LIZOLID (tab)
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Chemical Name:
Linezolid -
Therapeutic Category:
Antimicrobial -
Pharmacologic Category:
Antibiotic, Oxazolidinone -
Pharmaceutical Form:
Tablets -
Composition:
Linezolid 600mg
LIZOLID
Film coated tablets
Linezolid
1-COMPOSITION:
LIZOLID- Film coated tablets: Each Film coated tablet contains Linezolid 600 mg.
Excipients:
Maize starch, Microcrystalline Cellulose, Hydroxypropyl cellulose, Sodium starch glycollate, Magnesium Stearate, Hypromellose, Titanium Dioxide, Macrogol 400, Carnauba wax.
2-PHARMACOLOGY:
Linezolid is a synthetic, antibacterial agent that belongs to the oxazolidinones. It has activity against aerobic Gram positive bacteria and anaerobic micro-organisms. 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.
Susceptibility
Susceptible organisms to Linezolid are:
Gram positive aerobes: Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Coagulase negative staphylococci, Streptococcus agalactiae, Streptococcus pneumonia, Streptococcus pyogenes, Group C streptococci, Group G streptococci.
Gram positive anaerobes: Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus species.
Resistant organisms to Linezolid are:
Haemophilus influenza, Moraxella catarrhalis, Neisseria species, Enterobacteriaceae, Pseudomonas species.
Resistance
Linezolid's mechanism of action differs from those of other antibiotic classes. In vitro studies with clinical isolates (including methicillin-resistant staphylococci, vancomycin-resistant enterococci, and penicillin- and erythromycin-resistant streptococci) indicate that linezolid is usually active against organisms which are resistant to one or more other classes of antimicrobial agents.
Resistance to linezolid is associated with point mutations in the 23S rRNA.
As documented with other antibiotics when used in patients with difficult to treat infections and/or for prolonged periods, emergent decreases in susceptibility have been observed with linezolid.
3-PHARMACOKINETICS:
Absorption: Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 2 hours of dosing. Absolute oral bioavailability of linezolid is complete (approximately 100%).
Distribution: Plasma protein binding is about 31% and is not concentration dependent.
Metabolism: Linezolid is primarily metabolised by oxidation of the morpholine ring resulting mainly in the formation of two inactive open-ring carboxylic acid derivatives.
Elimination: 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.
4-INDICATIONS:
LIZOLID is indicated for the treatment of the following infections:
- Nosocomial pneumonia.
- Community acquired pneumonia.
Linezolid is indicated in adults for the treatment of community acquired pneumonia and nosocomial pneumonia when known or suspected to be caused by susceptible Gram positive bacteria.
Linezolid is not active against infections caused by Gram negative pathogens. Specific therapy against Gram negative organisms must be initiated concomitantly if a Gram negative pathogen is documented or suspected.
- Complicated skin and soft tissue infections.
Linezolid is indicated in adults for the treatment of complicated skin and soft tissue infections only when microbiological testing has established that the infection is known to be caused by susceptible Gram positive bacteria.
Linezolid is not active against infections caused by Gram negative pathogens. Linezolid should only be used in patients with complicated skin and soft tissue infections with known or possible co-infection with Gram negative organisms if there are no alternative treatment options available. In these circumstances treatment against Gram negative organisms must be initiated concomitantly.
Linezolid should only be initiated in a hospital environment and after consultation with a relevant specialist such as a microbiologist or infectious diseases specialist.
5-CONTRAINDICATIONS:
Hypersensitivity to linezolid or to any of the excipients.
Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of taking any such medicinal product.
Unless there are facilities available for close observation and monitoring of blood pressure, linezolid should not be administered to:
- Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute confusional states.
- Patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists, 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.
Animal data suggest that linezolid and its metabolites may pass into breast milk and, accordingly, breast-feeding should be discontinued prior to and throughout administration
6-SIDE EFFECTS:
Common:
candidiasis, oral candidiasis, vaginal candidiasis, fungal infections, anaemia, insomnia, headache, taste perversion (metallic taste), dizziness, hypertension, diarrhoea, nausea, vomiting, localised or general abdominal pain, constipation, dyspepsia, abnormal liver function test; increased AST, ALT or alkaline phosphatase, pruritus, rash, increased BUN, fever, localised pain, Increased LDH, creatine kinase, lipase, amylase or non-fasting glucose, Decreased total protein, albumin, sodium or calcium, Increased or decreased potassium or bicarbonate, Increased neutrophils or eosinophils, decreased haemoglobin, haematocrit or red blood cell count. Increased or decreased platelet or white blood cell counts.
Uncommon:
vaginitis, leucopenia, neutropenia, thrombocytopenia, eosinophilia, hyponatraemia, paraesthesia , blurred vision, arrhythmia (tachycardia), pancreatitis, gastritis, abdominal distention, dry mouth, glossitis, stomatitis, tongue discolouration, increased total bilirubin, dermatitis, renal failure, increased creatinine, polyuria, increased sodium or calcium,decreased non fasting glucose, increased or decreased chloride, increased reticulocyte count, decreased neutrophils.
Rare:
antibiotic-associated colitis, including pseudomembranous colitis, pancytopenia, superficial tooth discolouration.
Frequency not known:
anaphylaxis, lactic acidosis, serotonin syndrome, optic neuritis, loss of vision, changes in visual acuity, changes in color vision, bullous disorders such as those described as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.
7-PRECAUTIONS:
Myelosuppression:
Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. 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. 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; have severe renal insufficiency; receive more than 10-14 days of therapy.
If significant myelosuppression occurs during linezolid therapy, treatment should be stopped unless it is considered absolutely necessary to continue therapy, in which case intensive monitoring of blood counts and appropriate management strategies should be implemented.
In addition, it is recommended that complete blood counts should be monitored weekly in patients who receive linezolid regardless of baseline blood count.
Cases of sideroblastic anaemia have been reported post-marketing. 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.
Antibiotic-associated diarrhoea and colitis:
Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, 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 serious 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.
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. Co-administration of linezolid and serotonergic agents is therefore contraindicated 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 the maximum recommended duration of 28 days.
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 Linezolid for longer than the recommended 28 days, their visual function should be regularly monitored.
If peripheral or optic neuropathy occurs, the continued use of Linezolid 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 antimycobacterial medications for the treatment of tuberculosis.
Convulsions:
Convulsions have been reported to occur in patients when treated with Linezolid. In most of these cases, a history of seizures or risk factors for seizures was 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.
Use with tyramine-rich foods:
Patients should be advised against consuming large amounts of tyramine-rich foods.
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.
It is recommended that linezolid should be given to patients with severe hepatic insufficiency only when the perceived benefit outweighs the theoretical risk.
8-PREGNANCY and LACTATION:
Pregnancy, Category C.
Linezolid should not be used during pregnancy unless clearly necessary i.e. only if the potential benefit outweighs the theoretical risk.
Lactation:
Breast-feeding should be discontinued prior to and throughout administration.
9-EFFECTS on ABILITY to DRIVE and USE MACHINES:
Patients should be warned about the potential for dizziness or symptoms of visual impairment whilst receiving linezolid and should be advised not to drive or operate machinery if any of these symptoms occurs.
10-DRUG INTERACTIONS:
Monoamine oxidase inhibitors:
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). There are very limited data from drug interaction studies and on the safety of 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 recipient is possible.
Potential interactions producing elevation of blood pressure:
In normotensive healthy volunteers, linezolid enhanced the increases in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Therefore, 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:
No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.
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 is contraindicated, management of patients for whom treatment with linezolid and serotonergic agents is essential.
Use with tyramine-rich foods:
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 food and beverages with a high tyramine content (e.g. mature cheese, yeast extracts, un-distilled alcoholic beverages and fermented soya bean products such as soy sauce).
Drugs metabolised by cytochrome P450:
No CYP450-induced drug interactions are expected with linezolid.
Rifampicin:
Rifampicin decreased the linezolid Cmax and AUC by a mean 21% and a mean 32%, respectively. The mechanism of this interaction and its clinical significance are unknown.
Warfarin:
When warfarin was added to linezolid therapy at steady-state, there was a 10% reduction in mean maximum INR on co-administration with a 5% reduction in AUC INR.
11-DOSAGE & ADMINISTRATION:
Posology
Linezolid solution for infusion, film-coated tablets or oral suspension may be used as initial therapy. Patients who commence treatment on the parenteral formulation may be switched to either oral presentation when clinically indicated. In such circumstances, no dose adjustment is required as linezolid has an oral bioavailability of approximately 100%.
Recommended dosage and duration of treatment for adults: The duration of treatment is dependent on the pathogen, the site of infection and its severity, and on the patient's clinical response.
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.
No increase in the recommended dosage or duration of treatment is required for infections associated with concurrent bacteraemia.
The dose recommendation for the solution for infusion and the tablets/granules for oral suspension are identical and are as follows:
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Infections
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Dosage
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Duration of treatment
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Nosocomial pneumonia
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600 mg twice daily
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10-14 Consecutive days
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Community acquired pneumonia
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||
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Complicated skin and soft tissue infections
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600 mg twice daily
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Paediatric population:
The safety and efficacy of linezolid in children aged (< 18 years old) has not been established.
Elderly:
No dose adjustment is required.
Renal impairment:
No dose adjustment is required. However, in severe renal impairment (i.e. CLCR < 30 ml/min), Due to the unknown clinical significance of higher exposure (up to 10 fold) to the two primary metabolites of linezolid in patients with severe renal insufficiency, linezolid should be used with special caution in these patients and only when the anticipated benefit is considered to outweigh the theoretical risk.
As approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis, linezolid should be given after dialysis in patients receiving such treatment. The primary metabolites of linezolid are removed to some extent by haemodialysis, but the concentrations of these metabolites are still very considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency.
Therefore, linezolid should be used with special caution in patients with severe renal insufficiency who are undergoing dialysis and only when the anticipated benefit is considered to outweigh the theoretical risk.
To date, there is no experience of linezolid administration to patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal failure (other than haemodialysis).
Hepatic impairment:
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.
Method of administration:
The recommended linezolid dosage should be administered orally twice daily.
The film-coated tablets may be taken with or without food.
12-OVERDOSE:
No specific antidote is known.
No cases of overdose have been reported. However, supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a linezolid 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.
13-PACKAGING:
LIZOLID- Film coated tablets: Carton package of 20 film coated tablets in blister.
14-STORAGE CONDITIONS:
Store LIZOLID- Film coated tablets at temperature between (15-30)°C.
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