Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use

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 thes 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 Page 4 of 24
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. More patients in the linezolid arm acquired Gram negative pathogens during the study 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 section 4.1).
In these circumstances treatment against Gram negative organisms must be initiated concomitantly.



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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 lacticacidosis, 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 (see section 4.3) 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.


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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 (see sections 4.3 and 4.5).

Use with tyramine-rich foods
Patients should be advised against consuming large amounts of tyramine rich foods (see section 4.5).

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.

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 sections 4.2 and 5.2).

It is recommended that linezolid should be given to patients with severe hepatic insufficiency only when the perceived benefit outweighs the theoretical risk (see sections 4.2 and 5.2).

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 (see section 5.3).

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Clinical trials
The safety and effectiveness of linezolid when administered for periods longer than 28 days have not been established.
Controlled clinical trials did not include patients with diabetic foot lesions, decubitus or ischaemic lesions, severe burns or gangrene. Therefore,
experience in the use of linezolid in the treatment of these conditions is limited.

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 for an adult. The sodium content should be taken into account in patients on a controlled sodium diet.
Linezan 2 mg/ml Solution for Infusion may be further prepared for administration with sodium-containing solutions (see sections 4.2, 6.2, and 6.6) and this should be considered in relation to the total sodium from all sources that will be administered to the patient


Pediatric Use
The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well- controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator- controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years (see THERAPEUTIC INDICATIONS):
• Nosocomial pneumonia
• Complicated skin and skin structure infections
• Community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)
• Vancomycin-resistant Enterococcus faecium infections

The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years.
•     Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.

Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF.
Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.

The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in Page 8 of 24
preterm (gestational age < 34 weeks) neonates < 7 days of age, linezolid clearance is often lower than in full-term neonates < 7 days of age.
Consequently, preterm neonates < 7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of a 10 mg/kg q8h regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg q8h by 7 days of life (see PHARMACOLOGICAL PROPERTIES, Pharmacokinetic Properties,
Pediatric and POSOLOGY AND METHODS OF ADMINISTRATION).
In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with (MICs) of 4 µg/mL treated with linezolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 µg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response (see PHARMACOLOGICAL PROPERTIES, Pharmacokinetic
Properties,      Pediatric   and      POSOLOGY         AND      METHODS           OF ADMINISTRATION).

Effects on Driving

4.7   Effects on ability to drive and use machines
Patients should be warned about the potential for dizziness or symptoms of visual impairment (as described in section 4.4 and 4.8) whilst receiving linezolid and should be advised not to drive or operate machinery if any of these symptoms occurs.