Active substanceLinezolidLinezolid
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  • Dosage form: & nbsptfilm-covered laths
    Composition:

    For one tablet:

    Active substance: linezolid - 600 mg;

    Excipients: lactose monohydrate 222.0 mg, hypromellose 12.0 mg, polacrilin potassium 12.0 mg, magnesium stearate 9.0 mg, silicon dioxide colloid 5.0 mg.

    Sheath: Opaprai white 03V58895 17.2 mg (hypromellose (E464) 61.5%, titanium dioxide (E171) 31.0%, macrogol 400 6.25%, carnauba wax (E903) 1.25%).

    Description:Oval, biconvex tablets covered with a film shell of white or almost white color, with a bevel, with an engraved "I" on one side and "22" on the other side.
    Pharmacotherapeutic group:Antibiotic-oxazolidinone
    ATX: & nbsp

    J.01.X.X.08   Linezolid

    J.01.X.X   Other antibacterial drugs

    Pharmacodynamics:

    Linezolid, a synthetic antibacterial drug, belongs to a new class of antimicrobial agents, oxazolidinones. Linezolid selectively inhibits protein synthesis in bacteria. By binding to the bacterial ribosome, it prevents formation of a functional initiation complex 70SWhich is an essential component of the translation process of protein synthesis.

    Linezolid active in vitro and in vivo in relation to the following microorganisms: Gram-positive aerobes - Enterococcus faecium (including strains resistant to vancomycin); Staphylococcus aureus (including methicillin-resistant strains); Streptococcus agalactiae, Streptococcus pneumoniae (including multidrug-resistant strains); Streptococcus pyogenes.

    Linezolid is active in vitro for the following microorganisms: Gram-positive aerobes - Enterococcus faecalis (including strains resistant to vancomycin); Enterococcus faecium (including strains sensitive to vancomycin); Staphylococcus epidermidis (including methicillin-resistant strains); Staphylococcus haemolyticus, Streptococcus spp. groups viridans; gram-negative aerobes - Pasteurella multocida.

    Resistant to linezolid microorganisms: Haemophilus influe psae, Moraxella catarrhalis, Neisseria spp., Enterobacteriaceae spp.. Pseudomonas spp.

    The mechanism of action of linezolid differs from the mechanisms of action of antimicrobials of other classes (for example, aminoglycosides, beta-lactams, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifampicins, streptogramins, tetracyclines and chloramphenicol), so there is no cross-resistance between linezolid and these drugs. Linezolid is active against pathogenic microorganisms, both sensitive and resistant to these drugs. Resistance to linezolid develops slowly through a multistage mutation 23S ribosomal ribonucleic acid (RNA) and occurs at a frequency of less than 1x10-9 - 1x10-11.

    Pharmacokinetics:

    Suction

    After oral administration linezolid quickly and intensively absorbed from the gastrointestinal tract (GIT). The maximum concentration of linezolid in blood plasma (CmOh) when applied at a dose of 600 mg every 12 hours is 21.2 mg / l, and when administered at a dose of 400 mg every 12 hours - 11 mg / l; the average period of time until the maximum concentration of linezolid in the blood plasma (TSmOh) -2 h, the absolute bioavailability is about 100%. The intake of food does not affect the absorption of linezolid. Equilibrium concentration of linezolid in blood plasma is achieved on the 2nd day of admission.

    Distribution

    The volume of distribution of linezolid at equilibrium concentration in a healthy adult is on the average 40-50 liters, which is approximately equal to the total water content in the body. Binding to plasma proteins is 31% and does not depend on the concentration of linezolid in blood plasma.

    Metabolism

    It is established that the isoenzymes of the cytochrome P450 system do not participate in the metabolism of linezolid in vitro. Linezolid does not inhibit or potentiate the activity of clinically important isoenzymes of the cytochrome P450 system (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).Metabolic oxidation leads to the formation of two inactive metabolites - hydroxyethyl glycine (the main metabolite in humans, formed as a result of a non-enzymatic process) and aminoethoxyacetic acid (formed in smaller amounts). Other inactive metabolites are also described.

    Excretion

    The extrarenal clearance is about 65% of the linezolid clearance. With increasing dose of linezolid, a small degree of nonlinearity of clearance is noted. This can be explained by a decrease in renal and extrarenal clearance with a high dose of linezolid. However, the differences in clearance are small and do not affect the apparent half-life.

    Linezolid in patients with normal renal function and with renal insufficiency of mild and moderate severity is excreted by the kidneys in the form of hydroxyethyl glycine (40%), aminoethoxyacetic acid (10%) and unchanged (30-35%). The intestine is excreted as hydroxyethyl glycine (6%) and aminoethoxyacetic acid (3%). Linezolid in an unmodified form is practically not excreted by the intestine.

    The half-life of linezolid is 5-7 hours on average.

    Pharmacokinetics in selected patient groups

    Patients with renal insufficiency

    After a single dose of 600 mg of linezolid in patients with severe renal insufficiency (creatinine clearance <30 ml / min), the plasma concentration of two major metabolites increases by 7-8 times. However, the increase in the area under the concentration-time curve (AUC) linezolid is not observed. Despite the fact that some basic metabolites are removed during hemodialysis, their concentration in the blood plasma after taking 600 mg of linezolid and carrying out the dialysis procedure remains significantly higher than the concentration in the blood plasma in patients with normal kidney function, mild or moderate renal insufficiency.

    Patients with hepatic insufficiency

    There is limited evidence that the pharmacokinetics of linezolid and its two major metabolites do not change in patients with mild to moderate hepatic insufficiency (class A and B according to the Child-Pugh classification). The pharmacokinetics of linezolid in patients with severe hepatic insufficiency (class C according to the Child-Pugh classification) has not been studied. However, since linezolid it is not metabolized by a non-enzyme route, it is not expected to significantly impair its metabolism in liver failure.

    Children and teens

    In adolescents (12-17 years old), the pharmacokinetics of linezolid, taken at a dose of 600 mg, does not differ from the kinetics in adults. Thus, when 600 mg of linezolid is used in adolescents every 12 hours, its plasma concentration will be the same as in adults when administered in the same dose.

    Elderly patients

    In elderly patients aged 65 years and older, the pharmacokinetics of linezolid do not change significantly.

    Female Patients

    In women, the distribution of linezolid is somewhat lower than that of men; they also reduced by 20% the average clearance in terms of body weight. The concentration of linezolid in the blood plasma of women is higher than that of men, which can partly be explained by differences in body weight. However, since the half-life of linezolid in men and women is not significantly different, there is no reason to expect an increase in the concentration of linezolid in the blood plasma of women above the tolerable level, so no dose adjustment is required.

    Indications:

    Treatment of infectious inflammatory diseases, if known or suspected, that they are caused by aerosol and anaerobic Gram-positive microorganisms sensitive to linezolid (including infections accompanied by bacteremia):

    - community-acquired pneumonia caused by Streptococcus pneumoniae (including multidrug-resistant strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (only methicillin-sensitive strains);

    - hospitalized pneumonia caused by Staphylococcus aureus (including strains sensitive and insensitive to methicillin) or Streptococcus pneumoniae (including multidrug-resistant strains);

    - complicated skin and soft tissue infections, including infections with diabetic foot syndrome not accompanied by osteomyelitis, caused by Staphylococcus aureus (including strains sensitive and insensitive to methicillin), Streptococcus pyogenes or Streptococcus agalactiae;

    - Uncomplicated skin and soft tissue infections caused by Staphylococcus aureus (only methicillin-sensitive strains) or Streptococcus pyogenes;

    - infections caused by Enterococcus faecium (strains resistant to vancomycin), including those accompanied by bacteremia.

    Contraindications:

    Hypersensitivity to linezolid and / or other components of the drug.

    Simultaneous administration of linezolid with preparations that inhibit monoamine oxidase A or B (for example, phenelzine, isocarboxazide), and also within two weeks after discontinuation of these drugs.

    In the absence of careful monitoring of patients and monitoring of blood pressure, linezolid should not be prescribed:

    - patients with uncontrolled arterial hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome, bipolar disorder, schizoaffective disorder and acute confusion;

    - patients receiving the following types of drugs: adrenomimetics (for example, pseudoephedrine, phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (eg, dopamine), serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT agonists1receptors (triptans), meperidine, or buspirone.

    Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

    Children under 12 years of age (for this dosage form in view of the impossibility of adequate dose selection).

    Carefully:

    Patients with renal insufficiency

    Due to the unexplained clinical significance of the two primary metabolites of linezolid in patients with severe renal failure, linezolid should be used with caution in such patients, and only if the intended benefit exceeds the potential risk. There is also no data on the use of linezolid in patients,who are on ambulatory peritoneal dialysis or other alternative methods of treating renal failure.

    Patients with hepatic insufficiency

    There are limited clinical data that recommend the use of linezolid in such patients only if the intended benefit exceeds the potential risk. Linezolid should be used with caution in patients with systemic infections posing a risk to life, such as those associated with venous catheters in intensive care units.

    Pregnancy and lactation:

    There were no studies of the safety of linezolid in pregnancy. The use of the drug during pregnancy is possible only if the expected benefit for the mother exceeds the potential risk to the fetus.

    It is not known whether linezolid in breast milk, and therefore breastfeeding should be discontinued for the period of treatment with the mother's drug during lactation.

    Dosing and Administration:

    The drug can be taken both during meals and between meals.

    Patients who at the beginning of therapy linezolid It was prescribed intravenously, in the future it can be transferred to any dosage form of linezolid for oral administration. the bioavailability of linezolid upon ingestion is almost 100%.

    The duration of treatment depends on the pathogen, the localization and severity of the infection, and also on the clinical effect.

    Adults and children 12 years and older

    Indications (including infections accompanied by bacteremia)

    Single dose

    Recommended duration of treatment

    - Community-acquired pneumonia Streptococcus pneumoniae (including multidrug-resistant strains), including cases accompanied by bacteraemia, or Staphylococcus aureus (only methicillin-sensitive strains);

    - hospital pneumonia caused by Staphylococcus aureus (including strains sensitive and insensitive to methicillin) or Streptococcus pneumoniae (including multidrug-resistant strains);



    - complicated skin and soft tissue infections, including infections with diabetic foot syndrome not accompanied by osteomyelitis, caused by Staphylococcus aureus (including strains sensitive and insensitive to methicillin), Streptococcus pyogenes or Streptococcus agalactiae;

    - uncomplicated rumen and soft tissue infections caused by Staphylococcus aureus (only methicillin-sensitive strains) or Streptococcus pyogenes;

    600 mg orally every 12 hours

    10-14 days

    - infections caused by vancomycin-resistant Enterococcus faecium, in number accompanied by bacteremia.

    600 mg orally every 12 hours

    14-28 days

    Elderly patients: correction of the dose is not required.

    Patients with renal insufficiency: dose adjustment is not required. Due to the fact that 30% of linezolid is removed during hemodialysis within 3 hours, linezolid should be taken after dialysis to patients who need it.

    Patients with hepatic insufficiency: dose adjustment is not required.

    Side effects:

    The frequency of the undesirable reactions listed below is represented by the following classification:

    Often:

    ≥10%

    Often:

    ≥1% and <10%

    Infrequently:

    ≥0.1% and <1%

    Rarely:

    ≥0.01% and <0.1%

    Rarely:

    <0,01%

    The undesirable phenomena associated with the use of linezolid are usually of mild or moderate severity. Most often, diarrhea, headache and nausea are noted.

    Adult patients

    From the digestive system: often - diarrhea, nausea, vomiting, constipation, abdominal pain (including spastic), candidiasis of the oral mucosa, dyspepsia,change in the results of functional liver tests; infrequently - change in staining of the tongue and other abnormalities of the tongue, pancreatitis, gastritis, bloating, dry mouth, glossitis, loose stools, stomatitis; rarely - antibiotic-associated colitis, including pseudomembranous colitis, discoloration of the enamel of the teeth.

    Laboratory indicators: often anemia, increased creatine kinase activity, increased fasting glucose concentration, decreased total protein, albumin, sodium or calcium, increased or decreased potassium or bicarbonate, neutrophilia, eosinophilia, decreased hemoglobin, hematocrit or red blood cell count, increased or decreased platelet count, leukocyte count, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (APF), lactate dehydrogenase (LDH), lipase, amylase; infrequently - leukopenia, neutropenia, thrombocytopenia, hyponatremia, increased concentration of sodium or calcium, reduced fasting glucose concentration, increase in the concentration of total bilirubin, creatinine, increase or decrease in the concentration of chlorine in the blood plasma, increase the number of reticulocytes; rarely - pancytopenia.

    From the nervous system: often - insomnia, headache, dizziness, perversion of taste ("metallic" aftertaste); infrequently - cramps, paresthesia, hypoesthesia.

    From the sense organs: infrequently - indistinctness of visual perception, tinnitus; rarely - the defect of the fields of view.

    From the genitourinary system: often vaginal candidiasis, increased urea blood levels; infrequently - polyuria, renal insufficiency, violations of the vagina and vulva, vaginitis.

    From the skin: often - a rash, itching; infrequently - dermatitis, profuse sweating, urticaria.

    From the side of the cardiovascular system: often - Increased blood pressure; infrequently - tachycardia, transient ischemic attack, phlebitis, thrombophlebitis.

    Other: often - fever, local pain; infrequently - an opportunistic fungal infection, chills, fatigue, thirst.

    Children and teens

    From the digestive system: often diarrhea, vomiting, nausea, abdominal pain (local and generalized), loose stools, candidiasis of the oral mucosa, gastrointestinal bleeding.

    Laboratory indicators: often - thrombocytopenia, anemia, hypokalemia, thrombocytosis,infrequently - eosinophilia, elevated blood triglycerides, increased ALT, lipase, amylase, elevated serum creatinine concentration and total bilirubin.

    From the nervous system: often - headache, vertigo, convulsions.

    From the skin: often - a rash, infrequently - a skin itch.

    From the respiratory system: often - infections of the upper respiratory tract, pharyngitis, cough, pneumonia, respiratory failure, apnea.

    Other: often - fever, pain of unspecified localization, sepsis, generalized edema.

    Spontaneous data

    Laboratory data: myelosuppression, sideroblastic anemia.

    From the sense organs: neuropathy of the optic nerve, change in visual acuity, optic neuritis, loss of vision, change in color vision.

    Allergic reactions: anaphylaxis, angioedema, bullous skin lesions similar to Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia.

    From the side of metabolism: lactic acidosis.

    From the nervous system: peripheral neuropathy.

    Other: serotonin syndrome.

    Overdose:

    No cases of overdose have been reported.Symptomatic treatment is recommended (including the need to maintain the glomerular filtration rate). There is no data on the acceleration of deducing linezolid in peritoneal dialysis or hemoperfusion.

    Interaction:

    It is established that cytochrome P450 isoenzymes do not participate in the metabolism of linezolid in vitro. Linezolid does not inhibit or potentiate the activity of clinically important cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Thus, no CYP450-induced interaction is expected when using linezolid.

    With simultaneous use of linezolid and (S) -varpharin, which is largely metabolized by isoenzyme CYP2C9. The pharmacokinetic characteristics of warfarin do not change. Such drugs as warfarin and phenytoin, which are the substrates of the isoenzyme CYP2C9, can be used simultaneously with linezolid without dose adjustment.

    Inhibitors of monoamine oxidase

    Linezolid is a non-selective reversible inhibitor of monoamine oxidase, therefore, in some patients receiving linezolid, there may be a moderate reversible strengthening of the pressor action pseudoephedrine and phenylpropanolamine. In this regard, it is recommended to reduce the initial doses of the following groups of drugs: adrenomimetics (for example, pseudoephedrine, phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (for example, dopamine) and subsequently to carry out the dose selection by titration.

    In studies, there was no development of serotonin syndrome in patients who received linezolid together with serotonergic drugs. However, there were several reports about the development of serotonin syndrome during treatment with linezolid and antidepressants - selective serotonin reuptake inhibitors.

    When used simultaneously with aztreonam and gentamicin there was no change in the pharmacokinetics of linezolid.

    Rifampicin caused a decrease in Cmax and AUC linezolid on average by 21% and 32%, respectively.

    Special instructions:

    With an established infection (or suspected infection) caused by concomitant Gram-negative microorganisms, additional use of agents acting on the Gram-negative microflora is indicated.

    In an open study, among severely ill patients with intravascular catheter-associated infections, there was an excess of mortality in the group of patients who received linezolid, Compared with patients who received vancomycin / dicloxacillin / oxacillin [78/363 (21.5%) vs. 58/363 (16.0%)]. The main factor influencing the mortality rate was the gram-positive pathogen of infection at the initial stage. The mortality rate was similar among patients whose infections were caused only by Gram-positive microorganisms, but was significantly higher in the linezolid group when other microorganisms were detected or could not be detected at the initial stage. The greatest imbalance was noted during treatment and within 7 days after the end of antibiotic therapy. In many patients of the linezolid group, Gram-negative microorganisms were detected during the study, and the cause of death was infections caused by Gram-negative microorganisms or polymicrobial infections. Thus, in case of complicated skin and soft tissue infections, linezolid should be used in patients with known or possible co-infection with Gram-negative microorganisms only if there are no alternative treatment options. In these cases, additional use of drugs acting on gram-negative microflora is shown simultaneously.

    In some patients taking linezolid, reversible myelosuppression may develop (with anemia, thrombocytopenia, leukopenia and pancytopenia), depending on the duration of therapy. In elderly patients, the risk of developing this condition is also increased. Thrombocytopenia occurred more often in patients with severe renal failure who are / are not on dialysis. In connection with this, during the treatment it is necessary to monitor blood values ​​in patients with anemia, granulocytopenia or thrombocytopenia; with an increased risk of bleeding, myelosuppression in the anamnesis, as well as with the simultaneous use of drugs that reduce hemoglobin or the number of platelets and / or affect their functional properties, with severe renal failure, as well as in patients taking linezolid more than 2 weeks. Linezolid these patients are only used when it is possible to carefully monitor the level of hemoglobin, the number of leukocytes and platelets. If during treatment with linezolid develops marked myelosuppression, treatment should be discontinued unless continuation of therapy is considered absolutely necessary.In this case, intensive monitoring of blood counts and appropriate treatment is necessary. In addition, it is recommended that a blood test (including determination of hemoglobin level, platelet count and leukocyte count (with the calculation of the leukocyte count)) be performed weekly in patients receiving linezolid regardless of the initial blood test. A higher incidence of severe anemia was observed in patients who received linezolid more than the maximum recommended duration of 28 days. These patients were more likely to require a blood transfusion. Cases of sideroblastic anemia were registered in the post-marketing period. In most cases, the duration of linezolid therapy exceeded 28 days. In most patients, the manifestations were completely or partially reversible after discontinuation of treatment with linezolid with / without specific treatment for anemia.

    In patients taking antibacterial drugs, including linezolid, should take into account the risk of developing pseudomembranous colitis of varying severity. About cases of diarrhea associated with Clostridium difficile, was reported in connection with the use of almost all antibacterial drugs, including linezolid. The severity of diarrhea can range from mild to severe forms. Treatment with antibacterial drugs disrupts the normal intestinal microflora, which leads to excessive growth Clostridium difficile. Clostridium difficile produces toxins A and B, which lead to the development of diarrhea associated with Clostridium difficile. Excessive amount of toxins produced by strains Clostridium difficile, may cause an increase in mortality among patients, since such infections can be resistant to antimicrobial therapy, and may require a colonectomy. The possibility of developing diarrhea associated with Clostridium difficile, should be considered in all patients with diarrhea that followed the use of antibiotics. Careful medical supervision for 2 months is necessary for patients who have had diarrhea associated with Clostridium difficile after the introduction of antibacterial drugs. If pseudomembranous colitis is confirmed or suspected, antibacterial drugs that do not have activity against FROM. difficile, it is necessary to cancel and prescribe a specific therapy.Drugs that inhibit the intestinal peristalsis are contraindicated.

    When symptoms of impaired visual function appear, such as changes in visual acuity, changes in color perception, blurred vision, visual field defects, it is recommended that you urgently consult an ophthalmologist for advice. Monitor visual function in all patients taking linezolid for a long time (more than 3 months), as well as in all patients with newly emerging symptoms of visual disturbances, regardless of the duration of therapy. In the case of peripheral neuropathy and optic nerve neuropathy, the risk / benefit ratio of linezolid therapy in these patients should be assessed. The risk of developing neuropathy is higher if linezolid It is used in patients who are currently using or who have recently taken antimycobacterial drugs for the treatment of tuberculosis.

    In connection with the use of linezolid, lactoacidosis was reported. Patients who, with the use of linezolid, experience repeated nausea or vomiting, abdominal pain, unexplained acidosis, or a decrease in the concentration of hydrocarbonate anions,require careful monitoring by the doctor.

    Linezolid inhibits the synthesis of the mitochondrial protein. Side effects such as lactic acidosis, anemia and neuropathy (peripheral or optic nerve), may occur as a result of inhibition; these effects are more common when the drug is used more than 28 days.

    Cramping was reported in patients taking linezolid, and in most cases in the history there was an indication of convulsions or the presence of risk factors for their development. Patients need to collect a detailed history of previous episodes of seizures.

    If the drug is to be used in combination with selective serotonin reuptake inhibitors, patients should be constantly monitored to identify signs and symptoms of serotonin syndrome, such as cognitive impairment, hyperpyrexia, hyperreflexia and impaired coordination of movements. If these symptoms appear, you should cancel one or both of the drugs taken. When discontinuing the use of a serotonergic drug, symptoms of the withdrawal syndrome may be observed.

    There have been reports of reversible surface changes in tooth enamel staining with linezolid. These changes in staining were removed by professional dental cleaning.

    There were reported cases of symptomatic hypoglycemia in patients with diabetes mellitus who received linezolid simultaneously with insulin or hypoglycemic drugs. Although a causal relationship between the use of linezolid and the development of hypoglycemia has not been established, patients with diabetes should be warned about the possibility of developing hypoglycemia. In case of hypoglycaemia, correction of insulin dose / hypoglycemic drugs or cancellation of linezolid is necessary.

    Patients using linezolid, you should avoid eating foods or drinks with a high content of tyramine.

    The effect of linezolid on normal microflora has not been studied in clinical studies.

    The use of antibacterial drugs, including linezolid, can lead to excessive growth of insensitive microorganisms.

    In clinical trials, it was shown that approximately 3% of patients receiving recommended doses of linezolid developed candidiasis,associated with taking antibiotics. In case of development of superinfection, appropriate measures must be taken.

    The safety and efficacy of linezolid, applied more than 28 days, have not been studied.

    Patients with diabetic foot syndrome, pressure ulcers or ischemic impairment, severe burns or gangrene did not participate in controlled clinical trials. Thus, the experience of using linezolid in the therapy of these conditions is limited.

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

    During the use of linezolid, it is not recommended to operate vehicles, special equipment or engage in activities requiring increased attention and speed of psychomotor reactions.

    Form release / dosage:

    Film-coated tablets, 600 mg.

    Packaging:

    For 10 tablets in a blister of PVC / aluminum foil. 1, 2, 3 or 6 blisters together with instructions for use in a cardboard pack.

    For 20 or 100 tablets in a can of low density polyethylene (HDPE), sealed with a plastic cap with a cellulose pad and protected from accidental opening by children. If necessary, each can contain a container of silica gel.

    Bank together with instructions for medical use in a pack of cardboard.

    Storage conditions:

    In the 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-003968
    Date of registration:16.11.2016
    Expiration Date:16.11.2021
    The owner of the registration certificate:Heterose Labs LimitedHeterose Labs Limited India
    Manufacturer: & nbsp
    Representation: & nbspHeterose Labs LimitedHeterose Labs LimitedIndia
    Information update date: & nbsp08.04.2018
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