Chemical formula: C₁₆H₂₀FN₃O₄ Molecular mass: 337.346 g/mol PubChem compound: 441401
Linezolid interacts in the following cases:
Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected haematologic parameters have risen toward pretreatment levels. The risk of these effects appears to be related to the duration of treatment. Elderly patients treated with linezolid may be at greater risk of experiencing blood dyscrasias than younger patients. Thrombocytopenia may occur more commonly in patients with severe renal insufficiency, whether or not on dialysis. Therefore, close monitoring of blood counts is recommended in patients who: have pre-existing anaemia, granulocytopenia or thrombocytopenia; are receiving concomitant medications that may decrease haemoglobin levels, depress blood counts or adversely affect platelet count or function; have severe renal insufficiency; receive more than 10-14 days of therapy. Linezolid should be administered to such patients only when close monitoring of haemoglobin levels, blood counts and platelet counts is possible.
If significant myelosuppression occurs during linezolid therapy, treatment should be stopped unless it is considered absolutely necessary to continue therapy, in which case intensive monitoring of blood counts and appropriate management strategies should be implemented.
In addition, it is recommended that complete blood counts (including haemoglobin levels, platelets, and total and differentiated leucocyte counts) should be monitored weekly in patients who receive linezolid regardless of baseline blood count.
In compassionate use studies, a higher incidence of serious anaemia was reported in patients receiving linezolid for more than the maximum recommended duration of 28 days. These patients more often required blood transfusion. Cases of anaemia requiring blood transfusion have also been reported post marketing, with more cases occurring in patients who received linezolid therapy for more than 28 days.
Cases of sideroblastic anaemia have been reported post-marketing. Where time of onset was known, most patients had received linezolid therapy for more than 28 days. Most patients fully or partially recovered following discontinuation of linezolid with or without treatment for their anaemia.
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).
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.
In normotensive healthy volunteers, linezolid enhanced the increases in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Co-administration of linezolid with either pseudoephedrine or phenylpropanolamine resulted in mean increases in systolic blood pressure of the order of 30-40 mmHg, compared with 11-15 mmHg increases with linezolid alone, 14-18 mmHg with either pseudoephedrine or phenylpropanolamine alone and 8-11 mmHg with placebo. Similar studies in hypertensive subjects have not been conducted. It is recommended that doses of drugs with a vasopressive action, including dopaminergic agents, should be carefully titrated to achieve the desired response when co-administered with linezolid.
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.
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.
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.
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.
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 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.
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.
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).
There are limited data from the use of linezolid in pregnant women. Studies in animals have shown reproductive toxicity. A potential risk for humans exists.
Linezolid should not be used during pregnancy unless clearly necessary i.e. only if the potential benefit outweighs the theoretical risk.
Animal data suggest that linezolid and its metabolites may pass into breast milk and, accordingly, breastfeeding should be discontinued prior to and throughout administration.
In animal studies, linezolid caused a reduction in fertility.
Patients should be warned about the potential for dizziness or symptoms of visual impairment whilst receiving linezolid and should be advised not to drive or operate machinery if any of these symptoms occurs.
The list below provides a listing of adverse drug reactions with frequency based on all-causality data from clinical studies that enrolled more than 2,000 adult patients who received the recommended linezolid doses for up to 28 days.
Those most commonly reported were diarrhoea (8.4%), headache (6.5%), nausea (6.3%) and vomiting (4.0%).
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 list 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).
Common: candidiasis, oral candidiasis, vaginal candidiasis, fungal infections
Uncommon: vaginitis
Rare: antibiotic-associated colitis, including pseudomembranous colitis
Common: anaemia^†^
Uncommon: leucopenia, neutropenia, thrombocytopenia, eosinophilia
Rare: pancytopenia
Frequency not known: myelosuppression, sideroblastic anaemia
Frequency not known: anaphylaxis
Uncommon: hyponatraemia
Frequency not known: lactic acidosis
Common: insomnia
Common: headache, taste perversion (metallic taste), dizziness
Uncommon: convulsions*, hypoaesthesia, paraesthesia
Frequency not known: serotonin syndrome, peripheral neuropathy
Uncommon: blurred vision
Rare: changes in visual field defect
Frequency not known: optic neuropathy, optic neuritis, loss of vision, changes in visual acuity, changes in colour vision
Uncommon: tinnitus
Uncommon: arrhythmia (tachycardia)
Common: hypertension
Uncommon: transient ischaemic attacks, phlebitis, thrombophlebitis
Common: diarrhoea, nausea, vomiting, localised or general abdominal pain, constipation, dyspepsia
Uncommon: pancreatitis, gastritis, abdominal distention, dry mouth, glossitis, loose stools, stomatitis, tongue discolouration or disorder
Rare: superficial tooth discolouration
Common: abnormal liver function test; increased AST, ALT or alkaline phosphatase
Uncommon: increased total bilirubin
Common: pruritus, rash
Uncommon: urticaria, dermatitis, diaphoresis
Frequency not known: bullous disorders such as those described as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia
Common: increased BUN
Uncommon: renal failure, increased creatinine, polyuria
Uncommon: vulvovaginal disorder
Common: fever, localised pain
Uncommon: chills, fatigue, injection site pain, increased thirst
Common:
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.
Uncommon:
Chemistry: Increased sodium or calcium. Decreased non fasting glucose. Increased or decreased chloride.
Haematology: Increased reticulocyte count. Decreased neutrophils.
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.
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.
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