Linevex

300 mL infusion bag contains: Linezolid 600 mg, Glucose (Dextrose) monohydrate 15.07 g, Sodium Citrate Dihydrate 492 mg.

Pharmacology: Linezolid primarily contains (s)-linezolid which is biologically active and is metabolised to form inactive derivatives.
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 (oral and intravenous dosing in a crossover study) is complete (approximately 100%). Absorption is not significantly affected by food and absorption from the oral suspension is similar to that achieved with the film-coated tablets.
Plasma linezolid C_max and C_min (mean and [SD]) at steady-state following twice daily intravenous dosing of 600 mg have been determined to be 15.1 [2.5] mg/L and 3.68 [2.68] mg/L, respectively.

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. In determining whether Linezolid is an appropriate treatment, the results of microbiological tests or information on the prevalence of resistance to antibacterial agents among Gram positive bacteria should be taken into consideration.
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 adults 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.

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 following recommendations for duration of therapy reflect those used in the clinical trials. Shorter treatment regimens may be suitable for some types of infection but have not been evaluated in clinical trials.
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: See table.

Click on icon to see table/diagram/image

Pediatric population: There are insufficient data on the safety and efficacy of linezolid in children and adolescents (<18 years old) to establish dosage recommendations. Therefore, until further data are available, use of linezolid in this age group is not recommended.
Elderly patients: No dose adjustment is required.
Patients with renal insufficiency: No dose adjustment is required.
Patients with severe renal insufficiency (i.e. CLCR <30 mL/min): No dose adjustment is required. 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).
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.
Method of administration: The recommended linezolid dosage should be administered intravenously twice daily.
Route of administration: Intravenous use.
The solution for infusion should be administered over a period of 30 to 120 minutes.

No specific antidote is known.
No cases of overdose have been reported. However, the following information may prove useful: 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.
Signs of toxicity in rats following doses of 3000 mg/kg/day linezolid were decreased activity and ataxia whilst dogs treated with 2000 mg/kg/day experienced vomiting and tremors.

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 the following underlying clinical conditions or on the following types of concomitant medications: 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 (see Precautions), 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.

Myelosuppression: Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected haematologic parameters have risen toward pretreatment levels. 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; 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, blood counts and platelet counts is possible.
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 (including haemoglobin levels, platelets, and total and differentiated leucocyte counts) should be monitored weekly in patients who receive linezolid regardless of baseline blood count.
In compassionate use studies, a higher incidence of serious anaemia was reported in patients receiving linezolid for more than the maximum recommended duration of 28 days. These patients more often required blood transfusion. Cases of anaemia requiring blood transfusion have also been reported post marketing, with more cases occurring in patients who received linezolid therapy for more than 28 days.
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.
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, in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs 58/363 (16.0%)]. The main factor influencing the mortality rate was the Gram positive infection status at baseline. Mortality rates were similar in patients with infections caused purely by Gram positive organisms (odds ratio 0.96; 95% confidence interval: 0.58-1.59) but were significantly higher (p=0.0162) in the linezolid arm in patients with any other pathogen or no pathogen at baseline (odds ratio 2.48; 95% confidence interval: 1.38- 4.46). The greatest imbalance occurred during treatment and within 7 days following discontinuation of study drug.
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.
Superinfection: The effects of linezolid therapy on normal flora have not been evaluated in clinical trials.
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 during clinical trials. Should superinfection occur during therapy, appropriate measures should be taken.
Excipients: Each mL of the solution contains 45.7 mg (i.e. 13.7 g/300 mL) glucose. This should be taken into account in patients with diabetes mellitus or other conditions associated with glucose intolerance. Each mL of solution also contains 0.38 mg (114 mg/300 mL) sodium. The sodium content should be taken into account in patients on a controlled sodium diet.
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.
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.
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.

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. Linezolid should not be used during pregnancy unless clearly necessary i.e. only if the potential benefit outweighs the theoretical risk.
Breast-feeding: 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.
Fertility: Linezolid decreased fertility and reproductive performance of male rats at exposure levels approximately equal to those expected in humans. In dogs treated for 1 month, changes in the weights of prostate, testes and epididymis were apparent.
It is not known whether these findings have an impact on human fertility.

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. 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: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20 mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.
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, undistilled alcoholic beverages and fermented soya bean products such as soy sauce).
Drugs metabolised by cytochrome P450: Linezolid is not detectably metabolised by the cytochrome P450 (CYP) enzyme system and it does not inhibit any of the clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, no CYP450-induced drug interactions are expected with linezolid.
Rifampicin: The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers administered linezolid 600 mg twice daily for 2.5 days with and without rifampicin 600 mg once daily for 8 days. Rifampicin decreased the linezolid C_max and AUC by a mean 21% [90% CI, 15, 27] and a mean 32% [90% CI, 27, 37], 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. There are insufficient data from patients who have received warfarin and linezolid to assess the clinical significance, if any, of these findings.

Store in the original package in order to protect from light.
After opening: From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Other Antibiotics

J01XX08 - linezolid ; Belongs to the class of other antibacterials. Used in the systemic treatment of infections.

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