Lariam® (Lariam®)

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  • Lariam®
    pills inwards 
    Hoffmann-La Roche Ltd.     Switzerland
  • Meflokhin
    pills inwards 
    FARMZASCHITA NPC, GP     Russia
    • Dosage form: & nbsppills
    Composition:

    One tablet contains:

    active substance: mefloquine - 250 mg (in the form of mefloquine hydrochloride - 274.09 mg);

    Excipients: poloxamer 3800 - 2.94 mg, microcrystalline cellulose - 63.02 mg, lactose monohydrate - 50.61 mg, corn starch - 28.88 mg, crospovidone - 40.00 mg, calcium ammonium alginate - 11.76 mg, talc - 11.00 mg, magnesium stearate - 11.00 mg.

    Description:

    Tablets are white or almost white in color, flat-cylindrical, with a bevelled edge.

    Two mutually perpendicular risks are placed on the tablet on both sides, dividing the tablet into four parts. On one side, tablets in three parts are engraved RO-C-HE, in the fourth part - a hexagon (hexagon).

    The diameter of the tablet: 11.5 - 2.7 mm; thickness of the tablet: 3,3-4,1 mm.

    Pharmacotherapeutic group:Anti-malarial drug
    ATX: & nbsp

    P.01.B.C.02   Meflokhin

    Pharmacodynamics:

    Lariam® acts on asexual intracellular erythrocyte forms of human malaria pathogens Plasmodium falciparum, Plasmodium vivax, on circulating schizonts Plasmodium malariae and Plasmodium ovale.

    Heis active against hepatic stages of parasites.

    Effective against malaria pathogens resistant to other antimalarial drugs, for example, chloroquine, proguanil, pyrimethamine and combinations of pyrimethamine with sulfonamides.

    For R. falciparum it is possible to develop resistance to mefloquine mainly in Southeast Asia. In some regions cross-resistance between mefloquine and halofantrine, mefloquine and quinine has been noted.

    To obtain up-to-date information on resistance in different geographic regions, it is necessary to consult with national expert organizations.

    The drug does not cause hemolysis associated with insufficiency of glucose-6-phosphate dehydrogenase.

    Pharmacokinetics:

    Suction

    Absolute bioavailability of mefloquine after oral administration was not evaluated (there is no intravenous form of release). Bioavailability of the tablet form is more than 85% of that when the solution is taken orally.

    Food intake significantly speeds up the rate and increases the degree of absorption by 40%.

    The average time to reach the maximum concentration of mefloquine after a single dose is 17 hours (6-24 hours).The maximum plasma concentrations in μg / L are approximately equal to the dose taken in mg (for example, a single dose of 1000 mg gives a maximum concentration of about 1000 μg / l). After taking 250 mg once a week, the equilibrium maximum plasma concentration, equal to 1000-2000 μg / l, is achieved after 7-10 weeks. To achieve 95% effectiveness of prevention, a concentration of mefloquine in the blood, equal to 620 ng / ml.

    Distribution

    The volume of mefloquine distribution is 20 l / kg, which indicates the penetration of the drug into many tissues. It accumulates in erythrocytes, inside which there are malarial parasites, in concentrations about twice as large as plasma ones. Penetrates through the placenta and into breast milk. Excretion in breast milk, apparently, is minimal (see the section "Application during pregnancy and during breast-feeding"). Communication of the preparation with plasma proteins 98%.

    Metabolism

    Metabolism of mefloquine is mostly carried out in the liver with the participation of cytochrome P450. In studies in vitro and in vivo it was shown that mefloquine is metabolized mainly by isoenzyme CYP3A4 with the formation of 2 metabolites: the main metabolite is 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid and alcohol. The main metabolite is inactive with respect to R. falciparum, appears in the plasma 2-4 hours after a single oral intake of the drug, its maximum plasma concentrations are 50% higher than those of mefloquine and are reached after 2 weeks. After that, the decrease in the concentrations of the main metabolite and mefloquine in plasma occurs at the same rate. The area under the concentration-time curve of the main metabolite is 3-5 times higher than that for the initial preparation. Another metabolite, alcohol, is present in very small quantities.

    Excretion

    The mean half-life of mefloquine is 3 weeks (2 to 4 weeks), does not change with prolonged antimalarial prophylaxis. It is excreted in the form of metabolic products mainly with bile and feces. The total clearance, most of which is hepatic, is 30 ml / min. The excretion of unchanged mefloquite and its main metabolite by the kidneys is about 9% and 4%, respectively. Other metabolites in the urine are not detected.

    Pharmacokinetics in special cases

    In acute malaria, changes in pharmacokinetic parameters may occur.

    Children and senile patients

    Age does not affect the pharmacokinetics of mefloquine.

    Renal insufficiency

    Pharmacokinetic studies in patients with renal insufficiency have not been carried out, since very small amounts of the drug are excreted with the kidneys.

    In any significant quantities mefloquine and its main metabolite with the help of hemodialysis are not deduced.

    Dose adjustments for hemodialysis patients are not required.

    Liver failure

    In patients with impaired hepatic function, the excretion of mefloquine can be slowed down, so that plasma concentrations of the drug increase.

    Pregnancy does not have a clinically significant effect on the pharmacokinetics of mefloquine.

    Race

    Pharmacokinetic differences are of very little clinical importance in comparison with the immune status of the infected patient and the sensitivity of the pathogen.

    Indications:

    Treatment mild to moderate forms of malaria caused by strains R. falciparum, resistant to other antimalarial drugs, R. vivax and malaria of mixed etiology.

    Given that the sensitivity of the pathogen can vary over time and depending on the geographical area, it is recommended that the guidelines of national and international guidelines are followed.

    Prevention malaria in persons traveling to malaria-dangerous regions, especially in regions with a high risk of infection with strains R. falciparum, resistant to other antimalarial drugs.

    Emergency therapy (self-help): self-administration as an emergency therapy in case of suspected malaria, if urgent medical assistance is not possible.

    Contraindications:

    Hypersensitivity to mefloquine, any components of the drug or drugs close to it (quinine, quinidine).

    Joint use with halofantrine, reception of halofantrine after mefloquine therapy for 15 weeks after the abolition of the latter.

    Joint application with ketoconazole, the administration of ketoconazole after mefloquine therapy for 15 weeks after the abolition of the latter.

    Use for prophylactic purposes with an active form of depression and severe mental disorders, convulsions (including in the anamnesis).

    Children up to 3 months of age or weighing less than 5 kg (experience with the drug is limited).

    Lactose intolerance, lactase deficiency, glucose-galactose malabsorption (due to the presence of lactose in the formulation).

    Carefully:

    Hepatic insufficiency, epilepsy, mental illness, heart disease, age over 65 years. In combination with quinine and quinidine.

    Pregnancy and lactation:

    Pregnancy

    When assigning mefloquine at doses 5-20 times higher than therapeutic for humans, it is teratogenic in mice and rats and embryotoxic effect in rabbits. However, the experience of clinical use of the drug Lariam® did not reveal any embryotoxic or teratogenic effects. Nevertheless, Lariam® should be given in the first trimester of pregnancy only if the expected benefit to the mother exceeds the potential risk to the fetus.

    Women of childbearing age must assign treatment only with the application of reliable contraception during the whole reception time mefloquine and 3 months after the last dose. But when there is a pregnancy against the background of chemoprophylaxis of malaria, the drug Lariam® has no indications for its interruption.

    When administering mefloquine, pregnant women should refer to current international guidelines (eg WHO).

    Breastfeeding period

    The activity of small amounts of mefloquine falling into breast milk is unknown. In children breastfed, whose mothers took Lariam®, no adverse reactions were noted.

    When administering mefloquine, lactating mothers should refer to current international guidelines (eg WHO).

    Dosing and Administration:

    Inside, after eating, squeezed a large amount of fluid (at least 200 ml), in 2-3 hours.

    Mefloquine has a bitter and slightly burning taste. Tablets should be swallowed whole. When prescribed to children or persons who can not swallow the whole tablet, it can be crushed and dissolved in a small amount of water, milk or other beverage. Until the pill is taken, do not remove it from the blister, as they are sensitive to moisture.

    Prevention

    Standard dosing regimen

    Adults and children weighing more than 45 kg - 5 mg / kg (250 mg, 1 tablet) once a week.

    Adults and children with a body weight of 30-45 kg - 3/4 tablets; 20-30 kg - 1/2 tablets; 10-20 kg - 1/4 tablets and pillsWith a body weight of 5-10 kg - 1/8 tablets (approximate part of the pill at the rate of 5 mg / kg body weight).

    The exact doses of the drug for children weighing less than 10 kg if possible, should be prepared and issued by pharmacists.

    Weekly doses of Lariam® should always be taken on the same day of the week. For the first time, the drug should be taken at least a week before arriving in a malaria-endemic region.

    Dosing in special cases

    If the preparation is not started for at least a week before arrival in a malaria-endemic region, it is necessary to prescribe a shock dose of the drug equal to a weekly dose of Lariat®, taken daily for 3 days, and then go to the standard dosing regimen. The use of shock doses increases the likelihood of adverse events. To reduce the risk of malaria after leaving the endemic region, prevention continues for another 4 weeks.

    If the patient is taking other medications, it is advisable to begin prophylaxis 2-3 weeks before departure to ensure that the concomitant medication is well tolerated (see "Interactions with Other Drugs" section).

    If malaria develops during the course of prophylaxis with Larium®, the doctor should carefully consider which drug to choose for therapy.For the appointment of halofantrine, see the section "Interaction with other drugs".

    Treatment

    Standard dosing regimen

    The recommended total therapeutic dose of mefloquine is 20-25 mg / kg.

    Body weight (kg)

    Total dose

    Dose distribution at receptions *

    5-10

    1 / 2-1 tablet


    10-20

    1-2 tablets


    20-30

    2-3 tablets

    2 + 1 tablets

    30-45

    3-4 tablets

    2 + 2 tablets

    45-60

    5 tablets

    3 + 2 tablets

    >60

    6 tablets

    3+2+1 pills

    * The distribution of the total therapeutic dose for 2-3 doses with an interval of 6-8 hours can reduce the frequency and severity of side effects.

    The experience of using total doses exceeding 6 tablets in individuals with excessive body weight is not.

    Dosing in special cases

    Mefloquine is intended for the treatment of uncomplicated malaria caused by R. falciparum. It is common practice to use combination therapy for uncomplicated malaria caused by R. falciparum. Since the sensitivity of the pathogen can vary over time and depending on the geographic region, it is recommended that the guidelines of national and international guidelines be followed during therapy.

    For persons with partial immunity against malaria, for example, residents of malaria endemic regions, a smaller total dose may be sufficient.

    If within 30 minutes after taking the drug the patient has vomiting, you should repeatedly take the full dose of Lariat®. If vomiting occurs 30-60 minutes after admission, an additional half of the dose is prescribed.

    After treatment of malaria caused by R. vivax, for the elimination of hepatic forms of plasmodia, the prophylaxis of relapses using preparations that are derivatives of 8-aminoquinoline (for example, primaquine) is indicated.

    If the full course of treatment with Lariam® medication after 48-72 hours does not lead to an improvement in the patient's condition, it is necessary to decide on the appointment of another remedy.

    If during the prophylaxis, conducted with the help of the drug Lariam®, malaria develops, the doctor should carefully consider which drug to choose for therapy. For the appointment of halofantrine, see the section "Interaction with other drugs".

    In severe acute malaria, Larym® can be given after an initial intravenous course of quinine therapy lasting at least 2-3 days.

    Most drug interactions leading to the development of adverse reactions can be prevented if Laryam® is taken no less than 12 hours after the last dose of quinine.

    In regions with multiresistant pathogens of malaria, initial treatment with artemisinin or its derivatives may be advisable, followed by Laryam® therapy, if possible.

    Independent emergency therapy

    Independent emergency therapy Laryam® is carried out if it is not possible to get emergency medical care within 24 hours after the onset of symptoms.

    The initial dose of Laryam® is 15 mg / kg. Thus, for patients with a body weight of 45 kg or more, 3 tablets (750 mg).

    If medical care continues to be unavailable within 24 hours and there are no serious adverse reactions, then the second part of the total therapeutic dose can be taken in 6-8 hours (for patients with a body weight of 45 kg or more, 2 tablets, 500 mg).

    Sick with a body weight of more than 60 kg After 6-8 hours after repeated administration, take another pill.

    To confirm or exclude a presumptive diagnosis, patients should be advised to see a doctor even if, after self-treatment, they feel completely recovered.

    Side effects:

    In doses prescribed for the treatment of acute malaria, Larym® can produce side effects similar to those of the underlying disease.

    The most frequent side effects during the prophylaxis of the drug Lariam® are usually poorly expressed and may decrease with continued use of the drug, regardless of the increasing concentration of the drug in the plasma: nausea, vomiting, dizziness.

    The safety profile of mefloquine in preventive use is characterized by the predominance of neuropsychic reactions (see section "Special instructions").

    The following data on adverse reactions are given on the basis of clinical studies of the drug Lariam® and post-marketing experience of the drug.

    According to a study of the preventive use of mefloquine in patients who do not have immunity and plan a trip, adverse events from the nervous system and the psychic sphere arose in 28.8% of patients who received mefloquine, compared with 14% of patients who received atovaquone in combination with proguanil (see tables below). Serious adverse events associated with the use of the drug in both groups were not observed.

    Undesirable effects associated with the use of the drug *

    Phenomenon

    Meflokhin

    n=483

    Number (%)

    Atovokwon-proganyan

    n=493

    Number(%)

    Any undesirable phenomenon

    204 (42,2)

    149 (30,2)

    Any neuropsychic phenomenon

    139 (28,8)

    69 (14)

    - Unusual or vivid dreams

    66 (13,7)

    33 (6,7)

    - Insomnia

    65 (13,5)

    15 (3)

    - Vertigo or vertigo

    43 (8,9)

    11 (2,2)

    - Visual disturbances

    16 (3,3)

    8 (1,6)

    - Anxiety

    18 (3,7)

    3 (0,6)

    - Depression

    17 (3,5)

    3 (0,6)

    Any phenomenon from the gastrointestinal tract

    94 (19,5)

    77 (15,6)

    - Diarrhea

    34 (7)

    37 (7,5)

    - Nausea

    40 (8,3)

    15 (3)

    - Abdominal pain

    23 (4,8)

    26 (5,3)

    - Ulcers in the mouth

    17(3,5)

    29 (5,9)

    - Vomiting

    9 (1,9)

    7 (1,4)

    Headache

    32 (6,6)

    19 (3,9)

    Itching

    15 (3,1)

    12 (2,4)

    * The mean duration of treatment ± SD was 53 ± 16 days with mefloquine and 28 ± 8 days with atovaquone-proguanil.

    Undesirable effects associated with the use of the drug, limited to the period of treatment*

    Phenomenon

    Meflokhin

    n=483

    Number (%)

    Atovokwon-proganyan

    n=493

    Number (%)

    Any phenomenon during the treatment period

    24 (5)

    6 (1,2)

    Any neuropsychic phenomenon

    19 (3,9)

    3 (0,6)

    - Insomnia

    12 (2,5)

    2 (0,4)

    - Anxiety

    9 (1,9)

    1 (0,2)

    - Unusual or vivid dreams

    7 (1,4)

    1 (0,2)

    - Vertigo or vertigo

    7 (1,4)

    1 (0,2)

    - Depression

    3 (0,6)

    0 (0)

    - Visual disturbances

    3 (0,6)

    0 (0)

    - Concentration disorders

    3 (0,6)

    0 (0)

    - Other

    4 (0,8)

    0 (0)

    Any phenomenon from the gastrointestinal tract

    7 (1,4)

    1 (0,2)

    Headache

    6 (1,2)

    1 (0,2)

    Other

    6 (1,2)

    2 (0,4)

    * Average duration of treatment ± CO was 53 ± 16 days with mefloquine and 28 ± 8 days with atovaquone-proguanil.

    In studies in vitro and in vivo it was shown that the drug does not cause hemolysis associated with insufficiency of glucose-6-phosphate dehydrogenase.

    Experience of post-registration application

    Undesirable reactions are classified according to the classes of organ systems and the absolute frequency of occurrence of MedDRA. The incidence was determined as follows: very often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and <1 / 1000), very rarely (<1/10000), the frequency is unknown (it is impossible to determine the frequency based on the available data). Due to the long-term presence of the drug on the market, the data presented in the list of undesirable reactions listed below reflect the frequency of occurrence of the messages received, and not the frequency of cases observed in controlled studies.

    Violations of the blood and lymphatic system

    Often: thrombocytopenia.

    Infrequently: leukopenia, leukocytosis.

    The frequency is unknown: agranulocytosis and aplastic anemia.

    Disorders from the metabolism and nutrition

    Often: anorexia.

    Disorders of the psyche

    Very often: sleep disturbances (insomnia, nightmarish dreams).

    Often: agitation, anxiety, anxiety,depression, aggression, emotional lability, panic attacks, confusion, hallucinations, bipolar disorder, psychotic reactions, including delusional disorder, depersonalization and mania, paranoia. Infrequently, these symptoms persisted for a long time after the discontinuation of mefloquine.

    There have been reports of suicide, suicidal thoughts, behavior at risk of self-harm, for example, suicidal attempts.

    Disturbances from the nervous system

    Very often: dizziness, loss of balance, headache, drowsiness.

    Often: fainting, memory impairment, sensory and motor neuropathies (including paresthesia, tremor, ataxia), seizures.

    Infrequently: encephalopathy.

    Disturbances on the part of the organ of sight

    Often: impaired vision.

    The frequency is unknown: blurred vision, cataracts, retinal lesions and neuropathy of the optic nerve with the possibility of delayed manifestation, both during and after the end of therapy.

    Hearing disorders and labyrinthine disorders

    Very often: vertigo.

    Often: hearing impairment, vestibular disorders, including ringing in the ears.

    Heart Disease

    Often: tachycardia, palpitations, bradycardia, arrhythmia, extrasystoles, other transient disorders of cardiac conduction.

    Infrequently: AV-blockade.

    Vascular disorders

    Often: circulatory disorders (decrease, increase in blood pressure, hot flashes).

    Disturbances from the respiratory, thoracic and mediastinal organs

    Often: shortness of breath.

    Very rarely: pneumonia, pneumonitis (possibly allergic etiology).

    Disorders from the gastrointestinal tract

    Very often: nausea, diarrhea, abdominal pain, vomiting.

    Often: indigestion.

    Disturbances from the liver and bile ducts

    The frequency is unknown: liver dysfunction associated with the use of the drug (from asymptomatic transient increase in the activity of transaminases to liver failure).

    Disturbances from the skin and subcutaneous tissues

    Often: skin rash, exanthema, erythema, urticaria, pruritus, alopecia, hyperhidrosis.

    Infrequently: erythema multiforme, Stevens-Johnson syndrome.

    Disturbances from musculoskeletal and connective tissue

    Often: muscle weakness, muscle cramps, myalgia, arthralgia.

    Laboratory and instrumental data

    Often: transient increase in transaminase activity.

    General disorders and disorders at the site of administration

    Often: swelling, chest pain, weakness, poor health, fatigue, chills, fever.

    Overdose:

    Symptoms: see section "Side effect", but more pronounced.

    Treatment: In case of an overdose, symptomatic and supportive therapy is recommended. There is no specific antidote.

    Interaction:

    Simultaneous reception of the drug Lariam® and quinine, quinidine and chloroquine can cause changes on the ECG and increase the risk of seizures (see section "Method of administration and dose").

    The use of halofantrine concomitantly with the Larym® preparation and also within 15 weeks after the last dose of Laryam® preparation resulted in a significant lengthening of the interval QTc (interval QT, corrected for heart rate, is calculated by the formula: QTc=QT/RRl/2, where RR - the time interval between adjacent teeth R on the ECG, equal to the duration of the cardiac cycle) (see section "Special instructions").

    Simultaneous reception of the drug Lariam® and ketoconazole increases the concentrations of mefloquine in the plasma and its half-life.The administration of ketoconazole concomitantly with Laryam®, as well as within 15 weeks after the last dose of Lariat®, may prolong the interval QTc. When treating only mefloquine clinically significant lengthening QTc can not be.

    Simultaneous reception of other drugs that affect cardiac conduction (antiarrhythmics, beta-blockers, blockers of "slow" calcium channels, antihistamines, in particular blockers H1-gistaminovyh receptors, tricyclic antidepressants and phenothiazines) also theoretically can play a role in the lengthening of the interval QTc.

    The effect of simultaneous use of mefloquine and the above drugs on cardiac function has not been fully established.

    Simultaneous use of mefloquine with drugs that reduce the epileptogenic threshold (tricyclic antidepressants, selective serotonin reuptake inhibitors, bupropion, antipsychotics, tramadol and chloroquine), may increase the risk of seizures.

    Reduces the effectiveness of anticonvulsants (valproic acid, carbamazepine, phenobarbital or phenytoin), reducing their concentrations in the plasma.It is necessary to monitor the concentration of drugs in the plasma. In some cases, a dose adjustment of anticonvulsants may be required.

    Lariam® can reduce the immunogenicity of oral live typhoid vaccines when taken concomitantly, so vaccination with live attenuated vaccines should be completed at least 3 days before the first dose of Lariat®.

    Other medicinal interactions of the drug Lariam® are unknown. But people who receive other drugs, in particular anticoagulants or hypoglycemic agents, must undergo medical supervision before leaving for the endemic region.

    Other possible interactions

    Mefloquine is not an inhibitor or inducer of cytochrome P450. Therefore, it can be expected that the metabolism of drugs prescribed simultaneously with mefloquine will remain unchanged. However, isoenzyme inhibitors CYP3A4 can alter the pharmacokinetics and metabolism of mefloquine, which can lead to an increase in the concentration of mefloquine in the plasma and the possible development of undesirable reactions. In this regard, care should be taken when using mefloquine and isoenzyme inhibitors CYP3A4.

    Inductors of isoenzyme CYP3A4 can also alter the pharmacokinetics and metabolism of mefloquine, which may lead to a decrease in plasma mefloquine concentrations.

    Inhibitors isoenzyme CYP3A4

    A study with healthy volunteers showed that simultaneous administration of ketoconazole, a strong inhibitor of isoenzyme CYP3A4, and mefloquine led to an increase in the concentration of the latter in the plasma and the period of its half-elimination.

    Inductors isoenzyme CYP3A4

    Prolonged use of rifampicin, a powerful isoenzyme inducer CYP3A4, led to a decrease in the concentration of mefloquine in the plasma and its half-life.

    Substrates and inhibitors of P-glycoprotein

    Mefloquine is an inhibitor of P-glycoprotein according to studies in vitro. Therefore, the possibility of drug interaction of mefloquine with preparations that are substrates of P-glycoprotein or having the ability to change the expression of this transporter can not be ruled out. The clinical significance of this interaction is currently unknown. In clinical trials ritonavir, which is a potent inhibitor of P-glycoprotein and CYP3A4, had no effect on the pharmacokinetics of mefloquine in healthy volunteers.

    Special instructions:

    The drug Lariam® may increase the risk of seizures in patients with epilepsy. Therefore, for such patients, the drug can be administered only for the purpose of treatment and in the presence of absolute indications for its use (see also section "Interaction with other drugs").

    After taking quinine or quinidine, take mefloquine can not be earlier than 12 hours.

    In patients with impaired hepatic function, delayed excretion of mefloquine is possible, which may lead to an increase in plasma concentrations of the latter and an increased risk of unwanted reactions.

    With a preventive appointment for a long time (taking the drug for more than 1 year is not desirable), periodic analysis of the liver function and ophthalmological examination is necessary.

    The safety profile of mefloquine in preventive use is characterized by a predominance of neuropsychic reactions, such as anxiety, depression, anxiety or confusion. In case of occurrence of these undesirable phenomena, therapy with Laryam® should be discontinued and another drug should be prescribed.

    Due to the long half-life of mefloquine, unwanted reactions can develop or persist after completion of the drug.

    A small number of patients described the development of psychoneurological disorders (including depression, dizziness and vertigo, and loss of balance) that were observed for several months or more after discontinuation of the drug.

    With the use of mefloquine, cases of impaired vision were reported, including optic nerve neuropathy and retinal lesions (including maculopathy). If visual impairment occurs, you should consult your doctor to consider the possibility of continuing treatment with Lariam®.

    If the symptoms of polyneuropathy develop, including pain, burning, tingling, numbness and / or weakness, treatment with the drug should be discontinued.

    The choice of a drug for the prevention of malaria depends on the resistance to it R. falciparum in a particular region (see section "Pharmacological action").

    When the drug was used, cases of agranulocytosis and aplastic anemia were reported (see "Side effect").

    The presence of drugs in the environment should be minimized. Do not dispose of the drug Lariam® with the help of waste water or together with household waste.

    If possible, it is necessary to use special systems for the disposal of medicinal products.

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

    During treatment it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

    Form release / dosage:

    Tablets, 250 mg.

    Packaging:

    4 tablets per blister of a three-layer film (OPA/Al/PVC) and aluminum foil.

    2 blisters together with instructions for use are placed in a cardboard box.

    Storage conditions:

    Store at a temperature of no higher than 30 ° C, in a dry place.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:П N016036 / 01
    Date of registration:05.10.2009 / 21.04.2010
    Expiration Date:Unlimited
    Date of cancellation:2018-02-27
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp27.02.2018
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