Date of approval.
Date of modification.
Levetiracetam Oral Solution Instructions for Use
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Levetiracetam Oral Solution
English name: Levetiracetam Oral Solution
Hanyu Pinyin: Zuoyilaxitan Koufurongye
Ingredients
The main ingredient of this product is Levetiracetam.
Its chemical name (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide
Chemical structure formula.
Molecular formula: C8H14N2O2
Molecular weight: 170.21
The excipients are maltitol liquid, propylene glycol, glycerin, citric acid, sodium citrate, methyl hydroxybenzene, propyl hydroxybenzene, acesulfame, grape-flavored liquid flavor and purified water.
【Properties】.
This product is a colorless or almost colorless clarified solution.
Indications】
It is used for the additional treatment of partial seizures in adults, children and infants over one month old.
Specification
150ml:15g.
Dosage
It can be taken diluted with water and is not affected by eating. It is supplied with a graduated oral medicine dispenser. The daily dose is divided into 2 equal doses.
Adults (≥18 years old) and adolescents (12-17 years old) weighing 50 kg or more.
The starting therapeutic dose is 500 mg per dose, twice daily. This dose can be started on the first day of treatment.
Depending on clinical outcome and tolerability, the dose may be increased to 1500 mg per dose, twice daily. Dose adjustments of 500 mg/dose (i.e., adjustments of 1000 mg/day) should be made every 2 to 4 weeks.
Elderly (≥65 years).
Adjust the dose according to the status of renal function (see the description of patients with renal impairment below).
Pediatrics.
Physicians should select the appropriate drug formulation and dose based on the patient’s age, weight, and dose administered.
Infants 6 to 23 months of age, children 2 to 11 years of age and adolescents (12 to 17 years of age) weighing <50 kg.
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 2 weeks. The lowest effective dose should be used as much as possible. For children weighing ≥50kg, the dose is the same as for adults.
Recommended doses for infants, children and adolescents over 6 months of age.
Body weight starting dose.
10mg/kg twice daily Maximum dose.
30mg/kg twice daily 6kg (1) 60mg (0.6ml) per dose, 180mg (1.8ml) per dose twice daily 10kg (1) 100mg (1ml) per dose, 300mg (3ml) per dose twice daily 15kg (1) 150mg (1.5ml) per dose, 450mg (4.5ml) per dose twice daily 4.5ml), 2 times daily 20kg (1) 200mg (2ml), 2 times daily 600mg (6ml), 2 times daily 25kg 250mg, 2 times daily 750mg, 2 times daily from 50kg (2) 500mg, 2 times daily 1500mg, 2 times daily (1) Children ≤25kg should start treatment with with 100mg/ml oral solution.
(2) For children and adolescents weighing ≥50kg, the dose is the same as that for adults.
Infants and children aged 1 to 6 months.
Initial treatment dose 7mg/kg twice daily.
The dose may be increased to 21mg/kg twice daily depending on clinical outcome and tolerability. Dose changes should be based on an increase or decrease of 7 mg/kg twice daily every 2 weeks. The lowest effective dose should be used as much as possible. Levetiracetam oral solution (100mg/ml) is recommended as starting treatment for infants and children.
Recommended dose for infants and children 1 to 6 months of age.
Body weight starting dose.
7mg/kg twice daily Maximum dose.
21mg/kg twice daily 4kg 28mg (0.3ml) per dose, 84mg (0.85ml) per dose twice daily 5kg 35mg (0.35ml) per dose, 105mg (1.05ml) per dose twice daily 7kg 49mg (0.5ml) per dose, 147mg (1.5ml) per dose twice daily 150ml twice daily package size, with graduated 5ml oral pick-up device, the pick-up device can draw up to 500mg of levetiracetam (equivalent to 5ml), and each scale of the pick-up device is 20mg, i.e. 0.2ml.
Patients with renal impairment
The daily dose needs to be adjusted according to the individual renal function status.
For adult patients with renal impairment, adjust the daily dose according to the different creatine clearance (CLcr) ml/min in the table below according to the renal function status. Creatinine clearance (CLcr) ml/min is obtained by measuring creatinine (mg/dl) values in serum using the following formula.
CLcr was adjusted according to the body surface area BSA.
The adult dose was adjusted according to the renal function status of the patient
Patient group creatinine clearance (ml/min/1.73m2) Dose and frequency of administration Normal patients>80 500 to 1500 mg per dose, twice daily Mild abnormalities 50 to 79 500 to 1000 mg per dose, twice daily Moderate abnormalities 30 to 49 250 to 750 mg per dose, twice daily Severe abnormalities<30 250 to 500 mg per dose, twice daily 2 times daily in patients with end-stage renal disease who are on dialysis (1) – 500 to 1000 mg , once daily (2) (1) The recommended loading dose of levetiracetam 750 mg on day 1.
(2) After dialysis, an additional dose of 250-500 mg is recommended.
The dose should be adjusted according to renal function status in pediatric patients with renal impairment, as the clearance of levetiracetam is related to renal function. All based on studies in adult patients with renal impairment.
Creatinine clearance CLcr (ml/min/1.73m2) was estimated by detecting creatinine (mg/dl) values in serum, and creatinine clearance in adolescent, pediatric and infant patients can be obtained from the following equation.
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 for the status of patients with renal impairment in infants, children, and adolescents weighing less than 50 kg
Patient group creatinine clearance (ml/min/1.73m2) Dose and number of doses (1) Infants and children under 6 months of age 6 to 23 months of age, children and adolescents weighing <50kg normal patients>80 7 to 21 mg/kg (0.07 to 0.21 ml/kg) twice daily 10 to 30 mg/kg (0.10 to 0.30ml/kg), twice daily for mild abnormalities 50 to 79 7 to 14mg/kg (0.070 to 0.14ml/kg) each time, 10 to 20mg/kg (0.10 to 0.20ml/kg) each time, twice daily for moderate abnormalities 30 to 49 3.5 to 10.5mg/kg (0.035 to 0.105ml/ kg), 5 to 15 mg/kg (0.05 to 0.15 ml/kg) twice daily, 2 times daily for severe abnormalities<30 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) each time, 5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily, and 2 times daily for patients with end-stage renal disease who are on dialysis ( (1) - 7 to 14 mg/kg (0.07 to 0.14 ml/kg) per dose, once daily (2) (4) 10 to 20 mg/kg (0.10 to 0.20 ml/kg) per dose, once daily (3) (5) (1) Levetiracetam oral solution is used for patients who cannot swallow tablets and for patients who use doses under 250 mg .
(2) The recommended loading dose on the first day of administration is levetiracetam 10.5 mg/kg (0.105 ml/kg).
(3) The recommended loading dose on the first day of administration is levetiracetam 15mg/kg (0.15ml/kg).
(4) After dialysis, an additional dose of 3.5-7mg/kg (0.035-0.07ml/kg) is recommended.
(5) After dialysis, it is recommended to give an additional dose of 5 to 10mg/kg (0.05 to 0.10ml/kg).
Patients with liver disease
For patients with mild and moderate hepatic impairment, no adjustment of the administered dose is required. In patients with severe hepatic impairment, the degree of renal impairment may be underestimated by creatinine clearance; therefore, if a patient’s creatinine clearance is less than 60 ml/min/1.73m2, the daily dose should be reduced by half.
[Adverse reactions].
Pooled safety data from adult clinical studies showed that the incidence of adverse reactions was similar in the drug and placebo groups, at 46.4% and 42.2%, respectively. Among them, the 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 were no significant dose-related adverse reactions to levetiracetam.
Clinical studies in pediatric patients (4 to 16 years of age) with partial-onset seizures showed that the incidence of adverse reactions was 55.4% and 40.2% in the drug and placebo groups, respectively, with no serious adverse reactions in the drug group (1.0% in the placebo group). The most common adverse reactions in children were sleepiness, hostility, nervousness, emotional instability, agitation, loss of appetite, malaise, and headache. Pooled analyses found that the overall safety 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), but the risk of adverse reactions was comparable in adults and children.
One study in pediatric partial-onset patients (1 month to <4 years of age) showed an incidence of adverse reactions of 21.7% and 7.1% in the drug and placebo groups, respectively, with no serious adverse reactions occurring in either group. The long-term follow-up study NO1148 showed that the most common adverse reactions associated with drug treatment occurring in pediatric patients (1 month to 4 years of age) with partial-onset seizures were irritability (7.9%), convulsions (7.2%), sleepiness (6.6%), increased psychomotor response (3.3%), sleep disturbance (3.3%), and aggression (3.3%). Safety results were consistent with those of studies in pediatric patients aged 4 to 16 years.
One 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.
Based on the results of adult and pediatric clinical studies and post-marketing experience, the classification according to the organ and frequency of adverse reactions is tabulated as follows: according to clinical research trials, the terms for different frequencies are expressed as: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/ 1000); very rare (<1/10,000); unknown (cannot be evaluated based on the available information). Data from post-marketing clinical applications are not sufficient to estimate the incidence of adverse reactions in the treated population.
-Systemic reactions and site of administration abnormalities.
Very common: malaise/fatigue.
-Neurological abnormalities.
Very common: drowsiness/weakness.
Common: amnesia, ataxia, convulsions, dizziness, headache, hyperkinesia, tremor, balance disorders, attention deficit, memory impairment.
Post-marketing experience, unknown: sensory abnormalities, choreoathetosis, dyskinesia, lethargy.
-Psychiatric abnormalities.
Common: irritability, depression, mood swings/mood swings, hostility, aggression, insomnia, neuroticism, personality changes, abnormal thinking, agitation.
Post-marketing experience, unknown: abnormal behavior, irritability, panic attacks, anxiety, confusion, hallucinations, psychosis, suicide, suicide attempts, suicidal ideation.
-Gastrointestinal abnormalities.
Common: abdominal pain, diarrhea, dyspepsia, nausea, vomiting.
Post-marketing experience, unknown: pancreatitis.
-Hepatobiliary system abnormalities.
Post-marketing experience, unknown: liver failure, hepatitis.
-Abnormalities of the renal and urinary systems
Postmarketing experience, unknown: acute kidney injury.
-Metabolic and nutritional abnormalities.
Common: loss of appetite, weight gain; increased risk of loss of appetite when patient is also taking topiramate.
-Ear and vagal system abnormalities.
Common: vertigo.
-Ocular abnormalities.
Common: diplopia, blurred vision.
-Skeletal muscle and connective tissue abnormalities.
Common: Myalgia.
Post-marketing experience, unknown: muscle weakness.
-Injury, toxicity and complications during manipulation.
Common: Injury.
-Infections and infections.
Common: Infection, nasopharyngitis.
-Abnormalities of respiratory, thoracic and mediastinal systems.
Common: cough.
-Abnormal skin and subcutaneous tissue changes.
Common: rash, eczema, pruritus.
Postmarketing experience, unknown: toxic epidermal necrolysis relaxans, Stevens-Johnson syndrome, erythema multiforme, alopecia areata. For patients who developed alopecia areata, there have been isolated cases of recovery after discontinuation of levetiracetam.
-Abnormal hematologic and lymphatic system changes.
Common: thrombocytopenia.
Post-marketing experience, unknown: leukopenia, neutropenia, allogeneic cytopenia (skeletal suppression has been found in some cases), granulocyte deficiency.
-Immune system abnormalities.
Postmarketing experience, unknown: drug rash with eosinophilia and systemic symptoms ((DRESS).
-Tests.
Post-marketing experience, unknown: Abnormal liver function tests, weight loss.
[Contraindications].
Levetiracetam is 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: reduce by 500 mg twice daily at 2 to 4 week intervals; infants over 6 months, children and adolescents weighing less than 50 kg: reduce by no more than 10 mg/kg twice daily at 2 week intervals; infants less than 6 months: reduce by no more than 7 mg/kg twice daily at 2 week intervals).
Renal insufficiency
For patients with renal impairment levetiracetam dosing requires dose adjustment. For severe hepatic impairment, renal function testing is required before selecting the dose to be taken, and patients should refer to [dosage] 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 in cognition, intelligence, growth, endocrine function, puberty, and fertility potential remain unknown.
A comprehensive evaluation of safety and efficacy has not been performed in infant patients under 1 year of age. In previous clinical studies, only 35 patients less than 1 year of age and 13 patients less than 6 months of age were observed.
Excipients
Levetiracetam Oral Solution contains methyl paraben (E218) and propyl paraben (E216), both of which have the potential to cause allergic reactions. Levetiracetam Oral Solution contains maltitol liquid, which should not be taken by patients with hereditary fructose tolerance abnormalities.
Effects on driving and application of machines
There are no studies on the effect of taking the drug on the ability to operate machines and to 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, operation of machines requiring skill, such as driving a car or operating machinery, is not recommended for these patients who require medication.
For Pregnant and Lactating Women
Pregnant 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 that of monotherapy. Animal studies have demonstrated some reproductive toxicity of the drug. Do not administer levetiracetam to pregnant women or women of childbearing age who are not using contraception if not clinically necessary. Physiological changes during pregnancy can affect levetiracetam concentrations when combined with other antiepileptic drugs, and a decrease in plasma concentrations of levetiracetam during pregnancy has been reported. The decrease in levetiracetam concentrations is more pronounced in late pregnancy (up to 60% of the pre-pregnancy baseline concentration). It should be ensured that pregnant women taking levetiracetam are given appropriate clinical instructions. Abrupt discontinuation of antiepileptic drug therapy may worsen the condition and thus be harmful to the pregnant woman and the fetus.
Lactation
Animal studies have shown that levetiracetam can be secreted from breast milk; therefore, patients are not advised to breastfeed while taking the drug. However, if treatment with levetiracetam is necessary during breastfeeding, the benefits/risks of this treatment and the importance of breastfeeding should be carefully considered.
Fertility
Animal studies have confirmed no effect on fertility in animals (see preclinical safety data), but no clinical studies are available to provide information on whether there is an effect on fertility in humans.
Pediatric Dosage]
There is insufficient clinical efficacy and safety information on levetiracetam for the treatment of infant patients less than 1 month of age.
Geriatric Use]
See [Dosage and Administration].
Drug Interactions
Other antiepileptic drugs
Premarketing clinical studies in adults have shown that the administration of levonorgestrel does not affect the blood levels of other existing antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, paromidone); nor does the use of these antiepileptic drugs affect the pharmacokinetic properties of this product.
As in adults, there are no clinically meaningful drug-drug interactions when levetiracetam (maximum dose up to 60 mg/kg/day) is administered to children.
A retrospective evaluation of adolescent and pediatric patients with epilepsy (4 to 17 years of age) confirmed that oral add-on therapy with levetiracetam does not affect the steady-state blood concentrations of the combined application of carbamazepine and valproic acid. Similarly there are data that some enzyme-inducible antiepileptic drugs increase the clearance of levetiracetam by approximately 22%, a phenomenon that is not clinically significant and for which no adjustment in patient dosing is required.
Propofol
Propofol (a renal tubular secretion blocker) 500 mg four times daily has been reported to inhibit renal clearance of the major metabolite but not levetiracetam. However, the residual concentration of the major metabolite of levetiracetam is low. Theoretically, other drugs that are actively excreted through the renal tubules may also reduce the renal clearance of this metabolite. There are no studies on the effect of levetiracetam on probenecid, while the effect of levetiracetam on other drugs actively excreted via the renal tubules, such as NSAIDs, sulfonamides, and methotrexate, is also unknown.
Oral contraceptive and other pharmacokinetic interactions
Daily administration of levetiracetam 1000 mg does not affect the pharmacokinetics of oral contraceptives (ethinylestradiol, levonorgestrel); endocrine parameters (luteinizing hormone, progesterone) are not altered in patients. Daily administration of levetiracetam 2000 mg did not affect the pharmacokinetic properties of digoxin and warfarin; prothrombin time was not altered; and the combination with digoxin, oral contraceptives or warfarin did not affect the own pharmacokinetic properties of levetiracetam.
Antacids
There are no studies on the effect of antacids on the absorption of levetiracetam.
Food and alcohol
Eating does not affect the degree of absorption of levetiracetam, but it does mildly decrease its rate of absorption.
There are no studies on the interaction between alcohol and levetiracetam.
[Drug overdose].
Symptoms
Sleepiness, agitation, aggressiveness, decreased level of consciousness, respiratory depression and coma.
Treatment of overdose
After an acute overdose, the stomach should be emptied by gastric lavage or induced vomiting. There is no specific antidote for levetiracetam. Symptomatic treatment should be administered, which may also include hemodialysis. Dialysis elimination rate: 60% for levetiracetam and 74% for major metabolites.
【Clinical trial】.
Foreign clinical studies
Three double-blind, placebo-controlled studies were conducted in adult patients to demonstrate the effectiveness of levetiracetam. The doses were 1000 mg, 2000 mg, and 3000 mg twice a day, with a maximum treatment duration of 18 weeks. Pooled analysis showed that patients with partial seizures taking 1000 mg, 2000 mg, and 3000 mg (for 12 or 14 weeks) had a 50% or greater reduction in weekly seizure frequency compared to baseline in 27.7%, 31.6%, and 41.3% of patients, respectively. This compares with 12.6% in the placebo group.
In pediatric patients (4 to 16 years of age), a double-blind, placebo-controlled study was conducted to demonstrate the effectiveness of levetiracetam. The treatment was administered to 198 patients and continued for 14 weeks. In this study, patients were given a fixed dose of 60 mg/kg/day (twice a day). Patients with partial seizures had a 50% or greater reduction in weekly seizure frequency compared to baseline in 44.6% of the levetiracetam group and 19.6% of the placebo group. After continued long-term treatment, 11.4% of patients were seizure-free after at least 6 months and 7.2% after at least 1 year.
A double-blind placebo-controlled clinical study in pediatric patients (1 month to 4 years of age) with 116 patients and a 5-day dosing schedule was conducted to evaluate the effectiveness of levetiracetam. In the study, patients received oral solutions at daily doses of 20 mg/kg, 25 mg/kg, 40 mg/kg, or 50 mg/kg according to the appropriate age-specific dose recommendation table. kg per day in two divided doses for all patients.
The primary efficacy measure was response rate (the proportion of patients with a 50% reduction in mean daily partial seizure frequency from baseline), which was performed by centrally blinded analysis of 48-hour video EEG. 109 patients who completed at least 24 hours of video EEG evaluation in each of the baseline and evaluation periods were analyzed for efficacy. The results showed response rates of 43.6% and 19.6% in the levetiracetam and placebo groups, respectively. The results were consistent across age groups. In the continued long-term treatment, 8.6% of patients achieved at least 6 months seizure-free and 7.8% achieved at least 1 year seizure-free.
Chinese Registered Clinical Studies
Bioequivalence study
A randomized, single-center, open, two-stage crossover, single-dose bioequivalence study was conducted in 18 healthy fasting male subjects, each of whom received 500 mg of levetiracetam tablets (control) and 5 mL of a 10% oral solution of levetiracetam (trial) orally in randomized order. There was a 7-day washout period between the two dosage forms. 18 Chinese male subjects were randomized to the trial, 17 received both dosage forms (tablet and oral solution) and 1 subject received only the oral solution.
The blood concentration-time profiles showed that the major pharmacokinetic parameters (AUC(0-t), AUC and Cmax) of levetiracetam were similar for both dosage forms.
Error
The geometric least squares mean ratios (%) and corresponding 90% confidence intervals for the oral solution/tablet groups for AUC, AUC(0-t), and Cmax were calculated by ANOVA and fell well within the 80%-125% range, such that in healthy Chinese male volunteers, 5 mL of 10% levetiracetam oral solution and 500 mg of Levetiracetam tablets were bioequivalent in healthy Chinese male volunteers.
Bioequivalence analysis of levetiracetam dosage forms (PP population)
Indicator (unit) Oral solution Oral tablet residual (%) Oral solution group/tablet group estimate 90% Confidence interval AUC (0-t) (µg*h/mL) 122.1
(113.3; 131.5) 131.1
(121.7; 141.3) 3.18 93.11 (91.34; 94.91) AUC (µg*h/mL) 125.8
(116.7; 135.7) 135.4
(125.5; 146.0) 3.20 92.93 (91.15; 94.74) Cmax (µg/mL) 16.87
(15.07; 18.90) 16.03
(14.27; 18.01) 19.14 105.3 (94.02; 117.9) tmax (h) 0.25
(0.25; 0.75) 0.50
(0.25; 2.00) NC -0.38 (-0.63; -0.13)
(a) Geometric mean (95% confidence interval), tmax is the median (full distance)
(b) ANOVA residuals, indicating subjects’ own variation
(c) Ratio of least squares means (%) and 90% confidence interval calculated from ANOVA, tmax is the median difference between the test and control groups and 90% confidence interval
NC: Not calculated
There was no significant difference in the pharmacokinetic parameters tested between the two dosage forms.
Seven mild adverse events related to the study drug occurred in four subjects in the bioequivalence trial of this product. All of these adverse events subsided by the completion of the trial. Other than what is known about the safety profile of levetiracetam (in healthy subjects), there were no further findings. No serious adverse events or severe adverse events occurred in the study. No clinically significant abnormalities in laboratory tests, vital signs, electrocardiograms, or physical examinations were identified.
Clinical Trial Data for Levetiracetam Tablets
A multicenter, randomized, double-blind, parallel, placebo-controlled clinical study was conducted in six hospitals in China (in Shanghai, Beijing, Chongqing, and Chengdu) on the efficacy and safety of oral levetiracetam tablets for 16 weeks as add-on therapy for partial-onset seizures in adults and adolescents over 16 years of age in two treatment groups of placebo and levetiracetam at a daily dose of 3000 mg. A total of A total of 224 patients were screened, and 189 completed the trial (98 in the levetiracetam group and 91 in the placebo group). All subjects were Chinese, with a 52% and 48% male to female ratio, respectively. Demographics and other baseline characteristics were comparable between the two treatment groups, and the weekly seizure frequency at baseline was similar, (1.81 seizures/week in the levetiracetam group and 1.75 seizures/week in the placebo group).
The primary efficacy indicator 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 for the subjects was evaluated at the end of the 16-week trial using the overall clinical efficacy assessment scale.
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.
The proportion of partial seizures that were 50% effective was 57/102 (55.9%) in the levetiracetam group over the 16-week treatment period, 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 to 6.5), (p<0.001). Eleven cases (10.8%) in the levetiracetam group did not have 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 sleepiness (18 subjects, 17.5%), followed by reduced platelets.
Efficacy/pharmacokinetic/pharmacodynamic study results
Frequency analysis of the number of partial seizures per week in the intention-to-treat (ITT) population
Weekly partial seizure frequency levetiracetam
(N=102) Placebo
(N=100) Baseline period Mean (standard deviation)
Median (25% quartile – 75% quartile) 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 Median percent change from baseline period (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 (%) 55.9 26.0% Median ratio of ratios (OR) (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 estimation.
(b) The percentage reduction relative to the placebo group was calculated using the following equation.
100 × [1 – Exp (LSM levetiracetam – LSM placebo)].
(c) Comparison with placebo.
(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 pyrrolidone derivative 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 effects of levetiracetam have been evaluated in various antiepileptic animal models. Levetiracetam did not inhibit simple seizures induced by maximal stimulation with electric current or multiple convulsants 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 erythromelanin, 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 vivo and in vitro 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. Levetiracetam neuronal binding sites were found to be present in rat brain tissue and to be saturable and stereoselective; however, the binding site has not been identified and its function is unclear.
Toxicological studies
Genotoxicity
Levetiracetam Ames test, CHO/HGPRT motif mammalian cell gene mutation test, CHO cell chromosome aberration test, and mouse micronucleus test results were all negative. 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. Reduced litter weight and increased incidence of fetal skeletal variation were seen in pregnant rats when administered during the organogenesis phase at a dose of 3600 mg/kg/day (extrapolated to 12 times the MRHD in mg/m2). The no-effect dose for developmental toxicity was 1200 mg/kg/day, and no maternal toxicity was seen in this test. In pregnant rabbits administered during organogenesis 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 seen; 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 seen. An increase in maternal toxicity was observed. The no-effect dose for developmental toxicity was 200 mg/kg/day.
In female rats administered during pregnancy and lactation, fetal skeletal abnormalities, prenatal and/or postnatal growth retardation were observed at a dose of ≥350 mg/kg/day (equivalent to MRHD at mg/m2); increased pup mortality and abnormal offspring behavior were observed at a dose of 1800 mg/kg/day (equivalent to MRHD at 6 times the dose at mg/m2); in this assay The no-effect dose for developmental toxicity 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 (6 times the MRHD at mg/m2 ).
Carcinogenicity
No carcinogenicity was seen with levetiracetam given in the rat 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 doses were extrapolated to 2 times the MRHD by mg/m2 or exposure) in the adulteration method, and no carcinogenicity was observed. However, the potential carcinogenicity to this animal species could not be fully evaluated due to the low dose administered.
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 are no gender or racial differences or differences in physiological rhythm. Pharmacokinetic studies of this product showed comparable pharmacokinetic data in healthy volunteers and patients.
Blood concentration monitoring of levetiracetam is not necessary because levetiracetam is completely absorbed in a linear fashion and its blood concentration can be predicted based on the oral dose of mg/kg.
Saliva and blood concentrations in adult and pediatric patients showed a significant correlation (saliva/blood drug concentration ratio was 1 to 1.7 after 4 h of administration of the tablet or liquid formulation of the product).
Adults and adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration, and the absolute oral bioavailability is close to 100%. Blood concentrations peak after 1.3 h of administration, and steady-state concentrations are reached after 2 days if administered twice daily. Peak concentrations were 31 and 43 µg/ml for a single dose of 1000 mg or 1000 mg twice daily. absorption was dose-independent and was not affected by feeding.
Distribution
No data on human tissue distribution are available. Neither levetiracetam nor its major metabolite is readily bound to plasma proteins (binding rate <10%). The volume of distribution is 0.5 to 0.7 L/kg, which is close to the total body volume.
Biotransformation
Levetiracetam is poorly metabolized in humans. The main metabolic pathway is the enzymatic hydrolysis of the acetamide moiety (24% of the administered dose). The major metabolite, UCBL057, does not pass through the hepatic cytochrome P450 isoenzyme pathway. Acetamide group hydrolysates are present in many tissues in the body, including blood cells. The metabolite UCBL057 is not pharmacologically active.
Two minor metabolic pathways have also been identified, a hydroxylation of the pyrrolidone ring (1.6% of the administered dose) and a ring opening of the pyrrolidone ring (0.9% of the administered dose). The metabolites of other metabolic pathways that could not be identified accounted for 0.6% of the administered dose. The current in vitro trial data indicate no chiral flip-flopping of either levetiracetam or its major metabolite.
In vitro data suggest that levetiracetam and its major metabolites do not inhibit the activity of hepatochrome P450 isozymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2) glucuronosyltransferases (UGT1A6 and UGT1A1) and epoxide hydroxylases. In addition, in vitro assays have shown that levetiracetam does not affect the glucuronidation of valproic acid. In cultured human hepatocytes, levetiracetam had no or only minor effects on CYP1A2, SULTIEI or UGT1A1. Levetiracetam slightly produces CYP2B6 and CYP3A4 enzyme induction. In vitro studies and in vivo studies of oral contraceptive, digoxin and warfarin interactions did not show the expected significant enzyme induction in vivo. This leads to the conclusion that levetiracetam has no interaction with other substances. The converse is also true.
Elimination
Adult plasma half-life: 7±1 h, not altered by dose, route of administration, or repeated dosing. The mean total body clearance is 0.96 ml/min/kg.
The drug is excreted mainly in the urine, approximately 95% of the administered dose (approximately 93% is excreted within 48h). Only 0.3% of the drug was excreted in the feces.
The cumulative urinary excretion rates of levetiracetam and its major metabolite were 66% and 24% of the administered dose, respectively, within 48 h of initiation of administration.
The renal clearance of levetiracetam and UCB L057 was 0.6 and 4.2 ml/min/kg, respectively, indicating that levetiracetam was excreted by glomerular filtration with renal tubular reabsorption. In contrast, its main metabolite was active tubular excretion with glomerular filtration excretion. The elimination rate of levetiracetam correlates with the clearance of creatinine.
Geriatric patients
The half-life of levetiracetam is approximately 40% longer in elderly patients (10-11 h). This is associated with a decrease in their renal function.
Children (4-12 years)
The plasma half-life of levetiracetam administered as a single dose (20 mg/kg) in children with epilepsy (6 to 12 years of age) is 6.0 h. The apparent clearance (weight-corrected) is approximately 30% higher than in adult patients.
Levetiracetam is rapidly absorbed after repeated oral dosing (20-60 mg/kg/day) in children (4 to 12 years). Peak concentrations were reached 0.5 to 1 h after dosing. Peak concentration and area under the curve increased proportionally and linearly. The clearance half-life is 5h, and the apparent in vivo clearance is about 1.1ml/min/kg.
Infants and young children (1 month to 4 years)
The absorption was rapid in pediatric patients (1 month to 4 years of age) after a single dose administration of a 10% oral solution volume (20 mg/kg). The blood dose peaked 1 h after administration. Pharmacokinetic data showed a shorter half-life (5.3h) than in adults (7.2h) and a faster apparent clearance in infants (1.5ml/min/kg) than in adults (0.96ml/min/kg). The amount of UCB L057, the major metabolite, was lower in children than in adults.
In the pharmacokinetic analysis of patients aged 1 month to 16 years, body weight was significantly correlated with apparent clearance and apparent body weight (apparent clearance increased with body weight). Age also had an effect on these two parameters, especially in younger children, and changed with age until there was no effect after 4 years of age.
The above pharmacokinetic analysis showed a 20% increase in apparent clearance when levetiracetam was administered concomitantly with AEDs with enzyme-inducing effects.
Patients with renal impairment
In patients with renal impairment, the in vivo clearance of levetiracetam and the major metabolites is dependent on creatinine clearance. Therefore, in patients with moderate or severe renal impairment, it is recommended that the daily maintenance dose be adjusted according to creatinine clearance. In adult patients with end-stage renal disease without urine, the plasma half-life of levetiracetam during dialysis and dialysis was 2.5 h and 3.1 h, respectively. levetiracetam clearance during a 4-h dialysis session was 51%.
Patients with hepatic impairment
In patients with mild and moderate hepatic impairment, there was no corresponding change in the clearance of levetiracetam. In most patients with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50% due to concomitant renal impairment.
Storage
Airtight, store below 25℃.
Package
150ml/bottle, 1 bottle/box (with 5ml oral medicine extractor).
Expiration date
Unopened product: 24 months.
After the first opening: 7 months.
Execution standard
Approval number】
【Manufacturer】
Enterprise name: Chongqing Shenghuaxi Pharmaceutical Co.
Address: No.8 Jiangqiao Road, Nanan District, Chongqing
Postal Code
Telephone number: 023-62515566
Fax Number: 023-62506940