Ukraine Product

Lion Tablets

Lion Tablets

Why you have been prescribed this medicine?

You have been prescribed this medicine if you have any of the following:

Infections, caused by sensitive anaerobic and aerobic gram-positive microorganisms, including infections, accompanied with bacteremia, such as:

- Nosocomial pneumonia;
- Community acquired pneumonia;
- Complicated infections of the skin and its structures, including infection on background diabetic foot without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae;
- Uncomplicated infections of the skin and its structures caused by Staphylococcus aureus (methicillin-susceptible only isolates) or Streptococcus pyogenes;
- Infections caused by enterococci, including vancomycin-resistant strains of Enterococcus faecium and faecalis.

If infection pathogens include Gram-negative microorganisms, then it is clinically indicated purpose combination therapy.

 

When you should consult your doctor?

You should consult your doctor if you experience any of the following:

You should consult your doctor if you experience any of the following:
Infections and infestations: candidiasis (viz. oral candidiasis and vaginal candidiasis) or fungal infections, vaginitis, antibiotic-associated colitis, including pseudomembranous colitis.

Blood and the lymphatic system disorders:  eosinophilia, leucopenia, neutropenia, thrombocytopenia, myelosuppression, pancytopenia, sideroblastic anaemia.

Immune system disorders: anaphylaxis.

Metabolism and nutrition disorders: hyponatraemia, lactic acidosis.

Psychiatric disorders: insomnia.

Nervous system disorders:         headache, taste perversion (metallic taste), dizziness, hypoaesthesia, paraesthesia, serotonin syndrome, convulsions, peripheral neuropathy.

Eye disorders:       visual deterioration, optic neuritis, optic neuropathy, loss of vision, altered vision, changes in colour vision, visual field defect.

Ear and labyrinth disorders:     tinnitus.

Cardiac disorders: arrhythmia (tachycardia).

Vascular disorders:         hypertension,        phlebitis, thrombophlebitis, transient ischemic attacks.

Gastrointestinal disorders: diarrhea, nausea, vomiting, abdominal pain, constipation, dry mouth, dyspepsia, gastritis, abdominal distention, glossitis, loose stools, pancreatitis, stomatitis, tongue discolouration or disorder, superficial tooth discoloration.

Hepatobiliary disorders: abnormal liver function test, increased AST, ALT levels or alkaline phosphatase, total bilirubin.

Skin and subcutaneous tissue disorders: dermatitis, hyperhidrosis, pruritus, rash
urticaria, bullous disorders, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.

Renal and urinary disorders:    polyuria, renal failure, increased blood urea nitrogen, increased creatinine.

Reproductive system and breast disorders: vulvovaginal disorders.

General disorders and administration site conditions: fever, fatigue, chills, increased thirst, localised pain.

Investigations.

Biochemistry.

  1. increased: AST, ALT, LDH, alkaline phosphatase, blood urea nitrogen, creatinine kinase, lipase, amylase, bilirubin, creatinine, sodium, calcium.
  2. decreased: total protein, albumin, sodium, calcium.
  3. increased or decreased: potassium, bicarbonate, chloride, glucose (not fasting).

Haematology.

    • increased: eosinophils, reticulocytes.
    • decreased: haemoglobin, haematocrit, red blood cell count.
    • increased or decreased: platelets, leukocytes, neutrophils.



WHAT TO DO IF YOU MISS A DOSE?

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise take it as soon as you remember and then go back to taking it as you would normally.

Things you MUST NOT DO while on this medicine?

Myelosuppression
Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. After linezolid discontinuation, the indicants of altered blood parameters returned to values observed before treatment. Probably, the risk of these effects appears to be related to the duration of treatment. Elderly patients treated with linezolid may be at greater risk of experiencing blood dyscrasias than younger patients. Thrombocytopenia may occur more commonly in patients with severe renal insufficiency, (whether or not on dialysis). Therefore, close monitoring of blood counts is recommended in patients who: have pre-existing anaemia, granulocytopenia or thrombocytopenia; are receiving concomitant medications that may decrease haemoglobin levels, depress blood counts or adversely affect platelet count or function activity; have severe renal insufficiency; receive more than 10-14 days of therapy. Linezolid should be administered to such patients only when close monitoring of haemoglobin levels, clinical blood analysis and platelet counts is possible.
If significant myelosuppression occurs during linezolid therapy, treatment should be stopped. Unless the cases, when it is considered absolutely necessary to continue therapy. In such cases intensive monitoring of complete blood counts and appropriate management strategies should be implemented.
In addition, it is recommended that complete blood counts (including haemoglobin levels, platelets, and total and differentiated leucocyte counts) should be monitored weekly in patients who receive linezolid regardless of baseline blood count.
A higher incidence of serious anaemia was reported in patients receiving linezolid for more than 28 days (the maximum recommended duration of treatment). These patients more often required blood transfusion. Cases of anaemia requiring blood transfusion have also been reported post marketing. The anaemia of this type occurred more frequently in patients receiving linezolid for more than 28 days.
Cases of sideroblastic anaemia have also been reported. Where time of onset was known, most patients had received linezolid therapy for more than 28 days. Most patients fully or partially recovered following discontinuation of linezolid with or without treatment for their anaemia.

Mortality imbalance in a clinical trial in patients with catheter-related gram-positive bloodstream infections
Excess mortality was seen in patients treated with linezolid, relative to vancomycin/dicloxacillin/oxacillin, with serious intravascular catheter-related infections. The main factor influencing the mortality rate was the gram-positive infection status at baseline. Mortality rate was similar in patients with infections, caused only by gram-positive organisms, but were significantly higher in the linezolid treated population in patients with any other pathogen or no pathogen at baseline. The greatest imbalance occurred during treatment and within 7 days following discontinuation of study drug. It was reported, that more patients in the linezolid treatment acquired gram-negative pathogens and died from infection caused by gram-negative pathogens and polymicrobial infections. Therefore, in complicated skin and soft tissue infections linezolid should only be used in patients with known or possible co-infection with gram-negative organisms, if there are no alternative treatment options available (see sect. “Indications”). In these circumstances treatment against gram-negative organisms must be initiated concomitantly.

Antibiotic-associated diarrhoea and colitis
Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD), has been reported in association with the use of nearly all antibiotics including linezolid and may range in severity from mild diarrhoea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop diarrhoea during or after the use of linezolid. If antibiotic-associated diarrhoea or antibiotic-associated colitis is suspected or confirmed, ongoing treatment with antibacterial agents (including linezolid) should be discontinued and adequate therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in this situation.

Potential interactions that cause high blood pressure
Linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or concomitant intake of such types of drugs, as: direct and indirect sympathomimetics (e.g. pseudoephedrine), vasopressors (such as epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), unless the case, when the monitoring of patients for the increase in arterial tension is possible.

Lactic acidosis
Lactic acidosis has been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis including recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or hyperventilation while receiving linezolid should receive immediate medical attention. If lactic acidosis occurs, the benefits of continued use of linezolid should be weighed against the potential risks.

Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. Adverse events, such as lactic acidosis, anaemia and neuropathy (optic and peripheral), may occur as a result of this inhibition. These events are more common when the drug is used longer than 28 days.

Serotonin syndrome
Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and serotonergic agents, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)) have been reported. Therefore, co-administration of linezolid and serotonergic agents is contraindicated (see “Contraindications”), except where administration of linezolid and concomitant serotonergic agents is essential. In those cases patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians should consider discontinuing either one or both agents. If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can occur.

Peripheral and optic neuropathy
Peripheral neuropathy, as well as optic neuropathy and optic neuritis sometimes progressing to loss of vision, have been reported in patients treated with linezolid. These reports have primarily been in patients treated for longer than 28 days (the maximum recommended duration of treatment).
All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary. If any patients are taking Lion® for longer than the recommended 28 days, their visual function should be regularly monitored.
If peripheral or optic neuropathy occurs, the continued use of Lion® should be weighed against the potential risks.
There may be an increased risk of neuropathies when linezolid is used in patients currently taking or who have recently taken antibacterial drugs for the treatment of tuberculosis.

Convulsions
Convulsions have been reported to occur in patients when treated with Lion®. In most of these cases, such risk factors as a history of seizures were reported. Patients should be advised to inform their physician if they have a history of seizures.

Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). However, at the doses used for antibacterial therapy, it does not exert an anti-depressive effect. There are very limited data from drug interaction studies and on the safety of linezolid when administered to patients with underlying conditions and/or on concomitant medications which might put them at risk from MAO inhibition. Therefore, linezolid is not recommended for use in these circumstances unless close observation and monitoring of the recipient is possible (see sect. “Contraindications” and “Interaction with other medicinal products and other forms of interaction”).
Use with tyramine-rich products
Patients should be advised against consuming large amounts of tyramine rich products (see sect. “Interaction with other medicinal products and other forms of interaction”).

Superinfection
There are no data on the effect of linezolid on the normal microbial flora. The use of antibiotics may occasionally result in an overgrowth of non-susceptible organisms. For example, approximately 3% of patients receiving the recommended linezolid doses experienced drug-related candidiasis. If superinfection occurs during therapy, appropriate measures should be taken.

Special populations
Linezolid should be used with special caution in patients with severe renal insufficiency and only when the anticipated benefit is considered to outweigh the theoretical risk (see sec. “Posology and administration”).
It is recommended that linezolid should be given to patients with severe hepatic insufficiency only when the perceived benefit outweighs the theoretical risk (see sec. “Posology and administration”).
The patient’s gender does not influence the dose adjustment.

Impairment of fertility
Linezolid reversibly decreased fertility and induced abnormal sperm morphology in adult male rats at exposure levels approximately equal to those expected in humans.
Possible effects of linezolid on the human male reproductive system are not known.

Treatment duration
The safety and effectiveness of linezolid when administered for periods longer than 28 days have not been established.

Individual diseases
There is no experience of using linezolid in patients with diabetic foot lesions, decubitus or ischaemic lesions, severe burns or gangrene.

 

 

Influence on velocity reactions while driving motor transport and operating other mechanisms:

Patients should be warned about the potential for dizziness or symptoms of visual impairment (see sections “Special warnings and precautions” and “Adverse effects”) whilst receiving linezolid and should be advised not to drive or operate machinery if any of these symptoms occurs.

 

What to do if you accidentally take too much (overdose) of the medicine?

No specific antidote is known.
No cases of overdose have been reported.
In case of overdose, symptomatic treatment is advised together with maintenance of glomerular filtration. Approximately 30% of a drug dose is removed during 3 hours of haemodialysis, but no data are available for the removal of linezolid by peritoneal dialysis or haemoperfusion. The two primary metabolites of linezolid are also removed to some extent by haemodialysis.

Is it safe in pregnancy and breast-feeding?

Use in pregnancy. There are no adequate data from the use of linezolid in pregnant women. Studies in animals have shown reproductive toxicity. A potential risk for humans exists. Lion® should not be used during pregnancy unless the potential benefit outweighs the theoretical risk.

Use in lactation. Animal studies data have suggested that linezolid and its metabolites may pass into breast milk. Thus, breastfeeding should be discontinued during the drug treatment.

Fertility.
The animal studies have shown impairment of fertility during linezolid administration.

 

Storage Conditions:

Store below 25°С.
Keep out of the reach of children.

Drug Description

Active ingredients:
Each film coated tablet contains:    

Linezolid                            600 mg;

Inactive ingredients:
Microcrystalline cellulose, partially pregelatinised starch, sodium starch glycolate (type A) hydroxypropylcellulose, magnesium stearate, coating Opadry 03B58600 white:  hypromellose, titanium dioxide (E 171), polyethylene glycols.

Pharmaceutical form:

Film coated tablets.
Oval shaped, white film-coated tablets, smooth on both sides.


Indications and dosage.

Indications:
Infections, caused by sensitive anaerobic and aerobic gram-positive microorganisms, including infections, accompanied with bacteremia, such as:

- Nosocomial pneumonia;
- Community acquired pneumonia;
- Complicated infections of the skin and its structures, including infection on background diabetic foot without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae;
- Uncomplicated infections of the skin and its structures caused by Staphylococcus aureus (methicillin-susceptible only isolates) or Streptococcus pyogenes;
- Infections caused by enterococci, including vancomycin-resistant strains of Enterococcus faecium and faecalis.

If infection pathogens include Gram-negative microorganisms, then it is clinically indicated purpose combination therapy.

Dosage:
Prescribe Lion® 2 times a day, internally without regard to food.
The duration of treatment depends on the causative agent, source of infection and its severity, as well as the clinical effect. The maximum treatment duration is 28 days. The safety and effectiveness of linezolid when administered for periods longer than 28 days have not been established.

The maximum dose for adults and children over 12 years should not exceed 600 mg 2 times a day.

No increase in the recommended dosage or duration of treatment is required for infections associated with concurrent bacteraemia.

The recommended doses for adults and children over 12 years as follows:


Prescribed

Dosage
Adults and children
(aged 12 years)

Duration of treatment (days)

Nosocomial pneumonia

600 mg every 12 hours

10-14 days

Community acquired pneumonia (including forms, accompanied by bacteremia)

Complicated infections of the skin and its structures

Infections caused by Enterococcus faecium, resistant to vancomycin, including infections, accompanied by bacteremia

600 mg every 12 hours

14-28

Uncomplicated infections of the skin and its structures

Adults: 400 mg every 12 hours *
Children under 12 years: 600 mg every 12 hours

10-14

* Apply a different drug dosage form with the possibility of appropriate dosage
Patients who commence treatment on the parenteral formulation may be switched to either oral presentation, as oral bioavailability of linezolid is approximately 100%.
Elderly patients: no dose adjustment is required.
Patients with severe renal insufficiency (i.e. with creatinine clearence < 30 ml/min):
The pharmacokinetics of linezolid is not changed in patients with any degree of renal failure; however, two major metabolites accumulation linezolid in patients with renal insufficiency with increasing their accumulation in patients with greater severity of renal dysfunction. Regardless of renal function achieved the same linezolid concentrations in plasma, so patients with renal impairment is not recommended dose adjustment. However, given the lack of information on the clinical significance of the main metabolite accumulation, should consider the application of linezolid patients in the presence of renal failure and potential risks of accumulation of metabolites. Linezolid and the two metabolites are excreted by hemodialysis. Information on the effect of peritoneal dialysis on the pharmacokinetics of linezolid is not available. Since 3 hours after drug administration approximately 30% of the dose is excreted within 3-hour hemodialysis session, patients who received similar treatment, linezolid should be administered after hemodialysis.
Patients with hepatic insufficiency: no dose adjustment is required. However, there are limited clinical data and it is recommended that linezolid should be used in such patients only when the anticipated benefit is considered to outweigh the theoretical risk.

Side effects and drug interactions.

Side effects:
Infections and infestations: candidiasis (viz. oral candidiasis and vaginal candidiasis) or fungal infections, vaginitis, antibiotic-associated colitis, including pseudomembranous colitis.

Blood and the lymphatic system disorders:  eosinophilia, leucopenia, neutropenia, thrombocytopenia, myelosuppression, pancytopenia, sideroblastic anaemia.

Immune system disorders: anaphylaxis.

Metabolism and nutrition disorders: hyponatraemia, lactic acidosis.

Psychiatric disorders: insomnia.

Nervous system disorders:         headache, taste perversion (metallic taste), dizziness, hypoaesthesia, paraesthesia, serotonin syndrome, convulsions, peripheral neuropathy.

Eye disorders:       visual deterioration, optic neuritis, optic neuropathy, loss of vision, altered vision, changes in colour vision, visual field defect.

Ear and labyrinth disorders:     tinnitus.

Cardiac disorders: arrhythmia (tachycardia).

Vascular disorders:         hypertension,        phlebitis, thrombophlebitis, transient ischemic attacks.

Gastrointestinal disorders: diarrhea, nausea, vomiting, abdominal pain, constipation, dry mouth, dyspepsia, gastritis, abdominal distention, glossitis, loose stools, pancreatitis, stomatitis, tongue discolouration or disorder, superficial tooth discoloration.

Hepatobiliary disorders: abnormal liver function test, increased AST, ALT levels or alkaline phosphatase, total bilirubin.

Skin and subcutaneous tissue disorders: dermatitis, hyperhidrosis, pruritus, rash
urticaria, bullous disorders, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.

Renal and urinary disorders:    polyuria, renal failure, increased blood urea nitrogen, increased creatinine.

Reproductive system and breast disorders: vulvovaginal disorders.

General disorders and administration site conditions: fever, fatigue, chills, increased thirst, localised pain.

Investigations.

Biochemistry.

  1. increased: AST, ALT, LDH, alkaline phosphatase, blood urea nitrogen, creatinine kinase, lipase, amylase, bilirubin, creatinine, sodium, calcium.
  2. decreased: total protein, albumin, sodium, calcium.
  3. increased or decreased: potassium, bicarbonate, chloride, glucose (not fasting).

Haematology.

  1. increased: eosinophils, reticulocytes.
  2. decreased: haemoglobin, haematocrit, red blood cell count.
  3. increased or decreased: platelets, leukocytes, neutrophils.

 

 Drug interactions
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). There are very limited data on linezolid when administered to patients on concomitant medications that might put them at risk from MAO inhibition. Therefore, linezolid is not recommended for use in these circumstances unless close observation and monitoring of the patient is possible (see. sec. “Contraindications”, “Special warnings and precautions”).

Potential interactions producing elevation of blood pressure
In normotensive healthy volunteers, linezolid enhanced the increases in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Co-administration of linezolid with either pseudoephedrine or phenylpropanolamine resulted in mean increases in systolic blood pressure of the order of 30-40 mmHg, compared with 11-15 mmHg increases with linezolid alone, 14-18 mmHg with either pseudoephedrine or phenylpropanolamine alone and 8-11 mmHg with placebo. Similar studies in hypertensive subjects have not been conducted. It is recommended that doses of drugs with a vasopressive action, including dopaminergic agents, should be carefully titrated to achieve the desired response when co-administered with linezolid.

Potential serotonergic interactions
There are data on absence of serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in healthy volunteers receiving dextromethorphan (two 20 mg doses given 4 hours apart) with or without linezolid. However, in post marketing experience, there has been one report of a patient experiencing serotonin syndrome-like effects while taking linezolid and dextromethorphan; these effects were resolved on discontinuation of both medications.
During clinical use of linezolid with serotonergic agents, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)), cases of serotonin syndrome have been reported. Therefore, while co-administration of these drugs is contraindicated (see sect. “Contraindications”), treatment of patients for whom treatment with linezolid and serotonergic agents is essential, described in section “Special warnings and precautions”.

Use with tyramine-rich products
No significant pressor response was observed in subjects receiving both linezolid and less than 100 mg tyramine. This suggests that it is only necessary to avoid ingesting excessive amounts of product with high tyramine content (e.g. mature cheese, yeast extracts, undistilled alcoholic beverages and fermented soya bean products such as soy sauce).

Drugs metabolised by cytochrome P450
Linezolid is not P450 (CYP450) cytochrome inductor. In addition, Linezolid does not inhibit any of the clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no linezolid effect on pharmacokinetics of other drugs, metabolized by these main enzymes is expected.

Warfarin
Concomitant administration of linezolid does not significantly affect the pharmacokinetic characteristics of (S) -warfarin that is actively metabolized via CYP2C9. Such drug products as warfarin and phenytoin, which are substrates of CYP2C9, can be used with linezolid without changes in dosage regimen.

Strong inducers of CYP 3A4
Rifampicin. The concomitant administration of rifampicin and linezolid has been reduced the linezolid Cmax by 21% and linezolid AUC0-12 by 32%. The clinical significance of this interaction has not been established. The mechanism of this interaction is not fully studied and may be associated with the induction of liver enzymes. Other strong inducers of liver enzymes (e.g. carbamazepine, phenytoin, phenobarbital) may cause similar or less severe decrease in linezolid exposure.

Antibiotics
Aztreonam. The concomitant administration of linezolid and aztreonam does not affect the pharmacokinetics of these drugs.
Gentamicin. The concomitant administration of linezolid and gentamicin does not affect the pharmacokinetics of these drugs.

Antioxidants
The linezolid dose adjustment is not recommended during co-administration of the drug with vitamin C or vitamin E

 

Warnings and precautions

Myelosuppression
Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. After linezolid discontinuation, the indicants of altered blood parameters returned to values observed before treatment. Probably, the risk of these effects appears to be related to the duration of treatment. Elderly patients treated with linezolid may be at greater risk of experiencing blood dyscrasias than younger patients. Thrombocytopenia may occur more commonly in patients with severe renal insufficiency, (whether or not on dialysis). Therefore, close monitoring of blood counts is recommended in patients who: have pre-existing anaemia, granulocytopenia or thrombocytopenia; are receiving concomitant medications that may decrease haemoglobin levels, depress blood counts or adversely affect platelet count or function activity; have severe renal insufficiency; receive more than 10-14 days of therapy. Linezolid should be administered to such patients only when close monitoring of haemoglobin levels, clinical blood analysis and platelet counts is possible.
If significant myelosuppression occurs during linezolid therapy, treatment should be stopped. Unless the cases, when it is considered absolutely necessary to continue therapy. In such cases intensive monitoring of complete blood counts and appropriate management strategies should be implemented.
In addition, it is recommended that complete blood counts (including haemoglobin levels, platelets, and total and differentiated leucocyte counts) should be monitored weekly in patients who receive linezolid regardless of baseline blood count.
A higher incidence of serious anaemia was reported in patients receiving linezolid for more than 28 days (the maximum recommended duration of treatment). These patients more often required blood transfusion. Cases of anaemia requiring blood transfusion have also been reported post marketing. The anaemia of this type occurred more frequently in patients receiving linezolid for more than 28 days.
Cases of sideroblastic anaemia have also been reported. Where time of onset was known, most patients had received linezolid therapy for more than 28 days. Most patients fully or partially recovered following discontinuation of linezolid with or without treatment for their anaemia.

Mortality imbalance in a clinical trial in patients with catheter-related gram-positive bloodstream infections
Excess mortality was seen in patients treated with linezolid, relative to vancomycin/dicloxacillin/oxacillin, with serious intravascular catheter-related infections. The main factor influencing the mortality rate was the gram-positive infection status at baseline. Mortality rate was similar in patients with infections, caused only by gram-positive organisms, but were significantly higher in the linezolid treated population in patients with any other pathogen or no pathogen at baseline. The greatest imbalance occurred during treatment and within 7 days following discontinuation of study drug. It was reported, that more patients in the linezolid treatment acquired gram-negative pathogens and died from infection caused by gram-negative pathogens and polymicrobial infections. Therefore, in complicated skin and soft tissue infections linezolid should only be used in patients with known or possible co-infection with gram-negative organisms, if there are no alternative treatment options available (see sect. “Indications”). In these circumstances treatment against gram-negative organisms must be initiated concomitantly.

Antibiotic-associated diarrhoea and colitis
Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD), has been reported in association with the use of nearly all antibiotics including linezolid and may range in severity from mild diarrhoea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop diarrhoea during or after the use of linezolid. If antibiotic-associated diarrhoea or antibiotic-associated colitis is suspected or confirmed, ongoing treatment with antibacterial agents (including linezolid) should be discontinued and adequate therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in this situation.

Potential interactions that cause high blood pressure
Linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or concomitant intake of such types of drugs, as: direct and indirect sympathomimetics (e.g. pseudoephedrine), vasopressors (such as epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), unless the case, when the monitoring of patients for the increase in arterial tension is possible.

Lactic acidosis
Lactic acidosis has been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis including recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or hyperventilation while receiving linezolid should receive immediate medical attention. If lactic acidosis occurs, the benefits of continued use of linezolid should be weighed against the potential risks.

Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. Adverse events, such as lactic acidosis, anaemia and neuropathy (optic and peripheral), may occur as a result of this inhibition. These events are more common when the drug is used longer than 28 days.

Serotonin syndrome
Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and serotonergic agents, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs)) have been reported. Therefore, co-administration of linezolid and serotonergic agents is contraindicated (see “Contraindications”), except where administration of linezolid and concomitant serotonergic agents is essential. In those cases patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur physicians should consider discontinuing either one or both agents. If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can occur.

Peripheral and optic neuropathy
Peripheral neuropathy, as well as optic neuropathy and optic neuritis sometimes progressing to loss of vision, have been reported in patients treated with linezolid. These reports have primarily been in patients treated for longer than 28 days (the maximum recommended duration of treatment).
All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary. If any patients are taking Lion® for longer than the recommended 28 days, their visual function should be regularly monitored.
If peripheral or optic neuropathy occurs, the continued use of Lion® should be weighed against the potential risks.
There may be an increased risk of neuropathies when linezolid is used in patients currently taking or who have recently taken antibacterial drugs for the treatment of tuberculosis.

Convulsions
Convulsions have been reported to occur in patients when treated with Lion®. In most of these cases, such risk factors as a history of seizures were reported. Patients should be advised to inform their physician if they have a history of seizures.

Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). However, at the doses used for antibacterial therapy, it does not exert an anti-depressive effect. There are very limited data from drug interaction studies and on the safety of linezolid when administered to patients with underlying conditions and/or on concomitant medications which might put them at risk from MAO inhibition. Therefore, linezolid is not recommended for use in these circumstances unless close observation and monitoring of the recipient is possible (see sect. “Contraindications” and “Interaction with other medicinal products and other forms of interaction”).

Use with tyramine-rich products
Patients should be advised against consuming large amounts of tyramine rich products (see sect. “Interaction with other medicinal products and other forms of interaction”).

Superinfection
There are no data on the effect of linezolid on the normal microbial flora. The use of antibiotics may occasionally result in an overgrowth of non-susceptible organisms. For example, approximately 3% of patients receiving the recommended linezolid doses experienced drug-related candidiasis. If superinfection occurs during therapy, appropriate measures should be taken.

Special populations
Linezolid should be used with special caution in patients with severe renal insufficiency and only when the anticipated benefit is considered to outweigh the theoretical risk (see sec. “Posology and administration”).
It is recommended that linezolid should be given to patients with severe hepatic insufficiency only when the perceived benefit outweighs the theoretical risk (see sec. “Posology and administration”).
The patient’s gender does not influence the dose adjustment.

Impairment of fertility
Linezolid reversibly decreased fertility and induced abnormal sperm morphology in adult male rats at exposure levels approximately equal to those expected in humans.
Possible effects of linezolid on the human male reproductive system are not known.

Treatment duration
The safety and effectiveness of linezolid when administered for periods longer than 28 days have not been established.

Individual diseases

There is no experience of using linezolid in patients with diabetic foot lesions, decubitus or ischaemic lesions, severe burns or gangrene.


Overdosage and Contraindications

Overdosage:
No specific antidote is known.
No cases of overdose have been reported.
In case of overdose, symptomatic treatment is advised together with maintenance of glomerular filtration. Approximately 30% of a drug dose is removed during 3 hours of haemodialysis, but no data are available for the removal of linezolid by peritoneal dialysis or haemoperfusion. The two primary metabolites of linezolid are also removed to some extent by haemodialysis.

 Contraindications
It is known hypersensitivity to linezolid or any of the excipients.
Concomitant administration of any medicinal product which inhibit monoamine oxidases A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of taking such medicinal products.
Unless there are facilities available for close observation and monitoring of blood pressure, Lion should not be administered to patients with the following underlying clinical conditions or on the following types of concomitant medications:
- uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute confusional states.
- serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), directly and indirectly acting sympathomimetic agents (including the adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressive agents (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), pethidine or buspirone.

Clinical pharmacology.

Pharmacodynamic properties

Antimicrobial agents for systemic use. ATC code J01X X08.
Linezolid is a synthetic antibacterial agent that belongs to a new class of antimicrobial drugs - oxazolidinones. It has in vitro activity against aerobic gram-positive and some gram-negative bacteria and anaerobic microorganisms. Linezolid selectively inhibits bacterial protein synthesis via a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S of the 50S subunit) and prevents the formation of a functional 70S initiation complex which is an essential component of the translation process.
The following microorganisms are sensitive to linezolid: gram-positive aerobic bacteria Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus; coagulase negative staphylococci Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, group C and group G streptococci; gram-positive anaerobic bacteria Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus sp.
Resistant organisms: Haemophilus influenzae, Moraxella catarrhalis, Neisseria species, Enterobacteriaceae, Pseudomonas sp.
Resistance to linezolid is associated with point mutations in the 23S rRNA. When used in patients with difficult to treat infections and/or for prolonged periods, decreases in susceptibility have been observed with linezolid. Resistance to linezolid has been reported in enterococci, staphylococcus aureus and coagulase negative staphylococci.

Pharmacokinetic properties

Absorption. Linezolid is rapidly and extensively absorbed following oral administration. Maximum plasma concentration is reached within 2 hours after drug intake. Absolute bioavailability of linezolid in oral dosing is complete (approximately 100%). Concomitant food intake does not significantly affect the absorption of the drug. Minimum and maximum concentrations at steady-state following twice daily oral dosing of 600 mg have been determined to be 21.2 mg/l and 6.15 mg/l, respectively. A steady-state is reached on the second day of therapy.

Distribution in the body.
Volume of distribution at steady-state averages at about 40-50 liters that approximates to total body liquid. Plasma protein binding is about 31% and is not drug blood concentration dependent.
The ratio of linezolid in saliva and sweat relative to plasma was 1.2:1 and 0.55:1, respectively. The ratio for epithelial lining fluid and alveolar cells of the lungs relative to maximum blood plasma concentration at steady-state was 4.5:1 and 0.15:1, respectively. The ratio of concentration in cerebrospinal fluid to plasma at maximum concentration was 0.7:1 after multiple linezolid dosing.

Metabolism
Linezolid is primarily metabolized by oxidation of the morpholine ring resulting mainly in the formation of two inactive open-ring carboxylic acid derivatives: the aminoethoxyacetic acid metabolite (PNU-142300) and the hydroxyethyl glycine metabolite (PNU-142586). The hydroxyethyl glycine metabolite (PNU-142586) is the predominant human metabolite and is believed to be formed by a non-enzymatic process. The aminoethoxyacetic acid metabolite (PNU-142300) is less determined. Other minor, inactive metabolites have been identified.

Elimination
In patients with normal renal function or mild to moderate renal insufficiency, linezolid is primarily excreted under steady-state conditions in the urine as PNU-142586 (40%), unchanged drug (30%) and PNU-142300 metabolite (10%). No parent drug is found in the feces whilst approximately 6% and 3% of each dose appears as PNU-142586 and PNU-142300, respectively. The elimination half-life of linezolid averages at about 5-7 hours.
Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. A small degree of non-linearity in clearance is observed with increasing doses of linezolid. This appears to be due to lower renal and non-renal clearance at higher linezolid concentrations. However, the difference in clearance is small and is not reflected in the apparent elimination half-life.

Pharmacokinetics in special populations

Patients with renal insufficiency: after single doses of 600 mg, there was a 7-8 fold increase in exposure to the two primary metabolites of linezolid in the plasma of patients with severe renal insufficiency (i.e. creatinine clearance < 30 ml/min). However, there were no changes in exposure in terms of area under the curve <concentration-time> (AUC) of parent drug. Although there is some removal of the major metabolites of linezolid by haemodialysis, metabolite plasma levels after single 600 mg doses were still considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency.

Patients with hepatic insufficiency: limited data indicate that the pharmacokinetics of linezolid, PNU-142300 and PNU-142586 are not altered in patients with mild to moderate hepatic insufficiency (Child-Pugh class A or B). The pharmacokinetics of linezolid in patients with severe hepatic insufficiency (Child-Pugh class C) has not been evaluated. However, as linezolid is metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism.

Children under 18 years of age. There are insufficient data on the safety and efficacy of linezolid administration in children under 18 years of age.

Children 1 week to 12 years: linezolid clearance after single or multiple doses of linezolid was greater than in adult patients, but decreased with increasing age. Administration of 10 mg/kg every 8 hours daily gave exposure approximating to that achieved with 600 mg twice daily in adults.

Children 12 to 17 years old: linezolid pharmacokinetics was similar to that in adults following a 600mg dose. Therefore, drug administration in dose of 600 mg every 12 hours daily will have similar drug exposure to that observed in adults, receiving the same dosage.

Elderly patients: the pharmacokinetics of linezolid is not significantly altered in elderly patients aged 65 and over.

Female patients: females have a slightly lower volume of linezolid distribution than males and the mean clearance (adjusted for body weight) is reduced by approximately 20%. Linezolid plasma concentrations are higher in females and this can partly be attributed to body weight differences. However, because the mean half-life is not significantly different in males and females, plasma concentrations in females are not expected to substantially rise above those known to be well tolerated and, therefore, dose adjustments are not required.

 

Pharmaceutical characteristics:

Shelf-life: 2 years.

Package: 4 tablets are in blister, 1 blister is in a carton box.
10 tablets are in blister, 1 blister is in a carton box.

Conditions of supply:
By prescription.

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