Approval Date.
Lacosamide Injection Instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug Name]
Generic name: Lacosamide Injection
Trade name: Vipat® (English: VIMPAT®)
English name: Lacosamide Injection
Hanyu Pinyin: Lakaosha’an Zhusheye
Ingredients
The main ingredient of this product is lacosamide.
Chemical name: (R)-2-(acetylamino)-N-phenylmethyl-3-methoxypropionamide
Chemical structure formula.
Molecular formula: C13H18N2O3
Molecular weight: 250.30
Excipients: sodium chloride, hydrochloric acid (pH adjuster) and water for injection.
【Properties】.
This product is a colorless clear liquid.
Indications】
This product is suitable for the combined treatment of partial seizures in patients with epilepsy aged 4 years and above.
Specification
20ml:0.2g
Dosage
Recommended Dosage
Treatment with Lacosamide can be started with oral or intravenous administration. When oral administration is not feasible, this injection is an alternative dosing option for patients. The total duration of intravenous treatment with lacosamide is at the discretion of the physician; in combination therapy clinical trials, there has been experience with lacosamide administered as a second daily infusion for up to 5 days. Conversion between oral and intravenous administration can be made directly without dose adjustment. The total daily dose and secondary daily dosing should be maintained.
This product must be administered twice daily (usually once in the morning and once in the evening).
Adults (17 years and older)
Table 1 summarizes the recommended doses for adolescents and children (weight ≥ 50 kg) and adults. More detailed information can be found in the table below.
Table 1: Recommended doses for combination therapy in adult (17 years and older) patients Starting dose 100 mg/day Single loading dose (if applicable) 200 mg Dose adjustment (step-up) 50 mg Twice daily (100 mg/day)
Maximum recommended dose adjusted once a week up to 400 mg/day
The recommended starting dose is 50 mg twice daily and should be increased to an initial therapeutic dose of 100 mg twice daily after one week.
Based on efficacy and tolerability, the maintenance dose may be increased weekly by 50 mg twice daily (100 mg twice weekly) until increased to the maximum recommended daily dose of 400 mg (200 mg twice daily).
Starting Lacosamide Treatment with a loading dose
Treatment may also be initiated with a single loading dose of 200 mg, followed by a maintenance dose regimen of 100 mg twice daily (200 mg/day) for approximately 12 hours. Subsequent dose adjustments should be made as described above, according to individual efficacy and tolerability. A loading dose may be given to patients when the physician determines that rapid achievement of steady-state plasma concentrations and efficacy of lacosamide is required. Considering the potential for increased incidence of CNS adverse reactions, loading doses should be administered under medical monitoring (see [Adverse Reactions]). Loading doses have not been studied in acute situations, such as in persistent epilepsy.
Children and Adolescent Populations 4 Years and Older
Physicians should prescribe the most appropriate dosage form and size based on the patient’s age, weight, and dose administered. The preferred option for children and adolescents weighing <50 kg is to start treatment with Lacosamide syrup/oral solution. When oral administration is not feasible, lacosamide may be substituted with intravenous infusion of lacosamide injection.
Adolescents and children weighing ≥50 kg
Dosing for adolescents and children weighing ≥50 kg is the same as for adult patients (please refer to the recommended adult dose).
Adolescents and children weighing <50 kg
-The dosage for children and adolescents is based on pharmacokinetic modeling with the goal of achieving the same blood concentration range as adults (see [Pharmacokinetics]).
The recommended starting dose is 2 mg/kg/day, which should be increased to an initial therapeutic dose of 4 mg/kg/day after one week. Based on efficacy and tolerability, the maintenance dose may be increased weekly by 2 mg/kg/day. The dose should be adjusted gradually until optimal efficacy is achieved. In children weighing ≥11 kg and <30 kg, the recommended maximum dose does not exceed 12 mg/kg/day due to increased clearance compared to adults. For children weighing ≥30 kg but <50 kg, the recommended maximum dose is 8 mg/kg/day.
No studies of loading dose administration have been conducted in children. No loading doses are recommended for adolescents and children weighing <50 kg.
Table 2: Recommended doses for combination therapy in children and adolescents (4 years and older) weighing <50 kg
Starting dose 2 mg/kg/day Single loading dose No recommended dose adjustment (incremental steps) Maximum recommended dose up to 12 mg/kg/day for patients weighing ≥ 11 kg and< 30 kg Maximum recommended dose up to 8 mg/kg/day for patients weighing ≥ 30 kg and< 50 kg
Discontinuation
Based on current clinical practice, if lacosamide is to be discontinued, it is recommended that it be discontinued gradually (e.g., at a reduced daily dose of 200 mg/week).
Use in Special Populations
Geriatric patients (age >65 years)
Geriatric patients do not require dose reduction. In elderly patients, age-related decreased renal clearance with increased AUC levels should be considered (see [Pharmacokinetics]). There are limited clinical data in elderly patients with epilepsy receiving (especially >400 mg/day dose) treatment (see [Precautions], [Adverse Reactions] and [Clinical Trials]).
Renal Impairment
Adult and pediatric patients with mild and moderate renal impairment (CLCR> 30 ml/min) do not require dose adjustment. Pediatric and adult patients with mild or moderate renal impairment and weight ≥ 50 kg may be considered to receive a 200 mg loading dose, but further dose adjustments (>200 mg daily) should be made with caution. The recommended maximum maintenance dose for pediatric and adult patients with severely impaired renal function (CLCR ≤ 30 ml/min) and end-stage renal disease weighing ≥ 50 kg is 250 mg/day. Caution should be exercised when adjusting the dose in these patients. If a loading dose is indicated, a 100 mg starting dose should be used followed by a 50 mg per dose, twice daily dosing regimen for the first week. For patients with severe renal impairment (CLCR ≤ 30 ml/min) and weight < 50 kg and patients with end-stage renal disease, a 25% reduction in the maximum dose is recommended. For patients requiring hemodialysis, it is recommended that no more than 50% of the split daily dose be supplemented directly after the end of hemodialysis. Caution should be exercised when used in patients with end-stage renal disease because of the paucity of relevant clinical experience and the potential for accumulation of metabolites (with unknown pharmacological activity).
Hepatic Impairment
The maximum recommended dose for pediatric and adult patients with mild to moderate hepatic impairment weighing ≥50 kg is 300 mg/day.
Dose adjustments should be made with caution in patients with coexisting renal impairment. In adolescents and adults weighing ≥50 kg, a loading dose of 200 mg may be considered, but further dose adjustments (>200 mg/day) should be made with caution. Based on adult data, the maximum dose should be reduced by 25 % in patients with mild to moderate hepatic impairment weighing <50 kg. The pharmacokinetics of lacosamide have not been evaluated in patients with severe hepatic impairment (see [Pharmacokinetics]), and lacosamide should be given to adult and pediatric patients with severe hepatic impairment only if the expected therapeutic benefit outweighs the possible risks. Dose adjustments may be necessary and patients should be carefully monitored for disease activity and potential adverse reactions.
Directions for use
This product is recommended for intravenous infusion over a duration of 30 to 60 minutes per infusion; however, the fastest infusion duration may be 15 minutes when necessary. At doses of >200 mg per infusion (i.e., >400 mg/day), the duration of infusion should not be less than 30 minutes.
This product can be administered intravenously without further dilution or can be diluted with 0.9% sodium chloride injection, 5% dextrose injection or lactate Ringer injection.
When mixed with 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer Injection and stored in a glass vial or soft bag at a temperature not exceeding 25°C, the product was found to be physically compatible and chemically stable for at least 24 hours.
This product should not be mixed with diluents other than those mentioned above for injection.
Do not use if particulate matter or discoloration is found in this product. This product is for single use only and any unused solution should be discarded.
Intravenous infusion of Lacosamide may cause bradycardia or atrioventricular block. For patients with known cardiac conduction problems, who are receiving concomitant medications that prolong the PR interval, or who have severe heart disease, an electrocardiogram is recommended prior to initiating lacosamide therapy and after adjusting the lacosamide dose to a steady-state maintenance dose.
[Adverse Reactions].
Overview of safety characteristics
Based on the results of a pooled analysis of combination therapy placebo-controlled clinical trials conducted in 1308 patients with partial-onset seizures, at least 1 adverse reaction was reported in 61.9% and 35.2% of patients randomly assigned to receive this or placebo, respectively. The most frequently reported adverse reactions (≥10%) in the this treatment group were dizziness, headache, nausea, and diplopia. These reactions were usually mild to moderate in severity. Some reactions were dose related and were able to resolve with dose reduction. The incidence and severity of central nervous system and gastrointestinal adverse reactions usually decreased over time.
The rate of discontinuation due to adverse reactions was 12.2% in patients randomly assigned to receive this product and 1.6% in patients randomly assigned to receive placebo in all controlled studies. The most common adverse reaction leading to discontinuation of this product was dizziness.
The incidence of central nervous system adverse reactions such as dizziness may be elevated after administration of loading doses.
Based on analysis of data from non-inferiority monotherapy clinical trials comparing lacosamide with carbamazepine extended-release, the most frequently reported adverse reactions (≥10%) to lacosamide were headache and dizziness. The discontinuation rate due to adverse reactions was 10.6% in patients treated with lacosamide compared to 15.6% in patients treated with carbamazepine extended-release.
Adverse Reaction List
The following table lists the incidence of adverse reactions reported in clinical trials and post-marketing use experience. Incidence rates are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), unknown (incidence cannot be estimated based on available data). Within each incidence group, adverse reactions were listed in descending order of severity.
Table 3: Incidence of adverse reactions reported in clinical trials and postmarketing use experience
System Organ Classification Very common Common Common Uncommon Unknown Blood and lymphatic system abnormalities Granulocyte deficiency (1) Immune system abnormalities Drug
Hypersensitivity reactions (1) Drug reactions with eosinophilia and systemic symptoms (1, 2) Psychiatric abnormalities Depression
Mental confusion
Insomnia (1) Aggressive behavior (1)
Agitation (1)
euphoria (1)
Mental abnormalities (1)
Suicide attempt (1)
suicidal ideation (1)
Hallucinations (1) Abnormal neurological dizziness
Headache balance disorder
Coordination abnormalities
Memory impairment
Cognitive impairment
Drowsiness
Tremor
Nystagmus
hypesthesia
Difficulty in making sounds
Attention deficit
Sensory abnormalities Syncope (2) Convulsions (3) Eye abnormalities Diplopia Blurred vision Ear and vagus abnormalities Vertigo
Tinnitus Cardiac abnormalities Atrioventricular block (1, 2)
Bradycardia (1, 2)
Atrial fibrillation (1, 2)
Atrial flutter (1, 2) Digestive system abnormalities Nausea and vomiting
Constipation
Gastrointestinal distention
Indigestion
Dry mouth
Diarrhea Hepatobiliary abnormalities Abnormal liver function tests (2)
Elevated liver enzymes (>2×ULN) (1) Skin and subcutaneous tissue abnormalities Pruritus
Rash (1) Angioedema (1)
Urticaria (1)Stevens-Johnson syndrome (1)
Toxic epidermolysis bullosa (1) Musculoskeletal and connective tissue abnormalities Muscle spasms Systemic discomfort and site of administration abnormalities Gait disorders
Weakness
fatigue
irritability
Feeling of intoxication
Pain or discomfort at the injection site (4)
Irritation (4) Erythema (4) Complications due to injury, poisoning, and medical disposition Falls
Skin lacerations
Contusions (1) Adverse reactions reported in post-marketing use experience.
(2) See specific adverse reaction descriptions.
(3) Adverse reactions reported in open studies.
(4) Local adverse reactions associated with intravenous administration.
Specific Adverse Reaction Descriptions
Use of this product may cause a dose-related prolongation of the PR interval. Adverse reactions associated with prolonged PR interval (e.g., AV block, syncope, bradycardia) may occur. In combination therapy clinical trials, the incidence of degree I AV block reported in patients with epilepsy was uncommon, at 0.7%, 0%, 0.5% and 0% in the 200 mg, 400 mg and 600 mg Benadryl or placebo groups, respectively. Atrioventricular block of degree II or greater was not observed in these studies. However, second and third degree AV block following treatment with this product has been reported in post-marketing use experience.
In the pooled combination therapy clinical trials, syncope occurred infrequently and did not differ in incidence between patients with epilepsy treated with this product (n=944) versus placebo (n=364), at 0.1% versus 0.3%, respectively. In monotherapy clinical trials comparing lacosamide with carbamazepine extended-release, syncope was reported in 7/444 (1.6%) patients in the lacosamide group and in 1/442 (0.2%) patients in the carbamazepine extended-release group.
No atrial fibrillation or atrial flutter was reported in short-term clinical trials; however, atrial fibrillation or atrial flutter was reported in open epilepsy trials and postmarketing use experience.
Abnormal laboratory tests
Abnormal liver function tests were observed in controlled trials of this product in adult patients with partial-onset seizures who were receiving one to three combined antiepileptic drugs. The rate of ALT elevation to ≥3 x ULN occurred in 0.7% (7/935) of patients in the drug-treated group compared with 0% (0/356) in the placebo group.
Multi-organ hypersensitivity reactions
Multiorgan hypersensitivity reactions (also known as eosinophilia and systemic symptoms of drug reactions) have been reported in patients treated with certain antiepileptic drugs. The presentation of these reactions varies, but they generally present as fever and rash and may be associated with involvement of different organ systems. If multi-organ hypersensitivity reactions are suspected, lacosamide should be discontinued.
Pediatric Population
In placebo-controlled studies (see [Clinical Trials]) and open studies (n=408), the safety profile of lacosamide when used as combination therapy in children 4 years of age and older was consistent with that observed in adults, while an increased frequency of certain adverse reactions (drowsiness, vomiting, and convulsions) and other adverse reactions (nasopharyngitis, fever, pharyngitis, loss of appetite, sleepiness, and abnormal behavior): nasopharyngitis (15.7 %), vomiting (14.7 %), drowsiness (14.0 %), dizziness (13.5 %), fever (13.0 %), convulsions (7.8 %), loss of appetite (5.9 %), pharyngitis (4.7 %), sleepiness (2.7 %), and abnormal behavior (1.7 %).
In total, 67.8 % of the patients randomized to lacosamide and 58.1 % of the patients randomized to placebo reported at least 1 adverse reaction.
Behavioral, cognitive, and emotional functioning was measured by the Achenbach CBCL and BRIEF questionnaires, which were used at baseline and throughout the study, and scores remained largely stable over the course of the trial.
Geriatric population
In monotherapy studies comparing lacosamide with carbamazepine extended-release, the types of adverse reactions associated with lacosamide in elderly patients (≥ 65 years of age) appeared to be similar to those in patients younger than 65 years of age. However, higher rates of falls, diarrhea, and tremors were reported in older patients than (≥5% difference) younger adult patients. The most frequently reported cardiac-related adverse reaction in older patients compared with the younger adult population was first-degree AV block, reported in 4.8% (3/62) of the lacosamide group in older patients compared with 1.6% (6/382) in younger adult patients. The discontinuation rate for adverse events was 21.0% (13/62) in the lacosamide group in older patients compared with 9.2% (35/382) in younger adult patients. These differences between elderly patients and younger adult patients were similar to those in the positive control group.
Reports of Suspected Adverse Reactions
It is important to report suspected adverse reactions after marketing approval of this product. This allows for ongoing monitoring of the benefit/risk ratio of this product. Health care professionals are required to report suspected adverse reactions through the appropriate reporting system.
[Contraindication].
Contraindicated in persons with hypersensitivity to the active ingredient or to any of the excipients in this product.
Contraindicated in patients with known atrioventricular block of the second or third degree.
Precautions]
Suicidal ideation and behavior
Suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs for multiple indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs also showed a small increase in the risk of suicidal ideation and behavior. The mechanism of this risk is unclear, and the available data do not completely rule out the possibility that lacosamide increases this risk. Therefore, patients should be monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered. Patients (and their caregivers) should be advised to seek medical advice if signs of suicidal ideation or behavior develop (see [ADVERSE REACTIONS]).
Heart Rhythm and Cardiac Conduction
A dose-related prolongation of the PR interval has been observed with lacosamide in clinical studies. Lacosamide should be used with caution in patients with known conduction problems, severe cardiac disease (e.g., myocardial infarction or heart failure), in elderly patients, or in combination with products known to cause prolongation of the PR interval.
For these patients, electrocardiography should be considered prior to increasing the dose of Lacosamide above 400 mg/day and after adjusting the dose of Lacosamide to steady state. If lacosamide is given by the intravenous route in these patients, they should be monitored closely. Significant bradycardia was observed in one patient during a 15-minute 150 mg lacosamide infusion.
Atrioventricular block of second degree or greater has been reported in post-marketing experience with its use. No atrial fibrillation or atrial flutter was reported in placebo-controlled trials of this product in patients with epilepsy; however, atrial fibrillation and atrial flutter have been reported in open epilepsy trials and postmarketing use experience (see [Adverse Reactions]).
Patients should be made aware of symptoms of atrioventricular block of degree II or greater (e.g., slowed or irregular pulse, light-headedness, and feeling of fainting) and symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, rapid or irregular pulse, shortness of breath). Patients should be advised to seek medical advice if these symptoms occur.
Dizziness
Treatment with this product can cause dizziness, which may increase the incidence of accidental injury or falls. Therefore, patients should be advised to use caution until they are familiar with the potential effects of this product (see [ADVERSE REACTIONS]).
This product contains 2.6 mmol (or 59.8 mg) of sodium per dose. Caution should be taken in patients on a sodium-restricted diet.
Potential for worsening EEG-clinical manifestations in selected childhood epilepsy syndromes
The safety and efficacy of lacosamide in children with epilepsy syndromes in which focal and generalized seizures coexist has not been established.
Effects on the ability to drive and operate machinery
This product has a mild to moderate effect on the ability to drive and operate machinery. Treatment with this product may cause dizziness or blurred vision. Therefore, patients should be advised not to drive or operate other potentially hazardous machinery unless they are familiar with the extent of the effects of this product on their ability to drive and operate.
Stability during use
The physical and chemical properties of this product have been shown to be stable for up to 24 hours at temperatures not exceeding 25°C when mixed with the diluent as described in [Dosage] “Directions” and stored in glass bottles or soft bags.
For microbiological reasons, this product should be used immediately after opening. If not used immediately, the user should ensure the storage time and conditions before use, unless the dilution process is carried out under controlled and proven sterile conditions, then do not store the product for more than 24 hours under refrigerated conditions at 2℃~8℃.
For Pregnant and Lactating Women]
Pregnancy
Risks associated with epilepsy and overall antiepileptic drugs
All antiepileptic drug studies have shown that the prevalence of malformations in the offspring of women treated for epilepsy is two to three times higher than in the general population, with an incidence of approximately 3% in the general population. In the treated population, multiple drugs were observed to cause an increase in malformations, but the extent to which this was caused by treatment and/or disease was not indicated.
In addition, effective antiepileptic drug therapy must not be interrupted because exacerbation of the disease is harmful to both the mother and the fetus.
Risks associated with Lacosamide
There are insufficient data on the use of this product in pregnant women. Animal studies have not suggested teratogenic effects in rats or rabbits, but embryotoxicity has been observed in rats and rabbits at maternal toxicity dose levels (see [Pharmacologic Toxicology]). The potential risk of this product in humans is unknown.
This product should not be used during pregnancy unless clearly needed (if the benefit to the mother outweighs the potential risk to the fetus). If a woman decides to become pregnant, the use of this product should be carefully reevaluated.
Lactation
It is unknown whether lacosamide is secreted into human milk. Animal studies have shown that lacosamide is secreted into breast milk. As a precautionary measure, breastfeeding should be discontinued during treatment with this product.
Fertility
No adverse effects on male or female fertility or reproduction have been observed in rats at plasma exposures (AUC) achieved at approximately twice the plasma exposure at the maximum recommended human dose (MRHD).
Pediatric Dosage]
Safety and efficacy in children under 4 years of age have not been established.
See [Dosage] for more information on the use in children 4 years of age and older.
Geriatric Use
Geriatric patients (age over 65 years) do not require dose reduction. There is limited experience with the use of this product in elderly patients with epilepsy. Age-related decreased renal clearance and increased AUC levels should be considered when used in elderly patients (see [DOSAGE AND ADMINISTRATION] and [PHARCOSYNTHESIS]).
Drug Interactions]
This product should be used with caution in patients treated with drugs known to cause prolongation of the PR interval (e.g., carbamazepine, lamotrigine, eslicarbazepine, pregabalin) and in patients treated with class I antiarrhythmic drugs. However, subgroup analysis of clinical trials did not reveal an increase in the magnitude of PR interval prolongation in patients receiving the combined administration of carbamazepine or lamotrigine.
In Vitro Trial Data
The data overall suggest that lacosamide has a low potential for drug interactions. Multiple in vitro studies have demonstrated that lacosamide does not induce CYP1A2, CYP2B6, and CYP2C9 enzymes and does not inhibit CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP2E1 enzymes over the range of blood concentrations observed in clinical trials. An in vitro study showed that lacosamide is not transported via P-glycoprotein in the intestine. In vitro data showed that CYP2C9, CYP2C19 and CYP3A4 are able to catalyze the formation of O-demethyl metabolites.
In vivo test data
The extent to which lacosamide inhibits or induces CYP2C19 and CYP3A4 is not clinically significant. Lacosamide did not affect the AUC of midazolam (metabolized by CYP3A4; lacosamide was administered at a dose of 200 mg twice daily), but the Cmax of midazolam was slightly elevated (30%). Lacosamide did not affect the pharmacokinetics of omeprazole (metabolized by CYP2C19 and CYP3A4, with lacosamide administered at a dose of 300 mg per dose, twice daily).
The CYP2C19 inhibitor omeprazole (40 mg per dose, once daily) did not cause clinically meaningful changes in lacosamide exposure. Therefore, it is unlikely that a moderate inhibitor of CYP2C19 would have a clinically meaningful effect on systemic exposure to lacosamide.
Combination therapy with CYP2C9 potent inhibitors (e.g., fluconazole) and CYP3A4 potent inhibitors (e.g., itraconazole, ketoconazole, ritonavir, clarithromycin) may result in increased systemic exposure to lacosamide and caution is advised when using them. Such interactions have not been identified in in vivo trials, but may occur based on in vitro trial data.
Potent enzyme inducers such as rifampicin or St. John’s Wort (Kanzai) may moderately reduce systemic exposure to lacosamide. Therefore, caution should be exercised when starting or ending treatment with these enzyme inducers.
Antiepileptic drugs
In interaction tests, lacosamide did not significantly affect plasma concentrations of carbamazepine and valproic acid. Lacosamide plasma concentrations were unaffected by carbamazepine and valproic acid. Estimates from a population pharmacokinetic analysis showed that total systemic exposure to lacosamide was reduced by 25% and 17% in adult and pediatric patients, respectively, after combined treatment with other antiepileptic drugs known to be enzyme inducers (various doses of carbamazepine, phenytoin, and phenobarbital).
Oral contraceptives
In an interaction trial, no clinically meaningful interactions occurred between lacosamide and the oral contraceptives ethinylestradiol and levonorgestrel. Progesterone concentrations were not affected when these drugs were combined.
Other drugs
Interaction tests have shown that lacosamide does not affect the pharmacokinetics of digoxin. Lacosamide does not interact with metformin in a clinically meaningful manner.
Coadministration of warfarin with lacosamide does not result in clinically meaningful changes in the pharmacokinetics or pharmacodynamics of warfarin.
Although no pharmacokinetic interaction data were obtained for lacosamide with alcohol, an effect of alcohol on pharmacodynamics cannot be excluded.
The protein binding rate of lacosamide is low, less than 15%. Therefore, it is considered unlikely that clinically meaningful interactions with other drugs will occur through competition for protein-binding sites.
[Drug Overdose].
Clinical symptoms
Symptoms observed following accidental or intentional lacosamide overdose are primarily related to the central nervous system and gastrointestinal system.
The types of adverse reactions that occurred after patient exposure to 400 mg to 800 mg of lacosamide were not clinically different from the types of adverse reactions that occurred after patient exposure to the recommended dose of lacosamide.
Reactions reported after ingestion of doses greater than 800 mg were dizziness, nausea, vomiting, and seizures (generalized tonic clonic seizures, continuous status epilepticus). Cardiac conduction disturbances, shock, and coma have also been observed. Patient deaths have been reported following acute overdose doses of several grams of lacosamide given as a single dose.
Treatment
There is no specific antidote for lacosamide overdose. Treatment of lacosamide overdose should include systemic supportive measures, including hemodialysis if necessary (see [Pharmacokinetics]).
Clinical trials
Results of foreign clinical studies
In three multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period, the effectiveness of the recommended doses of lacosamide (200 mg/day, 400 mg/day) for combination therapy was established. Lacosamide 600 mg/day was also shown to be effective in combination therapy-controlled trials, but the effectiveness was similar to that of 400 mg/day and patients are unlikely to tolerate the 600 mg/day dose due to central nervous system and gastrointestinal-related adverse effects. Therefore, a dose of 600 mg/day is not recommended. The maximum recommended dose is 400 mg/day. These trials involved 1308 patients with a mean 23-year history of partial-onset seizures and were designed to evaluate the efficacy and safety of lacosamide when administered in combination with one to three antiepileptic drugs in patients with uncontrolled partial-onset seizures with or without secondary generalized seizures. Overall, the percentage of subjects with a 50% reduction in seizure frequency was 23%, 34%, and 40% in the placebo, lacosamide 200 mg/day, and lacosamide 400 mg/day groups, respectively.
A multicenter, open study was conducted to determine the pharmacokinetics and safety of a single intravenous loading dose of lacosamide. The study was designed to evaluate the safety and tolerability of a combination of a single intravenous loading dose (consisting of 200 mg) of lacosamide for rapid onset of action, followed by oral administration twice daily (equal to the intravenous dose) in adult subjects aged 16 to 60 years with partial-onset seizures.
Pediatric Population
The clinical presentation of partial-onset seizures is similar in children 4 years of age and older and in adults. The effectiveness of Lacosamide Injection in children 4 years of age and older was extrapolated from data in adolescents and adults with partial-onset seizures, and pediatric dose adjustments were determined, with similar expected efficacy.
These extrapolation principles were validated and supported by a double-blind, randomized, placebo-controlled study. The study consisted of an 8-week baseline period, followed by a 6-week dose adjustment period. Eligible patients for enrollment had to meet the following criteria: being treated with one to three stable-dose regimens of antiepileptic drugs; having had at least two partial seizures in the 4 weeks prior to screening; and having a seizure-free period of no longer than 21 days during the 8-week period prior to entry into the baseline period, and these patients were randomized to placebo (n=172) or lacosamide (n=171).
The starting dose was 2 mg/kg/day for subjects weighing <50 kg and 100 mg/day for subjects weighing ≥50 kg, divided into 2 doses. During the dose adjustment period, subjects weighing <50 kg are dosed at 1 or 2 mg/kg/day and subjects weighing ≥50 kg are dosed at 50 mg or 100 mg/day to achieve the target dose range for the maintenance period.
Subjects must achieve and maintain the lowest target dose given by weight range during the last 3 days of the adjustment period to be eligible for the 10-week maintenance period. Subjects’ lacosamide dose must remain stable throughout the maintenance period or withdraw from the study and enter a blinded taper period.
The data showed a more significant reduction in partial seizure frequency per 28 days from baseline to maintenance in the lacosamide group compared to the placebo group, and the difference was statistically significant (p=0.0003) and clinically meaningful. Based on analysis of covariance, the percentage reduction in seizure frequency was 31.72 % higher in the lacosamide group compared with the placebo group (95% CI: 16.342, 44.277)
Overall, the percentage of subjects with at least a 50 % reduction in partial seizure frequency per 28 days from baseline to maintenance was 52.9 % in the lacosamide group compared to 33.3 % in the placebo group.
The Childhood Quality of Life Survey assessment showed that subjects in the lacosamide and placebo groups had similar and stable health-related quality of life throughout the treatment period.
Chinese clinical study results
The effectiveness of the recommended doses (200 mg/day, 400 mg/day) of lacosamide as combination therapy in Japanese and Chinese adults with partial-onset seizures was confirmed in a multicenter, randomized, placebo-controlled clinical trial that included a 12-week maintenance period. The study randomly assigned 548 patients, aged ≥16 years, was designed to evaluate the efficacy and safety of lacosamide when administered in combination with one to three antiepileptic drugs in patients with poorly controlled partial-onset seizures with or without secondary generalized seizures.
Overall, the lacosamide 400 mg/day and 200 mg/day groups showed a statistically significant and clinically meaningful decrease in seizure frequency per 28 days from baseline to maintenance compared with the placebo group (p<0.001). The results in Chinese subjects were similar to the overall full analysis set (p<0.001 for both groups).
A total of 406 Chinese subjects were randomly grouped and 402 subjects were included in the full analysis set (FAS). In Chinese subjects, the lacosamide 400 mg/day and 200 mg/day groups showed statistically and clinically significant decreases in seizure frequency per 28 days from baseline to maintenance compared to the placebo group (p<0.001, respectively). The percentage decrease in seizure frequency per 28 days compared to placebo was 43.1% (95% CI: 32.8%, 51.8%) and 33.6% (95% CI: 21.0%, 44.1%) for the lacosamide 400 mg/day and 200 mg/day groups, respectively.
Table 4: Statistical analysis of change in frequency of partial seizures per 28 days from baseline to maintenance (FAS)
Treatment n % decrease compared to placebo % decrease compared to placebo 95% CI p-value Overall placebo 183 —— Lacosamide 200mg/day 18229.418.7, 38.7<0.001 Lacosamide 400mg/day 17939.630.5, 47.6<0.001 China placebo 135 —– -Lacosamide 200 mg/day 13533.621.0, 44.1<0.001Lacosamide 400 mg/day 13243.132.8, 51.8<0.001CI=confidence interval; FAS=full analysis set
Overall, 200 mg/day and 400 mg/day doses of lacosamide as combination therapy for poorly controlled partial-onset seizures were safe and well tolerated in Chinese and Japanese adult subjects. This is consistent with the overall safety profile in foreign studies of lacosamide as combination therapy for poorly controlled partial-onset seizures.
A randomized, open, double-crossover, single-dose clinical trial in 30 healthy Chinese male subjects (single dose of 200 mg: lacosamide tablets 100 mg/tablet x 2 tablets or lacosamide injection 10 mg/ml x 20 ml over 30 minutes intravenously) determined the bioequivalence of lacosamide injection to lacosamide tablets.
The geometric means of the main PK parameters were similar for lacosamide tablets (100 mg/tablet x 2 tablets) and lacosamide injection (10 mg/ml x 20 ml, 30 min IV drip) (AUC of 114.8 h*mg/L versus 110.7 h*mg/L, respectively; AUC[0-t] of 111.0 h*mg/L versus 107.0 h*mg/L, respectively. (Cmax was 6.670 mg/L versus 7.279 mg/L, respectively). Other PK parameters, t1/2, tmax, CL/F(oral) versus CL(iv), Vz/F(oral) versus Vz(iv) were also similar for both treatments. the AUC(0-t), AUC to Cmax ratios (0.9636, 0.9640, 1.091, respectively) for 200 mg lacosamide injection/oral tablets were close to 1, and the corresponding 90% confidence intervals were within the acceptable range of bioequivalence (0.80 ~ 1.25): AUC(0-t) (0.9462, 0.9814), AUC (0.9452, 0.9832), Cmax (1.015, 1.173).
Two 100 mg lacosamide tablets administered orally and 200 mg (20 ml 10 mg/ml) of lacosamide injection administered intravenously were safe and well tolerated.
The values of the pharmacokinetic parameters are listed in the following table.
Table 5: Pharmacokinetic parameter values of lacosamide by treatment group
Treatment A
N=30 Treatment BN=30 Parameters (units) Geometric mean (geometric CV [%]) AUC (h*mg/L) 114.8 (15.34) 110.7 (16.52) AUC(0-t) (h*mg/L) 111.0 (14.08) 107.0 (15.17) Cmax (mg/L) 6.670 (20.28) 7.279 (21.18)t½ (h)14.37 (13.84)14.34 (16.05)CL/F (oral) (L/h)1.741 (15.30)NACL(iv) (L/h)NA1.806 (16.58)Vz/F (oral) (L)36.08 (9.779)NAVz(iv) (L) NA37.37 (9.731) median (min, max) tmax (h)0.6250 (0.25, 4.00)0.5000 (0.25, 2.00)CV= coefficient of variation; LCM=lacosamide; iv=intravenous; max=maximum; min=minimum; NA=not applicable
Note: Mean and coefficient of variation were calculated only if at least 3 values of the parameter were properly measured (e.g., not calculated or not labeled).
Note: Treatment A: Single dose 200 mg for lacosamide tablets orally (100 mg/tablet x 2 tablets); Treatment B: Single dose lacosamide injection 200 mg administered intravenously over 30 minutes (10 mg/ml x 20 ml)
Pharmacology and toxicology
Pharmacological effects
The exact mechanism by which lacosamide exerts its antiepileptic effect in humans has not been fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances the slow inactivation of voltage-gated sodium channels, thereby stabilizing the cell membranes of overexcited neurons and inhibiting repetitive neuronal firing.
Toxicological studies
Genotoxicity
The Ames test and the in vivo micronucleus test in mice were negative for lacosamide and the in vitro lymphoma test in mice was positive.
Reproductive toxicity
No adverse effects on male or female fertility or reproduction were observed in rats given lacosamide orally at doses that produced plasma exposures (AUC) up to approximately two times the exposure produced by the maximum recommended human dose (MRHD) of 400 mg/day.
Oral administration of lacosamide (20, 75, 200 mg/kg/day in rats and 6.25, 12.5, 25 mg/kg/day in rabbits) during organogenesis in pregnant rats and rabbits did not affect the incidence of structural abnormalities in fetuses, however, the maximum dose administered was limited by maternal toxicity in both species and embryonic fetal death in rats. In rats and rabbits, these doses induced maternal plasma exposures (AUC) approximately twice and one time the exposures produced by MRHD, respectively.
In two experiments in which rats were given lacosamide (25, 70, 200 mg/kg/day or 50, 100, 200 mg/kg/day) orally on day 7 of gestation or from day 6 of gestation to day 20 of lactation, increased perinatal mortality and weight loss in the offspring were observed at the highest dose. The nonresponsive dose (70 mg/kg/day) for perinatal developmental toxicity in rats produced maternal plasma exposures (AUC) similar to those produced by MRHD.
Oral administration of lacosamide (30, 90, 180 mg/kg/day) to rats during neonatal and juvenile periods resulted in reduced brain weight and long-term neurobehavioral changes (altered absentee behavior, learning and memory deficits). It is generally accepted that the early postnatal period in rats corresponds to the late human gestation period in terms of brain development. The unresponsive dose of developmental neurotoxicity in rats produces lower maternal plasma exposure (AUC) than that produced by MRHD.
In vitro tests have shown that lacosamide interferes with the activity of cerebral decay response regulatory protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth. Potentially relevant adverse effects on central nervous system development cannot be ruled out.
Carcinogenicity
No drug-related carcinogenicity was observed in mice and rats given lacosamide orally once daily for 104 weeks at doses that produced plasma exposures (AUC) up to approximately one and three times the exposure produced by the maximum recommended human dose (MRHD) of 400 mg/day, respectively.
[Pharmacokinetics].
Absorption
After intravenous administration, the Cmax is reached at the end of the infusion. blood concentration increases proportionally to the dose after oral (100~800mg) and intravenous (50~300mg) administration.
Distribution
The volume of distribution is about 0.6L/kg. the binding rate of Lacosamide to plasma protein is less than 15%.
Metabolism
95% of the dose is excreted in the urine as drug and metabolites. The metabolic profile of lacosamide is not fully understood.
The major compound excreted via urine is the prototype lacosamide (approximately 40% of the dose), with less than 30% of its O-demethyl metabolites.
In urine, the polar fraction, which is considered to be a serine derivative, accounts for about 20%, but only small amounts (0-2%) of such substances were detected in the plasma of some subjects. Small amounts (0.5-2%) of other metabolites were found in urine.
Data from in vitro tests showed that CYP2C9, CYP2C19 and CYP3A4 are able to catalyze the formation of O-demetabolites, but the isoenzymes that play a major role were not identified in in vivo tests. When comparing the pharmacokinetics of lacosamide in strong metabolizers (containing functional CYP2C19) and weak metabolizers (lacking functional CYP2C19), clinically meaningful differences in lacosamide exposure between the two were not observed. In addition, interaction tests with omeprazole (a CYP2C19 inhibitor) showed no clinically meaningful changes in lacosamide plasma concentrations, suggesting that this pathway is of lesser importance. Plasma concentrations of O-desmethyl lacosamide are approximately 15% of lacosamide plasma concentrations. This major metabolite is known to have no pharmacological activity.
Clearance
Lacosamide is cleared from the systemic circulation primarily by renal excretion and biotransformation. Following oral and intravenous administration of radiolabeled lacosamide, approximately 95% of the radioactively administered drug is recovered in urine and less than 0.5% in feces. The clearance half-life of the drug prototype is approximately 13 hours. Pharmacokinetics are proportional to dose and remain constant over time, with low intra- and inter-subject variability. Steady-state blood concentrations were achieved after 3 days of twice-daily dosing. The cumulative factor at elevated blood concentrations was approximately 2.
Steady-state concentrations at a single loading dose of 200 mg approximated steady-state concentrations at 100 mg per dose, administered orally twice daily.
Pharmacokinetics in Special Patient Populations
Gender
Clinical trials have shown no clinically significant effect of gender on lacosamide plasma concentrations.
Impaired Renal Function
Compared to healthy subjects, lacosamide AUC is increased by approximately 30% in patients with mild and moderate renal impairment and by approximately 60% in patients with severe renal impairment and in patients with end-stage renal disease requiring hemodialysis, while Cmax is not affected.
Hemodialysis effectively removes lacosamide from plasma. lacosamide AUC is reduced by approximately 50% after 4 hours of hemodialysis treatment. Therefore, supplemental dosing after hemodialysis is recommended (see [Dosage]). Exposure to O-demethyl metabolites is elevated several-fold in patients with moderate and severe renal impairment. Levels of O-demethyl metabolites were elevated in patients with end-stage renal disease when not receiving hemodialysis and continued to be elevated during the 24-hour sampling period. It is not clear whether increased metabolite exposure in subjects with end-stage renal disease causes adverse effects, but it was determined that the metabolite was not pharmacologically active.
Impaired liver function
Subjects with moderate hepatic impairment (Child-Pugh B) had elevated lacosamide plasma concentrations (approximately 50% elevated AUCnorm). This elevated exposure was due in part to decreased renal function in the subjects studied. Estimated non-renal clearance decreases in the study subjects elevated the lacosamide AUC by 20%. The pharmacokinetics of lacosamide have not been evaluated in patients with severe hepatic impairment (see [DOSAGE]).
Geriatric patients (age over 65 years)
In a study of older men and women (including four > 75-year-old patients), the AUC was approximately 30% and 50% higher than in younger men, respectively. This was partly due to lower body weight. Weight-standardized differences were 26% and 23%, respectively. Increased exposure variability was also observed. Renal clearance of lacosamide was only slightly decreased in the older subjects of the study.
Dose reductions are not considered generally necessary unless required due to decreased renal function (see [DOSAGE AND ADMINISTRATION]).
Pediatric Population
The pediatric pharmacokinetic profile of lacosamide was determined in a population pharmacokinetic analysis. The analysis used data derived from blood concentrations obtained from a placebo-controlled randomized study and from sparse sampling of 414 pediatric patients with epilepsy between the ages of 6 months and 17 years from three open studies. The doses of lacosamide administered ranged from 2 to 17.8 mg/kg/day, taken twice daily. For children weighing ≥50 kg, the maximum dose administered was 600 mg/day.
Typical plasma clearance predictions are 1.04 L/h, 1.32 L/h and 1.86 L/h for children weighing 20 kg, 30 kg and 50 kg, compared to 1.92 L/h for adults weighing 70 kg.
Storage
Keep airtight, below 25℃. Avoid misuse by children.
Package】
Colorless type I glass celine bottle and fluoropolymer coated chlorobutyl rubber stopper.
Package specifications are 20ml/stick, 1 stick/box and 5 sticks/box.
Expiration date
36 months
【Execution standard
Imported drug registration standard: JX20140282.
Approval number】
【Licensee】 [Licensee
Name: UCB Pharma SA
Address: Allée de la Recherche 60, B-1070 Brussels, Belgium
Manufacturer
Name: UCB Pharma S.A.
Address: Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium
Domestic Contact Unit
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