Levetinol - instructions for use, dose, side effects, contraindications

Excipients: crospovidone 8.25 mg, povidone 7 mg, silicon dioxide colloidal anhydrous 3.5 mg, magnesium stearate 1.25 mg, film coating: Opadry® II Blue 85F20440 (polyvinyl alcohol partially hydrolyzed 40%, titanium dioxide (E171) 22.29%, macrogol 4000 20.2%, talc 14.8%, dye indigo carmine (E132) 2.71%) 8.1 mg .

One 500 mg tablet contains

active substance: levetiracetam-500 mg;

Excipients: crospovidone 16.5 mg, povidone 14 mg, silicon dioxide colloidal anhydrous 7 mg, magnesium stearate 2.5 mg, film coating: Opadrai II II Yellow 85F32371 (polyvinyl alcohol partially hydrolysed 40%, titanium dioxide (E171) 23.92%, macrogol 4000 20.2%, talc 14.8%, dye indigo carmine (E132) 0.11%, iron dye oxide yellow (E172) 0.97%) 16.2 mg.

One 1000 mg tablet contains

active substance: levetiracetam -1000 mg;

Excipients: crospovidone 33 mg, povidone 28 mg, silicon dioxide colloidal anhydrous 14 mg, magnesium stearate 5 mg, film coating: Opadrai® II White 85F18422 (polyvinyl alcohol partially hydrolyzed 40%, titanium dioxide (E171) 25%, macrogol 4000 20.2% , talc 14.8%) 32 mg.

Description:

Tablets 250 mg. Oval biconvex tablets, covered with a film coating of blue color, marked on one side by engraving "L",on the other hand, "250"; at the break the core of the tablets is white or white with a yellowish tint of color.

Tablets 500 mg. Oval biconvex tablets, covered with a film coating of yellow color, marked on one side by engraving "L", on the other - "500"; at the break the core of the tablets is white or white with a yellowish tint of color.

Tablets 1000 mg. Oval biconvex tablets covered with a white film membrane, marked on one side by engraving "L", on the other - "1000"; at the break the core of the tablets is white or white with a yellowish tint of color.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.14 Levetiracetam

Pharmacodynamics:

The active substance of the drug, levetiracetam, is a pyrrolidone derivative (S-enantiomer α-ethyl-2-oxo-1-pyrrolidineacetamide), a chemical structure different from other anticonvulsants.

Mechanism of action

The mechanism of action of levetiracetam is not fully understood, but it differs from the mechanism of action of other anticonvulsants. In experiments in vitro and in vivo it was shown that levetiracetam does not affect the basic properties of the cell and normal nervous transmission.

In vitro studies have shown that, partially reducing the N-type calcium currents and reducing the release of calcium ions from the intracellular neuronal depot, levetiracetam changes the concentration of calcium ions inside neurons. In addition, it partially eliminates the decrease in the currents of GABA and glycine channels caused by zinc and β-carbolines. Moreover, in vitro studies have shown that levetiracetam binds to specific areas of the rat brain. This site is a 2A synaptic vesicle protein, which is supposed to be involved in the fusion of vesicles and exocytosis of neurotransmitters. Levetiracetam and its analogues binding to the protein 2A of synaptic vesicles exhibit anticonvulsant activity in the audiogenic model of epilepsy in mice, and the stronger the bond, the higher the activity. These data imply that the binding of levetiracetam to the synaptic vial protein 2A realizes its anticonvulsant action.

Pharmacodynamic effects

Levetiracetam has an anticonvulsant effect on many models of partial and primarily generalizedconvulsions in animals without concomitant pro-cramping effect. The main metabolite of levetiracetam is inactive.

Levetiracetam exhibits anticonvulsant activity in partial and generalized epilepsy in humans (epileptiform burst / photoparosymal response), which confirms its wide spectrum of pharmacological action.

Pharmacokinetics:

Levetiracetam is a well-soluble and permeable compound. The pharmacokinetic profile is linear in nature with a low intra- and interindividual variation. After a long period of application, there is no change in the clearance. There is no evidence of sexual, racial or diurnal differences. The pharmacokinetic properties of levetiracetam in patients with epilepsy and healthy volunteers are comparable.

Due to complete and linear absorption, the plasma concentration is predictable for the dose of levetiracetam expressed in mg / kg of body weight. Therefore, it is not necessary to monitor the plasma concentration of levetiracetam.

Adults and children show a high correlation between concentrationlevetiracetam in plasma and saliva (the ratio of saliva / plasma ranges from 1-1.7 for oral tablets and for oral administration four hours after ingestion).

Adults and teenagers

Absorption

After oral administration levetiracetam quickly absorbed. Absolute bioavailability after oral administration is close to 100%.

The maximum concentration in plasma (C_max) is achieved after 1.3 hours. The equilibrium state is achieved two days after taking the drug twice a day.

C_max is usually 31 and 43 μg / ml after a single dose of 1000 mg and a dose of 1000 mg twice a day.

The amount of absorption does not depend on the dose and on the intake of food.

Distribution

There is no data on the distribution in humans.

Levetiracetam and its main metabolite weakly bind to plasma proteins (<10%).

The volume of distribution of levetiracetam is about 0.5-0.7 l / kg, which roughly corresponds to the volume of water in the body.

Biotransformation

Levetiracetam is poorly metabolized in the human body. The main metabolic pathway (24% dose) is the enzymatic hydrolysis of the acetamide group.Isozymes of liver cytochrome P450 do not participate in the formation of the main metabolite (ucb L057). Hydrolysis of the acetamide group occurs in many tissues, including blood cells. Metabolite ucb L057 is pharmacologically inactive.

Two secondary metabolites were also detected. The former is formed by hydroxylation of the pyrrolidone ring (1.6% of the dose), the second by the opening of the pyrrolidone ring (0.9% dose).

Other unidentified metabolites are only 0.6% of the dose. Optical isomerization of levetiracetam and its main metabolite in vivo was not detected.

Levetiracetam and its main metabolite do not inhibit the main isoenzymes of human cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxy hydroxylase in vitro. Levetiracetam also does not affect the glucuronation of valproic acid in vitro.

In human hepatocyte culture levetiracetam had little or no effect on the activity of the isoenzymes CYP1A2, SULT1E1 and UGT1A1. Levetiracetam weakly induced activity of the isoenzymes CYP2B6 and CYP3A4. In vitro data and data on drug interactions with oral contraceptives, digoxin and warfarin in vivo indicate that significant induction of enzymes in vivo is not expected.Therefore, the interaction of levetiracetam with other substances is unlikely.

Excretion

The half-life in adults is 7 ± 1 and does not depend on the dose, route of administration or duration of administration. The average overall clearance is 0.96 ml / min / kg.

The main way of elimination is excretion in the urine (about 95% of the dose, of which 93% is excreted within 48 hours). Excretion with faeces is only 0.3% of the dose.

The total excretion of levetiracetam and its main metabolite is 66 and 24%, respectively, for the first 48 hours. The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml / min / kg, respectively, indicating the excretion of levetiracetam by glomerular filtration followed by tubular reabsorption, and the main metabolite, along with glomerular filtration - active tubular secretion.

Elimination of levetiracetam correlates with creatinine clearance.

Elderly

The half-life of the elderly increases by 40% (up to 10-11 h), which is due to a decrease in kidney function in this population.

Renal insufficiency

The apparent clearance of levetiracetam and its main metabolite depends on the creatinine clearance.In this regard, in patients with moderate and severe renal insufficiency, it is recommended to adjust the maintenance dose of the drug depending on the creatinine clearance.

In adult patients with terminal renal insufficiency, the half-life is 25 h between hemodialysis sessions and 3.1 h during the procedure.

During a typical four-hour hemodialysis session, about 51% of levetiracetam is removed.

Impaired liver function

In patients with mild to moderate hepatic insufficiency, the clearance of levetiracetam varies insignificantly. In most patients with severe hepatic insufficiency, the clearance of levetiracetam declines by more than 50%, due to concomitant renal failure.

Children under 12 years of age

Children aged 4-12 years

After a single dose of 20 mg / kg, the half-life in children 6-12 years is 6 hours. The body weight corrected apparent apparent clearance by 30% exceeds that in adults with epilepsy. After prolonged use of the drug at a dose of 20-60 mg / kg / day, absorption of levetiracetam in children 4-12 years of age is rapid. C_max is achieved within 0.5-1 h. C_max and the area under the "concentration-time" curve is linear and proportional to the dose. The terminal elimination half-life is 5 hours. The apparent clearance is 1.1 ml / min / kg.

Indications:

Levetiracetam is indicated as a monotherapy for the treatment of partial seizures with secondary generalization or without it in patients with 16 years of age with a newly diagnosed epilepsy.

As an auxiliary therapy levetiracetam is indicated for treatment:

- partial seizures with secondary generalization or without it in patients with epilepsy from 6 years of age.

- myoclonic seizures in patients with juvenile myoclonic epilepsy from age 12.

- primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy from age 12.

Contraindications:

Hypersensitivity to levetiracetam or a derivative of pyrrolidone, other components of the drug.

Children under 6 years.

Pregnancy and lactation:

Pregnancy

Data on the use of levetiracetam during pregnancy are not enough. In animal studies, the presence of reproductive toxicity is indicated. A potential risk to a person is not known.

It is recommended to use levetiracetam during pregnancy, as well as in fertile women who do not use reliable methods of contraception, only with good reasons.

As with other anticonvulsants, physiological changes during pregnancy can affect the concentration of levetiracetam. During pregnancy, there is a decrease in the plasma concentration of levetiracetam. This decline is most pronounced during the third trimester (up to 60% of the baseline concentration observed before pregnancy). For pregnant women receiving levetiracetam, proper monitoring should be established. Cancellation of anticonvulsant therapy can lead to an exacerbation of the disease, which can negatively affect the condition of the mother and fetus.

Breastfeeding period

Levetiracetam penetrates into breast milk. Breastfeeding during the drug is not recommended.

However, if levetiracetam therapy should be continued during breastfeeding, the expected benefit and the potential risk of treatment and the importance of breastfeeding should be correlated.

Fertility

In animal studies, no effect on fertility was detected.Clinical data are not available, the potential risk to humans is not known.

Dosing and Administration:

Dosing regimen

Monotherapy in adults and adolescents with 16 years

The recommended initial dose is 250 mg twice daily, which must be increased two weeks before the initial therapeutic 500 mg twice daily. The dose may be increased in increments of 250 mg twice a day every two weeks, depending on the clinical response. The maximum dose is 1500 mg twice a day.

Adjuvant therapy in adults (≥18 years) and adolescents (12-17 years) with a body weight of 50 kg and more

The initial therapeutic dose is 500 mg twice a day. This dose can be used from the first day of treatment.

Depending on the clinical response and tolerability, the daily dose can be raised to 1500 mg twice a day. The dose may be increased or decreased by 500 mg twice a day every 2-4 weeks.

Special patient groups

Elderly (65 years and over)

In elderly patients with impaired renal function, it is recommended to adjust the dose (see "Renal failure" below).

Renal insufficiency

Depending on the degree of impaired renal function, the daily dose is selected individually.To use the dose adjustment table, calculate the creatinine clearance of the patient in ml / min. QC in ml / min can be determined using the magnitude of serum creatinine (mg / dl) by the following formula (for adults and adolescents weighing 50 kg or more):

CK (ml / min) = [140-yr (years)] x body weight (kg) / 72 x creatinine concentration (mg / dl)

Then, correction for the body surface area (TFT) is introduced as follows:

KK (ml / mn / 1.73 m²) = KK (ml / min) / PPT (m²) *1,73

Dose adjustment in adults and adolescents with renal dysfunction, whose body weight is> 50 kg

Group	Creatinine clearance (ml / min / 1.73 m²)	Dose and frequency of admission
Norm	>80	500-1500 mg 2 times a day
Lightweight	50-79	500-1000 mg twice daily
Medium	30-49	250-750 mg 2 times a day
Heavy	<30	250-500 mg 2 times a day
Terminal stage of renal failure - patients on hemodialysis (1)		500-1000 mg once a day (2)

(1) On the first day, a loading dose of 750 mg is recommended.

(2) Upon completion of hemodialysis, an additional 250 or 500 mg dose is recommended.

Due to the fact that the clearance of levetiracetam depends on the function of the kidneys, children with renal insufficiency are selected for its dose depending on the QC. These guidelines are based on studies in adult patients.KK in ml / min / 1.73 m² in children and adolescents can be estimated from the plasma concentration of creatinine (in mg / dL) according to the following formula (Schwarz formula):

KK (ml / min / 1,73 m²) = Height (cm) x ks / creatinine concentration (mg / dl)

where ks = 0.45 for children up to 1 year; 0.55 for children aged 1-13 years and females; 0,7 - adolescent male.

Correction of the dose in children and adolescents with impaired renal function, whose body weight is <50 kg

Group	KK (ml / min / 1.73 m²)	Dose and frequency of admission
Group	KK (ml / min / 1.73 m²)	From the age of 6
Norm	>80	10-30 mg / kg 2 times a day
Lightweight	50-79	10-20 mg / kg 2 times a day
Medium	30-49	5-15 mg / kg 2 times per day
Heavy	<30	5-10 mg / kg 2 times a day
Terminal stage of renal failure - patients on hemodialysis (1)		10-20 mg / kg once a day (2) (3)

(1) The oral solution is used for doses of <250 mg and in patients who are unable to swallow tablets.

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

(3) Upon completion of hemodialysis, an additional dose of 5-10 mg / kg (0.05-0.1 ml / kg) is recommended.

Impaired liver function

In patients with mild to moderate hepatic insufficiency, dose adjustment is not required. In patients with severe hepatic insufficiency, the value of QA can be misleading about the degree of renal failure.

Therefore, for KK <60 ml / min / 1.73 m² should reduce the maintenance dose of the drug by 50%.

Children

The drug is prescribed in the most convenient dosage form and dosage depending on the age, body weight and the required dose.

Tablets are not intended for use in children younger than 6 years. In such patients, the drug should be administered in a dosage form for oral administration. In addition, the available dosage of tablets is not intended for initial dose selection in children weighing less than 25 kg, patients who are unable to swallow tablets, and also if necessary to take a dose of <250 mg. In all these cases, it is recommended to use the solution for oral administration.

Monotherapy

The efficacy and safety of levetiracetam in children and adolescents under 16 years of age has not been established as monotherapy. No data available. Auxiliary therapy in children 6-17 years old and weighing less than 50 kg The initial dose is 10 mg / kg 2 times a day.

Depending on the clinical response and tolerability, the dose may be increased to 30 mg / kg 2 times a day. The dose may be increased or decreased in steps of 10 mg / kg twice a day every two weeks. It is necessary to apply the lowest effective dose. The dosage regimen in children with a body weight of 50 kg or more is not different from adults.

Recommended doses in children from 6 years of age

Body mass

Initial dose:

10 mg / kg twice daily

Maximum dose:

30 mg / kg 2 times a day

25 kg⁽¹⁾

250 mg twice daily

750 mg twice a day

From 50 kg⁽²⁾

500 mg twice a day

1500 mg twice a day

(1) For children with a body weight of 25 kg or less, it is recommended that the drug be administered in a dosage form for oral administration, 100 mg / ml

(2) The dosage regimen in children weighing 50 kg or more is not different from adults.

Mode of application

Inside, squeezed enough water, regardless of food intake. The daily dose is divided into two equal doses.

Side effects:

Summary of security profile

The adverse event profile presented below is based on the analysis of placebo-controlled clinical studies of levetiracetam for all indications (total number of patients is 3416). These data are supplemented by data on the use of levetiracetam in the context of open extended clinical trials, as well as post-registration data. The most frequently reported adverse reactions were nasopharyngitis, drowsiness, headache, weakness and dizziness. The safety profile of levetiracetam generally does not differ depending on age (in adults and children), and also does not depend on approved indications for use (various variants of epilepsy).

Table data on adverse reactions

Undesirable reactions revealed in clinical trials and in the framework of post-registration monitoring (in adults, adolescents and children over the first month) are presented in the table for system-organ classes and frequency. Frequency grading: very often (≥ 1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10,000 and <1/1000 ) and very rarely (<1/10 000).

System-Organ Class	Frequency Category
System-Organ Class	Often	Often	Infrequently	Rarely
Infections and invasions	Nasopharyngitis			Infections
From the side of blood and lymphatic systems			Thrombocytopenia, leukopenia¹	Pancytopenia^1,2, neutropenia¹
Metabolic and nutritional disorders		Anorexia	Decrease¹ or weight gain
Mental violations		Depression, hostility or aggression¹, sleep disturbance, nervousness, irritability	Suicidal attempts¹, suicidal thoughts¹, psychotic disorders¹, violation of behavior¹, hallucinations, anger, confusion consciousness, emotional lability. change mood, agitation	The suicide¹, disorder personality, violation of thinking
From the nervous system	Drowsiness, headache	Convulsions, imbalance, dizziness, lethargy, tremor	Amnesia, violation of memory, violation of coordination movements or ataxia, paresthesia¹, disorder attention	Choreoathetosis¹, dyskinesia¹, hyperkinesia
From the side of the organ of vision			Diplopia, impaired vision
From the side of the organ of hearing and balance		Vertigo
On the part of the respiratory system, the organs of the thorax and the mediastinum		Cough
From the gastrointestinal tract		Abdominal pain, diarrhea, indigestion, vomiting, nausea		Pancreatitis
From the side of the liver and bile excretory ways			Violation of functional liver tests¹	Liver failure¹, hepatitis¹
From the skin and subcutaneous tissues		Rash	Alopecia¹, eczema, itching	Toxic epidermal necrolysis¹, syndrome Stevens- Johnson, multiform erythema¹
From the musculoskeletal and connective tissues			Muscle weakness, myalgia
Are common disorders and disorders at the site of administration		Asthenia or fatigue
Injury, poisoning and complications of procedures			Injury
1Undesirable reactions identified in the post-marketing period 2In some cases, oppression of bone marrow hematopoiesis has been established

Description of individual adverse reactions

With the simultaneous use of topiramate and levetiracetam, the risk of anorexia increases.

In some cases of alopecia, it was reversed after the removal of levetiracetam.

Children

Within the placebo-controlled and open-ended extended trials, 645 patients aged 4-16 years were treated, 233 of whom received levetiracetam in the frame of placebo-controlled studies. For both age ranges, data are also available on the post-registration experience of levetiracetam.

The safety profile of levetiracetam generally does not differ depending on age (in adults and children), and also does not depend on approved indications for use (various variants of epilepsy). With the exception of behavioral and psychiatric adverse reactions that occurred more frequently in children than in adults, in placebo-controlled studies, the safety profile of levetiracetam in children was comparable to that of adults. In children aged 4-16 years, vomiting (very often, 11.2%), agitation (often, 3.4%), mood changes (often, 2.1%), emotional lability (often, 1.7%) , aggression (often, 8.2%), behavioral disorders (often 5.6%) and lethargy (often, 3.9%) were more frequent than in other age ranges.

Cognitive and neuropsychological effects of levetiracetam in children aged 4-16 with partial seizures were evaluated in double-blind, placebo-controlled studies of the safety profile using design of not less safety. It was shown that levetiracetam is no different (no less safe) from placebo in terms of changes from baseline values on the "Leiter-R Attention and Memory" scale, the "Memory Screen Composite" scale in patients subjected to analysis "by protocol." The results of a study of behavioral and emotional functions confirming the occurrence of aggressive behavior against levetiracetam have been obtained using a standardized method using the validated Achenbach Child Behavior Checklist.

However, in patients who took levetiracetam long-term in the framework of open studies, there were no violations of behavioral and emotional functions, in particular, the level of aggressive behavior did not differ from the initial one.

Overdose:

Symptoms

Drowsiness, agitation, aggression, oppression of consciousness, respiratory depression and coma.

Treatment

After an acute overdose, wash the stomach or induce vomiting.

The antidote of levetiracetam was not found. Treatment is symptomatic, may include the use of hemodialysis. Dialyzing activity against levetiracetam is 60%, with respect to the main metabolite - 74%.

Interaction:

Anticonvulsants

According to pre-registration clinical studies levetiracetam does not affect the serum concentrations of other anticonvulsants: phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone - and these anticonvulsants do not affect the pharmacokinetics of levetiracetam.

Similar to adults, in children at doses up to 60 mg / kg / day levetiracetam does not interact with other drugs.

A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4-17 years) confirms that levetiracetam as an auxiliary therapy does not affect the equilibrium serum concentrations of simultaneously used carbamazepine and valproic acid. However, there is evidence that the clearance of levetiracetam in children taking anticonvulsant drugs - inducers of microsomal liver enzymes - is increased by 20%.Correction of the dose is not required.

Probenecid

Probenecid (500 mg 4 times a day) is a blocker of tubular secretion in the kidneys, it is shown that it inhibits renal clearance of the main metabolite, but not levetiracetam. Nevertheless, the concentration of the main metabolite remains low.

It is expected that other drugs excreted through active tubular secretion can reduce the renal clearance of the main metabolite. The effect of levetiracetam on probenecid has not been studied; the effect of levetiracetam on other drugs excreted by active tubular secretion, including non-steroidal anti-inflammatory drugs, sulfonamide and methotrexate, it is not known.

Oral contraceptives and other pharmacokinetic interactions

Levetiracetam at a dose of 1000 mg per day had no effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); The hormonal status (the content of luteinizing hormone and progesterone) did not change. Levetiracetam in a dose of 2000 mg per day did not affect the pharmacokinetics of digoxin and warfarin, prothrombin time did not change.The simultaneous use of digoxin, oral contraceptives and warfarin did not affect the pharmacokinetics of levetiracetam.

Antacids

Data on the effect of antacids on the absorption of levetiracetam are absent.

Food and alcohol

Food does not affect the degree of absorption of levetiracetam, but somewhat reduces its rate.

Data on the interaction of levetiracetam with ethanol are absent.

Special instructions:

Abolition of therapy

It is recommended to cancel the drug gradually. For example, in adults and adolescents with a body weight of more than 50 kg: dose reduction should be carried out at a step of 500 mg 2 times a day no more often than every 2-4 weeks; in children from 6 years old with a body weight of less than 50 kg: dose reduction should be carried out in increments of no more than 10 mg / kg 2 times a day no more often than every two weeks.

Renal insufficiency

The use of levetiracetam in patients with renal insufficiency may require dose adjustment. In patients with severe hepatic insufficiency, it is recommended to evaluate the function of the kidneys before starting the dose selection (see the section "Dosage and Administration").

Suicide

In patients taking anticonvulsants (including levetiracetam), there was suicide, suicide attempts, suicidal thoughts and behavior. A meta-analysis of randomized placebo-controlled trials of anticonvulsant drugs showed a slight increase in the risk of suicidal thoughts and behavior. The mechanism of its implementation is not known.

In connection with the foregoing, it is necessary to monitor patients with symptoms of depression or suicidal thoughts and behavior and prescribe appropriate therapy. Patients (and carers) should be informed of the need to seek medical help if they develop symptoms of depression and / or suicidal thoughts and behavior.

Children

Tablets are not intended for use in children younger than 6 years. According to available data levetiracetam does not affect growth and puberty. However, the long-term impact on learning, intelligence, growth, endocrine function, puberty and child fertility is not known.

Effect on the ability to drive transp. cf. and fur:

Studies on the impact on the ability to drive vehicles and work with mechanisms have not been conducted.

Due to individual differences in susceptibility, some patients may experience drowsiness and other disorders from the central nervous system, especially at the beginning of therapy and after increasing the dose. Therefore, it is recommended to use caution when driving vehicles and engaging in other activities that require an increased concentration of attention and speed of psychomotor reactions. If these symptoms occur, patients should be denied such activities until they are convinced that these symptoms do not have a significant effect on them.

Form release / dosage:Tablets, film-coated 250 mg, 500 mg, 1000 mg.

Packaging:For 10 tablets in a contour mesh package (blister) from a polyvinylchloride film and aluminum foil. For 3 or 6 blisters together with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002021

Date of registration:05.03.2013 / 21.04.2016

Expiration Date:05.03.2018

The owner of the registration certificate:GEROPHARM, LLC GEROPHARM, LLC Russia

Manufacturer: & nbsp

ACTAVIS, Ltd. Iceland

GEROPHARM, LLC Russia

Information update date: & nbsp11.03.2018

Illustrated instructions

Instructions

Levitinol® (Levetinol)