4.1. Therapeutic indications

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. 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 (see section 5.1 for the appropriate organisms).

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 (see section 4.4)

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 (see section 4.4). 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.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

Linezolid 600mg film-coated tablets may be used as initial therapy.

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 (see section 4.4).

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

The dose recommendation for the tablets are as follows:

Infections

Dosage

Duration of treatment

Nosocomial pneumonia

600 mg twice daily

10-14 Consecutive days

Community acquired pneumonia

600 mg twice daily

10-14 Consecutive days

Complicated skin and soft tissue infections

600 mg twice daily

10-14 Consecutive days

Paediatric population:

The safety and efficacy of linezolid in children and adolescents (aged < 18 years old) has not been established. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Elderly:

No dose adjustment is required.

Renal impairment:

No dose adjustment is required (see sections 4.4 and 5.2).

Severe renal impairment (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).

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 (see sections 4.4 and 5.2).

Method of administration

The recommended linezolid dosage should be administered orally twice daily.

Route of administration: Oral use.

The film-coated tablets may be taken with or without food.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 section 4.4), 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.

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 (see section 4.6).

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 pre-treatment 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, and in patients with moderate to severe hepatic impairment. 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 or moderate to severe hepatic impairment; 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.

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) and opioids have been reported (see section 4.5). 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.

Rhabdomyolysis

Rhabdomyolysis has been reported with the use of linezolid. Linezolid should be used with caution in patients with pre-disposing factors for rhabdomyolysis. If signs or symptoms of rhabdomyolysis are observed, linezolid should be discontinued and appropriate therapy initiated.

Hyponatraemia and SIADH

Hyponatraemia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) have been observed in some patients treated with linezolid. It is recommended that serum sodium levels are monitored regularly in patients at risk of hyponatraemia such as elderly patients or patients taking medicines that may lower blood sodium levels (e.g. thiazide diuretics such as hydrochlorothiazide).

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 (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).

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.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 (see sections 4.3 and 4.4).

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 coadministered 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 and hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.

Post marketing experience: there has been one report of a patient experiencing serotonin syndrome-like effects while taking linezolid and dextromethorphan which resolved on discontinuation of both medications.

During clinical use of linezolid with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, cases of serotonin syndrome have been reported. Therefore, while co-administration is contraindicated (see section 4.3), management of patients for whom treatment with linezolid and serotonergic agents is essential, is described in section 4.4.

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 Cmax 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of linezolid in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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

In animal studies, linezolid caused a reduction in fertility (see section 5.3).

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.

4.8. Undesirable effects

The table below provides a listing of adverse drug reactions with frequency based on all-causality data from clinical studies that enrolled more than 6,000 adult patients who received the recommended linezolid doses for up to 28 days.

Those most commonly reported were diarrhoea (8.9%), nausea (6.9%), vomiting (4.3%) and headache (4.2%). The most commonly reported drug-related adverse events which led to discontinuation of treatment were headache, diarrhoea, nausea and vomiting. About 3 % of patients discontinued treatment because they experienced a drug-related adverse event.

Additional adverse reactions reported from post-marketing experience are included in the table with frequency category 'Not known', since the actual frequency cannot be estimated from the available data.

The following undesirable effects have been observed and reported during treatment with linezolid with the following frequencies: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); Not known (cannot be estimated from the available data)

System Organ Class

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Very Rare

(<1/10,000)

Frequency not known (cannot be estimated from available data)

Infections and infestations

candidiasis, oral candidiasis, vaginal candidiasis, fungal infections

antibiotic-associated colitis, including pseudomembranous colitis*, vaginitis

Blood and the lymphatic system disorders

thrombocytopenia*, anaemia*†

pancytopenia*, leucopenia*, neutropenia, eosinophilia

sideroblastic anaemia*

myelosuppression*

Immune system disorders

anaphylaxis

Metabolism and nutrition disorders

hyponatraemia, hypoglycaemia

lactic acidosis*

Psychiatric disorders

insomnia

Nervous system disorders

headache, taste perversion (metallic taste), dizziness

convulsions*, peripheral neuropathy*, hypoaesthesia, paraesthesia

serotonin syndrome**

Eye disorders

optic neuropathy*, blurred vision*

changes in visual field defect*

optic neuritis*, loss of vision*, changes in visual acuity*, changes in colour vision*

Ear and labyrinth disorders

tinnitus

Cardiac disorders

arrhythmia (tachycardia)

Vascular disorders

hypertension

transient ischaemic attacks, phlebitis, thrombophlebitis

Gastrointestinal disorders

diarrhoea, nausea, vomiting, localised or general abdominal pain, constipation, dyspepsia

pancreatitis, gastritis, abdominal distention, dry mouth, glossitis, loose stools, stomatitis, tongue discolouration or disorder

superficial tooth discolouration, black hairy tongue

Hepato-biliary disorders

abnormal liver function test; increased AST, ALT or alkaline phosphatase

increased total bilirubin

Skin and subcutaneous tissue disorders

pruritus, rash

angioedema, urticaria, dermatitis bullous, dermatitis, diaphoresis

toxic epidermal necrolysis#, Stevens-Johnson syndrome#, hypersensitivity vasculitis

alopecia

Musculoskeletal and connective tissue disorders

rhabdomyolysis*

Renal and urinary disorders

increased BUN

renal failure, increased creatinine, polyuria

Reproductive system and breast disorders

vulvovaginal disorder

General disorders and administration site conditions

fever, localised pain

chills, fatigue, injection site pain, increased thirst

Investigations

Chemistry Increased LDH, creatine kinase, lipase, amylase or non fasting glucose.

Decreased total protein, albumin, sodium or calcium.

Increased or decreased potassium or bicarbonate.

Haematology

Increased neutrophils or eosinophils.

Decreased haemoglobin, haematocrit or red blood cell count.

Increased or decreased platelet or white blood cell counts.

Chemistry Increased sodium or calcium.

Decreased non fasting glucose.

Increased or decreased chloride.

Haematology

Increased reticulocyte count.

Decreased neutrophils.

* See section 4.4.

** See sections 4.3 and 4.5

# ADR frequency estimated using “The Rule of 3”

† See below

The following adverse reactions to linezolid were considered to be serious in rare cases: localised abdominal pain, transient ischaemic attacks and hypertension.

† In controlled clinical trials where linezolid was administered for up to 28 days,2.0 % of the patients reported anaemia. In a compassionate use program of patients with life-threatening infections and underlying co-morbidities, the percentage of patients who developed anaemia when receiving linezolid for ≤ 28 days was 2.5 % (33/1326) as compared with 12.3 % (53/430) when treated for > 28 days. The proportion of cases reporting drug-related serious anaemia and requiring blood transfusion was 9 % (3/33) in patients treated for ≤ 28 days and 15 % (8/53) in those treated for > 28 days.

Paediatric population

Safety data from clinical studies based on more than 500 paediatric patients (from birth to 17 years) do not indicate that the safety profile of linezolid for paediatric patients differs from that for adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.

4.9. Overdose

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 3,000 mg/kg/day linezolid were decreased activity and ataxia whilst dogs treated with 2,000 mg/kg/day experienced vomiting and tremors.