Lidonit 600 mg FC tablets.

LIDONIT is indicated for the treatment of patients with the following infections caused by susceptible strains of the designated micro-organisms. LIDONIT is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy must be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected (see 4.4).

• Vancomycin - resistant: Enterococcus faecium infections, which includes cases with concurrent bacteraemia.
• Nosocomial pneumonia: caused by Streptococcus pneumoniae (including multi-drug resistant S. pneumoniae (MDRSP) strains) or Staphylococcus aureus (methicillin-susceptible and -resistant strains).
• Community - acquired pneumonia: caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains) or Streptococcus pneumoniae (including multi-drug resistant S. pneumoniae (MDRSP) strains), including cases with concurrent bacteraemia.

Prescribers should carefully consider alternatives before initiating treatment with LIDONIT in the outpatient setting due to the concern regarding the inappropriate use of antibiotics leading to an increase in resistant organisms. Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and their susceptibility to linezolid. Therapy may be introduced empirically while waiting for the test results. Once these tests are available, antimicrobial therapy should be adjusted accordingly.

LIDONIT tablets may be used as initial therapy. Patients who commence treatment on intravenous linezolid may be switched to LIDONIT when clinically indicated. In such circumstances, no dose adjustment is required as LIDONIT has an oral bioavailability of approximately 100 %. LIDONIT film coated tablets can be taken with or without food.

The recommended dose for LIDONIT is indicated in the table below:

Adult and adolescent (12 years and older) patients:

Special populations

• Elderly patients: No dose adjustment is necessary.
• Patients with renal insufficiency: No dose adjustment is necessary.
• Patients with severe renal insufficiency (CLCR < 30 mL/min): No dose adjustment is required. LIDONIT should be used with special caution in patients with severe renal insufficiency due to the unknown clinical significance of higher exposure (up to 10-fold) to the two primary metabolites of LIDONIT. In these patients LIDONIT should only be considered when the theoretical risk is outweighed by the anticipated benefit. Approximately 30 % of a LIDONIT dose is removed during 3 hours of haemodialysis, therefore LIDONIT should be given after dialysis in patients receiving such treatment. Haemodialysis removes the primary metabolites of LIDONIT to some extent, although the concentrations of these metabolites are still considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency. LIDONIT should be used with special caution in patients with severe renal insufficiency who are undergoing dialysis. In these patients LIDONIT should only be considered when the theoretical risk is outweighed by the anticipated benefit.
• Patients with hepatic insufficiency: Although no dose adjustment is required, due to limited clinical data, it is recommended that LIDONIT should be used with special precaution in patients with hepatic impairment and should only be considered when the theoretical risk is outweighed by the anticipated benefit.

Method of administration

LIDONIT film coated tablets are for oral use. LIDONIT may be taken with or without food. Missed dose: Doctors should advise patients who forget to take LIDONIT to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

• hypersensitivity to linezolid or to any of the ingredients of LIDONIT
• LIDONIT should not be used in patients treated with monoamine inhibitor oxidases A or B (e.g. phenelzine, isocarboxazid, moclobemide, selegiline) or within two weeks after discontinuation of taking such medicines
• LIDONIT should not be administered to patients with the following underlying clinical conditions or on the following types of concomitant medicines:
• patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, hyperthyroidism, bipolar depression, schizoaffective disorder, acute confusional states
• patients taking any of the following: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), serotonin-norepinephrine reuptake inhibitors (SNRIs), dopaminergic medicines (e.g. dopamine, dobutamine), direct and indirect acting sympathomimetic medicines including the adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine, vasopressor medicines (e.g. epinephrine (adrenaline), norepinephrine (noradrenaline)), meperidine, pethidine or buspirone (see sections 4.4 and 4.5)
• pregnancy and lactation (see section 4.6).

Serotonin syndrome
Spontaneous reports of serotonin syndrome associated with the co-administration of LIDONIT and serotonergic medicines, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported. Co-administration of LIDONIT and serotonergic medicines is therefore contraindicated (see section 4.3).

Myelosuppression
Reversible Myelosuppression (including anaemia, granulocytopenia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid, as in LIDONIT. 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.

Thrombocytopenia may occur more commonly in patients with severe renal insufficiency, whether or not on dialysis. Elderly patients treated with LIDONIT may be at greater risk of experiencing blood dyscrasias than younger patients. Monitoring of complete blood counts should therefore be considered for patients who have pre-existing myelosuppression, who are at increased risk for bleeding, patients who receive concomitant medicines that may decrease haemoglobin levels or platelet count or function, have severe renal insufficiency or are receiving LIDONIT treatment for more than 2 weeks. Therapy with LIDONIT should be stopped if significant myelosuppression occurs. In this case, intensive monitoring of blood counts and appropriate management strategies should be implemented.

Antibiotic - associated diarrhoea and colitis
Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhoea (CDAD) have been reported in association with the use of LIDONIT, and may range in severity from mild diarrhoea to fatal colitis. In antibiotic-associated colitis, treatment with LIDONIT should be discontinued. Appropriate therapy should be instituted. Therefore, it is important to consider this diagnosis in patients who develop severe diarrhoea during or after the use of LIDONIT. Medicines inhibiting gut motility/peristalsis are contraindicated in this situation. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. CDAD has been reported to occur over two months after the administration of antibacterial medicines such as LIDONIT, therefore careful medical history is necessary.

Lactic acidosis
Lactic acidosis has been reported with the use of LIDONIT. Patients who develop signs and symptoms of metabolic acidosis, including recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or hyperventilation while receiving LIDONIT should receive immediate medical attention.

Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis when given for prolonged courses. There is a decrease in cellular energy production in tissues that are highly dependent on oxidative phosphorylation such as the optic nerve, liver, skeletal muscles and kidneys. 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 LIDONIT is used for longer than 28 days.

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 LIDONIT. 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. Prompt evaluation is recommended with referral to an ophthalmologist. There may be an increased risk of neuropathies when LIDONIT is used in patients currently taking or who have recently taken antimycobacterial medicines for the treatment of tuberculosis (see section 4.5). Visual function should be monitored in all patients taking LIDONIT for extended periods (3 months and more) as well as in those patients reporting new visual symptoms, regardless of the length of therapy. If peripheral or optic neuropathy occurs, the continued use of LIDONIT in these patients should be weighed against the potential risks.

Convulsions
Convulsions have been reported in patients treated with LIDONIT. Patients should be advised to inform their medical practitioner if they have a history of seizures.

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

Superinfection
The effects of linezolid therapy on normal flora have not been established. The use of LIDONIT may result in an overgrowth of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken. Bacteriological examination of appropriate specimens should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to linezolid. While awaiting these test results, therapy may be instituted empirically. Once these results become available, antimicrobial therapy should be adjusted accordingly.

Other LIDONIT is not indicated for the treatment of Gram-negative infections. Patients with mixed Gram-negative and Gram-positive infections are at a higher risk of mortality when linezolid, as in LIDONIT, is given as monotherapy. LIDONIT must therefore be used concomitantly with appropriate antibacterial cover for Gram-negative organisms in such patients. In patients treated with linezolid excess mortality was seen in comparison to vancomycin/dicloxacillin/oxacillin. The most important factor influencing the mortality rate was the Gram-positive infection status at baseline. The greatest imbalance occurred during treatment and within 7 days following discontinuation of study medicine. More patients in the linezolid arm acquired gram negative pathogens during the study and died from infections caused by gram negative pathogens and polymicrobial infections. This clinical study was an open-label randomised study comparing linezolid to vancomycin, oxacillin or dicloxacillin in the treatment of seriously ill patients with intravascular catheter-related bloodstream infections. LIDONIT should be used with special caution in patients at high risk for life threatening systemic infections, such as those with infections related to central venous catheters in intensive care units. LIDONIT is not approved for the treatment of patients with catheter-related bloodstream infections. The safety and efficacy of LIDONIT has not been established when administered for periods longer than 28 days. Experience in the use of linezolid in the treatment of patients with diabetic foot lesions, decubitus or ischaemic lesions, severe burns or gangrene is limited.

Special populations
Caution is advised when LIDONIT is used in patients with severe renal and/or hepatic insufficiency.

Lactose
LIDONIT contains lactose. Patients with the rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take LIDONIT.

Linezolid, as in LIDONIT, does not induce or inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4) and is not detectably metabolised by the cytochrome P450 (CYP) enzyme system. Therefore, no CYP450-induced medicine interactions are expected. Medicines such as phenytoin and warfarin, which are CYP2C9 substrates, may be given with LIDONIT without changes in dosage regimen. Adding warfarin to steady-state linezolid therapy resulted in a 10 % reduction in the mean maximum INR on co-administration with a 5 % reduction in AUC INR. The data is insufficient on patients who received warfarin and linezolid and thus the clinical significance cannot be established. No interactions have been observed in pharmacokinetic studies with either aztreonam or gentamicin.

Linezolid, as in LIDONIT is a reversible, non-selective monoamine oxidase inhibitor (MAOI). It produces a reversible enhancement of pressor responses which is started by pseudoephedrine and phenylpropanolamine hydrochloride (as proven by clinical studies). Thus, the potential interaction with adrenergic or sympathomimetic medicines should be considered and doses of medicines, such as dopamine or epinephrine (adrenaline), should be titrated to attain the desired response. Linezolid when co-administered with pseudoephedrine or phenylpropanolamine hydrochloride enhanced the increases in blood pressure in normotensive healthy volunteers. Systolic blood pressure increased in the range of 30-40 mmHg. It is recommended that doses of medicine with vasopressive action, including dopaminergic agents, should be carefully titrated to achieve the desired response when co-administered with linezolid. No significant pressor response was observed in subjects receiving both LIDONIT and less than 100 mg tyramine. This suggests that it is only necessary to avoid ingesting large amounts of food and beverages with a high tyramine content (e.g. un-distilled alcoholic beverages, mature cheese, yeast extracts and fermented soya bean products such as soy sauce). Although LIDONIT has the potential for interaction with serotonergic agents, no serotonin effects (e.g. confusion, delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia) were observed in subjects receiving linezolid and dextromethorphan.

Spontaneous reports of serotonin syndrome associated with the co-administration of LIDONIT, and serotonergic medicines, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported. Where administration of LIDONIT and concomitant serotonergic agents is clinically appropriate, 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, doctors should consider discontinuation of either one or both agents. If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can be observed.

Rifampicin: Concomitant administration with LIDONIT may cause a decrease of about 21 % and 32 % in linezolid Cmax and AUC, respectively. The mechanism of this interaction and the clinical significance is not known.

Pregnancy
The use of LIDONIT in pregnancy is contraindicated as safety has not been established (see section 4.3).

Breastfeeding
The use of LIDONIT in lactation is contraindicated as safety has not been established (see section 4.3). Animal data revealed that linezolid as well as its metabolites can possibly pass into breast milk u2013 It is recommended that breastfeeding should be discontinued prior to and throughout administration.

Fertility
Study results in male rats revealed fertility and reproductive performance decreased at exposure levels approximately equal to those expected in humans. Prostrate, testes and epididymis weight changes were evident in dogs treated for 1 month. However, it is not known whether these findings have an impact on human fertility.

Patients should be warned about the potential for dizziness or symptoms of visual impairment whilst receiving LIDONIT and should be advised not to drive or operate machinery if any of these symptoms occur.

Summary of the safety profile
Headache, diarrhoea, nausea and candidiasis (particularly oral and vaginal candidiasis) were the most commonly reported adverse effects, with those leading to discontinuation of treatment including headache, diarrhoea, nausea and vomiting.

Tabulated summary of adverse reactions

Description of selected adverse reactions: Localised abdominal pain, transient ischaemic attacks and hypertension are, in less frequent cases, considered to be serious. Linezolid, administered for up to 28 days, revealed that less than 0,1% of the patients reported anaemia. 2,5 % (33/1326) as compared with 12,3 % (53/430) of patients with life-threatening infections and underlying co-morbidities developed anaemia, with 9 % (3/33) and 15 % (8/53) developing serious medicine-related anaemia that required a blood transfusion were reported in patients treated with linezolid for u2264 28 and >28 days respectively.

Signs and symptoms: In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8)

Management of overdose: In the event of overdosage with LIDONIT, supportive care is advised together with maintenance of glomerular filtration. Approximately 30 % of a LIDONIT dose is removed during 3 hours of haemodialysis, however, no data are available for the removal of LIDONIT by peritoneal dialysis or haemoperfusion.