Active ingredients: Levetiracetam
Keppra 250 mg film-coated tablets
Keppra 500 mg film-coated tablets
Keppra 750 mg film-coated tablets
Keppra 1000 mg film-coated tablets
Keppra package inserts are available for pack sizes: - Keppra 250 mg film-coated tablets, Keppra 500 mg film-coated tablets, Keppra 750 mg film-coated tablets, Keppra 1000 mg film-coated tablets
- Keppra 100 mg / ml oral solution
- Keppra 100 mg / ml concentrate for solution for infusion
Why is Keppra used? What is it for?
Keppra is an anti-epileptic medicine (a medicine used to treat seizures).
Keppra is used:
- on its own in adults and adolescents from 16 years of age with newly diagnosed epilepsy, to treat partial onset seizures with or without secondary generalization.
- as an addition to other antiepileptic medicines to treat:
- partial onset seizures, with or without generalization, in adults, adolescents, children and infants from 1 month of age
- myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy
- primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
Contraindications When Keppra should not be used
Do not take Keppra
- If you are allergic (hypersensitive) to levetiracetam or any of the other ingredients of this medicine
Precautions for use What you need to know before taking Keppra
Talk to your doctor before taking Keppra
- If you have kidney problems, follow your doctor's instructions. The latter can decide whether the dose needs to be corrected.
- If you notice a slowdown in growth or an unexpected development of puberty in your child, please contact your doctor.
- If you notice an increase in seizure severity (eg increased number), contact your doctor.
- A limited number of people being treated with antiepileptics such as Keppra have had thoughts of harming or thinking about suicide. If you have any symptoms of depression and / or suicidal thoughts, contact your doctor.
Interactions Which drugs or foods may change the effect of Keppra
Other medicines and Keppra
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Keppra with food, drink and alcohol
You can take Keppra with or without food. As a safety precaution do not take Keppra with alcohol.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
If you are pregnant or think you may be pregnant please tell your doctor. Keppra should not be used during pregnancy unless clearly necessary. A risk of birth defects for the fetus cannot be completely ruled out. Keppra has shown undesirable reproductive effects in animal studies with dose levels higher than those needed to control seizures.
Breastfeeding is not recommended during treatment.
Driving and using machines
Keppra may reduce the ability to drive or use tools or machines as Keppra may make you sleepy. This is more likely at the start of treatment or after a dose increase. You should not drive or operate machinery until you have verified that your ability to perform these activities is not affected.
Keppra 750 mg film-coated tablets contain Sunset Yellow FCF (E110)
Sunset Yellow FCF dye (E110) can cause allergic reactions. Other strengths of Keppra tablets do not contain this component.
Dose, Method and Time of Administration How to use Keppra: Posology
Always take this medicine exactly as your doctor or pharmacist has told you.
If in doubt, consult your doctor or pharmacist. Keppra must be taken twice a day, once in the morning and once in the evening, at about the same time each day.
Take the number of tablets according to your doctor's instructions.
Monotherapy
- Dose for adults and adolescents (from 16 years of age):
Typical dose: between 1000 mg and 3000 mg per day.
When you start taking Keppra for the first time, your doctor will prescribe a lower dose for 2 weeks before giving you the typical lower dose.
Example: if your daily dose is 1000 mg, you could take 2 tablets of 250 mg in the morning and 2 tablets of 250 mg in the evening.
Adjunct therapy
- Dose for adults and adolescents (12 to 17 years) weighing 50 kg or more:
Typical dose: between 1000 mg and 3000 mg per day.
Example: if your daily dose is 1000 mg, you could take 2 tablets of 250 mg in the morning and 2 tablets of 250 mg in the evening.
- Dose for infants (6 to 23 months), children (2 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg:
Your doctor will prescribe the most appropriate pharmaceutical form of Keppra depending on your age, weight and dose.
Keppra 100 mg / ml oral solution is the most suitable presentation for infants and children under the age of 6 years.
Typical dose: between 20 mg per kg of body weight and 60 mg per kg of body weight per day.
Example: For a typical daily dose of 20 mg per kg of body weight, if your child weighs 25 kg, you could give him 1 250 mg tablet in the morning and 1 250 mg tablet in the evening
- Dose for infants (1 month to less than 6 months):
Keppra 100 mg / ml oral solution is a more suitable presentation for infants.
Method of administration:
Swallow Keppra tablets with a sufficient amount of liquid (e.g. a glass of water).
Duration of treatment:
- Keppra is used as a chronic treatment. Keppra treatment should last as long as your doctor told you to.
- Do not stop treatment without your doctor's advice as this may increase the number of seizures. If your doctor decides to stop Keppra treatment, he will instruct you on gradually stopping Keppra.
Overdose What to do if you have taken too much Keppra
If you take more Keppra than you should:
Possible side effects of an overdose of Keppra are sleepiness, agitation, aggression, decreased alertness, breathing inhibition and coma. Contact your doctor if you have taken more tablets than you should. Your doctor will determine the best possible treatment for the overdose. .
If you forget to take Keppra:
Contact your doctor if you have forgotten to take one or more doses. Do not take a double dose to make up for a forgotten tablet
If you stop taking Keppra:
In case of discontinuation of treatment, as with any other antiepileptic medicine, Keppra should be discontinued gradually to avoid an increase in seizures.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Keppra
Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of the side effects such as sleepiness, tiredness and dizziness may be more common at the start of treatment or when the dose is increased. These effects should, however, diminish over time.
Very common: may affect more than 1 in 10 patients
- nasopharyngitis;
- drowsiness, headache.
Common: may affect 1 to 10 in 100 patients
- anorexia (loss of appetite);
- depression, hostility or aggression, anxiety, insomnia, nervousness or irritability;
- convulsion, balance disturbance, dizziness (feeling of unsteadiness), lethargy, tremor (involuntary tremors);
- vertigo (sensation of rotation);
- cough;
- abdominal pain, diarrhea, dyspepsia (indigestion), vomiting, nausea;
- rash;
- asthenia / fatigue (feeling weak).
Uncommon: may affect 1 to 10 in 1000 patients
- decrease in the number of platelets in the blood, decrease in the number of white blood cells;
- weight loss, weight gain;
- suicide attempt and suicidal ideation, mental disorder, abnormal behavior, hallucinations, anger, confusion, panic attack, emotional lability / mood swings, agitation;
- amnesia (memory loss), memory impairment (forgetfulness), abnormal coordination / ataxia (impaired motor coordination), paraesthesia (tingling), impaired attention (loss of concentration);
- diplopia (double vision), blurred vision;
- abnormal liver function test;
- hair loss, eczema, itching;
- muscle weakness, myalgia (muscle pain);
- trauma.
Rare: may affect 1 to 10 users in 10,000
- infection;
- decrease in the number of all types of blood cells;
- severe hypersensitivity reactions (DRESS)
- decrease in the concentration of sodium in the blood;
- suicide, personality disorder (behavioral problems), altered thinking (slow thinking, inability to concentrate);
- uncontrollable muscle spasms involving the head, trunk and limbs, difficulty in controlling movements, hyperkinesis (hyperactivity);
- pancreatitis;
- liver failure, hepatitis;
- skin rash which may blister and appear as small targets (central dark spot surrounded by a "lighter area, with a dark ring around the edge) (erythema multiforme), a widespread rash with blisters and peeling of the skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome) and a more severe form that causes skin peeling in more than 30% of the body surface (toxic epidermal necrolysis).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after EXP: and on the blister after EXP :. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Contents of the pack and other information
What Keppra contains
The active ingredient is called levetiracetam.
Each Keppra 250 mg tablet contains 250 mg of levetiracetam.
Each Keppra 500 mg tablet contains 500 mg of levetiracetam.
Each Keppra 750 mg tablet contains 750 mg of levetiracetam.
Each Keppra 1000 mg tablet contains 1000 mg of levetiracetam.
The other ingredients are:
Tablet core: croscarmellose sodium, macrogol 6000, anhydrous colloidal silica, magnesium stearate.
Coating: partially hydrolyzed polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc, dyes *.
* The dyes are:
250 mg tablets: indigo carmine aluminum lake (E132)
500 mg tablets: yellow iron oxide (E172)
750 mg tablets: sunset yellow FCF (E110), red iron oxide (E172)
1000 mg tablets: (no additional dyes).
Description of what Keppra looks like and contents of the pack
Keppra 250 mg film-coated tablets are blue, oval shaped, scored and debossed with "ucb" and "250" on one side.
Keppra 500 mg film-coated tablets are yellow, oval shaped, scored and debossed with "ucb" and "500" on one side.
Keppra 750 mg film-coated tablets are orange, oval shaped, scored and debossed with "ucb" and "750" on one side.
Keppra 1000 mg film-coated tablets are white, oval shaped, scored and debossed with "ucb" and "1000" on one side.
Keppra tablets are packaged in blister packs placed in cardboard boxes containing:
- 250 mg: 20, 30, 50, 60, 100 x 1, 100 film-coated tablets and multipacks containing 200 (2 packs of 100) film-coated tablets.
- 500 mg: 10, 20, 30, 50, 60, 100 x 1, 100, 120 film-coated tablets and multipacks containing 200 (2 packs of 100) film-coated tablets.
- 50 mg: 20, 30, 50, 60, 80, 100 x 1, 100 film-coated tablets and multipacks containing 200 (2 packs of 100) film-coated tablets.
- 1000 mg: 10, 20, 30, 50, 60, 100 x 1, 100 film-coated tablets and multipacks containing 200 (2 packs of 100) film-coated tablets.
Packs of 100 x 1 tablet are available in aluminum / PVC perforated unit dose blisters.
All other packs are available in the standard aluminum / PVC blister.
Not all pack sizes may be marketed
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
KEPPRA 500 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 500 mg of levetiracetam.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Yellow, oval-shaped, engraved and with the words "ucb" and "500" debossed on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Keppra 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.
Keppra is indicated as adjunct therapy
• in the treatment of partial onset seizures with or without secondary generalization in adults, adolescents, children and infants from 1 month of age with epilepsy
• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy
• in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalized Epilepsy.
04.2 Posology and method of administration
Dosage
Monotherapy for 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 two weeks. The dose may be further increased by 250 mg twice daily every two weeks based on the clinical response. The maximum dose is 1500 mg twice a day.
Add-on therapy for adults (≥ 18 years) and adolescents (12 to 17 years) weighing 50 kg or more
The initial therapeutic dose is 500 mg twice a day. This dose can be started on the first day of treatment.
Based on the clinical response and tolerability, the daily dose can be increased up to a maximum of 1500 mg twice daily. Dosage adjustments can be made in 500 mg increases or decreases twice daily every two to four weeks.
Special populations
Elderly (aged 65 and over)
Dosage adjustment is recommended in elderly patients with impaired renal function (see "Renal impairment" below).
Kidney failure
The daily dose should be individualized according to renal function.
For adult patients, refer to the following table and adjust the dosage as indicated. To use this dosing table it is necessary to estimate the patient's creatinine clearance (CLcr) in ml / min. CLcr in ml / min can be calculated from the determination of serum creatinine (mg / dl) using, for adults and adolescents weighing 50 kg or more, the following formula:
Additionally, CLcr is adjusted for body surface area (BSA) as follows:
Dosage adjustment for adult and adolescent patients weighing more than 50 kg with impaired renal function:
A loading dose of 750 mg is recommended on the first day of treatment with levetiracetam.
After dialysis, an additional dose of between 250 and 500 mg is recommended.
For children with impaired renal function, levetiracetam dose should be adjusted based on renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study performed with adult patients with impaired renal function.
In young adolescents, children and infants, CLcr, in ml / min / 1.73 m2, can be estimated from the determination of serum creatinine (in mg / dl) using the following formula (Schwartz's formula):
ks = 0.45 in term infants aged up to 1 year; ks = 0.55 in children less than 13 years of age and in adolescent females; ks = 0.7 in adolescent males.
Dosage adjustment for infants, children and adolescents weighing less than 50 kg with impaired renal function:
Keppra oral solution should be used for doses below 250 mg and for patients unable to swallow tablets.
A 10.5 mg / kg (0.105 ml / kg) loading dose is recommended on the first day of treatment with levetiracetam.
A 15 mg / kg (0.15 ml / kg) loading dose is recommended on the first day of treatment with levetiracetam.
After dialysis, a supplemental dose of 3.5 to 7 mg / kg (0.035 to 0.07 ml / kg) is recommended.
After dialysis, an additional dose of 5 to 10 mg / kg (0.05 to 0.10 ml / kg) is recommended.
Hepatic insufficiency
No dosage adjustment is required in patients with mild to moderate hepatic impairment. In patients with severe hepatic insufficiency, creatinine clearance may underestimate the degree of renal insufficiency. Therefore a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is 2.
Pediatric population
The physician should prescribe the most appropriate pharmaceutical form and strength based on age, weight and dose.
The tablet formulation is not suitable for use in infants and children less than 6 years of age. Keppra oral solution is the preferred formulation for use in this population. In addition, the available strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for administering doses below 250 mg. In all cases mentioned above Keppra oral solution should be used.
Monotherapy
The safety and efficacy of Keppra given as monotherapy to children and adolescents aged less than 16 years have not been established.
No data are available.
Add-on therapy for infants 6 to 23 months of age, children (2 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg
Keppra oral solution is the preferred formulation for use in infants and children under the age of 6 years.
The initial therapeutic dose is 10 mg / kg twice daily.
Based on the clinical response and tolerability, the dose can be increased up to 30 mg / kg twice daily. Dosage adjustments should not exceed increases or decreases of 10 mg / kg twice daily every two weeks. The lowest effective dose should be used.
The dose in children weighing 50 kg or more is the same as in adults.
Recommended dose for infants from 6 months of age, children and adolescents:
Children weighing 25 kg or less should preferably start treatment with Keppra 100 mg / ml oral solution.
The dose in children and adolescents weighing 50 kg or more is the same as in adults.
Add-on therapy for infants from 1 month to less than 6 months of age
The oral solution is the formulation for use in infants.
Method of administration
The film-coated tablets should be administered orally, swallowed with a sufficient amount of liquid and can be taken with or without food. The daily dose should be divided in half in two administrations.
04.3 Contraindications
Hypersensitivity to the active substance or to other pyrrolidone derivatives or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Discontinuation of treatment
In accordance with current clinical practice, a gradual withdrawal is recommended if treatment with Keppra is to be discontinued (e.g. in adults and adolescents weighing more than 50 kg: decrease by 500 mg twice daily at intervals including between two and four weeks; in infants over 6 months of age, in children and adolescents weighing less than 50 kg: dose reduction should not exceed 10 mg / kg twice daily every two weeks; in infants ( less than 6 months of age): dose reduction should not exceed 7 mg / kg twice a day every two weeks).
Kidney failure
Administration of Keppra to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, it is recommended to evaluate renal function before establishing the posology (see section 4.2).
Suicide
Cases of suicide, attempted suicide, suicidal ideation and behavior have been reported in patients treated with antiepileptics (including levetiracetam). A meta-analysis of randomized, placebo-controlled trials with antiepileptic medicinal products showed a slightly increased risk of suicidal ideation and behavior. The mechanism of this risk is not known.
Consequently, patients should be monitored for signs of depression and / or suicidal ideation and behavior, and appropriate treatment should be considered. Patients (and caregivers) should be advised that if signs of depression and / or suicidal ideation or behavior emerge, medical attention should be sought.
Pediatric population
The tablet formulation is not suitable for use in infants and children under 6 years of age.
Available data in children do not suggest an influence on growth and puberty. However, the long-term effects on learning, intelligence, growth, endocrine function, puberty and reproductive potential in children are unknown.
The safety and efficacy of levetiracetam have not been thoroughly evaluated in infants aged less than 1 year with epilepsy. In clinical studies, only 35 infants aged <1 year with partial onset seizures were exposed to Keppra, of which only 13 were under the age of 6 months.
04.5 Interactions with other medicinal products and other forms of interaction
Antiepileptic medicines
Data from pre-marketing clinical studies conducted in adults indicate that Keppra does not affect the serum concentrations of existing antiepileptics (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptics do not affect the pharmacokinetics of Keppra.
As in adults, there is no evidence of clinically significant interactions with other medicinal products in pediatric patients administered levetiracetam doses up to 60 mg / kg / day.
A retrospective evaluation of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that add-on therapy with orally administered levetiracetam did not affect the steady-state serum concentrations of carbamazepine and valproate administered concomitantly. . However, data suggested a 20% higher levetiracetam clearance in children taking enzyme inducing antiepileptic medicinal products. No dose adjustment is required.
Probenecid
Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. However, the concentration of this metabolite remains low. Other medicinal products excreted with active tubular secretion are expected to reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid has not been studied and the effect of levetiracetam on other actively secreted medicinal products, eg. NSAIDs, sulfonamides and methotrexate, is unknown.
Oral contraceptives and other pharmacokinetic interactions
Levetiracetam 1000 mg daily did not affect the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); the endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2000 mg daily did not affect the pharmacokinetics of digoxin and warfarin; the prothrombin times were not changed. Concomitant administration of digoxin, oral contraceptives and warfarin did not affect the pharmacokinetics of levetiracetam.
Antacids
No data are available on the influence of antacids on the absorption of levetiracetam.
Laxatives
There have been isolated reports of decreased efficacy of levetiracetam when the osmotic laxative macrogol was administered concomitantly with oral levetiracetam. Therefore, macrogol should not be taken orally between one hour before and one hour after taking levetiracetam.
Food and alcohol
The extent of levetiracetam absorption was not affected by food, but the rate of absorption was slightly reduced.
There are no data on the interactions of levetiracetam with alcohol.
04.6 Pregnancy and lactation
Pregnancy
Post-marketing data from several prospective pregnancy registries have documented the results of exposure to levetiracetam monotherapy in more than 1000 women during the first trimester of pregnancy. Overall, these data do not suggest a substantial increase in the risk of major congenital malformations, although a teratogenic risk cannot be completely excluded. Therapy with multiple AEDs is associated with a higher risk of congenital malformations than monotherapy and therefore monotherapy should be considered. Animal studies have shown reproductive toxicity (see section 5.3).
Keppra is not recommended, unless clinically necessary, during pregnancy and in women of childbearing potential who are not using contraceptive methods.
As with other antiepileptic medicinal products, physiological changes associated with pregnancy may affect the plasma concentrations of levetiracetam. During pregnancy, decreased plasma concentrations of levetiracetam were observed. This reduction is most pronounced during the third trimester (up to 60% of the baseline concentration before pregnancy). Pregnant women treated with levetiracetam should be carefully followed from a clinical point of view. Discontinuation of antiepileptic treatments can lead to an exacerbation of the disease which can be harmful to the mother and fetus.
Feeding time
Levetiracetam is excreted in human breast milk. Therefore, breastfeeding is not recommended. However, if treatment with levetiracetam becomes necessary during breastfeeding, the benefit / risk ratio of the treatment should be weighed, taking into account the importance of breastfeeding. .
Fertility
No impact on fertility was found in animal studies (see section 5.3). No clinical data are available; the potential risk in humans is unknown.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
Given the possible different individual sensitivity, some patients may experience somnolence or other symptoms related to the action on the central nervous system, especially at the beginning of treatment or following an increase in the dose. Therefore, caution is recommended in patients who are engaged in activities that require high concentration, such as driving vehicles or operating machinery. Patients should be advised not to drive or operate machinery until it is established that their ability to perform these activities is not affected.
04.8 Undesirable effects
Summary of the safety profile
The adverse event profile presented below is based on the analysis of pooled placebo-controlled clinical trials across all indications studied for a total of 3416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open label extension studies, as well as from post-marketing experience. The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar across age groups. (adult and pediatric patients) and the approved indications for the treatment of epilepsy.
Table of adverse reactions
Adverse reactions reported from clinical trials (adults, adolescents, children and infants over 1 month of age) and from post-marketing experience are listed in the following table by system organ class and frequency. is defined as: very common (≥1 / 10); common (≥1 / 100,
Description of selected adverse reactions
The risk of anorexia is higher when topiramate is co-administered with levetiracetam.
In numerous cases of alopecia, healing has been observed after discontinuation of levetiracetam treatment.
Bone marrow suppression was identified in some of the cases of pancytopenia.
Pediatric population
In patients aged 1 month to less than 4 years, a total of 190 patients were treated with levetiracetam in placebo-controlled and open-label extension studies. Sixty of these patients were treated with levetiracetam in placebo-controlled studies. In 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 of these pediatric age ranges, these data are integrated with post marketing experience with the use of levetiracetam.
The adverse event profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. In placebo-controlled clinical trials, the safety results in pediatric patients were consistent with the safety profile of levetiracetam in adults, with the exception of behavioral and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4-16 years, vomiting (very common, 11.2%), agitation (common, 3.4%) was reported more frequently than in other age groups or in the overall safety profile. ), mood swings (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), abnormal behavior (common, 5.6%), and lethargy (common , 3.9%) In infants and children aged 1 month to less than 4 years, irritability was reported more frequently than in other age groups or in the overall safety profile (very common, 11.7%) and abnormal coordination (common, 3.3%).
A safety study in pediatric patients, conducted according to a non-inferiority, double-blind, placebo-controlled design, evaluated the cognitive and neuro-psychological effects of Keppra in children 4 to 16 years of age with partial onset seizures. Keppra was shown to be no different (not inferior) to placebo in the change from baseline in the score obtained in the "Attention and Memory" subtest of the Leiter-R scale (Memory Screen Composite score) in the per-protocol population. The results related to behavioral and emotional functions indicated a worsening, in patients treated with Keppra, of aggressive behavior measured in a standardized and systematic way, with the use of a validated tool (CBCL - Achenbach Child Behavior Checklist). However, subjects who took Keppra in the open-label long-term follow-up study did not, on average, experience deterioration in their behavioral and emotional functions; in particular, the assessments of aggression in behaviors did not deteriorate compared to baseline.
04.9 Overdose
Symptoms
Somnolence, agitation, aggression, decreased level of consciousness, respiratory depression and coma have been observed with Keppra overdoses.
Treatment of overdose
After an acute overdose the stomach can be emptied by gastric lavage or induction of vomiting. There is no specific antidote for levetiracetam. Treatment of levetiracetam overdose should be symptomatic and may include hemodialysis. The extraction efficiency by dialysis is 60% for levetiracetam and 74% for the primary metabolite.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX14.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidin acetamide), chemically unrelated to existing antiepileptic substances.
Mechanism of action
The mechanism of action of levetiracetam has not yet been fully explained, but it appears to be different from the mechanisms of current antiepileptic drugs. Experiments in vitro and in vivo suggest that levetiracetam does not alter basic cellular characteristics and normal neurotransmission.
Education in vitro show that levetiracetam acts on intraneuronal levels of Ca2 + by partially inhibiting N-type Ca2 + currents and by reducing the release of Ca2 + from intraneuronal storage sites. In addition, it partially reverses the reduction, induced by zinc and β-carboline, of the currents induced by GABA and glycine. Education in vitro they also found that levetiracetam binds to a specific site in rodent brain tissue. This binding site is synaptic vesicle protein 2A, which is thought to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs show a degree of affinity for binding to synaptic vesicle protein 2A that correlates with the potency of their antiepileptic protection in the audiogenic model of epilepsy in mice. This finding suggests that the interaction between levetiracetam and synaptic vesicle protein 2A appears to play part in the drug's mechanism of antiepileptic action.
Pharmacodynamic effects
Levetiracetam induces protective action in a broad spectrum of animal models of partial and primary generalized epilepsy, without having a pro-convulsive effect. The primary metabolite is inactive.
In humans, activity in both partial and generalized epilepsy conditions (epileptic discharge / photoparoxysmal response) confirmed the broad spectrum of the pharmacological profile of levetiracetam.
Clinical efficacy and safety
Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalization in adults, adolescents, children and infants from 1 month of age with epilepsy.
In adults, the efficacy of levetiracetam was demonstrated in 3 double-blind, placebo-controlled studies with doses of 1000 mg, 2000 mg or 3000 mg / day, divided into 2 doses, for a treatment duration of up to 18 weeks. a comprehensive analysis the percentage of patients who achieved a reduction in partial onset seizure frequency per week, in the stable dose treatment period (12/14 weeks), equal to or greater than 50% from baseline, was 27 , 7%, 31.6% and 41.3% of patients treated with 1000, 2000 or 3000 mg of levetiracetam, respectively, and 12.6% for patients treated with placebo.
Pediatric population
The efficacy of levetiracetam in pediatric patients (4 to 16 years of age) was demonstrated in a double-blind, placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In this study patients received levetiracetam at a fixed dose of 60 mg / kg / day (twice daily).
44.6% of levetiracetam-treated patients and 19.6% of placebo-treated patients had a 50% or greater reduction in partial onset seizure frequency per week from baseline. With continued long-term treatment, 11.4% of patients were seizure-free for at least 6 months and 7.2% were seizure-free for at least 1 year.
In pediatric patients (1 month to less than 4 years of age), the efficacy of levetiracetam was demonstrated in a double-blind, placebo-controlled study, which included 116 patients and had a treatment duration of 5 days. In this study, patients were prescribed a daily dose of 20 mg / kg, 25 mg / kg, 40 mg / kg or 50 mg / kg of oral solution, based on their age-related dose titration schedule. the following doses were used: 20 mg / kg / day, titrated to 40 mg / kg / day, for infants from one month to less than six months of age; 25 mg / kg / day, titrated to 50 mg / kg / day for infants and children from 6 months to less than 4 years of age The total daily dose was divided into two administrations per day.
The main measure of treatment efficacy was the rate of patients responding (percentage of patients with ≥50% reduction in mean daily frequency of partial onset seizures from baseline), as assessed by a blinded single examiner using video EEG for a period of 48 hours. The efficacy analysis was performed on 109 patients who had undergone video EEG for at least 24 hours, both during the baseline period and during the evaluation period. 43.6% of patients Levetiracetam-treated patients and 19.6% of placebo-treated patients were considered responsive. Results were consistent across age groups. In continued long-term treatment, 8.6% of patients were seizure-free for at least 6 months and 7.8% were seizure-free for at least 1 year.
Monotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy.
The efficacy of levetiracetam monotherapy was demonstrated in a double-blind, parallel-group comparative non-inferiority study versus controlled-release carbamazepine (CR) in 576 patients aged 16 years or older with new or new epilepsy. recently diagnosed. Patients were required to have only unprovoked partial seizures or generalized tonic-clonic seizures. Patients were randomized to carbamazepine CR 400 - 1200 mg / day or levetiracetam 1000 - 3000 mg / day and treatment lasted up to 121 weeks based on response.
Seizure freedom for a period of 6 months was achieved in 73.0% of patients treated with levetiracetam and in 72.8% of patients treated with carbamazepine CR; the corrected absolute difference between treatments was 0.2% (95% CI: 7.8 - 8.2). More than half of the subjects remained seizure-free for 12 months (56.6% and 58.5% of subjects treated with levetiracetam and carbamazepine CR, respectively).
In a study reflecting clinical practice, concomitant antiepileptic treatment could be withdrawn in a limited number of patients who responded to levetiracetam add-on therapy (36 of 69 adult patients).
Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.
The efficacy of levetiracetam was demonstrated in a 16-week, double-blind, placebo-controlled study in patients aged 12 years or older with idiopathic generalized epilepsy with myoclonic seizures in different syndromes. majority of patients had juvenile myoclonic epilepsy.
In this study, levetiracetam dose was 3000 mg / day given in two divided doses.
58.3% of levetiracetam-treated patients and 23.3% of placebo-treated patients had at least a 50% reduction in myoclonic seizure days per week. Following continued long-term treatment, 28.6% of patients were free of myoclonic seizures for at least 6 months and 21.0% of patients were free of myoclonic seizures for at least 1 year.
Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
The efficacy of levetiracetam was demonstrated in a 24-week double-blind, placebo-controlled study which included adults, adolescents and a limited number of children with idiopathic generalized epilepsy with primary generalized tonic-clonic seizures (PGTCs). in different syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, infantile absence epilepsy, or epilepsy with seizure of Great Male on awakening). In this study the dose of levetiracetam was 3000 mg / day for adults and adolescents or 60 mg / kg / day for children, given in two divided doses.
72.2% of levetiracetam-treated patients and 45.2% of placebo-treated patients had a 50% or greater reduction in PGTC seizure frequency per week. Following continued long-term treatment, 47.4% of patients were free from tonic-clonic seizures for at least 6 months and 31.5% were free from tonic-clonic seizures for at least 1 year.
05.2 Pharmacokinetic properties
Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with little intra- and inter-individual variability. There is no change in clearance after repeated administration. There is no evidence of any relevant circadian and gender and race variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.
Given its complete and linear absorption, plasma levels of levetiracetam can be predicted from the oral dose expressed as mg / kg body weight. Therefore there is no need to monitor levetiracetam plasma levels.
There was a significant correlation between saliva and plasma concentrations in adults and children (the ratio of saliva / plasma concentrations ranged from 1 to 1.7 for the oral tablet formulation and, after 4 hours from " intake, for oral solution formulation).
Adults and adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration. Oral bioavailability is close to 100%.
Peak plasma concentrations (Cmax) are reached 1.3 hours after dosing. Steady state is achieved after two days of two daily doses.
Peak plasma concentrations (Cmax) are typically 31 and 43 mcg / mL following a single 1000 mg dose and repeated 1000 mg twice daily dose, respectively.
The extent of absorption is not dose dependent and is not affected by food.
Distribution
There are no data on tissue distribution in humans.
Neither levetiracetam nor its primary metabolite binds significantly to plasma proteins (
The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L / kg, and is close to the total body volume of water.
Biotransformation
Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24% of the dose) is the enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057 is not supported by hepatic cytochrome P450 isoforms. Hydrolysis of the acetamide group has been measurable in numerous tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive.
Two minor metabolites were also identified. One was obtained from the hydroxylation of the pyrrolidone ring (1.6% of the dose) and the other from the opening of the pyrrolidone ring (0.9% of the dose).
Other unknown components accounted for only 0.6% of the dose.
In vivo there was no evidence of enantiomeric interconversion for either levetiracetam or its primary metabolite.
In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the activities of the major isoforms of human hepatic cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase Furthermore, levetiracetam does not affect glucuronidation in vitro of valproic acid.
In human hepatocyte cultures, levetiracetam had little or no effect on CYP1A2, SULT1E1 or UGT1A1. Levetiracetam caused moderate induction of CYP2B6 and CYP3A4. The data in vitro and the data in vivo related to the interaction with oral contraceptives, digoxin and warfarin, indicate that no significant enzyme induction is expected in vivo. Hence, Keppra's interaction with other substances, or the other way around, it is unlikely.
Elimination
The plasma half-life in adults is 7 ± 1 hours and does not change with dose, route of administration or repeated administration. Mean total body clearance is 0.96 ml / min / kg.
The major route of excretion is the urinary route, responsible on average for the elimination of 95% of the administered dose (approximately 93% of the dose is excreted in 48 hours). Faecal elimination accounts for only 0.3% of the dose.
The cumulative urinary excretion of levetiracetam and its primary metabolite is responsible for the elimination of 66% and 24% of the dose, respectively, over the first 48 hours.
The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml / min / kg, respectively, indicating that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion beyond than with glomerular filtration. Elimination of levetiracetam is related to creatinine clearance.
Senior citizens
In the "elderly" half-life increased by about 40% (10 to 11 hours). This is due to decreased renal function in this population (see section 4.2).
Kidney failure
The apparent body clearance of both levetiracetam and its primary metabolite correlates with creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Keppra, based on creatinine clearance in patients with moderate and severe renal impairment (see section 4.2).
In anuric end-stage renal failure adult subjects the half-life was approximately 25 and 3.1 hours in the inter-dialysis and during dialysis periods, respectively.
The levetiracetam fraction removed was 51% during a typical 4-hour dialysis.
Hepatic insufficiency
In subjects with mild and moderate hepatic impairment, no significant modification of the clearance of levetiracetam was found. In the majority of subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50% due to concomitant renal insufficiency (see section 4.2).
Pediatric population
Children (from 4 to 12 years old)
Following a single oral administration (20 mg / kg) in children (6 to 12 years) with epilepsy, the half-life of levetiracetam was 6.0 hours. The apparent body weight corrected clearance was approximately 30% higher than in adults with epilepsy.
Following repeated dose oral administration (20 to 60 mg / kg / day) to epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentrations were observed 0.5 to 1.0 hours after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours. Apparent body clearance was 1.1 mL / min / kg.
Infants and children (1 month to 4 years)
Following administration of a single dose (20 mg / kg) of 100 mg / ml oral solution to epileptic children (1 month to 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1. hour after administration. Pharmacokinetic results indicated that the half-life is shorter (5.3 hours) than in adults (7.2 hours) and the apparent clearance was faster (1.5 ml / min / kg) than in adults (0 , 96 ml / min / kg).
In population pharmacokinetic analyzes conducted in patients 1 month to 16 years of age, body weight was significantly correlated with apparent clearance (clearance increased with increasing body weight) and apparent volume of distribution. Age also affected. both parameters. This effect was marked for the younger infants, and attenuated with increasing age, to become negligible around 4 years of age.
In both population pharmacokinetic analyzes, there was an approximately 20% increase in the apparent clearance of levetiracetam when co-administered with an enzyme-inducing antiepileptic drug.
05.3 Preclinical safety data
Non-clinical data reveal no risk for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.
Adverse events not observed in clinical studies, but seen in rats and to a lesser extent in mice, at exposure levels similar to human exposure levels and with possible relevance for clinical use, were liver changes indexes of response. adaptive, such as weight gain and centrilobular hypertrophy, adipose infiltration and elevation of liver enzymes in plasma.
No adverse effects on male and female fertility or reproductive capacity were observed in rats at doses up to 1800 mg / kg / day (6 times the MRHD (Maximum Recommended Human Daily Dose) based on mg / m2 or based on exposure), both in the parental generation and in the F1 generation.
Two embryo-fetal development studies (EFD: Embryo-Fetal Development) were conducted in rats at 400, 1200 and 3600 mg / kg / day. At 3600 mg / kg / day, in only one of the 2 EFD studies, there was a slight decrease in fetal weight associated with a marginal increase in skeletal changes / minor anomalies. There was no effect on embryonic mortality nor was there an increase in the incidence of malformations. The NOAEL (No Observed Adverse Effect Level) was 3600 mg / kg / day for pregnant female rats (12 times the maximum recommended human daily dose (MRHD) based on mg / m2) and 1200 mg / kg / day for fetuses.
Four embryo-fetal development studies were conducted in rabbits using doses of 200, 600, 800, 1200 and 1800 mg / kg / day. The dose of 1800 mg / kg / day induced marked maternal toxicity and decreased fetal weight in association with a higher incidence of fetuses with cardiovascular / skeletal abnormalities. The NOAEL was 2).
A peri- and postnatal development study was conducted in rats with levetiracetam doses of 70, 350, 1800 mg / kg / day. The NOAEL was ≥ 1800 mg / kg / day for F0 females and for the F1 generation for survival, growth and development to weaning (6 times the MRHD on a mg / m2 basis).
Studies in rats and dogs, in newborn and juvenile animals, have shown that no adverse effects occur in any of the standard developmental or maturation endpoints at doses up to 1800 mg / kg / day (6-17 times the MRHD based on mg / m2).
Environmental risk assessment (Environmental Risk Assessment, WAS)
The use of Keppra in accordance with the information in the Summary of Product Characteristics is unlikely to result in an unacceptable environmental impact (see section 6.6).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Nucleus:
Croscarmellose sodium
Macrogol 6000
Anhydrous colloidal silica
Magnesium stearate
Coating Opadry 85F32004:
Partially hydrolyzed polyvinyl alcohol
Titanium dioxide (E171)
Macrogol 3350
Talc
Yellow iron oxide (E172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / PVC blisters placed in cardboard boxes containing 10, 20, 30, 50, 60, 100, 120 film-coated tablets and multipacks containing 200 (2 packs of 100) film-coated tablets.
Aluminum / PVC perforated unit dose blisters placed in cardboard boxes containing 100 x 1 film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
UCB Pharma SA
Allée de la Recherche 60
B - 1070 Brussels
Belgium
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/00/146/006 - AIC 035039066
EU / 1/00/146/007 - AIC 035039078
EU / 1/00/146/008 - AIC 035039080
EU / 1/00/146/009 - AIC 035039092
EU / 1/00/146/010 - AIC 035039104
EU / 1/00/146/011 - AIC 035039116
EU / 1/00/146/012 - AIC 035039128
EU / 1/00/146/013 - AIC 035039130
EU / 1/00/146/035 - AIC 035039332
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 29 September 2000
Date of most recent renewal: 29 September 2010
10.0 DATE OF REVISION OF THE TEXT
August 2013
