Is it Safe to Use Levetiracetam in Pregnancy?

Levetiracetam (Levetiracetam), alias Levaniracetam, Levetiracetam, and Levetiracetam, is a white crystalline powder chemical. Chemical name ( S ) - -ethyl-2-oxo-1-pyrrolidine acetamide, the molecular formula is C ₈ H ₁₄ N ₂ O ₂ , and the molecular weight is 170.20900. Levetiracetam is an antiepileptic drug and is mainly used clinically for the treatment of partial seizures in adults and children over 4 years of age.

Chinese name: Levetiracetam
Foreign name: Levetiracetam

CAS number: 102767-28-2
Molecular formula: C8H14N2O2
Molecular weight: 170.20900

Brief Introduction to Levetiracetam Compounds

Levetiracetam Basic Information

Chinese name: Levetiracetam

Chinese alias: ( S ) -alpha-ethyl-2-oxo-1-acetamidopyrrolidine

English name: Levetiracetam

English alias: ( s ) -2- (2-oxopyrrolidin-1-yl) butanamide; ( S ) -1-pyrrolidineacetamid; (+-)-alpha-Ethyl-2-oxo-1-pyrrolidineacetamide; ( S ) -alpha -Ethyl-2-oxo-1-pyrrolidineacetamide; 1-Pyrrolidineacetamide; alpha-ethyl-2-oxo-; alpha-Ethyl-2-oxo-1-pyrrolidineacetamide; Etiracetam; Etiracetam [INN]; Etiracetamum [INN-Latin]; Keppra; Levetiracetam [INN]; Levetiracetamum [INN-Latin]; LEVITIRACETAM; UCB 6474; UCB-6474; UCB-L 059;

Name :( S ) -2- (2-Oxopyrrolidin-1-yl) butanamide (Levetiracetam); (2 R ) -2- (2-oxopyrrolidin-1-yl) butanamide; (2 S ) -2- (2- oxopyrrolidin-1-yl) butanamide

CAS number: 102767-28-2

Molecular formula: C ₈ H ₁₄ N ₂ O ₂

Molecular weight: 170.209 ^[1]

Chemical structure:

Physical and Chemical Properties of Levetiracetam

Appearance and properties: white crystalline powder

Density: 1.168 g / cm ³

Melting point: 118-119 ° C

Boiling point: 395.9ºC at 760 mmHg

Flash point: 193.2ºC

Refractive index: 1.518

Storage conditions: Store in original container in a cool dark place.

Vapor pressure: 1.78E-06mmHg at 25 ° C ^[1]

Overview of Levetiracetam Drug Basic Information

Levetiracetam Usage and Dosage

Levetiracetam route of administration

oral. It should be swallowed with an appropriate amount of water, and it is not affected by eating. ^[2]

Levetiracetam Storage

Storage at room temperature (25 ° C or below) ^[2]

Levetiracetam Validity Period

24 months

Levetiracetam administration method and dosage

Adults (> 18 years) and adolescents (12-17 years) (when weight 50 kg): The initial treatment dose is 500 mg each time, twice daily. According to clinical effects and tolerance, the daily dose can be increased to 1500 mg each time, twice daily. Dosage changes should be increased or decreased by 500 mg / times every 2-4 weeks, twice daily.

Elderly ( 65 years old) : Adjust the dose according to renal function (see the description of patients with impaired renal function below).

Children and adolescents (ages 12-17) ( ages 50 kg): the initial treatment dose is 10 mg / kg twice daily. Depending on the clinical effect and tolerance, the dose can be increased to 30 mg / kg twice daily. The dose change should be increased or decreased by 10 mg / kg every 2 weeks, twice daily. The lowest effective dose should be used whenever possible. For children and adolescents weighing 50 kg, the dosage is the same as that for adults. Recommended dosage for adolescents and children: a starting dose of 10 mg / kg twice daily, a maximum dose of 30 mg / kg twice daily. Weight 15 kg: The starting dose is 150 mg twice daily, and the maximum dose is 450 mg twice daily. Body weight 20 kg: The initial dose is 200 mg twice daily, and the maximum dose is 600 mg twice daily. Body weight 25 kg: The initial dose is 250 mg twice daily, and the maximum dose is 750 mg twice daily. Body weight 50 kg or more: The initial dose is 500 mg twice daily, and the maximum dose is 1500 mg twice daily. For children under 20 kg, oral solutions should be used for initial dose adjustments ^[2] .

Infants and pediatric patients younger than 4 years : No adequate data are available.

Patients with impaired renal function : Adult patients with impaired renal function adjust the daily dose according to the renal function status according to different creatinine clearance (CLcr) mL / min in the table (measured serum creatinine value according to the following calculation method). CLcr = 140- age (years) x body weight (kg) / 72 x serum creatinine value (mg / dl) female patients: the above calculated value x 0.85 <BR> normal dose patients with impaired renal function (creatinine clearance 80 mL / min): 500-1500 mg each time, twice daily. Mild abnormality (creatinine clearance 50-79 mL / min): 500-1000 mg each time, twice daily. Moderately abnormal (creatinine clearance 30-49 mL / min): 250-750 mg each time, twice daily. Severe abnormalities (creatinine clearance <30 mL / min): 250-500 mg each time, twice daily. Patients with advanced renal disease undergoing dialysis: 500-1000 mg once daily. The recommended loading dose for day 1 is 750 mg of Levetiracetam. After dialysis, an additional dose of 250-500 mg is recommended. Children with impaired renal function should adjust the dose according to the state of renal function, because the clearance of levetiracetam is related to renal function.

Patients with liver disease : For patients with mild and moderate hepatic impairment, there is no need to adjust the dosage. Patients with severe liver damage may underestimate the degree of renal insufficiency based on creatinine clearance. Therefore, if the patient's creatinine clearance is less than 70 mL / min, the daily dose should be halved ^[2] .

Levetiracetam adverse reactions

Levetiracetam Adult Clinical

The safety data summarized in the study showed that the incidence of adverse reactions was similar in the drug group and the placebo group, 46.4% and 42.2%, respectively. Among them, serious adverse reactions were 2.4% and 2.0%, respectively. The most common adverse reactions are drowsiness, fatigue, and dizziness, which often occur at the beginning of treatment. Over time, the incidence and severity of CNS-related adverse reactions will decrease. There was no significant dose-related effect of levetiracetam adverse reactions ^[2] .

Levetiracetam in children

Studies (4-16 years of age) showed that the incidence of adverse reactions was similar in the drug group and the placebo group, 55.4% and 40.2%, respectively. The most common adverse reactions in children are drowsiness, hostility, nervousness, emotional instability, irritability, loss of appetite, fatigue, and headache. Except for the higher incidence of behavioral and mental side effects than adults (38.6% children, 18.6% adults), the overall safety is similar to adults. The risk of adverse reactions in adults and children is comparable. Summarize the results of adult and pediatric clinical research and post-marketing experience, and evaluate the adverse reactions and frequency of each system: very common> 10%; common 1-10%; rare 0.1-1%; rare: 0.01-0.1%; very Rare <0.01%, including separate reports. Post-marketing clinical data are not enough to estimate the incidence of adverse reactions in the treated population.

Symptoms of Levetiracetam

-Systemic reactions and discomfort at the site of administration: fatigue is common.

-Nervous System Discomfort: Very common drowsiness, common forgetfulness, ataxia, convulsions, dizziness, headache, excessive exercise, tremor.

-Psychological changes: Common irritability, depression, emotional instability, hostility, insomnia, nervousness, personality changes, abnormal thinking. Post-market adverse events reported: abnormal behavior, aggressiveness, irritability, anxiety, confusion, hallucinations, irritability, mental disorders, suicide, suicidal ideation, suicide attempt. But there is not enough data to estimate their incidence or establish a causal relationship.

-Gastrointestinal Discomfort: Common diarrhea, indigestion, nausea, and vomiting.

-Metabolic and nutritional disorders: common loss of appetite. When patients take topiramate at the same time, the risk of anorexia increases.

-Discomfort in the ear and labyrinthine system: common vertigo.

-Eye discomfort: common diplopia.

-Injuries, poisoning and subsequent complications: common accidental injuries.

-Infections and infections: common infections.

-Respiratory Discomfort: Increased cough is common.

-Abnormal changes in skin and subcutaneous tissue: common rash. Post-Market Adverse Event Reporting-Hair loss, in some cases self-recovery after discontinuation.

-Abnormal changes in the blood system and lymphatic system: reports of adverse events on the market-leukopenia, neutropenia, pancytopenia, thrombocytopenia, but there is not enough data to estimate their incidence or establish a causal relationship ^[2] .

Levetiracetam Contraindications

It is contraindicated in patients allergic to levetiracetam or to pyrrolidone derivatives or any other component ^[2] .

Levetiracetam precautions

According to current clinical practice, if you need to stop taking this product, it is recommended to stop the drug gradually. (For example: adults should reduce 500 mg twice daily every 2-4 weeks; children should reduce 10 mg / kg twice daily every 2 weeks). In clinical studies, some patients have responded to the addition of levetiracetam and can discontinue the combination of antiepileptic drugs (36 of 69 patients in the study).

In clinical studies, 14% of adults and children taking levetiracetam reported more than a 25% increase in seizure frequency, but 26% and 21% of patients taking placebo also had seizures. increase. For patients with liver damage, refer to [Usage and Dosage]. For patients with severe hepatic impairment, renal function should be checked before adjustment.

Impact on driving and applying machines: There is no study on the effects of taking medicine on the ability to control the machine and the ability to drive vehicles.

Due to differences in individual sensitivities, drowsiness or other central nervous symptoms may occur during the initial stages of treatment or after an increase in dose. Therefore, for these patients who need to take drugs, it is not recommended to operate machines that require skill, such as driving a car or operating machinery ^[2] .

Levetiracetam for pregnant and lactating women

There is no information on pregnant women taking this product, and animal tests have proven that the drug has some reproductive toxicity. The potential dangers to humans are unknown. Do not use levetiracetam unless necessary. Sudden interruption of antiepileptic treatment may worsen the condition and be equally harmful to the mother and fetus. Animal tests have shown that levetiracetam can be excreted from milk, so patients are not advised to breastfeed while taking the drug.

Levetiracetam for children and elderly patients

See [Usage and Dosage].

Levetiracetam drug interactions

In vitro data show that levetiracetam and its main metabolites are not human liver cytochrome P450, epoxidative hydrolase, or uridine diphosphate-glucosidase at concentrations above the Cmax level obtained in the therapeutic dose range Inhibitors, nor are they substrates with high affinity. Therefore, pharmacokinetic interactions are unlikely to occur. In addition, levetiracetam did not affect the glucosidase effect of valproic acid in vitro.

Levetiracetam has a low plasma protein binding rate (<10%), and it is not easy to produce clinically significant interactions due to competing protein binding sites with other drugs.

Clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptives, digoxin, warfarin, and probenecid) and placebo-controlled clinical trials evaluated potential for potential pharmacokinetics through screening Pharmacokinetic interactions.

Drug-drug interactions between levetiracetam and other antiepileptic drugs (AEDs): phenytoin + levetiracetam (3000 mg daily) does not produce pharmacokinetic properties of phenytoin in patients with refractory epilepsy effect. The application of phenytoin does not affect the pharmacokinetic properties of this product.

Valproate + Levetiracetam (1500 mg twice daily) did not change the pharmacokinetics of sodium valproate in healthy volunteers. Valproate 500 mg, twice daily, does not change the rate or extent of levetiracetam absorption, its plasma clearance, or urine excretion. It does not affect exposure levels and excretion of major metabolites.

For placebo-controlled clinical studies of levetiracetam and other antiepileptic drugs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, deoxyphenobarbital, and sodium valproate) Serum concentrations were evaluated and the data showed that levetiracetam did not affect the blood concentrations of other antiepileptic drugs. These commonly used antiepileptic drugs do not affect the pharmacokinetics of this product.

The role of antiepileptic drugs in children while taking enzyme-induced antiepileptic drugs, the total apparent clearance of this product increased by about 22%. No dose adjustment is required. Levetiracetam did not affect plasma drug concentrations of carbamazepine, valproate, topiramate, or lamotrigine.

Other drug interactions: oral contraceptives + levethiracetam (500 mg twice daily) does not affect the pharmacokinetics of oral contraceptives containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel, or Luteinizing hormone and progesterone levels indicate that this product does not affect the efficacy of contraceptives. The use of oral contraceptives does not affect the pharmacological properties of this product.

Digoxin + taking Levetiracetam (1000 mg twice daily) does not affect the pharmacokinetics and pharmacodynamics (ECG) properties of digoxin at a daily dose of 0.25 mg. The application of digoxin does not affect the pharmacological properties of this product.

Warfarin + taking Levetiracetam (1000 mg twice daily) does not affect the pharmacokinetic properties of Warfarin R and S. Coagulation time was not affected by levetiracetam. The application of warfarin does not affect the pharmacokinetics of this product.

Probenecid (500 mg, 4 times daily) is a renal tubular secretion blocker that inhibits renal clearance of the main metabolite of levetiracetam, but is not a pharmacological property of levetiracetam (1000 mg , 2 times a day), but the concentrations of these metabolites are very low. Other drugs that need to be cleared through the renal tubules can also affect renal clearance of metabolites. There is no study of levetiracetam combined with probenecid, and the effect of levetiracetam combined with other active secretory drugs (such as non-steroidal anti-inflammatory drugs, sulfa drugs, and methotrexate) is unknown ^[2] .

Levetiracetam overdose

Levetiracetam symptoms

Drowsiness, agitation, aggressiveness, decreased consciousness, respiratory depression, and coma were observed.

Levetiracetam first aid measures

After an acute overdose, vomiting or gastric lavage should be taken to empty the stomach. There is no antidote for levetiracetam. Treatment requires symptomatic treatment and may also include hemodialysis. Effect of dialysis discharge: 60% of levetiracetam and 74% of main metabolite ^[2] .

Levetiracetam clinical trial

Levetiracetam Clinical Study

Three multicenter, randomized, double-blind, and placebo-controlled clinical studies of patients with refractory partial seizures (with or without secondary generalized seizures) established levetiracetam as an adult Effectiveness data for adjuvant therapy (adjuvant therapy with other antiepileptic drugs). Patients enrolled in Study 1 or Study 2 had a partial seizure of refractory epilepsy for at least 2 years and took more than 2 traditional antiepileptic drugs. Patients enrolled in Study 3 had at least one year of refractory epilepsy and were taking a conventional antiepileptic drug. At the time of the trial, patients were taking a stable dosing regimen of at least 1 and up to 2 antiepileptic drugs. At baseline, patients must have at least 2 partial episodes during each 4-week period.

Clinical Study 1 : A double-blind, placebo-controlled parallel trial in 41 study sites in the United States. After a 12-week baseline period, patients were randomly assigned to a dose of 1000 mg / day of Levetiracetam (N = 97) , Levetiracetam 3000 mg / day (N = 101) and placebo (N = 95) groups were administered twice daily. During the 18-week treatment period (6 weeks of dosing period + 12 weeks of evaluation period), the efficacy evaluation was performed, and the antiepileptic drug regimen could be maintained during the trial period. The primary efficacy measure was an intergroup comparison of the percentage reduction in the frequency of partial seizures per week relative to the placebo group over the entire randomized treatment period (dosage-addition phase + evaluation phase). Secondary efficacy indicators included the effective response rate (prevalence of partial seizures (greater than or equal to) 50% of patients). The results showed that the frequency of partial seizures per week in the levetiracetam treatment group was significantly reduced. During the randomized treatment period, the effective response rate of the levetiracetam treatment group was significantly higher than that of the placebo group, and it was dose-related. Levetiracetam 1000 mg / day (N = 97) group: 26.1% reduction in the frequency of partial seizures compared to the placebo group; Levetiracetam 3000 mg / day (N = 101) group: Relative to the placebo group The percentage reduction in the frequency of partial seizures in the placebo group was 30.1%, P <0.001.

Clinical Study 2 : A double-blind, placebo-controlled crossover trial conducted at 62 European research centers. Phase 1 (phase A) of the design trial was analyzed as a parallel group trial. After a baseline period of 12 weeks, patients were randomized. The patients were assigned to Levetiracetam 1000 mg / day (N = 106), Levetiracetam 2000 mg / day (N = 105) and Placebo (N = 111). A 16-week treatment cycle (including a 4-week dosing period and a 12-week stable dose evaluation period) was performed to evaluate the efficacy, and the same antiepileptic treatment regimen remained unchanged during the trial. The main efficacy indicators were compared between groups during the randomized treatment period (dosage-added period + evaluation period) relative to the placebo group. The frequency of partial seizures was significantly reduced. The comparison of the effective response rate of Levetiracetam 2000 mg / day to Levetiracetam 1000 mg / day was statistically significant (P = 0.02), and analysis of the crossover trial yielded similar results. Levetiracetam 1000 mg / day (N = 106) group: 17.1% reduction in the frequency of partial seizures compared to placebo; Levetiracetam 2000 mg / day (N = 105) group: Relative to placebo The percentage reduction in the frequency of partial seizures in the placebo group was 21.4%, P <0.001.

Clinical Study 3 is a double-blind, placebo-controlled, parallel group trial conducted at 47 research centers in Europe. This study compared patients with refractory partial seizures with or without secondary generalized seizures, only Taking the same antiepileptic drug, patients were randomly assigned to one of the two treatment groups after a 12-week baseline period. The 16-week treatment cycle consisted of a 4-week dosing phase and a 12-week stable-dose phase for efficacy evaluation. The main efficacy index was compared between the entire treatment period (dosage-addition period + evaluation period) relative to the placebo group, and the percentage of weekly partial seizure frequency decreased. There was a significant reduction in the effective response rate of the levetiracetam treatment group over the randomized treatment period, which was significantly higher than that of the placebo group. Levetiracetam 3000 mg / day (N = 180): The percentage reduction in the frequency of partial seizures compared to the placebo group was 23.0%, P <0.001 ^[2] .

Study on the effectiveness of levetiracetam

A multicenter, randomized, double-blind, and placebo-controlled clinical study of children with refractory epilepsy aged 4-16 years in 60 trial centers in North America established levetiracetam as an additional treatment in children (Adjuvant treatment with other antiepileptic drugs). Patients had at least 4 seizures in the 4 weeks before screening, and in the 8-week baseline period (at least 4 seizures in each 4-week baseline period), they were given 1-2 stable doses of antiepileptic drugs. A total of 198 children were randomly assigned (Levetiracetam group N = 101 and placebo group N = 97). The initial dose of levetiracetam is 20 mg / kg / day, divided into two doses. During the treatment period, it is adjusted in 20 mg / kg / day increments and can be increased to the target dose within 2 weeks. 60 mg / kg / day. The clinical study consisted of an 8-week baseline period, a 4-week dosing period, and a 10-week evaluation period. Levetiracetam (N = 101): The percentage reduction in the frequency of partial seizures compared to the placebo group was 26.8%, P <0.0002.

Levetiracetam Chinese Clinical Study

In six centers in China (Shanghai, Beijing, Chongqing, and Chengdu), the efficacy and safety of levetiracetam for 16 weeks as an additional treatment for partial seizures in adults and adolescents over 16 years of age were multi-centered, randomized, and double-dose. In a blind, parallel, placebo-controlled clinical study, the daily doses of the two treatment groups were placebo and levetiracetam at 3000 mg. A total of 224 patients were screened in the 16-week clinical trial. Finally, 189 patients were completed (98 in the levetiracetam group and 91 in the placebo group). All subjects were Chinese, with male and female ratios of 52% and 48%, respectively. Demographics and other baseline characteristics were comparable between the two treatment groups, and the frequency of seizures per week at baseline was similar (1.81 times / week in the levetiracetam group and 1.75 times / week in the placebo group). The main efficacy index was the frequency of partial seizures (type I) per week during the 16-week treatment period (4-week increment period + 12-week maintenance treatment period). At the end of the 16-week trial, the investigators evaluated the subject's overall efficacy using the overall clinical efficacy assessment form. Analysis of the intention-to-treat population showed that the frequency of partial seizures per week in the levetiracetam group was significantly lower than that of the placebo group during the 16-week treatment period (p <0.001), and the efficacy was significantly better than that of the placebo group. The percentage is 26.8% (95% confidence interval: 14.0-37.7%). The results of the regimen were similar. During the 16-week treatment period, the 50% effective rate of partial seizures in the levetiracetam group was 57/102 (55.9%), which was significantly higher than 26/100 (26.0%) in the placebo group. The OR value relative to placebo was 3.6 (95% confidence interval: 2.0-6.5, p <0.001). Eleven patients (10.8%) in the levetiracetam group did not experience any partial seizures, which was significantly higher than the placebo group (2 patients, 2.0%, p <0.001). The safety evaluation results of this study showed that the placebo group and the levetiracetam group were comparable. The most commonly reported adverse event in the levetiracetam group was drowsiness (18 subjects, 17.5%), followed by thrombocytopenia. Efficacy / Pharmacokinetics / Pharmacodynamics Results: Frequency analysis of partial seizures per week in intention-to-treat (ITT) population

(a) After the frequency of partial seizures per week is converted by natural logarithm [Ln (1 + X)], analysis is performed using a covariance model, with baseline values as covariates and study centers and treatment groups as fixed variables Make estimates. (b) The percent reduction relative to the placebo group was calculated using the formula: 100 × [1-Exp (LSM Levetiracetam-LSM Placebo)]. (c) Comparison with placebo. (d) Wilcoxon rank sum test. (e) The WILCOXON rank sum test is used. (f) Logistic regression analysis. (g) CMH analysis with stratification at the center. In general, Levetiracetam as a medicated therapy for the treatment of partial seizures in adults and adolescents over 16 years of age can significantly reduce the frequency of seizures per week during the 16-week treatment period, which is safe and well tolerated.

Pharmacological effects of Levetiracetam

Levetiracetam is a pyrrolidone derivative whose chemical structure is not related to existing antiepileptic drugs. The exact mechanism of the antiepileptic effect of levetiracetam is unknown. The antiepileptic effect of levetiracetam was evaluated in various animal models of epilepsy. Levetiracetam has no inhibitory effect on simple seizures induced by current or multiple stimulant maximal stimuli, and shows only weak activity in submaximum stimulus and threshold tests. However, protective effects have been observed on pilocarpine and kainic acid-induced systemic seizures. These two chemical convulsants can mimic the characteristics of complex partial seizures in some people with secondary systemic seizures . Levetiracetam has an inhibitory effect on the ignition process and the ignition state of a rat model of complex partial seizures. The predictive value of these animal models for specific types of epilepsy in humans is unknown. In vitro and in vivo tests show that levetiracetam inhibits epileptic bursts in the hippocampus without affecting the excitability of normal neurons, suggesting that levetiracetam may selectively inhibit the supersynchronization and Transmission of seizures. Levetiracetam has no affinity for many known receptors at concentrations as high as 10 uM, such as benzodiazepines, GABA, glycine, NMDA, reuptake sites, and the second messenger system. In vitro tests have shown that levetiracetam has no effect on neuron voltage-gated sodium ion channels or T-type calcium currents. Levetiracetam does not directly facilitate GABAergic neurotransmission, but studies have shown that it has a counteracting effect on the activity of GABA and glycine-gated current negative regulators of cultured neurons. Saturable and stereoselective neuron binding sites of levetiracetam have been found in rat brain tissues, but the identification and function of this binding site is unclear ^[2] .

Toxicology Study of Levetiracetam

Levetiracetam genotoxicity

Levetiracetam Ames test, CHO / HGPRT locus mammalian cell gene mutation test, CHO cell chromosome aberration test, and mouse micronucleus test were all negative. Levetiracetam hydrolysates, major human metabolites, Ames test, and mouse lymphoma test results were all negative ^[2] .

Levetiracetam reproductive toxicity

At doses up to 1800 mg / kg / day [equivalent to 6 times the maximum human recommended dose (MRHD) of 3000 mg calculated as mg / m2 or exposure (AUC)], no fertility or reproduction in male or female rats was seen Adverse effects of behavior.

In animal tests, levetiracetam can produce developmental toxicity similar to or higher than human therapeutic doses. When pregnant rats were administered during the organogenesis period at a dose of 3600 mg / kg / day (equivalent to 12 times the MRHD calculated as mg / m2), it was seen that the fetal weight decreased and the incidence of fetal bone variation increased. The no-effect dose for developmental toxicity was 1200 mg / kg / day, and no maternal toxicity was seen in this test. When pregnant rabbits were administered during the organogenesis period at a dose of (greater than or equal to) 600 mg / kg / day (equivalent to 4 times the MRHD calculated as mg / m2), the embryo-fetal mortality rate increased, and The incidence of skeletal abnormalities increased; at a dose of 1800 mg / kg / day (equivalent to 12 times the MRHD calculated as mg / m2), fetal weight was reduced, the incidence of fetal malformations increased, and maternal toxicity was seen. The non-affected dose of developmental toxicity is 200 mg / kg / day.

Female rats are administered during pregnancy and lactation. At a dose of (greater than or equal to) 350 mg / kg / day (equivalent to MRHD calculated as mg / m2), fetal bone abnormalities, prenatal and / or Growth retardation after birth; at a dose of 1800 mg / kg / day (equivalent to 6 times the MRHD calculated as mg / m2), the increase in pup mortality and abnormal behavior of offspring can be seen; the non-influencing dose of developmental toxicity in this test is 70 mg / kg / day without significant maternal toxicity. Rats were administered in the third trimester of pregnancy and throughout the lactation period, with a dose of up to 1800 mg / kg / day (equivalent to 6 times the MRHD calculated as mg / m2), and no adverse effects on development and mothers were seen.

Levetiracetam Carcinogenicity

Levoiracetam was administered to rats for 104 weeks at doses of 50, 300, and 1800 mg / kg / day (high doses were equivalent to 6 times the MRHD based on mg / m2 or exposure), and no carcinogenicity was observed. Mice were administered levetiracetam for 80 weeks at a dose of 60, 240, and 960 mg / kg / day (high doses were calculated as mg / m2 or exposure equivalent to 2 times the MRHD), and no carcinogenicity was observed. However, the potential for carcinogenicity to this animal species has not been fully evaluated due to the lower doses administered.

Pharmacokinetics of Levetiracetam

Levetiracetam is a compound that is extremely soluble and highly permeable. It has a linear metabolism with little difference between individuals. Multiple administrations did not affect its clearance. This product is free of gender, ethnic differences, and circadian rhythms. The pharmacokinetic study of this product shows that the pharmacokinetic data of healthy volunteers and patients are comparable. Due to the complete and linear absorption of levetiracetam, its blood concentration can be predicted based on the oral dose mg / kg, so there is no need to monitor the blood concentration of levetiracetam. The saliva and blood concentration of adult and pediatric patients showed a significant correlation (4 hours after taking the tablet or liquid preparation of this product, the saliva / blood drug concentration ratio was 1-1.7).

Levetiracetam absorption for adults and adolescents

Levetiracetam is rapidly absorbed after oral administration, and the absolute bioavailability of oral levitacetam approaches 100%. After 1.3 hours of administration, the plasma concentration reached a peak. If it was administered twice a day, it would reach a steady state plateau concentration after 2 days. If the single dose was 1000 mg and 1000 mg twice daily, the typical peak concentrations were 31 and 43. ug / mL. The absorption time is independent of the dose, and food intake does not affect the absorption rate.

Levetiracetam Distribution

Data on the distribution of human tissues are not currently available. Neither Levetiracetam nor its main metabolite is easily bound to plasma proteins (<10%). The distribution volume is 0.5-0.7 L / kg, which is close to the human water volume.

Levetiracetam Biotransport

Levetiracetam is not widely broken down in the human body, and the main metabolic pathway is acetamidation by hydrolase (24% of the administered dose). The main metabolite UCB L057 is not transformed by the liver pigment P450 transport system. Acetamide group hydrolysates can be measured in most tissues in the body, including blood cells. The metabolite UCB L057 has no pharmacological activity. Two small metabolic pathways have also been identified, one is the hydroxylated pyrrolidine pathway (1.6% of the administered dose), and the other is the pyrrolidine group ring-opening, which accounts for approximately 0.9% of the dose. Metabolites of other metabolic pathways that cannot be determined account for 0.6% of the administered dose. Data from in vitro tests indicate that neither Levetiracetam nor its major metabolites have a first-pass effect. In vitro test data show that levetiracetam and its main metabolites do not inhibit the isomerization of liver pigment P450 (CYP3A4, 2A6, 2X8 / 9/10, 2C19, 2D6, 2E1, and 1A2). UGT1 * 1 and UGT [pI6.2] and epoxide hydroxylase activity. In addition, in vitro tests of levetiracetam have not shown to affect glucovalerization of valproic acid. In human liver cell tissue, levetiracetam Tan does not produce an enzyme-inducing effect. Therefore, the joint application of this product and other substances usually does not cause interaction, and vice versa.

Levetiracetam Elimination

Adult plasma half-life: 7 ± 1 hour, and does not change due to different dosages, different routes of administration or repeated administration. The average total clearance in vivo was 0.96 mL / min / kg. The drug is mainly excreted from the urine, about 95% of the dose (about 93% is excreted within 48 hours). Only 0.3% of the drugs are excreted from the stool. During the first 48 hours of administration, the cumulative excretion rates of levetiracetam and its metabolites were 66% and 24% of the administered dose, respectively. Levetiracetam and UCB L057 have renal clearance rates of 0.6 and 4.2 mL / min / kg, respectively. This indicates that levetiracetam is filtered through the glomerulus and reabsorbed by the renal tubules, and the major metabolites are also passed through the renal tubules. Secretion and glomerular filtration are eliminated. Levetiracetam elimination and muscle elderly patients: The half-life of levetiracetam in elderly patients has been extended by approximately 40% (10-11 hours). This is related to decreased kidney function.

The plasma half-life of levetiracetam in children (4-12 years) in a single dose (20 mg / kg) was 6.0 hours (6-12 years). Apparent clearance (after weight adjustment) is approximately 30% higher than in adults with epilepsy. After repeated oral administration (20-60 mg / kg / day) in children (4-12 years), levetiracetam was rapidly absorbed. Peak concentration was reached 0.5-1 hour after administration. The peak concentration and the area under the curve are linear and increase in proportion to the dose. The clearance half-life is 5 hours, and the apparent in vivo clearance is about 1.1 mL / min / kg.

Levetiracetam Infants and Toddlers

After a single dose of 10% oral solution (20 mg / kg), pediatric patients (1 month to 4 years) were absorbed rapidly. The blood peaked after 1 hour of administration. Pharmacokinetic data show that its half-life (5.3 hours) is shorter than that of adults (7.2 hours), and the apparent in vivo clearance of infants and young children (1.5 mL / min / kg) is faster than that of adults (0.96 mL / min / kg). The main metabolite UCB L057 is lower in children than in adults.

Levetiracetam with renal impairment

Its in vivo clearance of levacetam and major metabolites depends on creatinine clearance. Therefore, patients with moderate or severe renal insufficiency are advised to adjust the daily maintenance dose based on creatinine clearance. In patients with advanced anemia of advanced nephropathy, the plasma half-life of adult drugs is 25 and 3.1 hours due to the interval between dialysis and dialysis.

During 4 hours of dialysis, 51% of levetiracetam was removed by fractionation.

Hepatic impairment of levetiracetam

There was no corresponding change in levetiracetam clearance in patients with moderate to mild liver damage. The clearance rate of levetiracetam in most patients with severe liver dysfunction decreased by more than 50%, which was mainly due to impaired renal function.