12~17 years old) weighing ≥50kg
The starting therapeutic dose is 500 mg/dose twice daily.
The daily dose may be increased to 1500 mg twice daily depending on clinical outcome and tolerability. Dose variation should be increased or decreased by 500mg twice daily every 2-4 weeks.
Elderly (≥65 years)
Dose adjustment according to renal function status (see description below for patients with impaired renal function).
Children and adolescents (12-17 years) aged 4-11 years weighing ≤50kg
The starting therapeutic dose is 10 mg/kg twice daily.
The dose may be increased to 30 mg/kg twice daily depending on clinical outcome and tolerability. Dose variation should be increased or decreased by 10 mg/kg twice daily every two weeks. The lowest effective dose should be used as much as possible.
For children and adolescents weighing ≥50kg, the dose is the same as for adults.
Depending on the patient’s weight, age and required dose, the physician may recommend the appropriate dosage form and size for the patient.
Recommended dosage for adolescents and children
Weight starting dose: 10mg/kg, maximum dose twice daily: 30mg/kg, 150mg twice daily for 15kg, 450mg twice daily for 450mg, 200mg twice daily for 20kg, 600mg twice daily for 600mg, 250mg twice daily for 25kg, 750mg twice daily for 750mg, 500mg twice daily for 50kg, 1500mg twice daily for 500mg. 500mg, 1500mg twice daily, 1500mg twice daily* for children under 25kg, for precise dose adjustment, oral solution should be used for starting treatment.
Infants and pediatric patients less than 4 years of age
There is no relevant and sufficient information available.
Patients with impaired renal function
For adult patients with impaired renal function, adjust the daily dose according to the renal function status according to the table with different inosine clearance (CLcr) ml/min (measured serum inosine values are calculated as described below).
[140 – age (years)] x body weight (kg)
CLcr= ———————————– (female patient × 0.85)
72 × serum inosine value (mg/dl)
CLcr adjusted for human body surface area BSA as follows.
CLcr (ml/min)
CLcr (ml/min/1.73m2) = ———————– x 1.73
BSA of the patient (m2)
Dose for patients with impaired renal function
Patient group inosine clearance
(ml/min/1.73 m2) Dose and number of doses Normal patients>80 500-1500mg per dose, twice daily Mild abnormalities 50-79 500-1000mg per dose, twice daily Moderate abnormalities 30-49 250-750mg per dose, twice daily Severe abnormalities<30 250-500mg per dose, twice daily Ongoing Dialysis
Patients with advanced kidney disease (1)- 500~1000mg once daily (2) (1) The recommended loading dose on the first day of administration is levetiracetam 750mg.
(2) After dialysis, an additional dose of 250~500mg is recommended.
The dose should be adjusted according to renal function status in pediatric patients with renal impairment because the clearance of levetiracetam is related to renal function. This is based on a study in adult patients with renal impairment.
Creatinine clearance CLcr (ml/min/1.73m2) is estimated by detecting creatinine (mg/dl) values in serum, and creatinine clearance in adolescent and pediatric patients can be obtained from the following formula.
Height (cm) × ks
CLcr (ml/min/1.73m2) = ———————–
Serum creatinine value (mg/dl)
ks = 0.45 (full-term infants to 1 year); ks = 0.55 (children under 13 years and female adolescents); ks = 0.7 (male adolescents)
Dose adjustment was performed for the status of renal impairment in children and adolescent patients weighing <50 kg.
Creatinine clearance in patient group
(ml/min/1.73m2) Dose and number of doses (1) Children and adolescents weighing <50 kg Normal patients>80 10-30 mg/kg, 2 times daily Mild abnormalities 50-79 10-20 mg/kg, 2 times daily Moderate abnormalities 30-49 5-15 mg/kg, 2 times daily Severe abnormalities<30 5-10 mg/kg , 2 times daily in patients with end-stage renal disease who are on dialysis - 10-20mg/kg, 2 times daily (2) (3) (1) Levetiracetam oral solution is used in patients who cannot swallow the tablet and in patients using doses under 250mg.
(2) The recommended loading dose on the first day of administration is levetiracetam 15mg/kg (0.15ml/kg).
(3) After dialysis, an additional dose of 5-10mg/kg (0.05-0.10ml/kg) is recommended.
Patients with liver disease
In patients with mild and moderate hepatic impairment, no adjustment of the administered dose is required. In patients with severe hepatic impairment, inosine clearance may underestimate the degree of renal insufficiency; therefore, if the patient’s inosine clearance is less than 60 ml/min/1.73 m2, the daily dose should be reduced by half.
[Adverse effects].
Add-on treatment for partial-onset seizures
Pooled safety data from adult clinical studies showed that the incidence of adverse reactions was similar in the levetiracetam and placebo groups, at 46.4% and 42.2%, respectively. Of these, serious adverse reactions were 2.4% and 2.0%, respectively. The most common adverse reactions were drowsiness, fatigue and dizziness. The incidence and severity of CNS-related adverse reactions decreased over time. There was no significant dose correlation for levetiracetam adverse reactions.
Clinical studies in pediatric patients (4-16 years of age) with partial-onset seizures showed a similar incidence of adverse reactions in the levetiracetam and placebo groups, 55.4% and 40.2%, respectively, with no serious adverse reactions in the levetiracetam group (1.0% in the placebo group). The most common adverse reactions in children were drowsiness, hostility, nervousness, emotional instability, agitation, loss of appetite, malaise, and headache. The pooled analysis found that the overall safety profile was similar in children and adults, except for a higher incidence of behavioral and psychiatric adverse reactions than in adults (38.6% in children versus 18.6% in adults). The risk of adverse reactions in adults and children was comparable.
A double-blind, placebo-controlled pediatric safety study assessed the cognitive and neuropsychological effects of levetiracetam in pediatric patients (4 to 16 years of age) with partial-onset seizures by a noninferiority design. No differences were found between levetiracetam and placebo with reference to changes from baseline in Leiter-R attention and memory and memory screening composite scores in the protocol-eligible population (non-inferiority analysis). Assessment of behavioral-emotional functioning using the CBCL-Achenbach Child Behavior Rating Scale suggested an increase in aggressive behavior in patients taking levetiracetam. However, the results of the open long-term follow-up study showed that patients taking levetiracetam did not experience a worsening of behavioral and emotional functioning overall and, in particular, no worsening of aggressive behavior compared to baseline.
Summary of Safety Characteristics
Summarizing the results of adult and pediatric clinical studies and post-marketing experience, adverse reactions and frequency of occurrence were evaluated for each system: very common (≥1/10); common (≥1/100,<1/10); uncommon: (≥1/1000,<1/100); rare (≥1/10,<1/1000); very rare (<1/ 10000), unknown (cannot be assessed based on the available information). Data from postmarketing clinical applications are not yet sufficient to estimate the incidence of adverse reactions in the treated population. In postmarketing experience, the most frequently reported abnormalities were neurologic and psychiatric in nature.
– Systemic reactions and dosing site abnormalities
Very common: malaise/fatigue.
– Neurological abnormalities
Very common: drowsiness.
Common: amnesia, ataxia, convulsions, dizziness, headache, hyperkinesia, tremor, balance disorders, attention deficit, memory impairment.
Postmarketing experience: unknown: sensory abnormalities, choreohypoparasitism, dyskinesia, lethargy.
– Psychiatric abnormalities
Common: aggression, anxiety, depression, mood instability/mood swings, hostility, insomnia, neuroticism, irritability, personality changes, abnormal thinking.
Post-marketing experience: unknown: abnormal behavior, irritability, panic attacks, anxiety, confusion, hallucinations, psychosis, suicide, suicide attempts, suicidal ideation
– Digestive tract abnormalities
Common: abdominal pain, diarrhea, dyspepsia, nausea, vomiting.
Post-marketing experience: unknown: pancreatitis.
– Abnormalities of the hepatobiliary system
Postmarketing experience: unknown: liver failure, hepatitis.
– Metabolic and nutritional abnormalities
Common: loss of appetite, weight gain.
– Abnormal testing indicators
Post-marketing experience: unknown: abnormal liver function tests, weight loss.
– Ear and vagus system abnormalities
Common: vertigo.
– Eye abnormalities
Common: diplopia, blurred vision.
– Musculoskeletal and connective tissue abnormalities
Common: myalgia.
Post-marketing experience: unknown
:.
Muscle weakness.
– Injury, toxicity and operational complications
Common: Injury.
– Infection and infection
Common: Infection, nasopharyngitis.
– Respiratory, thoracic and mediastinal abnormalities :
Common: Cough.
– Abnormal skin and subcutaneous tissue changes
Common: rash, eczema, pruritus.
Postmarketing experience: unknown: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, alopecia areata. For patients who developed alopecia areata, there have been isolated cases of self-recovery after discontinuation of levetiracetam.
– Abnormal hematologic and lymphatic system changes
Common: thrombocytopenia.
Postmarketing experience: unknown: complete thrombocytopenia (myelosuppression has been found in some cases), granulocyte deficiency. leukopenia, neutropenia.
-immune system abnormalities.
Post-marketing experience: unknown: drug rash with eosinophilia and systemic symptoms ((DRESS).
[Contraindications].
Contraindicated in patients with hypersensitivity to levetiracetam or hypersensitivity to pyrrolidone derivatives or any other ingredients.
Precautions]
Discontinuation
According to current clinical practice, if discontinuation of this product is required, gradual discontinuation is recommended. (e.g., adults and adolescents weighing 50 kg or more should reduce 500 mg twice daily every 2 to 4 weeks; children and adolescents weighing <50 kg should reduce 10 mg/kg twice daily every 2 weeks).
Renal insufficiency
The dose of levetiracetam needs to be adjusted for patients with renal impairment. For severe hepatic impairment, renal function tests are required before choosing the dose to be taken, and patients should refer to [Dosage and Administration] for the dose to be taken.
Suicide
Suicide, suicide attempts, suicidal ideation and behavior have been reported in patients with epilepsy treated with antiepileptic drugs including levetiracetam. A meta-analysis based on randomized placebo-controlled clinical studies of antiepileptic drugs showed a mildly increased risk of suicidal ideation and its behaviors. The mechanism for this increased risk is unknown.
Therefore, patients should be monitored for symptoms and behaviors of depression and/or suicidal ideation and managed appropriately. If symptoms and behaviors of depression and/or suicidal ideation occur, the patient (and the patient’s caregiver) should seek medical help.
Pediatric population
The available data from pediatric clinical studies do not indicate an effect on growth and adolescence in children. However, long-term effects on cognition, intelligence, growth, endocrine function, puberty, and fertility potential remain unknown.
Effects on driving and application of machines
There are no studies on the effects of drug administration on the ability to drive machines and drive vehicles.
Due to individual sensitivity differences, drowsiness or other central nervous symptoms can occur during the initial phase of treatment or after dose increases. Therefore, the operation of machines requiring skill, such as driving a car or operating machinery, is not recommended for these patients who require medication.
Pregnant and Lactating Women
Post-marketing data from several prospective pregnancy registries documented outcomes in over 1000 women exposed to levetiracetam monotherapy during the first trimester of pregnancy. Overall, these data do not suggest a significantly increased risk of serious congenital malformations, but the teratogenic risk cannot be completely excluded. The risk of congenital malformations accompanying treatment with multiple antiepileptic drugs is higher than with monotherapy, and animal studies have demonstrated some reproductive toxicity of the drug. The potential risk for humans is unclear. Do not use levetiracetam in pregnant women unless clinically necessary. Physiological changes during pregnancy can affect the concentration of levetiracetam when combined with other antiepileptic drugs. Decreases in levetiracetam concentrations during pregnancy have been reported. The decrease in levetiracetam concentrations is more pronounced in late pregnancy (up to 60% of the pre-pregnancy baseline concentration). Interruption of antiepileptic therapy may worsen the condition and be equally harmful to the mother and fetus.
Animal studies have shown that levetiracetam can be excreted from breast milk; therefore, patients are not advised to breastfeed while taking the drug. If treatment with levetiracetam is necessary during breastfeeding, the benefits/risks of this treatment should be weighed against the importance of breastfeeding.
Pediatric Dosage
See [Dosage and Administration].
Geriatric use
See [Dosage and Administration].
Drug Interactions
In vitro data show that levetiracetam and its major metabolites are neither inhibitors of human hepatic cytochrome P450, epoxide hydrolase or uridine diphosphate-glucosidase, nor are they high-affinity substrates at concentrations above Cmax levels obtained in the therapeutic dose range. Therefore, pharmacokinetic interactions are not likely to occur. In addition, levetiracetam does not affect the in vitro glucosidase action of valproic acid.
The low plasma protein binding of levetiracetam (<10%) makes it less likely to produce clinically significant interactions due to competition for protein binding sites with other drugs.
Potential pharmacokinetic interactions between drugs have been assessed by pharmacokinetic screening in clinical pharmacokinetic studies (phenytoin, sodium valproate, oral contraceptives, digoxin, warfarin, and probenecid) and placebo-controlled clinical trials.
Drug-drug interactions between levetiracetam and other antiepileptic drugs (AEDs)
Phenytoin
Levetiracetam (3000 mg daily) did not contribute to the phenytoin pharmacokinetic profile in patients with refractory epilepsy. Phenytoin application also does not affect the pharmacokinetic profile of this product.
Sodium valproate
Levetiracetam (1500 mg twice daily) did not alter the pharmacokinetic profile of sodium valproate in healthy volunteers. Valproate sodium 500 mg twice daily did not alter the rate or extent of levetiracetam absorption, or its plasma clearance, or urinary excretion. It also did not affect the exposure level or excretion of the major metabolite, ucb L057.
Serum concentrations of levetiracetam and other antiepileptic drugs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, deoxyphenobarbital, and sodium valproate) obtained from placebo-controlled clinical studies were evaluated and the data showed that levetiracetam did not affect the blood concentrations of other antiepileptic drugs. These commonly used antiepileptic drugs also do not affect the pharmacokinetic properties of this product.
The role of antiepileptic drugs in pediatric patients
The concomitant administration of enzyme-inducing antiepileptic drugs increased the apparent total clearance of this product in vivo by approximately 22%. However, no dose adjustment was required. Levetiracetam does not affect plasma drug concentrations of carbamazepine, sodium valproate, topiramate, or lamotrigine.
Other drug interactions
Oral contraceptives
Administration of levetiracetam (500 mg twice daily) did not affect the pharmacokinetic properties of oral contraceptives containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel, or the levels of luteinizing hormone and progesterone content, indicating that this product does not affect contraceptive efficacy. The application of oral contraceptives does not affect the pharmacokinetic properties of this product.
Digoxin
Administration of levetiracetam (1000 mg twice daily) did not affect the pharmacokinetic and pharmacodynamic (ECG) properties of digoxin at a daily dose of 0.25 mg. Application of digoxin does not affect the pharmacokinetic properties of this product.
Warfarin
Administration of levetiracetam (1000 mg twice daily) did not affect the pharmacokinetic properties of R and S forms of Warfarin. Coagulation time was not affected by levetiracetam. The application of warfarin does not affect the pharmacokinetic properties of this product.
Propofol
Propofol (500 mg four times daily), a renal tubular secretion blocker, inhibits the renal clearance of the major metabolites of levetiracetam but not the pharmacokinetic properties of levetiracetam (1000 mg twice daily), but the concentrations of these metabolites are low. Other drugs that require renal tubular secretion for clearance also affect the renal clearance of metabolites. There are no studies of levetiracetam in combination with probenecid dosing, and the effect of levetiracetam in combination with other active secretory drugs (e.g., NSAIDs, sulfonamides, and methotrexate) on efficacy is unclear.
Drug overdose]
Symptoms:
Drowsiness, agitation, aggressiveness, decreased level of consciousness, respiratory depression and coma have been observed.
Drug overdose first aid measures
After acute drug overdose, gastric emptying by inducing vomiting or gastric lavage should be performed. There is no antidote for levetiracetam. Treatment should be symptomatic and may also include hemodialysis. Effect of dialysis elimination: Levetiracetam 60%, main metabolite 74%.
【Clinical trial】.
Clinical studies
Add-on treatment of partial seizures
Three multicenter, randomized, double-blind, and placebo-controlled clinical studies in patients with refractory epilepsy with partial-onset seizures (with or without secondary generalized seizures). Established data on the effectiveness of levetiracetam as add-on therapy (adjunctive therapy to other antiepileptic drugs) in adults. Patients entering Study 1 or Study 2 had refractory partial-onset seizures for at least 2 years and were taking 2 or more conventional antiepileptic drugs. Patients entering Study 3 have had refractory partial-onset seizures for at least 1 year and are taking 1 traditional antiepileptic drug. At the time of the trial, patients were on a stable dosing regimen of at least 1 and up to 2 antiepileptic drugs. At baseline, patients must have at least 2 partial-onset seizures per 4-week phase.
Clinical Study 1
Clinical Study 1 was a double-blind, placebo-controlled, parallel trial conducted at 41 study sites in the U.S. After a 12-week baseline phase, patients were randomly assigned to levetiracetam doses of 1000 mg/day (N=97), levetiracetam 3000 mg/day (N=101), and placebo (N=95) groups administered in 2 daily doses. Efficacy assessment was performed over an 18-week treatment cycle (6-week dose by dose dosing period + 12-week evaluation period), and the concomitant antiepileptic drug regimen could be kept unchanged during the trial. The primary efficacy metric was a between-group comparison of the percentage reduction in weekly partial-onset seizure frequency throughout the randomized treatment period (dose by dose phase + evaluation phase) relative to the placebo group. Secondary efficacy metrics included effective response rate (incidence of patients with ≥50% reduction in partial-onset seizure frequency). The results showed a significant reduction in weekly partial seizure frequency in the levetiracetam-treated group. The effective response rate was significantly higher in the levetiracetam group than in the placebo group throughout the randomized treatment phase and was dose-related.
Placebo group
(N=95) Levetiracetam
1000mg/day
(N=97) Levetiracetam
3000mg/day
(N=101) Percentage decrease in frequency of partial seizures relative to placebo group- 26.1%*30.1%**P<0.001
Clinical Study 2
Clinical Study 2 was a double-blind, placebo-controlled crossover trial conducted at 62 study centers in Europe, designed to analyze the first phase of the trial (Phase A) as a parallel-group trial in which patients were randomly assigned to the levetiracetam 1000 mg/day (N=106), levetiracetam 2000 mg/day (N=105), and placebo groups (N=111) after a 12-week baseline phase , administered in 2 daily doses. A 16-week treatment cycle (including a 4-week dose addition period and a 12-week stable dose evaluation phase) was conducted to assess efficacy, and the treatment regimen of concomitant antiepileptic drugs remained unchanged during the trial. The primary efficacy metric was a between-group comparison of the percentage reduction in weekly partial seizure frequency throughout the randomized treatment phase (dose by dose period + evaluation phase) relative to the placebo group, and secondary efficacy metrics included effective response rate (incidence of patients with ≥50% reduction in partial seizure frequency). The results showed a significant reduction in weekly partial seizure frequency in the levetiracetam-treated group. The effective response rate was significantly higher in the levetiracetam treatment group than in the placebo group throughout the randomized treatment phase and was dose-related. The comparison of effective response rates for levetiracetam 2000 mg/day versus levetiracetam 1000 mg/day was statistically significant (P=0.02). Analysis of crossover trials yielded similar results.
Placebo group
(N=111) Levetiracetam
1000 mg/day
(N=106) Levetiracetam
2000mg/day
(N=105) Percentage decrease in frequency of partial seizures relative to placebo group- 17.1%*21.4%**P<0.001
Clinical Study 3
Clinical Study 3 was a double-blind, placebo-controlled, parallel-group trial conducted at 47 study centers in Europe that compared patients with refractory partial-onset seizures with or without secondary generalized seizures treated with only one antiepileptic drug, and after a 12-week baseline phase, patients were randomly assigned to one of the 2 treatment groups described above. 16-week treatment cycles had a 4-week dose-escalation phase. Efficacy was assessed during a 12-week stable dose phase. The primary efficacy metric was the intergroup comparison of the percentage reduction in weekly partial-onset seizure frequency throughout the treatment period (dose by dose + evaluation phase) versus the placebo group, and secondary efficacy metrics included the effective response rate (incidence of patients with ≥50% reduction in partial-onset seizure frequency). The results showed that there was a significant reduction in weekly partial seizure frequency in the levetiracetam-treated group. The effective response rate was significantly higher in the levetiracetam-treated group than in the placebo group throughout the treatment period.
Placebo group
(N=104) Levetiracetam
3000mg/day
(N=180) Percentage reduction in partial seizure frequency relative to the placebo group- 23.0%**P<0.001
Effectiveness study of partial-onset seizures in pediatric patients with epilepsy
A multicenter, randomized, double-blind and placebo-controlled clinical study in children aged 4 to 16 years with refractory partial-onset seizures at 60 trial centers in North America established data on the effectiveness of levetiracetam as add-on therapy (adjunctive treatment to other antiepileptic drugs) in pediatric patients. Children had at least 4 seizures in the 4 weeks prior to screening and were taking 1-2 concurrent stable doses of antiepileptic drugs during an 8-week baseline period (with at least 4 seizures in each 4-week baseline period). A total of 198 children were randomly assigned to (levetiracetam group N=101 and placebo N=97). The starting dose of levetiracetam was 20 mg/kg/day administered in two divided doses, which was adjusted in 20 mg/kg/day increments during the treatment period to a target dose of 60 mg/kg/day over a 2-week period. This clinical study includes an 8-week baseline period, a 4-week dose-by-dose-addition period, and a 10-week evaluation period. The primary efficacy metric is a between-group comparison of the percentage reduction in weekly partial-onset seizure frequency throughout the randomized treatment period (dose-dosing phase + evaluation phase) relative to the placebo group. Secondary efficacy metrics included effective response rate (incidence of patients with ≥50% reduction in partial-onset seizure frequency). The results showed a significant reduction in weekly partial seizure frequency in the levetiracetam-treated group. The effective response rate was significantly higher in the levetiracetam group than in the placebo group throughout the randomized treatment period.
Placebo group
(N=97) Levetiracetam
(N=101) Percentage reduction in partial seizure frequency relative to the placebo group – 26.8% **P=0.0002
Clinical studies in China
A multicenter, randomized, double-blind, parallel, placebo-controlled clinical study was conducted in six centers in China (Shanghai, Beijing, Chongqing, Chengdu) on the efficacy and safety of levetiracetam orally administered for 16 weeks as add-on therapy for partial-onset seizures in adults and adolescents over 16 years of age in two treatment groups: placebo and levetiracetam at a daily dose of 3000 mg. A total of 224 patients were screened in the 16-week clinical trial, and 189 completed the trial (98 in the levetiracetam group and 91 in the placebo group). All subjects were Chinese, with 52% and 48% of men and women, respectively. Demographics and other baseline characteristics were comparable between the two treatment groups, and the weekly seizure frequency was similar at baseline, (1.81 seizures/week in the levetiracetam group and 1.75 seizures/week in the placebo group).
The primary efficacy measure was the weekly partial seizure (type I) frequency during the 16-week treatment period (4-week booster period + 12-week maintenance period.) The overall efficacy of the subjects was evaluated by the investigators at the end of the 16-week trial using the overall clinical efficacy assessment form.
Analysis of the intention-to-treat population showed a significant reduction in weekly partial seizure frequency in the levetiracetam group compared to the placebo group during the 16-week treatment period (p<0.001), which was significantly more effective than placebo, with a 26.8% reduction (95% confidence interval: 14.0%-37.7%) relative to the placebo group. Results were similar in the regimen-treated population.
During the 16-week treatment period, the proportion of partial seizures that were 50% effective was 57/102 (55.9%) in the levetiracetam group, significantly higher than the 26/100 (26.0%) in the placebo group. The OR relative to placebo was 3.6 (95%)
confidence interval: 2.0-6.5), (p<0.001). Eleven cases (10.8%) in the levetiracetam group did not experience any partial seizures, which was significantly higher than in the placebo group (2 cases, 2.0%) (p<0.001).
The results of the safety assessment in this study showed that the placebo and levetiracetam groups were comparable. The most frequently reported adverse event in the levetiracetam group was drowsiness (18 subjects, 17.5%), followed by reduced platelets.
Efficacy/pharmacokinetic/pharmacodynamic study results
Frequency analysis of the number of partial seizures in the intention-to-treat (ITT) population
Weekly partial seizure frequency levetiracetam
(N=102) Placebo
(N=100) Baseline period Mean (standard deviation)
Median (25% quantile-75% quantile) 3.79 (5.76)
1.81 (1.1- 3.4) 4.81 (8.46)
1.75 (1.13- 4.00) After 16 weeks of dosing Mean (standard deviation)
Median (25th percentile – 75th percentile)
Least squares mean (a)
Percentage reduction relative to placebo group (b) (95% confidence interval)
P-value (c) 4.01 (13.84)
0.85 (0.25-0.90)
0.92
26.8% (14.0%, 37.7%)
<0.001 6.62 (15.46)
1.74 (0.73-4.04)
1.23
Absolute number of changes from baseline period Median (25% quantile – 75% quantile)
Median number of changes (levetiracetam-placebo) (95% confidence interval) 0.91 (0.02-1.75)
0.6 (0.2-1.0) 0.29 (-1.25-0.81) P-value(d)<0.001 Percent change from baseline period Median (25% quantile-75% quantile) 55.9 (0.88-87.61) 13.7 (-38.76-50.44) Median change (levetiracetam-placebo) (95% confidence interval )
P value (e) 42.2 (19.2-65.2)
<0.001 Effective rate (%) 55.926.0% Ratio (OR) median (levetiracetam-placebo; 95% confidence interval)
P-value (f)
3.6 (2.0-6.5)
<0.001
13.7 (-38.76-50.44) No partial seizures, n (%) 11 (10.8%) 2 (2.0%) P value (g) 0.012 (a) The frequency of weekly partial seizures was analyzed by natural log transformation [Ln(1+X)] using a covariance model with baseline values as covariates and study center and treatment group as fixed variables for estimated.
(b)
The percentage reduction relative to the placebo group was calculated using the following formula: 100 × [1 – Exp (LSM levetiracetam – LSM placebo)].
(c)
Comparison with placebo was performed.
(d)
WILCOXON rank sum test was used
(e) WILCOXON rank sum test was used.
(f)
Logistic regression analysis was used.
(g) CMH stratified analysis by center was used.
In conclusion, levetiracetam as add-on therapy for partial-onset seizures in adults and adolescents over 16 years of age significantly reduced the weekly seizure frequency during the 16-week treatment period and was safely tolerated.
Pharmacology and Toxicology
Pharmacological effects
Levetiracetam is a derivative of pyrrolidone and its chemical structure is not correlated with existing antiepileptic drugs. The exact mechanism of the antiepileptic effect of levetiracetam is not known. The antiepileptic effect of levetiracetam has been evaluated in various animal models of epilepsy. Levetiracetam did not inhibit simple seizures induced by maximal stimulation with electric current or multiple stunning agents and showed only weak activity in submaximal stimulation and threshold tests. However, protective effects were observed against generalized seizures secondary to focal seizures induced by trichothecene and red algae amino acids, two chemical convulsants that mimic the properties of complex partial seizures accompanied by secondary generalized seizures in some individuals. Levetiracetam inhibited both the ignition process and the ignition state in a rat ignition model of complex partial seizures. The predictive value of these animal models for specific types of epilepsy in humans is unclear.
In vitro and in vivo tests showed that levetiracetam inhibited hippocampal epileptiform burst firing without effect on normal neuronal excitability, suggesting that levetiracetam may selectively inhibit epileptiform burst firing hypersynchrony and seizure propagation.
Levetiracetam has no affinity for a variety of known receptors at concentrations as high as 10 μM, such as benzodiazepines, GABA, glycine, NMDA, reuptake sites, and second messenger systems. In vitro tests showed no effect of levetiracetam on neuronal voltage-gated sodium channels or T-type calcium currents. Levetiracetam does not directly ease GABAergic neurotransmission, but studies have shown antagonistic effects on the negative regulator activity of GABA and glycine-gated currents in cultured neurons. A saturable and stereoselective neuronal binding site for levetiracetam was identified in rat brain tissue, but the identification and function of this binding site is currently unknown.
Toxicological studies
Genotoxicity
Levetiracetam Ames assay, CHO/HGPRT locus gene mutation assay in mammalian cells, CHO cell chromosome aberration assay, and mouse micronucleus assay were all negative. The results of levetiracetam hydrolysis product and human major metabolite (ucb L057) were negative in Ames test and mouse lymphoma test.
Reproductive toxicity
No adverse effects on fertility or reproductive behavior were seen in male or female rats at doses up to 1800 mg/kg/day [extrapolated as mg/m2 or exposure (AUC) equivalent to 6 times the maximum recommended human dose (MRHD) of 3000 mg].
In animal studies, levetiracetam can produce developmental toxicity at doses similar to or higher than the human therapeutic dose. In pregnant rats administered during the organogenesis phase at a dose of 3600 mg/kg/day (equivalent to 12 times MRHD in mg/m2), a reduction in fetal weight and an increased incidence of fetal skeletal variation were seen. The no-effect dose for developmental toxicity was 1200 mg/kg/day, and no maternal toxicity was observed in this trial. In pregnant rabbits administered during the organogenesis phase at a dose of ≥600 mg/kg/day (4 times the MRHD at mg/m2), increased embryo-fetal mortality and increased incidence of fetal skeletal abnormalities were observed; at a dose of 1800 mg/kg/day (12 times the MRHD at mg/m2), decreased fetal body weight and increased incidence of fetal malformations were observed. Maternal toxicity was also observed. The no-effect dose for developmental toxicity was 200 mg/kg/day.
In female rats administered during gestation and lactation, fetal skeletal abnormalities, prenatal and/or postnatal growth retardation were seen at doses ≥350 mg/kg/day (equivalent to MRHD at mg/m2), and increased pup mortality and abnormal offspring behavior were seen at doses 1800 mg/kg/day (equivalent to MRHD at 6 times the dose at mg/m2). The no-effect dose for developmental toxicity in this assay was 70 mg/kg/day, and no significant maternal toxicity was observed. No adverse developmental or maternal effects were observed in rats administered during the third trimester and throughout lactation at doses up to 1800 mg/kg/day (extrapolated to 6 times the MRHD at mg/m2).
Carcinogenicity
No carcinogenicity was observed in rats given levetiracetam in the adulteration method for 104 weeks at doses of 50, 300 and 1800 mg/kg/day (high dose extrapolated to 6 times MRHD at mg/m2 or exposure). Levetiracetam was administered in mice for 80 weeks at doses of 60, 240 and 960 mg/kg/day (high dose equivalent to 2 times the MRHD by mg/m2 or exposure) in the adulteration method and no carcinogenicity was observed. However, due to the low dose administered, the potential carcinogenicity to this animal species could not be fully evaluated.
Pharmacokinetics]
Levetiracetam is an extremely soluble and highly permeable compound. It is linearly metabolized with little intra- and inter-individual variation. Multiple dosing does not affect its clearance rate. There is no gender or racial variability or physiological cycle variation. Pharmacokinetic studies of this product showed comparable pharmacokinetic data in healthy volunteers and patients.
Due to the complete absorption and linearity of levetiracetam, its blood concentration can be predicted based on the oral dose of mg/kg, making monitoring of levetiracetam’s blood concentration unnecessary.
Saliva and blood concentrations in adult and pediatric patients showed a significant correlation (saliva/blood drug concentration ratio of 1 to 1.7 4 hours after administration of tablets or liquid formulations of levetiracetam).
Adults and Adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration, with an absolute oral bioavailability approaching 100%. The blood concentration peaks after 1.3 hours of administration and reaches a steady-state ping concentration after 2 days if administered twice daily, with typical peak concentrations of 31 and 43 μg/ml for single doses of 1000 mg and 1000 mg twice daily. absorption time is independent of dose and ingestion of food does not affect the degree of absorption.
Distribution
There are no data on the tissue distribution in humans. Neither levetiracetam nor its major metabolites are readily bound to plasma proteins (<10%). The volume of distribution is 0.5-0.7 L/kg, which is close to the human water volume.
Biotransport
Levetiracetam is not extensively catabolized in the human body and the main metabolic pathway is through the hydrolase
of acetamidation (24% of the administered dose). The major metabolite, UCBL057, is not converted by the hepatic pigment P450 transport system. The acetamide moiety hydrolysate can be measured in most tissues in vivo, including blood cells. The metabolite UCBL057 is not pharmacologically active.
Two minor metabolic pathways have also been identified, a hydroxylated pyrrolidine pathway (1.6% of the administered dose), and a pyrrolidine moiety ring-opening, which accounts for approximately 0.9% of the dose.
The metabolites of other metabolic pathways that could not be identified accounted for 0.6% of the administered dose.
Current in vitro data indicate no chiral reversal for either levetiracetam or its major metabolites.
In vitro data suggest that levetiracetam and its major metabolites do not inhibit hepatic pigment P450 isomerization (CYP3A4, 2A6, 2X8/9/10, 2C19, 2D6, 2E1 and 1A2) glucuronosyltransferase (UGT1*6, UGT1*1 and UGT [pl6.2]) and epoxide hydroxylase activities. In addition, levetiracetam was shown to not affect the glucuronidation of valproic acid in in vitro assays.
In human hepatocyte tissue, levetiracetam does not produce enzyme-inducing effects. Thus, co-application of this product with other substances usually does not produce interactions. The converse is also true.
Elimination
Adult plasma half-life: 7 ± 1 h. It does not change depending on the dose administered, the route of administration, or repeated dosing. The mean total body clearance is 0.96 ml/min/kg.
The drug is excreted primarily in the urine at approximately 95% of the dose (approximately 93% is excreted within 48 hours). Only 0.3% of the drug was excreted in the feces.
The cumulative rate of excretion of levetiracetam and its metabolites within 48 hours of initiation of administration was 66% and 24% of the administered dose, respectively.
The renal clearance of levetiracetam and UCBL057 was 0.6 and 4.2 ml/min/kg, respectively.
This indicates that levetiracetam is eliminated by glomerular filtration followed by tubular reabsorption, and the major metabolites are also eliminated by tubular secretion and glomerular filtration. The elimination rate of levetiracetam correlates with the clearance of creatinine.
Geriatric Patients
The half-life of levetiracetam is prolonged by approximately 40% (10-11 hours) in elderly patients.
This is associated with decreased renal function.
Children (4 to 12 years)
The plasma half-life of levetiracetam in children is 6.0 hours when administered as a single dose (20 mg/kg) (6-12 years). Its apparent clearance (after weight adjustment) is approximately 30% higher than that of adults with epilepsy.
Levetiracetam is rapidly absorbed after repeated oral dosing (20-60 mg/kg/day) in children (4-12 years). Peak concentrations were reached 0.5-1 hour after dosing. Peak concentrations and area under the curve were linear and increased proportionally to the dose. The clearance half-life is 5 hours.
Apparent body clearance is approximately 1.1 ml/min/kg.
Infants and young children (1 month to 4 years)
Absorption was rapid in pediatric patients (1 month to 4 years of age) after a single dose of 10% oral solution (20 mg/kg) was administered. The blood dose peaked 1 hour after administration. Pharmacokinetic data showed a shorter half-life (5.3 hours) than in adults (7.2 hours) and a faster apparent in vivo clearance in infants (1.5 ml/min/kg) than in adults (0.96 ml/min/kg).
The amount of the major metabolite, UCBL057, was lower in children than in adults.
Patients with renal impairment
In patients with renal impairment, the in vivo clearance of levetiracetam and the major metabolites depends on the clearance of creatinine. Therefore, in patients with moderate or severe renal insufficiency, it is recommended that the daily maintenance dose be adjusted according to creatinine clearance.
In patients with advanced anuria in renal disease, the plasma half-life of the drug is 25 and 3.1 hours in adults as they undergo inter- and intra-dialysis periods, respectively.
During a 4-hour dialysis session, 51% levetiracetam was removed in a graded manner.
Hepatic impairment
In patients with moderate to mild hepatic impairment, there was no corresponding change in the clearance of levetiracetam. The majority of patients with severe hepatic impairment had a greater than 50% decrease in levetiracetam clearance, which was mainly due to the combination of impaired renal function.
Storage
Seal and store in a dry place.
Package
PVC solid pharmaceutical hard tablets and pharmaceutical aluminum foil packaging.
10 tablets/plate×1 plate/box; 10 tablets/plate×2 plate/box; 10 tablets/plate×3 plate/box.
[Expiration date
24 months
【Execution standard
Approval number】
State Drug Certificate H20143177
Manufacturer
Company Name: Zhejiang Jingxin Pharmaceutical Co.
Production Address: No. 800 East Xinchang Avenue, Yulin Street, Xinchang County, Zhejiang Province
Postal Code: 312500
Sales Hotline: (0575) 86096832
Complaint Telephone: (0575) 86098209
Fax number: (0575) 86096898
Website: http://www.jingxinpharm.com