Focale

Film-coated tablet: Focale 250: White to off white, oval, biconvex, film coated tablet, debossed "L 64" and break line on one side and plain on other side.
Focale 500: Yellow colored, oval, biconvex, film coated tablet, debossed "L 65" and break line on one side and plain on other side.
Injection: A sterile aqueous solution which is clear colorless solution presented in 5 mL USP type I clear glass vials.
Levetiracetam injection 500 mg/5 mL (100 mg/mL) concentrate to be diluted for intravenous infusion.

Pharmacology: Pharmacodynamics: The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures.
In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.
Pharmacokinetics: Absorption: Film-coated tablet: Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100%. Peak plasma concentrations (C_max) are achieved at 1.3 hours after dosing. Steady-state is achieved after two days of a twice daily administration schedule. Peak concentration (C_max) are typically 31 and 43 μg/mL following a single 1,000 mg dose and repeated 1,000 mg twice daily dose, respectively.
The extent of absorption is dose-independent and is not altered by food.
Injection: N/A (Intravenous injection).
Distribution: Levetiracetam and its major metabolite are less than 10% bound to plasma proteins. The volume of distribution of levetiracetam is 0.7 L/kg, close to volume of intracellular and extracellular water.
Metabolism: Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group. Cytochrome P450 isoenzyme system is not involved in the metabolism of levetiracetam. Levetiracetam and its major metabolite are neither inhibitors of or substrates for cytochrome P450 isoforms, epoxide hydrolase, or UDP-glucuronidation enzymes.
Excretion: Levetiracetam plasma half-life in adults is 7±1 hour and is unaffected by dose, route of administration, or repeated administration. Levetiracetam is eliminated from the systemic circulation as unchanged drug by renal excretion (66% of the dose). The total body clearance is 0.96 mL/min/kg, and the renal clearance 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion, with a renal clearance of 4 mL/min/kg. Levetiracetam clearance and elimination is correlated to CrCl.
Pharmacokinetics in special population: Geriatric patients 65 years of age and older: The greater frequency of decreased renal function observed in this age group, total body clearance was reduced by 38% and half-life was increased by 2.5 hours in geriatric patients with creatine clearances of 30-74 mL/minute.
Patients with hepatic impairment: Levetiracetam pharmacokinetics were unchanged in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. Total body clearance was reduced by 50% in patients with severe hepatic impairment (Child-Pugh Class C), principally because of decreased renal clearance.
Patients with renal impairment: Clearance is decreased and half-life is increased.

Levetiracetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy.
Levetiracetam is indicated as adjunctive therapy in the treatment of: Partial onset seizures with or without secondary generalization in adults, adolescents and children from 4 years of age with epilepsy.
Myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy.
Primary generalized tonic-clonic seizures in adults, adolescents and children from 6 years of age with idiopathic generalized epilepsy.

Mode of Administration: Film-coated tablet: For oral use (immediate release tablet): The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with food or without food. The daily dose is administered in two equally divided dose.
Injection: For IV use only as a 15-minute IV infusion.
Admixture compatibility: Levetiracetam is physically compatible and chemically stable when mixed with the following diluent: Sodium Chloride 0.9% injection, Dextrose 5% injection, and Ringer's lactate injection. Levetiracetam is compatible with the following AEDs: lorazepam, diazepam, and valproate sodium.
Levetiracetam injection was diluted to a target concentration of approximately 5 mg/mL by injection approximately 5.0 mL of the injection into the infusion bags of 0.9% Sodium Chloride Injection, Lactated Ringer's Injection and 5% Dextrose Injection individually. The procedure resulted in 100 mL of diluted injection.
A smaller volume of diluent may be used (e.g., in pediatric patients or patients who may be susceptible to fluid volume overload), but the final concentration of the diluted solution should not exceed 15 mg/mL. The product should be used immediately after dilution. If not used immediately, in-use storage time and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 30°C, unless dilution has taken place in controlled and validated aseptic conditions.
Levetiracetam injection and diluted solution of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Levetiracetam injection is for intravenous use only.
Recommended Dose: Adults: Monotherapy: Adults and adolescents from 16 years of age: The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after 2 weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1,500 mg twice daily.
Add-on therapy: Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more: The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment. Depending upon the clinical response and tolerance, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increased or decreases every two to four weeks.
Children: The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.
Monotherapy: The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established.
Add-on therapy for children (4 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg: The initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increments or decrements of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.
Dose in children 50 kg or greater is the same as in adults. (See Table 1.)

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Switching From or To Oral Levetiracetam: When switching from oral to IV levetiracetam therapy, the initial total daily dosage of IV levetiracetam should be equivalent to the daily dose and frequency of oral levetiracetam.
At the completion of the IV treatment period, the patient may be switched back to oral levetiracetam at the equivalent daily dose and frequency that was administered IV.
Dosage adjustments in Special populations: Geriatic use: Film-coated tablet: Controlled Clinical Studies evaluating levetiracetam have not included sufficient number patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. No substantial differences in safety have been observed in geriatric patients relative to younger adults.
Renal function impairment: The daily dose must be individualized according to renal function.
For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is needed.
The CLcr in mL/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighing 50 kg or more, using the following formula: See Equation 1.

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Then CLcr is adjusted for body surface area (BSA) as follows: See Equation 2.

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Dosing adjustment for adult and adolescent patients weighing more than 50 kg with impaired renal function. (See Table 2.)

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The recommendation is based on a study in adult renally impaired patients.
The CLcr in mL/min/1.73 m² may be estimated from serum creatinine (mg/dl) determination using, for young adolescents and children using the following formula (Schwartz formula): See Equation 3.

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Dosing adjustment for children and adolescent patients weighing less than 50 kg with impaired renal function. (See Table 3.)

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Hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is <60 mL/min/1.73m²

Overdose: Experience with levetiracetam is very limited. The highest known ingested dose was 6000 mg, and drowsiness was the only symptom reported in the few known cases of overdose.
Treatment of overdose: Note: There is no specific antidote for levetiracetam overdose.
To enhance elimination: Standard hemodialysis should be considered, particularly, in selected patients based on clinical state or renal impairment. Approximately 50% is removed in 4 hours.
Monitoring: Monitor vital signs and clinical status.
Supportive care: General supportive care.
Patients in whom intentional overdose remains confirmed or suspected should be referred for psychiatric consultation.

Focale is contraindicated in patients with known hypersensitivity to levetiracetam or other pyrrolidone derivatives or any other excipients.

Thai FDA mandatory warning: This medicine may cause drowsiness therefore should not drive or operate machinery and should not drink alcohol or anything that is mixed with alcohol while using this medicine.
This medicine may cause abnormalities of blood cell.
This medicine is contraindicated in pregnancy because it may cause teratogenic effects on the fetus.
The medicine should be used with caution in liver and renal disease.

Nervous System Effects: Adverse neuropsychiatric effects reported during levetiracetam therapy are classified into 3 categories: somnolence and fatigue, coordination difficulties, and behavioral/psychiatric abnormalities. Patients should be monitored for these adverse effects during therapy. In addition, patients should be advised not to drive or operate machinery until the effects of levetiracetam are known.
In controlled studies in adults, approximately 15% of patients with partial onset seizures who received levetiracetam (as an oral conventional preparation) experienced somnolence compared with 8% of placebo-treated patients, and about 3% of levetiracetam-treated patients discontinued treatment because of somnolence. Pediatric patients and adults with other seizure types who receive levetiracetam appear to experience similar rates of somnolence and fatigue. In controlled study in adults, asthenia was reported in about 15% of patients who received levetiracetam (as conventional preparations) compared with 9% of placebo-treated patients, and 0.8% of levetiracetam-treated patients discontinued treatment because of asthenia. Coordination difficulties (e.g., ataxia, abnormal gait, incoordination) were experienced by 3.4% of levetiracetam patients receiving levetiracetam (as conventional preparations) compared with 1.6% of placebo­-treated patients. Somnolence, asthenia, and coordination difficulties occurred most frequently within the first 4 weeks of treatment. In studies with extended-release levetiracetam, behavioral abnormalities (irritability and aggression) were reported in 7% of patients receiving the drug compared with none of the patients receiving placebo; however, the number of patients exposed to the extended release preparation is considerably less than that of the immediate-release preparation.
Suicidality Risk: The US FDA has alerted healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants, including levetiracetam, compared with placebo. The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%). This increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks. Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidal risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.
Based on the current analysis of the available data, US FDA recommends that clinicians inform patients, their families, and caregivers about the potential for an increase in the risk of suicidality with anticonvulsant therapy and that all patients currently receiving or beginning therapy with any suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. Symptoms such as anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.
Clinicians who prescribe levetiracetam or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.
Dermatologic Reactions: Serious dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in both adults and pediatric patients receiving levetiracetam. The median time of onset is reported to be between 14 and 17 days, although cases have occurred at least 4 months after initiation of therapy.
Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If manifestations suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis occur, levetiracetam therapy should be permanently discontinued and alternative therapy considered.
Discontinuance of Therapy: Because of the possibility of increased seizure frequency, anticonvulsant drugs, including levetiracetam, should not be discontinued suddenly. The manufacturer recommends that oral levetiracetam be withdrawn gradually by reducing the dosage by 1 g daily at 2-week intervals.
Hematologic Effects: Hematologic abnormalities (e.g., decreased red blood cell, white blood cell, and neutrophil counts) were reported in patients receiving levetiracetam in clinical studies. Agranulocytosis, leukopenia, neutropenia, pancytopenia, and thrombocytopenia also have occurred during postmarketing experience.
A complete blood count (CBC) is recommended in patients who experience any signs or symptoms of hematologic abnormalities (e.g., severe weakness, pyrexia, recurrent infections, coagulation disorders) during levetiracetam therapy.
Increased Blood Pressure: In a study of pediatric patients 1 month to younger than 4 years of age, increased diastolic blood pressure was observed in levetiracetam-treated patients (17%) compared with those receiving placebo (2%). However, there was no overall difference in mean diastolic blood pressure between the treatment groups. These findings were not observed in older children or adults receiving the drug.
Pediatric patients younger than 4 years of age should be monitored for increased diastolic blood pressure during levetiracetam therapy.
Sensitivity Reactions: Anaphylaxis and Angioedema: Anaphylaxis and angioedema, in some cases life-threatening and/or requiring emergency treatment, have been reported during postmarketing experience in patients receiving levetiracetam. (See Contraindications.) Manifestations have included hypotension, hives, rash, respiratory distress, facial swelling, and swelling of the tongue, throat, and feet. Such reactions can occur at any time during therapy.
If any signs or symptoms of anaphylaxis or angioedema occur, patients should discontinue levetiracetam immediately and seek medical attention. Levetiracetam therapy should be permanently discontinued if an alternative etiology cannot be identified.
Use in Pregnancy: Category C. The effect of levetiracetam on labor and delivery is unknown.
Seizure Control During Pregnancy: Physiologic changes that occur during pregnancy may gradually decrease plasma levels of levetiracetam in pregnant women. This effect is most notable during the third trimester.
Patients should be closely monitored during pregnancy and throughout the postpartum period, especially if levetiracetam dosage is adjusted during pregnancy.
Use in Lactation: Levetiracetam is distributed into milk. Because of the potential for serious adverse reactions to levetiracetam in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account possible risk to an infant and the importance of the drug to the woman.
Use in Children: Safety and efficacy of levetiracetam immediate-release tablets, and injection for the management of partial onset seizures have not been established in pediatric patients younger than 1 month of age. Behavioral abnormalities (e.g., paranoia, confusional state, increased aggression) have been observed in pediatric patients 4-16 years of age with partial onset seizures receiving the drug.
Safety and efficacy of levetiracetam immediate-release tablets, and injection for the management of myoclonic seizures have not been established in pediatric patients younger than 12 years of age.
Safety and efficacy of levetiracetam immediate-release tablets, and injection for the management of primary generalized tonic-clonic seizures have not been established in pediatric patients younger than 6 years of age.
Safety and efficacy of levetiracetam in sodium chloride injection have not been established in pediatric patients younger than 16 years of age.

Pregnancy: Category C. The effect of levetiracetam on labor and delivery is unknown.
Lactation: Levetiracetam is distributed into milk. Because of the potential for serious adverse reactions to levetiracetam in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account possible risk to an infant and the importance of the drug to the woman.

Adverse effects associated with IV levetiracetam generally appear to be consistent with those associated with oral administration of the drug.
Adverse effects occurring in 1% or more of adults receiving oral levetiracetam (as conventional preparations) for adjunctive management of partial seizures include somnolence, asthenia, headache, infection, dizziness, pain, pharyngitis, depression, nervousness, rhinitis, anorexia, ataxia, vertigo, amnesia, anxiety, emotional lability, hostility, paresthesia, increased cough, sinusitis, and diplopia.
Adverse effects occurring in 2% or more of pediatric patients older than 4 years of age receiving oral levetiracetam (as conventional preparations) for adjunctive management of partial seizures include headache, vomiting, nasopharyngitis, somnolence, fatigue, aggression, upper abdominal pain, cough, nasal congestion, decreased appetite, dizziness, pharyngolaryngeal pain, abdominal behavior, dizziness, irritability, diarrhea, lethargy, insomnia, head injury, anorexia, agitation, constipation, influenza, contusion, fall, depression, altered mood, ear pain, conjunctivitis, gastroenteritis, rhinitis, joint sprain, arthralgia, neck pain, sedation, labile affect, anxiety, confusional state, and mood swing. The most common adverse effects in patients younger than 4 years of age were somnolence and irritability.
The adverse effect profile of levetiracetam (as conventional preparations) in patients with myoclonic seizures or primary generalized tonic-clonic seizures is generally similar to that of patients with partial seizures.
Adverse effects occurring in 5% or more of patients receiving extended-release levetiracetam tablets for adjunctive management of partial seizures include influenza, somnolence, irritability, nasopharyngitis, dizziness, and nausea.

Drug Affecting or Metabolized by Hepatic Microsomal Enzymes: Because levetiracetam is neither a substrate nor inhibitor of cytochrome P-450 (CYP), pharmacokinetic interactions are likely with drugs affecting or metabolized by CYP isoenzymes.
Anticonvulsants: Clinically important pharmacokinetic interactions are unlikely when levetiracetam is administered concomitantly with other anticonvulsants (e.g., carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, valproic acid).
In pediatric patients, an approximately 22% increase in levetiracetam clearance was observed when the drug was administered concurrently with hepatic enzyme-inducing anticonvulsants (e.g., carbamazepine); however, dosage adjustment is not recommended by the manufacturer. Levetiracetam did not alter plasma concentrations of carbamazepine, lamotrigine, topiramate, or valproic acid in pediatric patients with epilepsy.
Digoxin: Levetiracetam does not appear to affect the pharmacokinetics or pharmacodynamics (e.g., cardiac rhythm effects) of digoxin; digoxin also does not affect the pharmacokinetics of levetiracetam.
Oral Contraceptives: Pharmacokinetic interactions are unlikely when levetiracetam is coadministered with oral contraceptives.
Probenecid: When levetiracetam was administered concomitantly with probenecid, no effect on levetiracetam pharmacokinetics was observed, but steady-state plasma concentrations of the principal inactive metabolite were approximately doubled due to a 60% reduction in renal clearance. The manufacturer states, however, that this effect is not clinically important.
Protein-bound Drugs: Pharmacokinetic interactions are unlikely with protein-bound drugs.
Warfarin: Levetiracetam does not appear to affect the pharmacokinetics or pharmacodynamics (e.g., prothrombin time) of warfarin; warfarin also does not affect the pharmacokinetics of levetiracetam.

Store below 30°C.

Anticonvulsants

N03AX14 - levetiracetam ; Belongs to the class of other antiepileptics.

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