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LINEZOLID DR. REDDYS 600 MG FILM-COATED TABLETS

Active substance(s): LINEZOLID / LINEZOLID / LINEZOLID

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Linezolid Dr. Reddy’s 600 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 600 mg linezolid.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
White to off-white, oblong (approximately 18 mm x 6 mm), biconvex film
coated tablets debossed with “L9II 600” on one side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Nosocomial pneumonia
Community acquired pneumonia
Linezolid is indicated 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 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
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. (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 solution for infusion and the tablets/granules
for oral suspension are identical and are as follows:
Infections
Dosage
Duration of treatment
Nosocomial pneumonia
600 mg twice daily
10-14 Consecutive days
Community
acquired
600 mg twice daily
Complicated skin and
soft tissue infections
Children: There are insufficient data on the safety and efficacy of linezolid in
children and adolescents (< 18 years old) to establish dosage recommendations
(see sections 5.1 and 5.2). 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 (see sections
4.4 and 5.2).
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 (see sections 4.4 and 5.2).
Method of administration: The recommended linezolid dosage should be
administered intravenously or orally twice daily.
Route of administration: Oral use.
The film-coated tablets may be taken with or without food.

4.3

Contraindications
Patients hypersensitive to linezolid or any of the excipients (see 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, breastfeeding 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 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 preexisting 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.
Antibiotic-associated diarrhoea and colitis

Pseudomembranous colitis has been reported with nearly all antibacterial
agents, including linezolid. Therefore, it is important to consider this diagnosis
in patients who present with diarrhoea subsequent to the administration of any
antibacterial agent. In cases of suspected or verified antibiotic-associated
colitis, discontinuation of linezolid may be warranted. Appropriate
management measures should be instituted.
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 coadministration 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.
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 nonsusceptible 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.

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. Coadministration 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.
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), 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
There are no adequate 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.
Animal data suggest that linezolid and its metabolites may pass into breast milk
and, accordingly, breastfeeding should be discontinued prior to and throughout
administration.

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 that occurred at
frequencies > 0.1% or considered to be serious in clinical studies that enrolled
more than 2,000 adult patients who received the recommended linezolid doses
for up to 28 days.
Approximately 22% of patients experienced adverse reactions; those most
commonly reported were headache (2.1%), diarrhoea (4.2%), nausea (3.3%)
and candidiasis (particularly oral [0.8%] and vaginal [1.1%] candidiasis, see
table below).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)

Infections and
infestations

Candidiasis, oral
candidiasis, vaginal
candidiasis, fungal
infections

Vaginitis

Antibiotic-associated
colitis, including
pseudomembranous
colitis*

Leucopenia*,
neutropenia,
thrombocytopenia*,
eosinophilia

Myelosuppression*,
pancytopenia*,
anaemia* †,
sideroblastic anaemia*

Blood and the
lymphatic
system disorders

Immune system
disorders
Metabolism
and nutrition
disorders
Psychiatric
disorders
Nervous system
disorders

Eye disorders

Ear and
labyrinth
disorders
Cardiac
disorders
Vascular
disorders

Rare
(1/10,000 to
<1/1,000)

Very Rare Frequency not known
(<1/
(cannot be estimated
10,000)
from available data)

Anaphylaxis
Lactic acidosis*,
hyponatraemia
Insomnia
Headache, taste
perversion (metallic
taste)

Dizziness,
hypoaesthesia,
paraesthesia

Serotonin
syndrome**,
convulsions*,
peripheral
neuropathy*

Blurred vision*

Optic neuropathy*, optic
neuritis*, loss of vision*,
changes in visual acuity*,
changes in colour
vision*, changes in visual
field defect*

Tinnitus

Hypertension,
phlebitis,
thrombophlebitis

Arrhythmia
(tachycardia)
Transient
ischaemic
attacks

Gastrointestinal
disorders

Diarrhoea, nausea,
vomiting.

Pancreatitis,
gastritis, localised or
general
abdominal
pain,
constipation,
dry mouth,
dyspepsia,
glossitis, loose
stools,
stomatitis,
tongue
discolouration
or disorder

Hepato-biliary
disorders

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

Increased total
bilirubin

Skin and
subcutaneous
tissue disorders

Renal and
urinary
disorders
Reproductive
system and breast
disorders

Urticaria,
dermatitis,
diaphoresis,
pruritus, rash

Increased BUN

General disorders
and
administration
site conditions
Investigations

Superficial tooth
discolouration

Polyuria,
increased
creatinine
Vulvovaginal
disorder
Chills, fatigue, fever,
injection site pain,
increased thirst,
localised pain

Chemistry Increased
LDH, creatine kinase,
lipase, amylase or non
fasting glucose.
Decreased total protein,
albumin, sodium or
calcium. Increased or
decreased potassium or
bicarbonate.

Chemistry Increased
sodium or calcium.
Decreased non
fasting glucose.
Increased or
decreased chloride.

Bullous disorders such as
those described as
Stevens-Johnson
syndrome and toxic
epidermal necrolysis,
angioedema, alopecia
Renal failure

Haematology
Increased
neutrophils or
eosinophils.
Decreased
haemoglobin,
haematocrit or
red blood cell
count. Increased or
decreased
platelet or white blood
cell counts.

Haematology
Increased
reticulocyte
count.
Decreased
neutrophils.

* See section 4.4.
** See sections 4.3 and 4.5
† 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, less than 0.1% of the patients reported anaemia. In a compassionate use
program of patients with life-threatening infections and underlying comorbidities, 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.
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, website:
www.mhra.gov.uk/yellowcard.

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 3000 mg/kg/day linezolid were
decreased activity and ataxia whilst dogs treated with 2000 mg/kg/day
experienced vomiting and tremors.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Other antibacterials.
ATC code: J01XX08
General Properties
Linezolid is a synthetic, antibacterial agent that belongs to a new class of
antimicrobials, the oxazolidinones. It has in vitro 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.
The in vitro postantibiotic effect (PAE) of linezolid for Staphylococcus aureus
was approximately 2 hours. When measured in animal models, the in vivo
PAE was 3.6 and 3.9 hours for Staphylococcus aureus and Streptococcus
pneumoniae, respectively. In animal studies, the key pharmacodynamic
parameter for efficacy was the time for which the linezolid plasma level
exceeded the minimum inhibitory concentration (MIC) for the infecting
organism.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the
European Committee on Antimicrobial Susceptibility Testing (EUCAST) for
staphylococci and enterococci are Susceptible ≤ 4mg/L and Resistant >4
mg/L. For streptococci (including S. pneumoniae) the breakpoints are
Susceptible ≤ 2 mg/L and Resistant >4 mg/L.
Non-species related MIC breakpoints are Susceptible ≤ 2 mg/L and Resistant
> 4 mg/L. Non-species related breakpoints have been determined mainly on
the basis of PK/PD data and are independent of MIC distributions of specific
species. They are for use only for organisms that have not been given a
specific breakpoint and not for those species where susceptibility testing is not
recommended.
Susceptibility
The prevalence of acquired resistance may vary geographically and with time
for selected species and local information on resistance is desirable,
particularly when treating severe infections. As necessary, expert advice
should be sought when local prevalence of resistance is such that the utility of
the agent in at least some types of infections is questionable.
Category
Susceptible organisms
Gram positive aerobes:
Enterococcus faecalis
Enterococcus faecium*
Staphylococcus aureus*
Coagulase negative staphylococci

Streptococcus agalactiae*
Streptococcus pneumoniae*
Streptococcus pyogenes*
Group C streptococci
Group G streptococci
Gram positive anaerobes:
Clostridium perfringens
Peptostreptococcus anaerobius
Peptostreptococcus species
Resistant organisms
Haemophilus influenzae
Moraxella catarrhalis
Neisseria species
Enterobacteriaceae
Pseudomonas species
*Clinical efficacy has been demonstrated for susceptible isolates in approved
clinical indications
Whereas linezolid shows some in vitro activity against Legionella, Chlamydia
pneumoniae and Mycoplasma pneumoniae, there are insufficient data to
demonstrate clinical efficacy.
Resistance
Cross 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. Resistance to linezolid has
been reported in enterococci, Staphylococcus aureus and coagulase negative
staphylococci. This generally has been associated with prolonged courses of
therapy and the presence of prosthetic materials or undrained abscesses. When
antibiotic-resistant organisms are encountered in the hospital it is important to
emphasize infection control policies.
Information from clinical trials
Studies in the paediatric population
In an open study, the efficacy of linezolid (10 mg/kg q8h) was compared to
vancomycin (10-15 mg/kg q6-24h) in treating infections due to suspected or
proven resistant Gram-positive pathogens (including nosocomial pneumonia,
complicated skin and skin structure infections, catheter-related bacteraemia,
bacteraemia of unknown source, and other infections), in children from birth to
11 years. Clinical cure rates in the clinically evaluable population were 89.3%

(134/150) and 84.5% (60/71) for linezolid and vancomycin, respectively
(95%CI: -4.9, 14.6).

5.2

Pharmacokinetic properties
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 Cmax and Cmin (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.
In another study following oral dosing of 600 mg twice daily to steady-state,
Cmax and Cmin were determined to be 21.2 [5.8] mg/l and 6.15 [2.94] mg/l,
respectively. Steady-state conditions are achieved by the second day of dosing.
Distribution
Volume of distribution at steady-state averages at about 40-50 litres in healthy
adults and approximates to total body water. Plasma protein binding is about
31% and is not concentration dependent.
Linezolid concentrations have been determined in various fluids from a limited
number of subjects in volunteer studies following multiple dosing. The ratio of
linezolid in saliva and sweat relative to plasma was 1.2:1.0 and 0.55:1.0,
respectively. The ratio for epithelial lining fluid and alveolar cells of the lung
was 4.5:1.0 and 0.15:1.0, when measured at steady-state Cmax, respectively.
In a small study of subjects with ventricular-peritoneal shunts and essentially
non-inflamed meninges, the ratio of linezolid in cerebrospinal fluid to plasma
at Cmax was 0.7:1.0 after multiple linezolid dosing.
Metabolism
Linezolid is primarily metabolised by oxidation of the morpholine ring
resulting mainly in the formation of two inactive open-ring carboxylic acid
derivatives; the aminoethoxyacetic acid metabolite (PNU-142300) and the
hydroxyethyl glycine metabolite (PNU-142586). The hydroxyethyl glycine
metabolite (PNU-142586) is the predominant human metabolite and is
believed to be formed by a non-enzymatic process. The aminoethoxyacetic
acid metabolite (PNU-142300) is less abundant. Other minor, inactive
metabolites have been characterised.
Elimination
In patients with normal renal function or mild to moderate renal insufficiency,
linezolid is primarily excreted under steady-state conditions in the urine as
PNU-142586 (40%), parent drug (30%) and PNU-142300 (10%). Virtually no
parent drug is found in the faeces whilst approximately 6% and 3% of each
dose appears as PNU-142586 and PNU-142300, respectively. 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. A small degree of non-linearity in clearance is observed with
increasing doses of linezolid. This appears to be due to lower renal and nonrenal clearance at higher linezolid concentrations. However, the difference in
clearance is small and is not reflected in the apparent elimination half-life.
Special Populations
Patients with renal insufficiency: After single doses of 600 mg, there was a 7-8
fold increase in exposure to the two primary metabolites of linezolid in the
plasma of patients with severe renal insufficiency (i.e. creatinine clearance <
30 ml/min). However, there was no increase in AUC of parent drug. Although
there is some removal of the major metabolites of linezolid by haemodialysis,
metabolite plasma levels after single 600 mg doses were still considerably
higher following dialysis than those observed in patients with normal renal
function or mild to moderate renal insufficiency.
In 24 patients with severe renal insufficiency, 21 of whom were on regular
haemodialysis, peak plasma concentrations of the two major metabolites after
several days dosing were about 10 fold those seen in patients with normal
renal function. Peak plasma levels of linezolid were not affected.
The clinical significance of these observations has not been established as
limited safety data are currently available (see sections 4.2 and 4.4).
Patients with hepatic insufficiency: Limited data indicate that the
pharmacokinetics of linezolid, PNU-142300 and PNU-142586 are not altered
in patients with mild to moderate hepatic insufficiency (i.e. Child-Pugh class A
or B). The pharmacokinetics of linezolid in patients with severe hepatic
insufficiency (i.e. Child-Pugh class C) have not been evaluated. However, as
linezolid is metabolised by a non-enzymatic process, impairment of hepatic
function would not be expected to significantly alter its metabolism (see
sections 4.2 and 4.4).
Children and adolescents (< 18 years old): There are insufficient data on the
safety and efficacy of linezolid in children and adolescents (< 18 years old)
and therefore, use of linezolid in this age group is not recommended (see
section 4.2). Further studies are needed to establish safe and effective dosage
recommendations. Pharmacokinetic studies indicate that after single and
multiple doses in children (1 week to 12 years), linezolid clearance (based on
kg body weight) was greater in paediatric patients than in adults, but decreased
with increasing age.
In children 1 week to 12 years old, administration of 10 mg/kg every 8 hours
daily gave exposure approximating to that achieved with 600 mg twice daily in
adults.
In neonates up to 1 week of age, the systemic clearance of linezolid (based on
kg body weight) increases rapidly in the first week of life. Therefore, neonates
given 10 mg/kg every 8 hours daily will have the greatest systemic exposure
on the first day after delivery. However, excessive accumulation is not
expected with this dosage regimen during the first week of life as clearance
increases rapidly over that period.
In adolescents (12 to 17 years old), linezolid pharmacokinetics were similar to
that in adults following a 600mg dose. Therefore, adolescents administered
600 mg every 12 hours daily will have similar exposure to that observed in
adults receiving the same dosage.

In paediatric patients with ventriculoperitoneal shunts who were administered
linezolid 10 mg/kg either 12 hourly or 8 hourly, variable cerebrospinal fluid
(CSF) linezolid concentrations were observed following either single or
multiple dosing of linezolid. Therapeutic concentrations were not consistently
achieved or maintained in the CSF. Therefore, the use of linezolid for the
empirical treatment of paediatric patients with central nervous system
infections is not recommended.
Elderly patients: The pharmacokinetics of linezolid are not significantly altered
in elderly patients aged 65 and over.
Female patients: Females have a slightly lower volume of distribution than
males and the mean clearance is reduced by approximately 20% when
corrected for body weight. Plasma concentrations are higher in females and
this can partly be attributed to body weight differences. However, because the
mean half life of linezolid is not significantly different in males and females,
plasma concentrations in females are not expected to substantially rise above
those known to be well tolerated and, therefore, dose adjustments are not
required.

5.3

Preclinical safety data
Linezolid decreased fertility and reproductive performance of male rats at
exposure levels approximately equal to those expected in humans. In sexually
mature animals these effects were reversible. However, these effects did not
reverse in juvenile animals treated with linezolid for nearly the entire period of
sexual maturation. Abnormal sperm morphology in testis of adult male rats,
and epithelial cell hypertrophy and hyperplasia in the epididymis were noted.
Linezolid appeared to affect the maturation of rat spermatozoa.
Supplementation of testosterone had no effect on linezolid-mediated fertility
effects. Epididymal hypertrophy was not observed in dogs treated for 1 month,
although changes in the weights of prostate, testes and epididymis were
apparent.
Reproductive toxicity studies in mice and rats showed no evidence of a
teratogenic effect at exposure levels 4 times or equivalent, respectively, to
those expected in humans. The same linezolid concentrations caused maternal
toxicity in mice and were related to increased embryo death including total
litter loss, decreased fetal body weight and an exacerbation of the normal
genetic predisposition to sternal variations in the strain of mice. In rats, slight
maternal toxicity was noted at exposures lower than expected clinical
exposures. Mild fetal toxicity, manifested as decreased fetal body weights,
reduced ossification of sternebrae, reduced pup survival and mild maturational
delays were noted. When mated, these same pups showed evidence of a
reversible dose-related increase in pre-implantation loss with a corresponding
decrease in fertility. In rabbits, reduced fetal body weight occurred only in the
presence of maternal toxicity (clinical signs, reduced body weight gain and
food consumption) at low exposure levels 0.06 times compared to the
expected human exposure based on AUCs. The species is known to be
sensitive to the effects of antibiotics.

Linezolid and its metabolites are excreted into the milk of lactating rats and the
concentrations observed were higher than those in maternal plasma.
Linezolid produced reversible myelosuppression in rats and dogs.
In rats administered linezolid orally for 6 months, non-reversible, minimal to
mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day;
minimal degeneration of the sciatic nerve was also observed in 1 male at this
dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of
perfusion-fixed tissues was conducted to investigate evidence of optic nerve
degeneration. Minimal to moderate optic nerve degeneration was evident in 2
of 3 male rats after 6 months of dosing, but the direct relationship to drug was
equivocal because of the acute nature of the finding and its asymmetrical
distribution. The optic nerve degeneration observed was microscopically
comparable to spontaneous unilateral optic nerve degeneration reported in
aging rats and may be an exacerbation of common background change.
Preclinical data, based on conventional studies of repeated-dose toxicity and
genotoxicity, revealed no special hazard for humans beyond those addressed in
other sections of this Summary of Product Characteristics. Carcinogenicity /
oncogenicity studies have not been conducted in view of the short duration of
dosing and lack of genotoxicity in the standard battery of studies.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Cellulose, microcrystalline (E460)
Crospovidone
Hydroxypropylcellulose (E463)
Silica, colloidal anhydrous
Magnesium stearate (E572)
Coating:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 400

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
oPA/Al/PVC-Al blister
Boxes containing either 1, 10, 20, 30, 50 or 60 tablets, or 100 tablets (for
hospital use only).
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Dr. Reddy’s Laboratories (UK) Ltd.
6 Riverview Road
Beverley
East Yorkshire
HU17 0LD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 08553/0572

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/11/2015

10

DATE OF REVISION OF THE TEXT
23/11/2015

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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