ZYVOX should only be initiated in a hospital environment and after consultation with a relevant specialist such as a microbiologist or infectious diseases specialist1.
ZYVOX (linezolid): An Established Tolerability Profile
All-causality data from clinical studies that enrolled more than 2,000 adult patients receiving the recommended doses of ZYVOX for up to 28 days showed the following1:
- The most commonly reported adverse events 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 due to a drug-related adverse event.
- The following adverse reactions to ZYVOX were considered to be serious in rare cases: localised abdominal pain, transient ischaemic attacks and hypertension.
For further information on adverse reactions with ZYVOX, please refer to the ZYVOX SPC.
Please refer to the ZYVOX SPC for full details of contraindications.
- Hypersensitivity to linezolid or to any of the excipients.
- 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 2 weeks of taking any such product.
- Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, phaeochromocytoma, carcinoid thyrotoxicosis, bipolar depression, schizoaffective disorder, acute confusional states and/or patients taking any of the following: directly and indirectly acting sympathomimetic, vasopressive, and dopaminergic agents, serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), 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.
Special Warnings and Precautions for Use1
Please refer to the ZYVOX SPC for full details of special warnings and precautions for use.
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 hematologic parameters returned to pre-treatment levels. The risk of these effects appears to be related to the duration of treatment. Elderly patients 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.
Close monitoring of blood counts is recommended in patients who have pre-existing anaemia, granulocytopenia or thrombocytopenia, those who are receiving concomitant medications that may decrease haemoglobin levels, depress blood counts or adversely affect platelet count or function, those who have severe renal insufficiency or those who receive more than 10-14 days of therapy.
Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression. In addition it is recommended that complete blood counts should be monitored weekly in patients who receive linezolid regardless of baseline blood count.
Mortality imbalance in a clinical trial in patients with catheter-related Gram positive bloodstream infections1
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 but were significantly higher in the linezolid arm in patients with any other pathogen or no pathogen at baseline. In cSSTI, 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. In these circumstances treatment against Gram negative organisms must be initiated concomitantly.
Antibiotic-Associated Diarrhoea and Colitis1
Antibiotic-associated diarrhoea and colitis including pseudomembranous colitis and Clostridium difficile-associated diarrhoea has been reported with use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhoea to fatal colitis. If suspected or confirmed, discontinue treatment with linezolid.
Convulsions have been reported in patients treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.
Lactic acidosis has been reported with the use of linezolid. Patients receiving linezolid who develop recurrent nausea, vomiting, hyperventilation or a low bicarbonate level should receive immediate medical evaluation.
Linezolid inhibits mitochondrial protein synthesis. Adverse events, such as lactic acidosis, anaemia and neuropathy, may occur as a result of this inhibition; these events are more common when the drug is used longer than 28 days.
Peripheral and Optic Neuropathy1
Peripheral and optic neuropathy have been reported primarily in patients treated with linezolid for longer than the maximum recommended duration of 28 days. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended.
Potential Serotonergic Interactions1
Spontaneous reports of serotonin syndrome have been reported with the co-administration of linezolid and serotonergic agents. Co-administration of linezolid and serotonergic agents is therefore contraindicated. If signs or symptoms of serotonin syndrome, such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination occur, discontinuation of one or both agents should be considered.
Please refer to the ZYVOX SPC for full details of interactions with other medicinal products.
Monoamine oxidase inhibitors1
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.
Potential interactions producing elevation of blood pressure1
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 11-15mmHg increases with linezolid alone, 14-18 mmHg with either pseudoephedrine or phenylpropanolamine alone and 8-11mmHg 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 interactions1
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), cases of serotonin syndrome have been reported.
Use with tyramine-rich foods1
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 P4501
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.
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.
- ZYVOX® Summary of Product Characteristics