Acode 50

Lacosamide (Acode 50) 50 mg Film-Coated Tablet is a light pink, oval, film-coated tablets debossed with 'E1' on one side and plain on other side.
Each film-coated tablet contains: Lacosamide 50 mg.

Antiepileptic.
Pharmacology: Pharmacodynamics: Mechanism of action:The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalized amino acid.
The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes.
Pharmacodynamic Effects: Lacosamide protected against seizures in a broad range of animal models of partial and primary generalized seizures and delayed kindling development.
In non-clinical experiments lacosamide in combination with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate or gabapentin showed synergistic or additive anticonvulsant effects.
Pharmacokinetics: Absorption: Lacosamide is rapidly and completely absorbed after oral administration. The oral bioavailability of lacosamide tablets is approximately 100%. Following oral administration, the plasma concentration of unchanged lacosamide increases rapidly and reaches Cmax about 0.5 to 4 hours post-dose. Food does not affect the rate and extent of absorption.
Distribution: The volume of distribution is approximately 0.6 L/kg. Lacosamide is less than 15% bound to plasma proteins.
Metabolism: 95% of the dose is excreted in the urine as drug and metabolites. The metabolism of lacosamide has not been completely characterized. The major compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose) and its O-desmethyl metabolite less than 30%. A polar fraction proposed to be serine derivatives accounted for approximately 20% in urine, but was detected only in small amounts (0-2%) in human plasma of some subjects. Small amounts (0.5-2%) of additional metabolites were found in the urine.
CYP2C19, 2C9 and 3A4 are mainly responsible for the formation of the O-desmethyl metabolite. No clinically relevant difference in lacosamide exposure was observed comparing its pharmacokinetics in extensive metabolizers (EMs, with a functional CYP2C19) and poor metabolizers (PMs, lacking a functional CYP2C19). No other enzymes have been identified to be involved in the metabolism of lacosamide.
The plasma concentration of O-desmethyl-lacosamide is approximately 15% of the concentration of lacosamide in plasma. This major metabolite has no known pharmacological activity.
Elimination: Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of radiolabeled lacosamide, approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces. The elimination half-life of the unchanged drug is approximately 13 hours.
The pharmacokinetics is dose-proportional and constant over time, with low intra- and inter-subject variability. Following twice daily dosing, steady state plasma concentrations are achieved after a 3-day period. The plasma concentration increases with an accumulation factor of approximately 2.
A single loading dose of 200 mg approximates steady-state concentrations comparable to 100 mg twice daily oral administration.
Pharmacokinetics in special population: Elderly: In a study in elderly men and women including 4 patients >75 years of age, AUC was about 30 and 50% increase compared to young men, respectively. This is partly related to lower body weight. The body weight normalized difference is 26 and 23%, respectively. An increased variability in exposure was also observed. The renal clearance of lacosamide was only slightly reduced in elderly subjects in this study.
A general dose reduction is not considered to be necessary unless indicated due to reduced renal function.
Renal impairment: The AUC of lacosamide was increased by approximately 30% in mildly and moderately and 60% in severely renal impaired patients and patients with end stage renal disease requiring hemodialysis compared to healthy subjects, whereas Cmax was unaffected. Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of lacosamide is reduced by approximately 50%. Therefore, dosage supplementation following hemodialysis is recommended. The exposure of the O- desmethyl metabolite was several-fold increase in patients with moderate and severe renal impairment. In absence of hemodialysis in patients with end stage renal disease, the levels were increased and continuously rising during the 24-hour sampling. It is unknown whether the increased metabolite exposure in end stage renal disease subjects could give rise to adverse effects but no pharmacological activity of the metabolite has been identified.
Hepatic impairment: Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50% higher AUCnorm). The higher exposure was partly due to a reduced renal function in the studied subjects. The decrease in non-renal clearance in the patients of the study was estimated to give a 20% increase in the AUC of lacosamide. The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment.
Gender: Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of lacosamide.
Race: There are no clinically relevant differences in the pharmacokinetics of Lacosamide between Asian, Black, and Caucasian subjects.

Lacosamide is indicated as: Monotherapy in the treatment of partial-onset seizures in patients with epilepsy aged 16 years and older.
Adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in patients with epilepsy aged 16 years and older.

Monotherapy: Initial Monotherapy: Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with lacosamide. The recommended starting dose is 100 mg twice a day (200 mg/day) which should be increased to a therapeutic dose of 150 mg twice a day (300 mg/day) after one week. Depending on response and tolerability, the dose can be further increased at weekly interval by 50 mg twice a day (100 mg/day), to a maximum recommended maintenance daily dose of 200 mg twice a day (400 mg/day).
Conversion to monotherapy: For patients who will convert to lacosamide monotherapy, the recommended starting dose is 100 mg twice a day (200 mg/day) which should be increased to a therapeutic dose of 150 mg twice a day (300 mg/day) after one week. Depending on response and tolerability, the dose can be further increased at weekly interval by 50 mg twice a day (100 mg/day), to a maximum recommended maintenance daily dose of 200 mg twice a day (400 mg/day).
The recommended maintenance daily dose should be maintained for at least 3 days before initiating conversion to lacosamide monotherapy. A gradual withdrawal of the concomitant antiepileptic drug over at least 6-weeks is recommended. If the patient is on more than one antiepileptic drug, the antiepileptic drugs should be withdrawn sequentially. Safety and efficacy of Lacosamide have not been established for simultaneous conversion to monotherapy from two or more concomitant antiepileptic drugs.
Adjunctive Therapy: The recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 50 mg twice a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day).
Initiation of lacosamide treatment with a loading dose: Lacosamide treatment (e.g., for adjunctive therapy, initial monotherapy and conversion to monotherapy) may also be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a 100 mg twice daily (200 mg/day) maintenance dose regimen. A loading dose should be administered under medical supervision with consideration of the lacosamide pharmacokinetics (see Pharmacology: Pharmacokinetics under Actions) and the potential for increased incidence of CNS adverse reactions (see Adverse Reactions). Administration of a loading dose has not been studied in acute conditions such as status epilepticus. Depending on response and tolerability, the maintenance dose can be further increased by 50 mg twice a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day).
Discontinuation: In accordance with current clinical practice, if lacosamide has to be discontinued, it is recommended this be done gradually (e.g., taper the daily dose by 200 mg/week).
Special populations: Elderly Population: No dose reduction is necessary in elderly patients. The experience with lacosamide in elderly patients with epilepsy is limited. Age associated decreased renal clearance with an increase in AUC levels should be considered in elderly patients.
Renal impairment: No dose adjustment is necessary in mildly and moderately renally impaired patients (CLCR >30 mL/min).
A maximum dose of 300 mg/ day is recommended for patients with severe renal impairment (CLCR ≤30 mL/min) and in patients with end-stage renal disease.
For patients requiring haemodialysis a supplement of up to 50% of the divided daily dose directly after the end of haemodialysis should be considered.
Treatment of patients with end-stage renal disease should be made with caution as there is little clinical experience and accumulation of a metabolite (with no known pharmacological activity).
In all patients with renal impairment, the dose titration should be performed with caution (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment.
The dose titration in these patients should be performed with caution considering co-existing renal impairment. The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired patients (see Pharmacology: Pharmacokinetics under Actions). Lacosamide should be administered to patients with severe hepatic impairment only when the expected therapeutic benefits outweigh the possible risks, and the dosage and administration need to be adjusted while carefully observing the symptoms of patient.
Pediatric population: Lacosamide is not recommended for use in children and adolescents below the age of 16 as there is no data on safety and efficacy in these age groups.
Method of administration: Lacosamide film-coated tablets must be taken twice a day. Lacosamide may be taken with or without food.

Symptoms: Symptoms observed after an accidental or intentional overdose of lacosamide are primarily associated with CNS and gastrointestinal system.
The types of adverse reactions experienced by patients exposed to doses above 400 mg up to 800 mg were not clinically different from those of patients administered recommended doses of lacosamide.
Reactions reported after an intake of more than 800 mg are dizziness, nausea, vomiting, seizures (generalized tonic-clonic seizures, status epilepticus). Cardiac conduction disorders, shock and coma have also been observed. Fatalities have been reported in patients following an intake of acute single overdose of several grams of lacosamide.
Management: There is no specific antidote for overdose with lacosamide. Treatment of lacosamide overdose should include general supportive measures and may include hemodialysis if necessary.

Hypersensitivity to the active substance or to any of its excipients.

Dizziness: Treatment with lacosamide has been associated with dizziness which could increase the occurrence of accidental injury or falls. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medicine (see Adverse Reactions).
Cardiac rhythm and conduction: Prolongations in PR interval with lacosamide have been observed in clinical studies.
Lacosamide should be used with caution in patients with known conduction problems or severe cardiac disease such as a history or myocardial infarction or heart failure.
Second degree or higher AV block has been reported in post-marketing experience. In the placebo-controlled trials of lacosamide in epilepsy patients, atrial fibrillation or flutter were not reported; however, both have been reported in open-label epilepsy trials and in post-marketing experience.
Patients should be made aware of the symptoms of second-degree or higher AV block (e.g., slow or irregular pulse, feeling of lightheaded and fainting) and of the symptoms of atrial fibrillation and flutter (e.g., palpitations, rapid or irregular pulse, shortness of breath). Patients should be counseled to seek medical advice should any of these symptoms occur.
Suicidal ideation and behavior: Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behavior. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for lacosamide.
Therefore, patients should be monitored for signs of suicidal ideation and behaviors and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behavior emerge.
Effects on ability to drive and use machines: Lacosamide may have minor to moderate influence on the ability to drive and use machines. Lacosamide treatment has been associated with dizziness or blurred vision.
Accordingly, patients should be advised not to drive a car or to operate other potentially hazardous machinery until they are familiar with the effects of lacosamide on their ability to perform such activities.

Women of childbearing potential/Contraception in males and females: There was no clinically relevant interaction between lacosamide and oral contraceptives (ethinylestradiol and levonorgestrel) in clinical studies (see Interactions).
Pregnancy: There are no adequate data from the use of Lacosamide in pregnant women. Studies in animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats and rabbits at maternal toxic doses. The potential risk for humans is unknown.
Lacosamide should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the fetus). If women decide to become pregnant, the use of this product should be carefully re-evaluated.
Lactation: It is unknown whether lacosamide is excreted in human breast milk. Animal studies have shown excretion of lacosamide in breast milk.
Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue lacosamide, taking into account the importance of the drug to the mother.
Fertility: No adverse reactions on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the maximum recommended human dose (MRHD).

List of adverse reactions: The following shows the frequencies of adverse reactions by system organ class which have been reported in clinical trials. The frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Psychiatric disorders: Common: depression, confusional state, insomnia.
Nervous system disorders: Very common: dizziness, headache.
Common: cognitive disorder, nystagmus, balance disorder, coordination abnormal, memory impairment, tremor, somnolence, dysarthria, disturbance in attention, hypoesthesia, paresthesia.
Eye disorders: Very common: diplopia.
Common: vision blurred.
Ear and labyrinth disorders: Common: vertigo, tinnitus.
Gastrointestinal disorders: Very common: nausea.
Common: vomiting, constipation, flatulence, dyspepsia, dry mouth, diarrhea.
Skin and subcutaneous tissue disorders: Common: pruritus.
Musculoskeletal and connective tissue disorders: Common: muscle spasms.
General disorders and administration site conditions: Common: gait disturbance, asthenia, fatigue, irritability, feeling drunk.
Injury, poisoning and procedural complications: Common: fall, skin laceration, confusion.
Description of selected adverse reactions: The use of lacosamide is associated with dose-related increase in the PR interval. Adverse reactions associated with PR interval prolongation (e.g., atrioventricular block, syncope, bradycardia) may occur. In epilepsy patients the incidence rate of reported first degree AV Block is uncommon, 0.7%, 0%, 0.5% and 0% for lacosamide 200 mg, 400 mg, 600 mg or placebo, respectively. No second- or higher-degree AV Block was seen in lacosamide treated epilepsy patients.
The incidence rate for syncope is uncommon and did not differ between lacosamide treated epilepsy patients (0.1%) and placebo treated epilepsy (0.3%).
Atrial fibrillation or flutter were not reported in short term clinical trials; however, both have been reported in open-label epilepsy trials and in post-marketing experience.
Laboratory abnormalities: Abnormalities in liver function tests have been observed in controlled trials with lacosamide in adult patients with partial-onset seizures who were taking 1 to 3 concomitant antiepileptic drugs. Elevations of ALT to ≥3x ULN occurred in 0.7% (7/935) of Lacosamide patients and 0% (0/356) of placebo patients.
Loading dose administration: Incidence of CNS adverse reactions such as dizziness may be higher after a loading dose.
Post-marketing experience: In addition to the adverse reactions reported during clinical studies and listed previously, the following adverse reactions have been reported in post-marketing experience. Data are insufficient to support an estimate of their incidence in the population to be treated.
Blood and lymphatic system disorders: Agranulocytisos.
Immune system disorders: Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, DRESS) have been reported in patients treated with some antiepileptic agents. These reactions are variable in expression but typically present with fever and rash and can be associated with involvement of different organ systems. Potential cases have been reported rarely with lacosamide and if multiorgan hypersensitivity reaction is suspected, lacosamide should be discontinued.
Nervous system disorders: Seizure. Very few cases of seizure worsening (including occurrence of status epilepticus) have been reported.
Psychiatric disorders: Suicide attempt, suicidal ideation, psychotic disorder, hallucination, aggression, agitation, insomnia, euphoric mood.
Cardiac disorders: Atrioventricular block, atrial flutter, atrial fibrillation, bradycardia.
Hepatobiliary disorders: Liver function test abnormal, hepatic enzyme increased (>2x ULN).
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, urticaria, rash.

Lacosamide should be used with caution in patients treated with medicinal products known to be associated with PR prolongation (e.g., carbamazepine, lamotrigine, pregabalin) and in patients treated with class I antiarrhythmic drugs. However, subgroup analysis did not identify an increased magnitude of PR prolongation in patients with concomitant administration of carbamazepine or lamotrigine in clinical trials.
In vitro data: Data generally suggest that lacosamide has a low interaction potential.
In vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4.
Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies.In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations. Lacosamide was not a substrate or inhibitor for P-glycoprotein.
In vivo data: Clinical data indicate that lacosamide does not inhibit or induce CYP2C19 and 3A4.
Furthermore, an interaction trial with omeprazole (CYP2C19 inhibitor) demonstrated no clinically relevant changes in lacosamide plasma concentrations and no inhibitory effect on omeprazole pharmacokinetics.
Antiepileptics: In interaction trials lacosamide did not significantly affect the plasma concentrations of carbamazepine and valproic acid. Lacosamide plasma concentrations were not affected by carbamazepine and by valproic acid.
A population PK analysis estimated that concomitant treatment with other anti-epileptics known to be enzyme inducers (carbamazepine, phenytoin, phenobarbital, in various doses) decreased the overall systemic exposure of lacosamide by 25%.
Oral contraceptives: In an interaction trial there was no clinically relevant interaction between lacosamide and the oral contraceptives ethinylestradiol and levonorgestrel. Progesterone concentrations were not affected when the medicinal products were co-administered.
Others: Interaction trials showed that lacosamide had no effect on the pharmacokinetics of digoxin. There was no clinically relevant interaction between lacosamide and metformin.
Co-administration of warfarin with lacosamide does not result in a clinically relevant change in the pharmacokinetics and pharmacodynamics of warfarin.
Protein binding: Lacosamide has a low protein binding of less than 15%. Therefore, clinically relevant interactions with other drugs through competition for protein binding sites are considered unlikely.

Store at temperatures not exceeding 30°C.

Anticonvulsants

N03AX18 - lacosamide ; Belongs to the class of other antiepileptics.

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