Date of approval.
Date of revision.
Levetiracetam Extended Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Levetiracetam Sustained-release Tablets
English name: Levetiracetam Sustained-release Tablets
Hanyu Pinyin: Zuoyilaxitan Huanshipian
Ingredients
Ingredients
The active ingredient of this product is Levetiracetam.
Chemical name: (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide
Chemical structure formula.
Molecular formula: C8H14N2O2
Molecular weight: 170.21
Properties
Appearance
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Application
Indications
Indications】For the treatment of partial seizures in patients with epilepsy aged 12 years and above.
Specification
Specification】0.5g
Dosage
Recommended Dosage
Take orally, once daily. It should be swallowed whole, not chewed, broken or crushed.
The starting therapeutic dose is 1000mg once daily. The daily dose should be increased by 1000 mg every two weeks until the maximum recommended dose of 3000 mg/day is reached.
Dose adjustment for adult patients with renal insufficiency
The dose must be adjusted according to the patient’s renal function status and the recommended dose adjustment is shown in the table below. To calculate the recommended dose for patients with renal insufficiency, creatinine clearance (CLCR) ml/min is first calculated using the following formula.
[140 – age (years)] × body weight (kg)
72×Serum creatinine value (mg/dl)
Then, creatinine clearance was adjusted according to body surface area (BSA) as follows.
CLcr (mL/min)
BSA subject (m2)
Group creatinine acid clearance (ml/min/1.73m2) Dose (mg) Dosing interval normal >801000-3000 once daily mild 50-801000-2000 once daily moderate 30-50500-1500 once daily severe <30500-1000 once daily
[Adverse Reactions].
The following adverse reactions are discussed in detail in other parts of the instruction.
Abnormal behavior and psychotic symptoms, suicidal behavior and perceptions, drowsiness and malaise, hypersensitivity and angioedema, severe skin reactions, coordination difficulties, and hematologic abnormalities [see PRECAUTIONS].
Clinical trial experience
Because clinical trials are conducted under a variety of different conditions, the incidence of adverse drug reactions cannot be directly compared between clinical trials, and the incidence of adverse reactions in clinical trials may not reflect the incidence of adverse reactions during drug use.
Levetiracetam extended-release tablets
In controlled clinical studies in patients with partial-onset seizures, the most common adverse reactions in patients receiving levetiracetam extended-release tablets in combination with other antiepileptic drug (AED) medications, and at a greater incidence than in the placebo group, were irritability and drowsiness.
In the placebo-controlled clinical study, the adverse reactions that occurred at a greater rate of 5% in the levetiracetam treatment group than in the placebo group are listed in the table below. In this study, patients in both groups were treated with either levetiracetam extended-release tablets or placebo in addition to their existing AED therapy.
Levetiracetam extended-release tablets
(N=77) % Placebo
(N=79) % Influenza 84 Drowsiness 83 Irritability 70 Nasopharyngitis 75 Dizziness 53 Nausea 53
Discontinuation or Dose Reduction in Controlled Clinical Studies of Levetiracetam Extended-Release Tablets
In the controlled clinical study, 5% of patients in the levetiracetam extended-release tablet treatment group and 3% of patients in the placebo treatment group discontinued the drug due to adverse effects. The adverse reactions that occurred more frequently in the levetiracetam extended-release group than in the placebo group included malaise, seizures, mouth ulcers, rash, and respiratory failure. All of these adverse reactions led to discontinuation in the levetiracetam extended-release group, but not in the placebo group.
Levetiracetam Tablets
The following table lists the adverse reactions that occurred in adult patients with partial-onset seizures treated with levetiracetam tablets in controlled clinical studies. Although the types of adverse reactions in the levetiracetam extended-release tablet study appear to be different from those in the levetiracetam tablet study, this may be caused by the fact that the number of patients in the levetiracetam extended-release tablet study was much smaller than in the levetiracetam tablet study. Adverse reactions to levetiracetam extended-release tablets are expected to be similar to those of levetiracetam tablets.
Adults
In clinical controlled studies treating adult patients with partial-onset seizures, the most common and more frequent adverse reactions to levetiracetam tablets as an adjunct to other AEDs than in the placebo group included drowsiness, malaise, infection, and dizziness.
In the placebo-controlled, treatment of adult patients with epilepsy, the adverse reactions that occurred at an incidence greater than 1% in the levetiracetam tablet group and were higher than those in the placebo group are shown in the table below. In these studies, patients in both groups were treated with levetiracetam tablets or placebo in addition to their existing AED therapy.
Levetiracetam
(N=769)
% placebo
(N=439)
% weakness 159 drowsiness 158 headache 1413 infection 138 dizziness 94 pain 76 pharyngitis 64 depression 42 nervousness 42 rhinitis 43 anorexia 32 ataxia 31 vertigo 31 amnesia 21 anxiety 21 increased cough 21 diplopia 21 emotional instability 20 hostile tendencies 21 sensory abnormalities 21 sinusitis 21
Pediatric patients aged 4 years-<16 years
In a combined analysis of two clinically controlled studies conducted in pediatric patients aged 4-16 years with partial-onset seizures, adverse reactions that were reported most frequently and occurred more frequently in the levetiracetam tablets in combination with other AEDs than in the placebo group included malaise, aggressiveness, nasal congestion, loss of appetite, and irritability.
The table below lists the adverse reactions that occurred at a greater rate of >2% in pediatric patients treated with levetiracetam tablets than in the placebo control group. In these studies, patients were treated with levetiracetam tablets or placebo in addition to their existing AED therapy, and the grade of adverse reactions that occurred was usually mild to severe.
Levetiracetam
(N=165)
% Placebo (N=131)
% headache1915 nasopharyngitis1512 vomiting1512 drowsiness139 malaise115 aggressiveness105 epigastric pain98 cough95 nasal congestion92 decreased appetite82 abnormal behavior74 dizziness75 irritability71 sore throat74 diarrhea62 drowsiness65 insomnia53 agitation41 anorexia43 head injury40 constipation31 contusions31 depression31 falls32 flu31 mood changes31 Emotional instability21 anxiety21 arthralgia20 state of confusion20 conjunctivitis20 earache21 gastroenteritis20 joint sprain21 mood swings21 neck pain21 rhinitis20 sedation21
In a controlled clinical study in pediatric patients aged 4-16 years, 7% of patients in the levetiracetam tablet treatment group and 9% of patients in the placebo group discontinued the drug due to adverse effects.
In addition, the following adverse reactions have been seen in other controlled studies of levetiracetam tablets: balance disturbance, inattention, eczema, hypermobility, memory impairment, myalgia, personality disorder, pruritus, and blurred vision.
There are insufficient data to support the distribution of levetiracetam extended-release tablets adverse reactions across gender, age and race.
Postmarketing Experience
The following are adverse reactions that have occurred during post-marketing clinical use of levetiracetam tablets. Because these adverse reactions were spontaneously reported from populations of unknown size, it is usually not possible to reliably estimate the frequency of adverse reactions or to determine their correlation with drug exposure.
Events include: abnormal liver function, chorea, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, myasthenia gravis, pancreatitis, allogeneic cytopenia (and in some cases, myelosuppression), panic attacks, thrombocytopenia, and weight loss. Hair loss has also been reported with levetiracetam tablets, and most cases recovered after discontinuation of the drug.
Contraindications
Contraindications
Levetiracetam is contraindicated in patients with hypersensitivity to levetiracetam or to pyrrolidone derivatives or any other ingredients. Allergic reactions to levetiracetam include anaphylaxis and angioedema [see PRECAUTIONS].
Precautions
Levetiracetam extended-release tablets may cause behavioral abnormalities and psychiatric symptoms; patients should be monitored for psychiatric signs and symptoms during treatment with levetiracetam extended-release tablets.
Behavioral abnormalities and psychiatric symptoms
Levetiracetam extended-release tablets may cause behavioral abnormalities and psychotic symptoms. When treating with levetiracetam extended-release tablets, patients should be monitored for psychiatric signs and symptoms.
Behavioral abnormalities
Levetiracetam Extended-Release Tablets
A total of 7% of patients treated with levetiracetam extended-release tablets experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared with 0% of patients in the placebo-treated group. In the levetiracetam extended-release tablet-treated group, irritability was reported by 7% of patients and aggression was reported by 1% of patients.
No patients discontinued treatment or had their dose reduced due to these adverse reactions.
In controlled studies, the number of patients taking levetiracetam extended-release tablets was much smaller than the number of patients taking levetiracetam tablets; therefore, adverse reactions that occurred in controlled trials with levetiracetam tablets may also occur in patients treated with levetiracetam extended-release tablets.
Levetiracetam Tablets
A total of 13% of adult patients and 38% of pediatric patients (aged 4-16 years) treated with levetiracetam tablets experienced nonpsychotic behavioral symptoms (including aggression, agitation, anger, anxiety, affective apathy, depersonalization, depression, emotional instability, hostility, motor hyperfunction, irritability, nervousness, neurosis, and personality disorders), compared with a total of 6% of the placebo group of adult patients and 19% of pediatric patients. In a randomized, double-blind, placebo-controlled clinical study evaluating the effects of levetiracetam tablet adjunctive therapy on neurocognition and behavior in pediatric patients (4-16 years old), results of an exploratory analysis showed that aggressive behavior was exacerbated after treatment with levetiracetam tablets.
A total of 1.7% of adult patients treated with levetiracetam tablets discontinued treatment due to abnormal behavioral adverse effects, compared with only 0.2% of patients in the placebo treatment group; 0.8% of adult patients in the levetiracetam tablet treatment group had a reduced treatment dose, compared with 0.5% of adult patients in the placebo treatment group. Overall, 11% of pediatric patients treated with levetiracetam tablets discontinued or reduced their dose due to behavioral symptoms, compared with 6.2% of the placebo-treated group.
Psychotic symptoms were seen in 1% of adult patients and 2% of pediatric patients (aged 4-16 years) in the levetiracetam tablet-treated group, compared with 0.2% of adults and 2% of children in the placebo-treated group. In a controlled study evaluating the neurocognitive and behavioral effects of levetiracetam in pediatric patients aged 4-16 years, delusional disorder occurred in 1.6% of patients in the levetiracetam-treated group, compared with no patients in the control group. In the levetiracetam tablet treatment group, 3.1% of patients experienced a blurred state of consciousness, while this occurred in no patients in the placebo treatment group.
Psychotic symptoms
Levetiracetam Tablets
Psychotic symptoms occurred in 1% and 0.2% of adult patients in the levetiracetam and placebo treatment groups, respectively.
Two (0.3%) adult patients in the levetiracetam-treated group were hospitalized for psychosis and discontinued treatment. Both events were reported as psychosis, with illness occurring within the first week of treatment and resolving within 1-2 weeks after discontinuation of treatment. Among medically treated and placebo-treated pediatric patients, there was no significant difference in the incidence of discontinuation of treatment for psychotic and non-psychotic adverse events in the two groups.
Suicidal behavior and ideation
When patients are treated with AEDs (including levetiracetam extended-release tablets), the medications increase the risk of suicidal ideation or behavior, and therefore patients should be monitored for the onset and worsening of depression, suicidal ideation or behavior, and/or any abnormal changes in mood or behavior, regardless of the type of AED medication used for any treatment.
A combined analysis of 199 placebo-controlled clinical studies of 11 different AEDs (monotherapy and adjunctive therapy) showed that patients randomized to one AED had approximately twice the risk of suicidal ideation or behavior as patients randomized to placebo (corrected relative risk
1.8, 95% CI: 1.2, 2.7). In these trials, the median duration of treatment was 12 weeks. The incidence of suicidal behavior or ideation was approximately 0.43% in the 27,863 patients treated with AEDs, compared with approximately 0.24% in the 16,029 patients in the placebo-treated group, meaning that for every 530 patients treated with AEDs, the number of patients who developed suicidal ideation or behavior increased by approximately 1. In the trial, 4 patients in the drug treatment group committed suicide, while no patients in the placebo treatment group committed suicide, but the number of cases was too small to draw conclusions about the effect of drugs on suicidal behavior.
An increased risk of suicidal ideation or behavior associated with AEDs was seen 1 week after initiation of treatment with AEDs and could persist within the treatment assessment, and because most of the trials in the analysis did not extend beyond 24 weeks, it was not possible to assess the risk of suicidal ideation or behavior after 24 weeks.
The risk of suicidal ideation or behavior was generally consistent across drugs in the analyzed data, with increased risk across different mechanisms of action and different ranges of indications for AEDs, suggesting that the risk applies to all AED drugs treated for each indication and did not vary substantially across patients of all ages (5-100 years) in the analyzed clinical trials. The table below shows the absolute and relative risks for all AEDs evaluated, by indication.
Indication Placebo group patients with events per 1000 patients Drug group patients with events per 1000 patients Relative risk: Incidence of events in drug group patients/incidence in placebo group patients Risk difference: Other drug group patients with events per 1000 patients Epilepsy 1.03.43.52.4 Psychosis 5.78.51.52.9 Other 1.01.81.90.9 Total 2.44.31.81.9
The relative risk of suicidal ideation or risk was higher in clinical trials in epilepsy compared with clinical trials in psychosis or other disorders, while the difference in absolute risk was similar in epilepsy and psychiatric treatment.
When considering giving patients levetiracetam extended-release tablets or other AED prescriptions, the risk of suicidal ideation/behavior must be weighed against the risk of untreated illness. Increased morbidity, mortality, and risk for suicidal ideation and behavior are associated with AED treatment for epilepsy and many other disorders, and if suicidal thoughts or behaviors occur in patients during treatment, physicians must consider whether these symptoms occurring in patients taking the medication may be related to the treatment being received for the disorder.
Patients, caregivers, and family members should be informed that AEDs increase the risk of suicidal thoughts and behaviors and that they need to be alert for the onset or worsening of signs and symptoms of depression, abnormal mood or behavior, suicidal thoughts, behaviors, or self-harm awareness in patients, and to report immediately to health care providers when relevant behaviors occur.
Drowsiness and fatigue
Levetiracetam extended-release tablets may cause drowsiness and fatigue, and patients should be monitored for these signs and symptoms.
Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery unless they have had adequate experience with levetiracetam extended-release tablets and can gauge for themselves whether these reactions adversely affect the ability to drive or operate machinery.
Drowsiness
Levetiracetam extended-release tablets
In a double-blind, controlled trial in patients with partial-onset seizures, drowsiness occurred in 8% of patients in the levetiracetam extended-release tablet treatment group compared with 3% of patients in the placebo treatment group.
No patients in the study discontinued treatment or lowered the dose administered due to these adverse effects.
In the controlled study, the number of patients taking levetiracetam tablets was much less than the number of patients taking levetiracetam tablets; therefore, the adverse reactions that occurred in the controlled trial of levetiracetam tablets may have been seen in patients treated with levetiracetam extended-release tablets.
Levetiracetam Tablets
In a controlled trial in adult patients with partial-onset seizures, 15% of patients in the levetiracetam-treated group reported drowsiness compared with only 8% of patients in the placebo-treated group. No significant dose response was seen when doses reached 3000 mg/day. In a study without dose titration, drowsiness was reported in 45% of patients taking 4000 mg/day. Severe somnolence occurred in 0.3% of patients in the levetiracetam-treated group, while no patients in the placebo group experienced severe somnolence. Approximately 3% of patients in the levetiracetam-treated group discontinued treatment due to drowsiness, compared with 0.7% of patients in the placebo-treated group who discontinued treatment due to drowsiness. Dose reduction due to drowsiness occurred in 1.4% of patients in the levetiracetam-treated group and 0.9% of patients in the placebo-treated group, and 0.3% of patients in both groups were hospitalized due to drowsiness.
Lethargy
Levetiracetam tablets
In a controlled trial of adult patients with partial-onset seizures, 15% of patients in the levetiracetam-treated group reported malaise compared with 9% in the placebo-treated group. Levetiracetam treatment was discontinued due to malaise in 0.8% of patients in the levetiracetam-treated group compared with 0.5% in the placebo-treated group. The dose was reduced due to weakness in 0.5% of patients in the levetiracetam-treated group and 0.2% of patients in the placebo-treated group.
The most frequent adverse reactions during the first 4 weeks of treatment were drowsiness and malaise.
Allergies and Angioedema
Levetiracetam extended-release tablets can cause hypersensitivity and angioedema at any time after the first dose or during dosing. Signs and symptoms in patients treated with levetiracetam have included hypotension, urticaria, rash, dyspnea, and swelling of the face, lips, mouth, eyes, tongue, throat, and feet, according to postmarketing reports of the drug. In some reports, some reactions were life-threatening and required emergency treatment. If signs or symptoms of an allergic reaction or angioedema occur, the patient should discontinue levetiracetam extended-release tablets and seek urgent medical attention. If the patient is unable to identify another cause of the reaction, levetiracetam extended-release tablets should be discontinued permanently.
Severe Skin Reactions
Serious skin reactions have been reported in patients treated with levetiracetam, including Stevens-Johnson syndrome (SJS) and toxic epidermolysis bullosa. The median time to onset of these disorders was 14-17 days, but these cases were reported at least 4 months after initiation of treatment. There have also been reports of recurrence of severe skin reactions following reintroduction of levetiracetam. At the first onset of rash symptoms, patients should discontinue levetiracetam extended-release tablets unless the rash episode is clearly not drug-related, and if signs or symptoms suggest SJS/TEN, the drug should not be resumed and alternative therapies should be considered.
Coordination difficulties
Coordination difficulties were not observed in patients in controlled clinical trials with levetiracetam extended-release tablets. The number of patients in controlled trials with levetiracetam extended-release tablets was much smaller than with levetiracetam tablets; therefore, the adverse reactions observed in clinical trials with levetiracetam tablets may also occur in patients treated with levetiracetam extended-release tablets.
Levetiracetam Tablets
Coordination difficulties (including ataxia, gait abnormalities or incoordination) occurred in a total of 3.4% of adult patients treated with levetiracetam tablets compared to 1.6% of patients in the placebo-treated group. In the controlled trial, a total of 0.4% of patients in the levetiracetam tablet group discontinued treatment due to ataxia, while no patients in the placebo group experienced this event. 0.7% of patients in the levetiracetam tablet group and 0.2% of patients in the placebo group had dose reductions due to coordination difficulties, and one patient in the levetiracetam tablet group was hospitalized due to worsening of preexisting ataxia. The incidence of these events was highest in the first 4 weeks of the treatment period.
Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery unless they have had adequate experience with levetiracetam extended-release tablets and are able to gauge for themselves whether these reactions will have an adverse effect on the ability to drive or operate machinery.
Seizures after discontinuation of medication
To minimize the possibility of increased seizure frequency, treatment with antiepileptic drugs (including levetiracetam extended-release tablets) should be discontinued gradually.
Hematologic abnormalities
Levetiracetam extended-release tablets may cause hematologic abnormalities. Hematologic abnormalities have occurred in clinical trials, including decreased red blood cell (RBC) counts, hemoglobin and hematocrit, and increased eosinophil counts, and decreased white blood cell (WBC) and neutrophil counts have also occurred in clinical trials. Cases of granulocyte deficiency have also been reported after the drug became available.
In clinical trials of levetiracetam tablets in patients with partial-onset seizures, patients in the levetiracetam-treated group had a small but statistically significant reduction in mean total RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%) compared to patients in the placebo group.
In the levetiracetam tablet-treated and placebo-treated groups, 3.2% and 1.8% of patients had at least one possible significant reduction in WBC (≤2.8 x 109/L) and 2.4% and 1.4% of patients had at least one significant (≤1.0 x 109/L) reduction in neutrophil count, respectively, and patients in the levetiracetam tablet-treated group had lower neutrophil count values, but after continued After treatment, all but one patient showed a trend toward an increase in neutrophil count toward or to baseline values, and no patient in the study discontinued the drug secondary to a decrease in neutrophil count.
In pediatric patients (4 – <16 years of age), both WBC and neutrophil counts were statistically significantly lower in the levetiracetam tablet-treated group compared with the placebo group, with a decrease of -0.4 × 109/L and -0.3 × 109/L from baseline mean values in the levetiracetam tablet-treated group, respectively, and a small increase in both counts in the placebo group, with a small increase in the levetiracetam tablet-treated group. In the levetiracetam tablet treatment group, 1.7% of patients had a significant increase in mean relative lymphocyte counts, while 4% of patients in the placebo group had a decrease in counts.
In the pediatric controlled trial, a potentially clinically significant abnormal decrease in WBC values occurred in 3% of patients in the levetiracetam-treated group, while no patients in the placebo group experienced this event, but there were no significant differences in neutrophil counts between the two treatment groups, and no patients in the study discontinued medication secondary to a decrease in WBC or neutrophil counts.
In the controlled cognitive and neuropsychological safety study in children, two subjects in the placebo group (6.1%) and five subjects in the levetiracetam tablet treatment group (8.6%) had higher and possibly clinically significant eosinophil counts (≥10% or
≥0.7×109 /L).
Epilepsy control during pregnancy
Physiologic changes in patients throughout pregnancy may result in a gradual decrease in levetiracetam blood levels, with this decrease being more pronounced in late pregnancy; therefore, careful monitoring of patients during pregnancy is recommended and should be continued closely during the postpartum period, especially if the patient’s dose changes during pregnancy.
Pregnant women and nursing mothers
Pregnancy
The concentration of levetiracetam extended-release tablets may decrease during pregnancy.
There are no adequate, well-controlled clinical studies in pregnant women.
In animal studies, levetiracetam at doses similar to or higher than human therapeutic doses can cause developmental toxicity, including teratogenic effects, and should therefore be administered during pregnancy only if the potential benefit of levetiracetam extended-release tablets outweighs the potential risk to the fetus.
Following oral administration of levetiracetam to female rats throughout gestation and lactation, the drug can cause an increased incidence of minor fetal skeletal abnormalities and delayed prenatal and/or postnatal offspring development when administered at doses ≥350 mg/kg/day (calculated on a mg/m2 basis at a dose equivalent to the maximum recommended human dose of 3000 mg [MRHD]), and when administered at doses The incidence of pup mortality and offspring behavioral changes was increased when doses of 1800 mg/kg/day (6 times that of MRHD calculated by mg/m2) were administered. The drug had no effect on offspring development at a dose of 70 mg/kg/day (0.2 times MRHD by mg/m2), and there was no significant maternal toxicity at the dose used in this study.
After oral administration of levetiracetam to pregnant rabbits during the organogenesis period, the rate of embryo-fetal mortality and minor fetal skeletal abnormalities increased at doses ≥600 mg/kg/day (4 times that of MRHD by mg/m2), and at doses of 1800 mg/kg/day (12 times that of MRHD by mg/m2), fetal weight loss and fetal malformation rates The drug had no effect on offspring development at a dose of 200 mg/kg/day (equal to MRHD by mg/m2), and maternal toxicity was also seen when 1800 mg/kg/day was given.
When levetiracetam was given orally to pregnant rats during the organogenesis period, the fetal weight loss and the incidence of fetal skeletal abnormalities increased when administered at a dose of 3600 mg/kg/day (12 times the MRHD), and the drug had a no effect on offspring development at a dose of 1200 mg/kg/day (4 times the MRHD).
When oral levetiracetam was given to rats in late pregnancy and throughout gestation, the drug had no harmful effects on offspring development and the mother at doses up to 1800 mg/kg/day (6 times higher than MRHD calculated by mg/m2).
Delivery
The effect of levetiracetam extended-release tablets on delivery is not known.
Lactating women
Levetiracetam is excreted in human milk. Since levetiracetam extended-release tablets may cause serious adverse reactions in nursing infants, the importance of the drug to the mother should be considered when administering to a nursing woman in order to decide whether to discontinue nursing or to discontinue the drug.
Pediatric Use]
The safety and efficacy of levetiracetam in pediatric patients 12 years of age and older were determined based on the pharmacokinetic results of levetiracetam extended-release tablets in adults and adolescents and the efficacy and safety results of a controlled study of levetiracetam tablets in children [see Adverse Reactions and Clinical Studies].
A 3-month randomized, double-blind, placebo-controlled study evaluated the effects of levetiracetam tablet adjunctive therapy on neurocognition and behavior in children in 98 pediatric patients aged 4-16 years with poorly controlled partial seizures (levetiracetam tablets N=64; placebo
N=34) with a target dose of 60 mg/kg/day of levetiracetam tablets.The Leiter-R Attention and Memory (AM) test assesses various aspects of memory and attention in children. In this study, the Leiter-R attention and memory (AM) test was used to determine the effect of the drug on neurocognitive function. Although there was no substantial difference in the change in patient outcomes from median baseline values between the placebo and levetiracetam-treated groups in this test, the study could not adequately assess the statistical non-inferiority between the drug and placebo.The Achenbach Child Behavior Checklist (CBCL/6-18) is a standardized instrument validated for assessing children’s abilities and behavioral/emotional problems. The scale was used for assessment in this study, and analysis of the CBCL/6-18 showed that aggressive behavior was exacerbated in children in the levetiracetam-treated group in the 8-item syndrome score.
In levetiracetam administration studies in juvenile rats (administered from day 4 to day 52 of life) and dogs (administered from week 3 to week 7 of life) at doses up to 1800 mg/kg/day (approximately 7 and 24 times the maximum recommended dose of 60 mg/kg/day for children, respectively, calculated on the basis of mg/m2), there was no potential age-specific toxicity of the drug.
[Geriatric use].
In controlled trials in patients with epilepsy, the number of elderly subjects was insufficient to adequately assess the effectiveness of levetiracetam extended-release tablets in these patients. The safety profile of levetiracetam extended-release tablets in elderly patients 65 years of age and older is expected to be comparable to the safety results in clinical studies of levetiracetam tablets.
In clinical studies of levetiracetam tablets in 347 subjects aged 65 years and older, the results of the study showed no substantial difference in the safety of levetiracetam tablets in younger subjects and subjects. In controlled trials in patients with epilepsy, the number of elderly subjects was insufficient to adequately assess the effectiveness of levetiracetam tablets in these patients.
Levetiracetam is known to be largely excreted by the kidneys, so the risk of adverse reactions to this drug may be greater in patients with renal impairment. Since elderly patients are more likely to have reduced renal function, caution should be exercised in dose selection, and renal function monitoring may be helpful.
[Drug Interactions].
In vitro metabolic interaction data suggest that levetiracetam is unlikely to undergo pharmacokinetic “drug-drug” interactions.
In the therapeutic dose range, levetiracetam and its major metabolites (at concentrations above Cmax) are neither inhibitors of human hepatic cytochrome P450, epoxide hydrolase, or UDP-glucosidase, nor are they high-affinity substrates. In addition, levetiracetam does not affect the glucuronidation of valproic acid in vitro.
Potential pharmacokinetic interactions of levetiracetam were evaluated in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptives, probenecid) and placebo-controlled clinical studies in patients with epilepsy in which the pharmacokinetic screening of levetiracetam tablets evaluated the potential pharmacokinetic interactions of levetiracetam, and the drug interaction potential of levetiracetam extended-release tablets was expected to be essentially the same as that of levetiracetam tablets.
Phenytoin
Levetiracetam tablets (3000 mg/day) had no effect on the pharmacokinetic properties of phenytoin in patients with refractory epilepsy, and phenytoin did not affect the pharmacokinetics of levetiracetam.
Sodium valproate
Levetiracetam tablets (1500 mg twice daily) did not alter the pharmacokinetic properties of valproate in healthy subjects, nor did the rate or extent of absorption, plasma clearance, or urinary excretion of levetiracetam in subjects receiving 500 mg of valproate twice daily, nor did it have any effect on the exposure level or excretion of the major metabolite, ucb L057.
Other antiepileptic drugs
Placebo-controlled clinical studies evaluated potential drug interactions between levetiracetam tablets and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, paracetamol, and sodium valproate) by evaluating serum concentrations of levetiracetam and other AEDs, and the results indicated that levetiracetam did not affect the blood concentrations of other AEDs and that these AEDs had no effect on the pharmacokinetics of levetiracetam. The pharmacokinetics of levetiracetam were also unaffected.
Oral contraceptives
Levetiracetam tablets (500 mg twice daily) did not affect the pharmacokinetic properties or the levels of luteinizing hormone and progesterone of oral contraceptives containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel, indicating that levetiracetam did not affect the efficacy of the contraceptives. There was also no effect on the pharmacokinetics of levetiracetam when administered in combination with these oral contraceptives.
Digoxin
Administration of levetiracetam tablets (1000 mg twice daily) did not affect the pharmacokinetic and pharmacodynamic (ECG) properties of digoxin at a daily dose of 0.25 mg. There was no effect on the pharmacokinetics of levetiracetam when co-administered with digoxin.
Warfarin
Administration of levetiracetam tablets (1000 mg twice daily) did not affect the pharmacokinetic properties of R and S warfarin, and prothrombin time was not affected by levetiracetam. When co-administered with warfarin, the pharmacokinetics of levetiracetam are not affected.
Probenecid
Propofol is a renal tubular secretion blocker. 500 mg of propofol administered four times daily did not alter the pharmacokinetics of 1000 mg of levetiracetam administered twice daily. propofol approximately doubled the Css_max of the metabolite ucb L057, but urinary excretion of levetiracetam was unchanged. renal clearance of ucb L057 was reduced by 60% in the presence of propofol, which may be related to the competitive inhibition of ucb L057 renal tubular secretion. The effect of levetiracetam tablets on probenecid has not been studied.
Drug overdose]
Signs, symptoms and laboratory findings of acute drug overdose in humans
Signs and symptoms of levetiracetam extended-release tablets overdose are expected to be similar to those of levetiracetam tablets.
In the clinical development program, the maximum known dose of levetiracetam tablets was 6000 mg/day. In several known drug overdose cases in clinical trials, no adverse reactions other than drowsiness were observed, and drowsiness, agitation, aggressive behavior, depression, respiratory depression, and coma due to drug overdose were also seen in patients in post-marketing use of levetiracetam tablets.
Treatment of Overdose
There is no specific antidote for levetiracetam extended-release tablets overdose. Depending on the patient’s condition, attempts should be made to remove the unabsorbed drug by vomiting or gastric lavage, and common precautions should be taken to maintain a clear airway. General supportive therapy for applicable patients includes vital signs monitoring and clinical status observation, and certified poison control centers should be contacted for the latest treatment information in the treatment of levetiracetam extended-release tablets overdose.
Hemodialysis
Standard hemodialysis results in significant clearance of levetiracetam (approximately 50% clearance within 4 hours), and hemodialysis should be considered in the event of drug overdose. Although hemodialysis was not performed in several known drug overdose cases, it may be used depending on the clinical status of the patient or in patients with significantly impaired renal function.
[Clinical Trials].
The effectiveness of levetiracetam extended-release tablets as adjunctive therapy in adult patients with partial-onset epilepsy was based on a multicenter, randomized, double-blind, placebo-controlled clinical study that enrolled patients with refractory partial-onset epilepsy (with or without secondary generalized seizures). Data from three multicenter, randomized, double-blind, placebo-controlled clinical studies of the effectiveness of levetiracetam tablets as adjunctive therapy in adult patients with partial-onset epilepsy and a relative bioavailability trial of levetiracetam extended-release tablets versus levetiracetam tablets support the effectiveness of levetiracetam extended-release tablets in partial-onset epilepsy. Results from a pharmacokinetic trial showed that the relative bioavailability of levetiracetam extended-release tablets was comparable in adults and adolescents, confirming the effectiveness of levetiracetam extended-release tablet adjunctive therapy in pediatric patients aged 12 years and older with partial-onset seizures.
Levetiracetam Extended-Release Tablets in Adult Patients
A multicenter, randomized, double-blind, placebo-controlled clinical study confirmed the effectiveness of adjunctive treatment (added to other antiepileptic drugs) with levetiracetam extended-release tablets in patients with refractory partial-onset epilepsy (with or without secondary generalized seizures) in seven countries (Study 1).
Study 1
Study 1 enrolled patients who had at least 8 partial-onset seizures with or without secondary generalized seizures during an 8-week baseline period and at least 2 partial-onset seizures every 4 weeks during the baseline period. Patients were taking at least one stable dose of AED and up to 3 AEDs. 158 patients were randomized after the 8-week expected baseline period to either a placebo group (N=79) or levetiracetam extended-release tablets
1000 mg (500 mg tablets x 2) (N=79) treatment group, with patients taking the drug once daily during the 12-week treatment period.
The primary efficacy endpoint of this study was the percentage reduction in the frequency of partial seizures per week in patients relative to the placebo group. During the treatment period, levetiracetam extended-release tablets
Patients in the 1000 mg treatment group (N=74) had a mean reduction in weekly partial seizure frequency of 46.1% from baseline values compared to 33.4% in the placebo group (N=78), and the percentage reduction in weekly partial seizure frequency was estimated to be 14.4% higher in patients in the treatment group compared to the placebo group during the treatment period (a statistically significant difference).
The relationship between the efficacy of the two treatments when patients received the same daily oral dose of levetiracetam extended-release tablets and levetiracetam tablets is unclear and has not been studied.
Therapeutic effects of levetiracetam tablets in adult patients
The effectiveness of levetiracetam tablets as an adjunctive therapy in patients with refractory partial seizures was based on three (Studies 2, 3, and 4) multicenter, randomized, double-blind, placebo-controlled clinical studies in patients with refractory partial seizures (with or without secondary generalized seizures). The three studies included a total of 904 patients randomized to the placebo group, the levetiracetam 1000 mg/day group, the levetiracetam 2000 mg/day group, or the levetiracetam 3000 mg/day group. Patients included in studies 2 and 3 were those with refractory partial epilepsy for at least 2 years and were receiving treatment with two or more AEDs. Study 4 included patients who had refractory partial epilepsy for at least 1 year and were receiving treatment with 1 type of AED. During the study period, patients were being treated with 1 stable dose of AED but no more than 2 AEDs. at baseline, patients had at least 2 partial seizures every 4 weeks.
Study 2
Study 2 was a double-blind, placebo-controlled, parallel trial conducted at 41 research centers in the U.S. After 12 weeks of baseline treatment, patients were randomized to the levetiracetam tablet 1000 mg/day group (N=97), the levetiracetam tablet 3000 mg/day group (N=101), and the placebo (N=95) group, twice daily. After a 12-week baseline period, patients in Study 2 were randomized to the above three treatment groups. 18-week treatment period consisted of a 6-week dose titration period and a 12-week fixed-dose assessment period, and the co-administered AED regimen remained unchanged during the trial. The primary efficacy measure for Study 2 was the percentage reduction in weekly partial seizure frequency relative to the placebo group throughout the randomized treatment period (dose titration period + evaluation period), and the secondary efficacy measure was the effective response rate (the incidence of patients with ≥50% reduction in partial seizure frequency from baseline values). The results of Study 2 are shown in the table below.
Placebo
(n = 95) 1000 mg/day
(N = 97) Levetiracetam tablets 3000 mg/day
(N = 101) Percentage reduction in partial seizure frequency relative to the placebo group -26.1%*30.1%*
*Statistically significant compared to the placebo group
In Study 2, the percentage of patients in each of the 3 treatment groups (x-axis) who experienced a ≥50% reduction in weekly partial seizure frequency from baseline values (y-axis) throughout the randomized treatment period (titration period + evaluation period) is shown in Figure 1.
*Statistically significant compared to the placebo group
Figure 1 Effective response rate (≥50% reduction from baseline values) in study 2
Study 3
Study 3 was a double-blind, placebo-controlled, crossover trial conducted at 62 study centers in Europe comparing the efficacy and safety of different therapeutic doses of levetiracetam tablets [1000 mg/day (N=106), levetiracetam tablets 2000 mg/day (N=105)] versus placebo (N=111). Phase 1 of the study (Phase A) was a parallel trial design with a baseline treatment period of 12 weeks. After baseline, patients in Study 3 were randomized to the 3 treatment groups described above. 16-week treatment period consisted of a 4-week dose titration period and a 12-week fixed-dose evaluation period, and the concomitant AED regimen remained unchanged during the trial. The primary efficacy measure for Study 3 was a between-group comparison of the percentage reduction in weekly partial-onset seizure frequency during the trial period (including the dose titration period and the fixed-dose treatment period) relative to the placebo group, and secondary efficacy measures included the effective response rate (the incidence of patients with ≥50% reduction in partial-onset seizure frequency). The results of the analysis of cycle A are shown in Table 3. The results of the analysis of cycle A are shown in the following table.
Placebo (n = 111) Levetiracetam tablets
1000 mg/day (n = 106) Levetiracetam tablets 2000 mg/day (n = 105) Percentage reduction in partial seizure frequency relative to the placebo group -17.1% *21.4%*
*Statistically significant compared to the placebo group
In Study 3, the percentage of patients in each of the 3 treatment groups (x-axis) with a ≥50% reduction in weekly partial seizure frequency from baseline values (y-axis) throughout the randomized treatment period (titration period + evaluation period) is shown in Figure 2.
*Statistically significant compared to the placebo group
Figure 2 Effective response rate (≥50% reduction from baseline values) in study 3 cycle A
In this study, the difference in effective response rate between the levetiracetam tablets 2000 mg/day group and the levetiracetam tablets 1000 mg/day group was statistically significant (p=0.02), and similar results were obtained when the trial was analyzed as a crossover study.
Study 4
Study 4 was a double-blind, placebo-controlled, parallel trial conducted at 47 study centers in Europe evaluating the efficacy and safety of oral levetiracetam tablets 3000 mg/day (N=180) for the treatment of refractory partial seizures in epilepsy with or without secondary generalized seizures in patients treated with one other antiepileptic drug in combination, and after a 12-week baseline period, patients were randomized to one of the 2 aforementioned After a 12-week baseline period, patients were randomized to one of the 2 treatment groups described above and administered continuously for 16 weeks (including a 4-week dose titration period and a 12-week fixed-dose treatment period). The primary efficacy measure was the between-group comparison of the percentage reduction in weekly partial-onset seizure frequency during the trial period (including the dose titration period and fixed-dose treatment period) versus the placebo group, and secondary efficacy measures included the effective response rate (the incidence of patients with ≥50% reduction in partial-onset seizure frequency). The results of Study 4 are shown in the table below.
Placebo (n = 104) Levetiracetam tablets 3000 mg/day (N = 180) versus placebo group Percentage reduction in partial seizure frequency -23.0%*
* statistically significant compared to placebo group
The percentage of patients in the 2 treatment groups (x-axis) with ≥50% reduction in weekly partial seizure frequency from baseline values (y-axis) throughout the randomized treatment period (titration period + evaluation period) of Study 4 is shown in Figure 3.
* Statistically significant compared to the placebo group
Figure 3 Effective response rate (≥50% reduction from baseline values) in study 4
Levetiracetam Tablets in Pediatric Patients Aged 4-16 Years
Levetiracetam extended-release tablets are available for use in pediatric patients 12 years of age and older based primarily on data from clinical studies of levetiracetam tablets (Study 5). Levetiracetam extended-release tablets are not indicated for pediatric patients under 12 years of age.
Study
5
Study 5 is a multicenter, randomized, double-blind, placebo-controlled study conducted at 60 research centers in North America.5 Study 5 enrolled pediatric patients aged 4-16 years with partial-onset seizures that were uncontrolled on standard antiepileptic medication, and the results of the study confirmed the effectiveness of adjunctive treatment with levetiracetam tablets in pediatric patients. Enrolled patients were treated with 1-2 stable doses of AEDs, had at least 4 partial seizures in the 4 weeks prior to screening, and had at least 4 partial seizures in each 4-week baseline period (2 in total). Patients were randomized to receive treatment in either the levetiracetam tablet group or the placebo group. A total of 198 pediatric patients with refractory partial seizures with or without secondary generalized seizures were enrolled in the study (levetiracetam group
N=101, placebo group
N=97). Study 5 consisted of an 8-week baseline period, a 4-week dose titration period, and a subsequent 10-week evaluation period in which patients were given an initial dose of 20 mg/kg/day in two divided doses, with levetiracetam tablets adjusted in 20 mg/kg/day increments during treatment, allowing for an increase in dose to the target dose of 60 mg/kg/day over a 2-week period. The primary efficacy metric for study 5 was a between-group comparison of the percentage reduction in weekly partial seizure frequency in patients compared with the placebo group throughout the 14-week randomized treatment period (titration period + evaluation period), and secondary efficacy metrics included the effective response rate (the incidence of patients with ≥50% reduction in weekly partial seizure frequency from baseline values). The results of this study are shown in Table 9.
Table 9 Mean reduction in weekly partial seizure frequency in patients relative to the placebo group in Study 5
Placebo (N = 97) Levetiracetam tablets (N = 101) Percentage reduction in partial seizure frequency relative to the placebo group -26.8%*
* Statistically significant compared to placebo group
The percentage of patients in the 2 treatment groups (x-axis) with a ≥50% reduction in weekly partial seizure frequency from baseline values (y-axis) throughout the randomized treatment period (titration period + evaluation period) of Study 5 is shown in Figure 4.
* Statistically significant compared to the placebo group
Figure 4 Effective response rate (≥50% reduction from baseline values) in study 5
[Pharmacological Toxicology].
Pharmacological effects
Levetiracetam is a pyrrolidone derivative. The exact mechanism of the antiepileptic effect of levetiracetam is unknown. 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 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 tragacanthine and erythromelanin, two chemical convulsants that mimic the characteristics of complex partial seizures in some individuals with secondary generalized seizures. 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 affecting normal neuronal excitability, suggesting that levetiracetam may selectively inhibit epileptiform burst firing hypersynchronization and seizure propagation.
Levetiracetam has no affinity for multiple known receptors (e.g., benzodiazepines, GABA, glycine, NMDA), reuptake sites, and second messenger systems at concentrations as high as 10 μM. In vitro tests showed that levetiracetam has no effect on neuronal voltage-gated sodium channels or T-type calcium currents and does not directly ease GABAergic neurotransmission, but in vitro studies showed that levetiracetam counteracts the activity of negative regulators of GABA-activated currents and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells.
A saturable and stereoselective neuronal binding site for levetiracetam was identified in rat brain tissue, and tests showed that the specific binding site was the synaptic vesicle protein SV2A, which is thought to be involved in vesicle transmitter efflux (exocytosis). Although the molecular significance of levetiracetam binding to SV2A is unclear, in a mouse model of auditory epilepsy, levetiracetam and its related analogs have a strong and weak order of affinity for SV2A, and this affinity strength correlates with anti-seizure activity. This suggests that the interaction of levetiracetam with SV2A protein may be related to its anti-seizure mechanism of action.
Toxicological studies
Genotoxicity
Levetiracetam Ames test, in vitro CHO/HGPRT gene mutation test in mammalian cells, in vitro chromosomal aberration test in CHO cells, and in vivo micronucleus test in mice all showed negative results. The results of levetiracetam hydrolysis product and human major metabolite (ucb L057) were negative in the Ames test and in vitro 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 [6 times the maximum recommended human dose (MRHD) of 3000 mg/day in mg/m2 or exposure (AUC)].
In animal studies, levetiracetam can produce developmental toxicity, including teratogenic effects, at doses similar to or higher than human therapeutic doses. In pregnant rats, oral administration of levetiracetam at a dose of 3600 mg/kg/day (equivalent to 12 times MRHD in mg/m2) during the organogenesis phase was associated with reduced fetal body weight and increased incidence of fetal skeletal variation, and a no-effect dose of 1200 mg/kg/day for developmental toxicity; no maternal toxicity was observed in this test. In pregnant rabbits administered during organogenesis at doses ≥600 mg/kg/day (4 times the MRHD in mg/m2), an increase in embryo-fetal mortality and an increase in the incidence of minor fetal skeletal malformations was observed; at a dose of 1800 mg/kg/day (12 times the MRHD in mg/m2), a decrease in fetal body weight and an increase in the incidence of fetal malformations were observed. Maternal toxicity was observed at a dose of 1800 mg/kg/day (12 times the MRHD in mg/m2) and a no-effect dose of 200 mg/kg/day for developmental toxicity.
In female rats given levetiracetam orally during gestation and lactation at doses ≥350 mg/kg/day (equivalent to MRHD in mg/m2), an increased incidence of minor skeletal malformations, prenatal and/or postnatal growth retardation was observed in fetuses; at a dose of 1800 mg/kg/day (equivalent to MRHD in mg/m2), increased pup mortality and abnormal offspring behavior was observed. Increased pup mortality and abnormal offspring behavior were seen at a dose of 1800 mg/kg/day (equivalent to 0.2 times MRHD at mg/m2); no significant maternal toxicity was seen at the no-effect dose of 70 mg/kg/day (equivalent to 0.2 times MRHD at mg/m2) for developmental toxicity in this assay. No adverse developmental or maternal effects were observed in rats given levetiracetam at doses up to 1800 mg/kg/day (equivalent to 6 times the MRHD in mg/m2) during the third trimester and throughout lactation.
Carcinogenicity
No carcinogenicity was seen in rats given levetiracetam by adulteration for 104 weeks at doses of 50, 300 and 1800 mg/kg/day [high dose equivalent to 6 times MRHD in mg/m2 or exposure (AUC)]. Levetiracetam was given to mice by adulteration for 80 weeks at doses of 60, 240, and 960 mg/kg/day (high dose equivalent to 2 times the MRHD in mg/m2 or exposure (AUC)), and levetiracetam was given to mice orally for 2 years at doses of 1000, 2000, and 4000 mg/kg/day (reduced to 3000 mg/kg/day after 45 weeks due to intolerance, the The dose was equivalent to 5 times the MRHD in mg/m2) and no carcinogenicity was observed.
Pharmacokinetics
Overview
The bioavailability of levetiracetam extended-release tablets is similar to that of levetiracetam tablets. The pharmacokinetics (AUC and Cmax) of levetiracetam extended-release tablets after a single dose of 1000 mg, 2000 mg and 3000 mg in subjects are proportional to the dose, and the plasma half-life of levetiracetam extended-release tablets is approximately 7 hours.
Levetiracetam is almost completely absorbed after oral administration. The pharmacokinetics of levetiracetam are linear and do not change over time, with little inter- and intra-individual variation. Levetiracetam is not significantly bound to plasma proteins (<10% binding rate) and its volume of distribution is close to the volume of intracellular and extracellular water. 66% of the administered dose is excreted renally in its original form. The major metabolic pathway for levetiracetam (24% of the dose) is enzymatic hydrolysis of the acetamide moiety, which is not hepatic cytochrome P450 dependent, and the metabolite has no known pharmacological activity and is excreted renally. In various studies, the plasma half-life of levetiracetam was approximately 6-8 hours, with a prolonged drug half-life in elderly patients (mainly due to impaired renal clearance) and in subjects with renal insufficiency.
Absorption and distribution
After oral administration of levetiracetam extended-release tablets, the blood concentration peaks at approximately 4 hours, and the time to peak for extended-release tablets is approximately 3 hours longer than for regular tablets.
Under fasting conditions, the Cmax and area under the curve (AUC) after a single dose of two 500 mg levetiracetam extended-release tablets administered once daily were comparable to the Cmax and AUC of one 500 mg levetiracetam tablet administered orally twice daily. Exposure levels (AUC0-24h) of the drug after multiple doses of levetiracetam extended-release tablets were similar to those after multiple doses of tablets, and Cmax and Cmin of the drug were reduced by 17% and 26%, respectively, after multiple oral doses of levetiracetam extended-release tablets compared with multiple doses of tablets. Administration of levetiracetam extended-release tablets after eating a high-fat, high-calorie breakfast resulted in higher peak concentrations of the drug, longer mean time to peak, and a 2-hour longer mean time to peak (Tmax) when administered after a meal.
Two 750 mg levetiracetam extended-release tablets were bioequivalent to a single dose of three 500 mg levetiracetam extended-release tablets.
Metabolism
Levetiracetam is not extensively metabolized in humans and the primary metabolic pathway is enzymatic hydrolysis of the acetamide moiety, which is metabolized to the carboxylic acid metabolite ucb L057 (24% of dose) and is not dependent on hepatic cytochrome P450 enzymes. The major metabolite of levetiracetam is ineffective in animal convulsion models, and the two minor metabolites are the hydroxylated product of the 2-oxo-pyrrolidine ring (2% of the dose) and the ring-opening product of the 5-position of the 2-oxo-pyrrolidine ring (1% of the dose). neither levetiracetam nor its major metabolite undergoes enantiomeric interconversion.
Elimination
In adult subjects, the plasma half-life of levetiracetam was 7 ± 1 h and was not affected by dose or repeated dosing. The renal excretion of levetiracetam in the body circulation as a prodrug accounted for 66% of the administered dose, with a total body clearance of 0.96 mL/min/kg and a renal clearance of 0.6 mL/min/kg, with glomerular filtration and subsequent partial tubular reabsorption as the mechanism of drug excretion. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. The elimination of levetiracetam is related to creatinine clearance, which is reduced in patients with renal insufficiency.
Pharmacokinetics in Special Populations
Geriatric patients
There are insufficient data to elucidate the pharmacokinetic profile of levetiracetam extended-release tablets in the elderly population.
The pharmacokinetics of levetiracetam tablets were evaluated in 16 elderly subjects (61-88 years of age) with creatinine clearance of 30-74 mL/min. The elderly subjects had a 38% lower clearance and a 2.5 hour longer half-life after twice-daily oral dosing of levetiracetam over 10 days than healthy adult subjects, most likely due to reduced renal function in the subjects.
Pediatric Patients
An open-label, multicenter, two-arm parallel-group clinical study evaluated the pharmacokinetics of levetiracetam extended-release tablets in pediatric (13-16 years of age) and adult (18-55 years of age) patients with epilepsy. In the study, 12 pediatric patients and 13 adult patients received once-daily oral levetiracetam extended-release tablets (1000 mg-3000 mg) for a minimum of 3 days and a maximum of 7 days, and the results showed that the exposure parameters (Cmax and AUC) at steady state were comparable in pediatric and adult patients after dose correction.
Pregnancy
The concentration of levetiracetam extended-release tablets may be reduced during pregnancy.
Gender
Cmax and AUC were 21-30% and 8-18% higher in females (N=12) than in males (N=12) after administration of levetiracetam extended-release tablets, but clearance was comparable in males and females after correction for body weight.
Race
No formal racial pharmacokinetic studies have been conducted for either levetiracetam extended-release tablets or tablets; however, crossover studies comparing Caucasians (N=12) and Asians (N=12) have shown that the pharmacokinetics of levetiracetam tablets are comparable between the two ethnic groups. Since levetiracetam is primarily excreted by the kidneys and there are no significant ethnic differences in creatinine clearance, race is not expected to cause pharmacokinetic differences in levetiracetam.
Renal Insufficiency
The effectiveness of levetiracetam extended-release tablets in patients with renal insufficiency has not been evaluated in clinical studies; however, it is expected that levetiracetam extended-release tablets will have a therapeutic effect in patients similar to that seen in clinical studies with levetiracetam tablets. Levetiracetam tablets are recommended in place of levetiracetam extended-release tablets in patients with end-stage renal disease who are on dialysis.
Trials have studied the metabolism of levetiracetam tablets in patients with varying degrees of renal function. The total body clearance of levetiracetam was reduced by 40% in patients with mild renal insufficiency (CLcr = 50-80 mL/min), by 50% in patients with moderate renal insufficiency (CLcr = 30-50 mL/min), and by 60% in the severe renal insufficiency group (CLcr <30 mL/min), with levetiracetam clearance was correlated with creatinine clearance.
In anuric (end-stage renal disease) patients, the total body clearance of levetiracetam was 70% lower than in normal subjects (CLcr >80 mL/min), and approximately 50% of levetiracetam was removed from the body during standard 4-hour hemodialysis [see Dosage and Administration (2.2)].
Hepatic impairment
In patients with mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment, the pharmacokinetics of levetiracetam are unchanged, and in patients with severe hepatic impairment (Child-Pugh class C), the total body clearance of levetiracetam is approximately 50% of that of normal subjects, although most of the reduction is caused by decreased renal clearance. No dose adjustment is required for levetiracetam in patients with hepatic impairment.
Storage
Storage
Store in a tightly sealed container at a temperature of not more than 30°C under shade.
Package
Package
Oral solid medicine in HDPE bottle, 60 tablets/bottle, 1 bottle/box.
Expiration date】 24 months.
Execution Standard
Approval number】
【Manufacturer】
Enterprise name: Shenzhen Xinlitai Pharmaceutical Co.
Production Address: No. 1, Planning Road 5, Longtian Street, Pingshan District, Shenzhen
Zip code: 518118
Telephone number: (0755) 83867888
Fax number: (0755) 83867338
Website
www.salubris.cn