Krampalika film-coated tablets 250 mg No. 30

Instructions for Krampalika film-coated tablets 250 mg No. 30

Composition

active ingredient levetiracetam;

1 film-coated tablet contains 250 mg or 500 mg of levetiracetam; excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, crospovidone (type A), hydroxypropylcellulose

film coating

tablets 250 mg Opadry 02H20569 (blue) hypromellose, titanium dioxide (E 171), talc, propylene glycol, FD&C blue #2 aluminum dye (E 132), FD&C yellow #6 aluminum dye (E 110), quinoline yellow dye (E 104);

tablets 500 mg Opadry 20J22730 (yellow) hypromellose, titanium dioxide (E 171), hydroxypropylcellulose, propylene glycol, sorbitan oleate, sorbic acid, vanillin, quinoline yellow dye (E 104)

Dosage form

Film-coated tablets

Main physicochemical properties

250 mg tablets Blue, oblong, biconvex tablets without defects Dimensions 13.8 mm±0.1 mm by 6.7 mm±0.1 mm, thickness 4.0 mm±0.2 mm;

500 mg tablets Yellow, oblong, biconvex tablets without defects

Dimensions 19.4 mm±0.1 mm by 7.8 mm±0.1 mm, thickness 5.1 mm±0.2 mm

Pharmacotherapeutic group

Antiepileptic drugs Levetiracetam

ATX code N03A X14

Pharmacological properties

Pharmacodynamics

The active substance levetiracetam is a pyrrolidone derivative (S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide), which differs in chemical structure from known antiepileptic drugs.

The mechanism of action of levetiracetam is not well understood. Based on in vitro and in vivo studies, it is assumed that levetiracetam does not change the basic characteristics of the nerve cell and normal neurotransmission. In vitro studies have shown that levetiracetam affects intracellular Ca2+ levels by partially inhibiting the current through N-type Ca2+ channels and reducing the release of Ca2+ from intracellular depots. It also partially eliminates the inhibition of GABA- and glycine-regulated currents caused by the action of zinc and β-carbolines. In addition, in vitro studies, levetiracetam bound to specific sites in rodent brain tissues. The binding site is synaptic vesicle protein 2A, which is involved in vesicle fusion and neurotransmitter release. The affinity (in rank order) of levetiracetam and corresponding analogues for synaptic vesicle protein 2A correlated with the potency of their anticonvulsant action in in mouse models of audiogenic epilepsy. These results suggest that the interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the mechanism of the drug's antiepileptic action.

Levetiracetam provides protection against seizures in a wide range of partial and primary generalized seizure models in animals without causing proconvulsant effects. The main metabolite is inactive.

In humans, the drug has been shown to be active against both focal and generalized epileptic seizures (epileptiform manifestations/photoparoxysmal response), indicating a broad spectrum of the pharmacological profile of levetiracetam.

Pharmacokinetics

Levetiracetam is characterized by high solubility and permeability. Pharmacokinetics are linear and characterized by low inter- and intrasubject variability. Clearance does not change after repeated administration of the drug. There was no evidence of the influence of gender, race, or circadian rhythm on pharmacokinetics. The pharmacokinetic profile was similar in healthy volunteers and patients with epilepsy.

Due to complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed in mg/kg body weight. Therefore, there is no need to monitor plasma levetiracetam levels.

In adults and children, a significant correlation was observed between the drug concentration in saliva and blood plasma (the ratio of saliva/plasma concentrations ranged from 1 to 1.7 after taking the oral tablets and 4 hours after taking the oral solution).

Adults and adolescents

Absorption

Levetiracetam is rapidly absorbed after oral administration Absolute oral bioavailability is approximately 100% Peak plasma concentration (Cmax) is reached 1.3 hours after dosing Steady state is reached after 2 days of twice daily dosing Peak concentrations (Cmax) are typically 31 and 43 μg/mL after a single 1000 mg dose and a repeated 1000 mg dose twice daily, respectively The extent of absorption is independent of dose and is not affected by food intake Distribution

There are no data on the distribution of the drug in human tissues. Neither levetiracetam nor its main metabolite binds significantly to plasma proteins (

Metabolism

Two minor metabolites were also identified. One was formed by hydroxylation of the pyrrolidone ring (1.6% of the dose), the other by opening of the pyrrolidone ring (0.9% of the dose). Other unidentified components accounted for only 0.6% of the dose. No interconversion of levetiracetam enantiomers or its major metabolite was observed in vivo.

In vitro studies showed that levetiracetam and its major metabolite did not inhibit the activity of the major human hepatic cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferases (UGT1A1 and UGT1A6) and epoxide hydroxylase. Levetiracetam also did not inhibit the glucuronidation of valproic acid in vitro. In cultured human hepatocytes, levetiracetam had little or no effect on conjugation of CYP1A1/2, SULT1E1 or UGT1A1. Levetiracetam induced a weak induction of CYP2B6 and CYP3A4. In vitro and in vivo data on interactions with oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected under in vivo conditions. Therefore, the interaction of the drug Krampalic with other substances or vice versa is unlikely

Breeding

The plasma elimination half-life in adults was 7±1 hours and was independent of dose, route of administration, or repeated administration. The mean total clearance was 0.96 mL/min/kg. The major portion of the drug, on average 95% of the dose, was excreted by the kidneys (approximately 93% of the dose was excreted within 48 hours). Only 0.3% of the dose was excreted in the feces.

Cumulative urinary excretion of levetiracetam and its major metabolite was 66% and 24% of the dose, respectively, in the first 48 hours. Renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 mL/min/kg, respectively, indicating that levetiracetam is eliminated by glomerular filtration with subsequent tubular reabsorption and that the major metabolite is also eliminated by active tubular secretion in addition to glomerular filtration. Levetiracetam excretion correlates with creatinine clearance. Elderly patients

In elderly patients, the half-life increases by approximately 40% (10-11 hours). This is due to the deterioration of renal function in this population (see section "Method of administration and dosage").

Kidney dysfunction

The apparent total clearance of levetiracetam and its main metabolite correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, it is recommended to adjust the maintenance daily dose of the drug according to creatinine clearance (see section 4.2).

In anuric patients with end-stage renal disease, the elimination half-life was approximately 25 and 3.1 hours, respectively, between and during dialysis. During a typical 4-hour dialysis session, 51% of levetiracetam was excreted.

Liver dysfunction

Levetiracetam clearance was not altered in patients with mild to moderate hepatic impairment. In most patients with severe hepatic impairment, levetiracetam clearance was reduced by more than 50% due to concomitant renal impairment (see section 4.2).

Pediatric population

Children aged 4−12 years

After a single dose (20 mg/kg) in children with epilepsy (6 to 12 years), the elimination half-life of levetiracetam was 6 hours. The apparent clearance, adjusted for body weight, was approximately 30% higher than in adult patients with epilepsy. After repeated oral administration (20-60 mg/kg/day) in children with epilepsy (4-12 years), levetiracetam was rapidly absorbed. Peak plasma concentrations were reached 0.5-1 hour after dosing. Peak concentrations and area under the concentration-time curve increased linearly and were dose-dependent. The elimination half-life was approximately 5 hours; apparent total clearance was 1.1 mL/min/kg.

Indication

Monotherapy (first-line drug) in the treatment

- partial seizures with or without secondary generalization in adults and adolescents aged 16 years and older with newly diagnosed epilepsy

As an adjunctive therapy in treatment

- partial seizures with or without secondary generalization in adults, adolescents and children aged 6 years and over with epilepsy;

- myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy;

- primary generalized convulsive (tonic-clonic) seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy

Contraindication

Hypersensitivity to levetiracetam or other pyrrolidone derivatives, as well as to any of the excipients of the drug.

Interaction with other medicinal products and other types of interactions

Antiepileptic drugs

There are no data on clinically significant drug interactions in pediatric patients, as well as in adults receiving up to 60 mg/kg/day of levetiracetam. A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (aged 4 to 17 years) confirmed that adjunctive therapy with oral levetiracetam did not affect the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggest that levetiracetam clearance is 20% higher in children taking enzyme-inducing antiepileptic drugs. No dose adjustment is required.

Probenecid

Probenecid (500 mg 4 times a day) – a drug that blocks renal tubular secretion, inhibits renal clearance of the main metabolite, but not levetiracetam itself. However, concentrations of this metabolite remain low.

Methotrexate

Concomitant use of levetiracetam and methotrexate has been reported to reduce the clearance of methotrexate, leading to increased/prolonged blood concentrations of methotrexate to potentially toxic levels. Methotrexate and levetiracetam blood levels should be closely monitored in patients receiving both drugs concurrently. Oral contraceptives and pharmacokinetic interactions with other drugs Levetiracetam at a daily dose of 1000 mg did not alter the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone levels) were not altered. Levetiracetam at a daily dose of 2000 mg did not alter the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Digoxin, oral contraceptives and warfarin did not affect the pharmacokinetics of levetiracetam when administered concomitantly.

Laxatives

In isolated cases, reduced efficacy of levetiracetam has been reported when the osmotic laxative macrogol was used concomitantly with oral levetiracetam. Therefore, oral macrogol should not be taken within 1 hour before and 1 hour after taking levetiracetam.

Food and alcohol

The extent of absorption of levetiracetam is independent of food intake, but the rate of absorption is slightly reduced when taken with food. There are no data on the interaction of levetiracetam with alcohol.

Application features

Kidney failure

Patients with renal impairment may require dose adjustment of levetiracetam. In patients with severe hepatic impairment, it is recommended that renal function be assessed before dose adjustment (see section 4.2).

Acute kidney injury

The use of levetiracetam has been very rarely associated with acute kidney injury, the time to onset of which ranged from a few days to a few months. Complete blood count

Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leukopenia, thrombocytopenia and pancytopenia) have been reported in association with levetiracetam, usually at the start of treatment. A complete blood count is recommended in patients who present with significant weakness, fever, recurrent infections or coagulation disorders (see section 4.8).

Suicide

Cases of suicide, suicide attempts, suicidal thoughts and behaviour have been reported in patients treated with antiepileptic drugs (including levetiracetam). A meta-analysis of randomised placebo-controlled trials of antiepileptic drugs has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Because of this risk, patients should be monitored for signs of depression and/or suicidal thoughts and behaviour and treatment should be adjusted as necessary. Patients (and their carers) should be advised to report any symptoms of depression and/or suicidal thoughts or behaviour to their doctor.

Unusual or aggressive behavior

Levetiracetam may cause psychotic symptoms and behavioral disturbances, including irritability and aggression. Patients taking levetiracetam should be monitored for the development of psychiatric symptoms indicative of significant changes in mood and/or personality. If such behaviour occurs, it is recommended to adapt the treatment or gradually discontinue it. If treatment discontinuation is necessary, see information in section “Method and dosage”

Increased seizures

As with any antiepileptic drug, levetiracetam may lead to an increase in the frequency and severity of seizures. This paradoxical effect was mostly reported within the first month after starting levetiracetam or increasing the dose, and was reversible upon discontinuation of the drug or reducing the dose. Patients should be advised to contact their doctor immediately if seizures increase.

QT prolongation on ECG

Rare cases of QT prolongation on ECG have been reported during post-marketing surveillance. Levetiracetam should be used with caution in patients with QTc prolongation, in patients receiving concomitant medications that affect the QTc interval, or in patients with pre-existing cardiac disease or electrolyte disturbances.

The medicine in the form of film-coated tablets is not suitable for use in infants and children under 6 years of age.

Available data in children do not indicate any effects on development and puberty. However, the long-term effects on learning ability, intelligence, development, endocrine function, puberty and reproductive function in children remain unknown.

Use during pregnancy or breastfeeding

Women of reproductive age

Special advice should be given to women of childbearing potential Levetiracetam treatment should be reconsidered if a woman is planning pregnancy As with all antiepileptic drugs, abrupt withdrawal of levetiracetam should be avoided as it may lead to seizures, which could have serious consequences for the woman and the unborn child Monotherapy should be preferred whenever possible, as treatment with multiple antiepileptic drugs may be associated with a higher risk of birth defects than monotherapy, depending on the drug combination Pregnancy

A large amount of post-marketing data from pregnant women exposed to levetiracetam (more than 1800 women, including 1500 women exposed during the first trimester) do not indicate an increased risk of major birth defects. There are only limited data on the development of the nervous system in children exposed to levetiracetam monotherapy in utero. However, available epidemiological studies (approximately 100 children) do not indicate an increased risk of disorders or delays in the development of the nervous system. Levetiracetam can be used during pregnancy if, after careful assessment, it is considered clinically necessary. In such cases, the lowest effective dose is recommended.

Physiological changes during pregnancy may alter levetiracetam concentrations. Decreases in plasma levetiracetam concentrations have been observed during pregnancy. This decrease is most pronounced in the third trimester (up to 60% of the initial concentration before pregnancy). Appropriate clinical supervision should be provided for pregnant women receiving levetiracetam.

Breast-feeding

Levetiracetam passes into breast milk. Breastfeeding is therefore not recommended. However, if levetiracetam must be used during breast-feeding, the benefits and risks of treatment should be weighed against the importance of breast-feeding. Effects on reproductive function

No effects on reproductive function were observed in animal studies. The potential risk for humans is unknown as no clinical data are available.

Ability to influence reaction speed when driving vehicles or other mechanisms

Levetiracetam has minor or moderate influence on the ability to drive and use machines. Due to possible individual sensitivity, some patients may experience drowsiness or other symptoms related to the effects on the central nervous system, especially at the beginning of treatment or during dose increases. Therefore, such patients should be careful when engaging in activities that require increased concentration, such as driving or operating other machines. Patients are advised to refrain from driving or operating other machines until it is established that their ability to perform such activities is not impaired.

Method of administration and doses

Tablets should be taken orally with sufficient liquid, with or without food. When taken orally, levetiracetam may have a bitter taste. The daily dose should be divided into 2 equal doses.

Monotherapy

Adults and adolescents aged 16 and over

Monotherapy in adults and children aged 16 years and older should be initiated at the recommended dose of 500 mg/day (250 mg twice daily) with subsequent increase of the initial therapeutic dose to 1000 mg/day (500 mg twice daily) after 2 weeks. The dose may be increased by 500 mg/day (250 mg twice daily) every 2 weeks, depending on the clinical effect. The maximum daily dose is 3000 mg/day (1500 mg twice daily).

Children and adolescents under 16 years of age

The safety and efficacy of Krampalic in children and adolescents under 16 years of age as monotherapy have not been established. Data are not available.

Additional therapy

Add-on therapy for adults (≥ 18 years) and adolescents (12 to 17 years) weighing 50 kg or more

The initial therapeutic dose is 1000 mg/day (500 mg 2 times a day) This is the initial dose, which is prescribed on the first day of treatment. Depending on the clinical picture and tolerability of the drug, the daily dose can be increased to a maximum of 3000 mg/day (1500 mg 2 times a day). The dose can be changed to 1000 mg/day (500 mg 2 times a day) every 2-4 weeks.

Add-on therapy for children aged 6 years and older and adolescents (aged 12 to 17 years) weighing less than 50 kg

For infants and children under 6 years of age, it is preferable to use the drug in the form of an oral solution.

The lowest effective dose should be used. The starting dose for a child or adolescent weighing 25 kg should be 250 mg twice daily, the maximum dose is 750 mg twice daily.

Children weighing more than 50 kg should be dosed according to the scheme given for adults. Adjunctive therapy for infants aged 1 to 6 months

Infants should be given the drug in the form of an oral solution. Discontinuation of treatment

If it is necessary to stop taking the drug, it is recommended to do so gradually (for example, for adults and adolescents with a body weight of 50 kg or more, reduce the dose by 500 mg 2 times a day every 2-4 weeks; for children and adolescents with a body weight of up to 50 kg, reduce the single dose by no more than 10 mg/kg 2 times a day every 2 weeks)

Special patient groups

Elderly patients (65 years and older)

Dose adjustment is recommended for elderly patients with impaired renal function (see below "Renal failure")

Kidney failure

The daily dose should be individually adjusted according to the state of renal function.

For adult dose adjustments, use the table below:

To adjust the dose according to the table, it is necessary to determine the level of creatinine clearance (CC) in ml/min.

The creatinine clearance for adults and adolescents weighing more than 50 kg can be calculated from the serum creatinine concentration (mg/dL) using the formula

[140 - age (years)] × body weight (kg)

CC (ml/min) = --------------------------------------------------------------× 0.85 (for women)

72 × serum creatinine (mg/dL)

Then adjust the CK according to body surface area (BSA) as shown below

CC (ml/min)

CC (ml/min/1.73m2) = --------------------------- × 1.73

Patient's PPT (m2)

Dosage regimen for adults and adolescents with renal insufficiency

with a body weight of more than 50 kg

Table 1

(1) A loading dose of 750 mg is recommended on the first day of levetiracetam treatment (2) An additional dose of 250-500 mg is recommended after dialysis

For children with renal impairment, the dose of levetiracetam should be adjusted according to renal function, as the clearance of levetiracetam is related to renal function. This recommendation is based on a study in adult patients with renal impairment.

For adolescents, children and infants, the creatinine clearance in ml/min/1.73 m2 can be calculated from the serum creatinine concentration (mg/dl) using the following formula (Schwarz formula):

Height (cm) × ks

CC (ml/min/1.73 m2) = ---------------------------------

Serum creatinine (mg/dL)

In children under 13 years of age and adolescent girls ks = 0.55; in adolescent boys ks = 0.7

Dose adjustment recommendations for children and adolescents with impaired renal function

kidneys with a body weight of less than 50 kg

Table 2

(1) For doses up to 250 mg, for doses not multiples of 250 mg when the recommended dosage cannot be achieved by taking multiple tablets, and for patients who cannot swallow tablets, levetiracetam oral solution should be used.

(2) On the first day of treatment, a loading dose of levetiracetam of 15 mg/kg (0.15 ml/kg) is recommended.

(3) After dialysis, an additional dose of 5-10 mg/kg (0.05-0.10 ml/kg) is recommended.

Liver failure

No dose adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, creatinine clearance may not fully reflect the degree of renal impairment. Therefore, for patients with creatinine clearance <2, a 50% reduction in the daily maintenance dose is recommended. Children

The physician should prescribe the most appropriate dosage form, dosage and release form depending on age, body weight and calculated dose.

The tablet formulation is not recommended for use in children under 6 years of age. Levetiracetam oral solution is preferable for this patient group. In addition, the available tablet dosages are not suitable for initial treatment of children weighing less than 25 kg, for patients who cannot swallow tablets, or for doses up to 250 mg. In all of the above cases, treatment should be initiated with levetiracetam oral solution.

Children

The medicine in tablet form is not recommended for use in children under 6 years of age.

Overdose

Symptoms

In case of overdose with the drug Krampalika, drowsiness, agitation, aggression, respiratory depression, depression of consciousness, coma were observed.

Treatment

In case of acute overdose, gastric lavage or induce vomiting is necessary. There is no specific antidote for levetiracetam. If necessary, symptomatic treatment should be carried out, including hemodialysis (up to 60% of levetiracetam and 74% of the main metabolite are removed).

Adverse reactions

The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The adverse event profile presented is based on a pooled analysis of placebo-controlled clinical trials across all indications, involving a total of 3416 patients treated with levetiracetam. These data are supplemented by the use of levetiracetam in relevant open-label extension studies and post-marketing experience. The safety profile of levetiracetam is generally similar across age groups (adults and children) in the various established indications.

Adverse reactions reported in clinical trials (in adults, adolescents, children and infants from 1 month of age) and during the post-marketing period are listed in Table 3 by system organ class and frequency. Adverse reactions are presented in order of decreasing incidence, and their frequency is defined as very common (≥1/10); common (≥1/100 to <1/100);

Table 3

* Prevalence is significantly higher in Japanese compared to non-Japanese patients

Description of selected adverse reactions

The risk of anorexia increases with concomitant use of levetiracetam with topiramate. In cases of alopecia, hair regrowth has been observed in some cases after discontinuation of levetiracetam.

In cases of pancytopenia, bone marrow suppression has been observed in some cases. Encephalopathy cases have usually occurred early in treatment (from a few days to a few months) and were reversible after discontinuation of treatment.

Among patients aged 1 month to 4 years, a total of 190 patients were treated with levetiracetam in placebo-controlled and open-label extension studies. 60 of these patients were treated with levetiracetam in placebo-controlled studies. Among patients aged 4 to 16 years, a total of 645 patients were treated with levetiracetam in placebo-controlled and open-label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both age groups, these data are supplemented by data on the use of levetiracetam in the post-marketing period.

In addition, 101 infants under 12 months of age were treated in a post-marketing safety study. No new safety data were obtained for levetiracetam in infants with epilepsy under 12 months of age. The adverse reaction profile of levetiracetam is generally similar across age groups and across all approved epilepsy indications. The safety profile of levetiracetam in children from placebo-controlled clinical trials was consistent with the safety profile of levetiracetam in adults, except for behavioural and psychiatric adverse reactions, which were more frequent in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%) and lethargy (common, 3.9%) were observed at a higher frequency than in other age groups or in the overall safety profile In infants and children aged 1 month to 4 years, irritability (very common, 11.7%) and incoordination (common, 3.3%) were observed at a higher frequency than in other age groups or in the overall safety profile In a double-blind, placebo-controlled, non-inferiority safety study in children, levetiracetam was evaluated on cognitive and neuropsychological measures in children aged 4 to 16 years with partial onset seizures. Levetiracetam was non-inferior to placebo in terms of change from baseline in attention and memory on the Leiter-R scale, a population-based summary measure of memory testing, as per protocol. Results related to behavioral and emotional functions, indicated an increase in aggressive behavior in levetiracetam-treated patients, as measured in a standardized and systematic manner using validated instruments (Achenbach Child Behavior Checklist). However, in patients treated with levetiracetam in a long-term open-label follow-up study, there was no average deterioration in behavioral and emotional functions, in particular, aggressive behavior scores were not worse than baseline.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after the registration of a medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Expiration date

3 years

Storage conditions

This medicinal product does not require any special temperature storage conditions. Keep out of the reach of children.

Packaging

10 tablets in a blister; 3 blisters in a cardboard box

Vacation category

By prescription

Producer

PHARMATEN SA

Location of the manufacturer and address of its place of business

Dervenakion 6, Pallini Attica, 15351, Greece.