Millitam

Millitam

levetiracetam

Manufacturer:

Millimed

Distributor:

Prosp Pharma
Full Prescribing Info
Contents
Levetiracetam.
Description
Each MILLITAM 250 and MILLITAM 500 film coated tablet contains Levetiracetam 250 mg and Levetiracetam 500 mg, respectively.
Action
Pharmacology: Pharmacodynamics: Levetiracetam, a pyrrolidine derivative, is an anticonvulsant agent that is structurally unrelated to other currently available anticonvulsants. The mechanism of anticonvulsant action of levetiracetam is unknown. Levetiracetam does not exhibit binding affinity for benzodiazepine, γ-aminobutyric acid (GABA), glycine, or N-methyl-D-aspartate (NMDA) receptors, reuptake sites, or second messenger systems. Levetiracetam does not appear to directly facilitate GABA-mediated neurotransmission or have an effect on neuronal voltage-gated sodium or T-type calcium currents. However, the drug has been shown to oppose the activity of negative modulators of GABA- and glycine-gated currents in neuronal cell cultures.
Pharmacokinetics: Absorption: Absorption of levetiracetam is rapid and almost complete, with plasma concentrations occurring in approximately 1 hour following oral administration in fasted subjects. The oral bioavailability of levetiracetam tablets is 100%. The pharmacokinetics of levetiracetam are linear over the dose range 500 to 5,000 mg. Steady state is achieved after 2 days of multiple, twice-daily dosing. Food does not affect the extent of absorption of levetiracetam, but it decreases Cmax by 20% and delays Tmax by 1.5 hours.
Distribution: Levetiracetam and its metabolite are less than 10% bound to plasma proteins. Its volume of distribution is close to the 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, which produces the carboxylic acid metabolites (24% of the dose) and is not dependent on any liver cytochrome P450 (CYP-450) isoenzymes.
Excretion: Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by dose or repeated administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as unchanged drug, which represents 66% of the administered dose. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. Levetiracetam clearance is reduced in patients with renal impairment.
Indications/Uses
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 in adults and children 4 years of age and older with epilepsy; myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.
Dosage/Direction for Use
Recommended dose: Monotherapy: The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two 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.
Adjunctive therapy: Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more: The initial therapeutic dose is 1,000 mg/day. The dose can be started on the first day of treatment. Depending upon the clinical response and tolerance, the day can be increased up to 3,000 mg/day. Dose changes can be made in 1,000 mg/day increments or decrements every two to four weeks.
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 tolerance, the day 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 to four weeks. The lowest effective dose should be used. (See Table 1.)

Click on icon to see table/diagram/image

Elderly: Dosage should be selected carefully in geriatric patient 65 years of age and older because of the limit experience and greater frequency of decrease renal function observed in this age group. Adjustment of the dose is recommended dependent on renal function.
Patient with renal impairment: 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 weighting 50 kg or more, the following formula: See Equation 1.

Click on icon to see table/diagram/image

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

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This 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, for young adolescents, children and infants, using the following formula (Schwartz formula): See Equation 3.

Click on icon to see table/diagram/image

Patient with hepatic impairment: No dosage adjustment is necessary in patient with hepatic impairment. Levetiracetam pharmacokinetics were unchanged in patient with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. Total body clearance was reduced by 50% in patient with severe hepatic impairment (Child-Pugh Class C), creatinine clearance may be underestimated of renal impairment than the true value. If creatinine clearance less than 60 ml/min/1.73 m2 should reduce 50% of maintenance dose per day, principally because of decreased renal clearance.
Mode of Administration: Levetiracetam is given orally, with or without food.
Overdosage
Symptoms: Drowsiness, aggression, agitation, coma, depressed level of consciousness, respiratory depression and somnolence.
Treatment: There is no specific antidote for overdose with levetiracetam. If indicated, attempt elimination of unabsorbed drug by gastric lavage; observe the usual precautions to maintain the airway. In cases of overdose, consider standard hemodialysis procedures, which result in significant clearance of levetiracetam (approximately 50% in 4 hours).
Contraindications
Contraindicated in patient with known hypersensitivity to levetiracetam or pyrrolidone derivatives and any component of the formulation.
Warnings
This medicine may cause drowsiness, should not drive or operate heavy machinery and should not use this medicine with alcohol or alcoholic ingredients.
This medicine may cause hematologic disorders.
Contraindication in pregnancy may have fetal abnormalities.
Use with caution in patient with hepatic impairment and renal impairment.
Special Precautions
Antiepileptics are associated with an increased risk of suicidal behavior/thoughts with use. Patients should be monitored for signs/symptoms of depression, suicidal tendencies and other unusual behavior changes during therapy and instructed to inform their healthcare provider immediately if symptoms occur.
Severe dermatologic reactions (toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported. Onset usually within approximately 2 weeks of treatment initiation but may be delayed (>4 months), discontinue for any signs of a hypersensitivity reaction or unspecific rash.
Psychotic symptoms (psychosis, hallucinations) and behavioral symptoms (including aggression, anger, anxiety, depersonalization, depression, personality disorder) may occur. The incidence may be increased in children. Dose reduction or discontinuation may be required.
Levetiracetam should be withdrawn gradually, when possible, to minimize the potential of increased seizure frequency.
Effects on ability to drive and use machines: Levetiracetam has influence on the ability to drive and use machines. It may cause dizziness and somnolence. Patients are advised not to drive or use machines until they have again sufficient experience to perform such activities.
Use In Pregnancy & Lactation
Pregnancy: The data from several prospective pregnancy registries have documented outcomes in over 1,000 women exposed to levetiracetam monotherapy during the first trimester of pregnancy. These data do not suggest a substantial increase in the risk for major congenital malformations. Therapy with multiple antiepileptic medicinal products is associated with a higher risk of congenital malformations than monotherapy and, therefore, monotherapy should be considered. Studies in animals have shown reproductive toxicity.
Contraindication in pregnancy may have fetal abnormalities.
Lactation: Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.
Adverse Reactions
Infections and infestations: Very common: Nasopharyngitis. Rare: Infection.
Blood and lymphatic system disorders: Uncommon: thrombocytopenia, leukopenia. Rare: pancytopenia, neutropenia, agranulocytosis.
Immune system disorders: Rare: Drug reaction with eosinophilia and systemic symptoms (DRESS).
Metabolism and nutrition disorders: Common: Anorexia. Uncommon: weight decreased, weight increase. Rare: hyponatremia.
Psychiatric disorders: Common: depression, hostility/aggression, anxiety, insomnia, nervousness/irritability. Uncommon: suicide attempt, suicidal ideation, confusional state. Rare: completed suicide.
Nervous system disorders: Very common: somnolence, headache. Common: convulsion, dizziness, lethargy, tremor. Uncommon: amnesia, ataxia, paresthesia, disturbance in attention. Rare: choreoathetosis, dyskinesia, hyperkinesia.
Eye disorders: Uncommon: diplopia, vision blurred.
Ear and labyrinth disorders: Common: vertigo.
Respiratory, thoracic and mediastinal disorders: Common: cough.
Gastrointestinal disorders: Common: abdominal pain, diarrhea, dyspepsia, vomiting, nausea. Rare: pancreatitis.
Hepatobiliary disorders: Uncommon: liver function test abnormal. Rare: hepatic failure, hepatitis.
Skin and subcutaneous tissue disorders: Common: Rash. Uncommon: alopecia, eczema, pruritus. Rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.
Musculoskeletal and connective tissue disorders: Uncommon: muscular weakness, myalgia.
General disorders and administration site conditions: Uncommon: asthenia/fatigue.
Injury, poisoning and procedural complications: Uncommon: injury.
The risk of anorexia is higher when levetiracetam is coadministered with topiramate. In several cases of alopecia, recovery was observed when levetiracetam was discontinued. Bone marrow suppression was identified in some of the cases of pancytopenia.
Drug Interactions
Anticonvulsants: Clinically important pharmacokinetic interaction unlikely with anticonvulsants (e.g. carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid). In pediatric patients, approximately 22% increase in levetiracetam clearance observed when concurrently administered with hepatic enzyme-inducing anticonvulsants, dosage adjustment is recommended. Levetiracetam did not alter plasma concentrations of carbamazepine, lamotrigine, topiramate or valproic acid in patients with epilepsy.
Probenecid: Probenecid administered at a dosage of 500 mg 4 times daily did not change the pharmacokinetics of levetiracetam 1,000 mg twice daily. However, the Cmax at steady-state of metabolite was approximately doubled in the presence of probenecid, while the fraction of drug excreted unchanged in the urine remain the same. Renal clearance of metabolite in the presence of probenecid decrease by 60%, probably related to competitive inhibition of tubular secretion of metabolite.
Methotrexate: Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with two drugs.
Oral contraceptives and other pharmacokinetics interactions: Levetiracetam did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. There did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.
Storage
Store below 30°C.
MIMS Class
ATC Classification
N03AX14 - levetiracetam ; Belongs to the class of other antiepileptics.
Presentation/Packing
FC tab 250 mg (blue, oval, biconvex, with engraved "250" on one side and plain on the other) x 3 x 10's. 500 mg (yellow, oval, biconvex, with engraved "500" on one side and plain on the other) x 6 x 10's.
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