Management of Linezolid in Children (1215)

• Hypersensitivity to linezolid or to any of the excipients in the formulation (See SPC for list of 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 two weeks of taking any such medicinal product.
• Antiepileptic: Where possible linezolid should be avoided in patients with increased risk of seizures.
• Unless there are facilities available for close observation and monitoring of blood pressure, linezolid should not be administered to patients with the following conditions or taking any of the following medications:
  • Uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute confusional states.
  • Serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin  5-HT1  receptor  agonists  (triptans), directly  or  indirectly  acting  sympathomimetic  agents  (including  the adrenergic  bronchodilators,  pseudoephedrine  and  phenylpropanolamine), vasopressive  agents  (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), analgesics including oxycodone, serotonergic antiemetic’s e.g. ondansetron, metoclopramide.

See SPC or discuss with clinical pharmacist for further information on drug interactions.

• Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. Thrombocytopenia may occur more commonly in patients with severe renal insufficiency, whether or not on dialysis.
  • 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.

• Linezolid has multiple serious drug interactions, refer to SPC for full list.
• Patients and their carers should be counselled to avoid food rich in tyramine (e.g. mature cheeses, soy sauce and yeast extract) due to the increased risk of hypertension.
• Patients and their carers should be instructed to report any tingling or altered sensation, blurred vision or visual changes throughout treatment.
• Lactic acidosis has been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis (recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or hyperventilation) while receiving linezolid should receive immediate medical attention.
• Convulsions have been reported to occur in patients when treated with linezolid. Linezolid should be used with caution in patients with a history or risk of developing seizures.
• 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.
• IV infusion contains 13.7g of glucose per 300ml, this should be taken into account in patients with diabetes mellitus or other conditions associated with glucose intolerance. 

600mg tablet

100mg/5ml granules for oral suspension

600mg/300ml infusion

Neonates: Refer to West of Scotland Neonatal Monographs

Child:

IV or Oral

• Child 1 month to 11 years: 10mg/kg every 8 hours (max per dose 600mg).
• Child 12 to 17 years: 600mg every 12 hours.
• Dosing in obesity: no dose adjustment is currently recommended
• Maximum recommended duration of therapy for oral and IV therapy is 28 days
• With ID/microbiology approval longer courses have been used; however there is an increased risk of significant long term side effects including visual impairment, peripheral neuropathy and blood disorders (including thrombocytopenia, anaemia, leucopenia and pancytopenia).
• Linezolid has high oral bioavailability (100%), consider switching to oral dosing as soon as clinically appropriate.

Renal Impairment

• Use with caution in patients with a creatinine clearance < 30ml/min as accumulation of metabolites may occur. Clinical significance of this is unknown, special caution should be applied and should only be used when anticipated benefit outweighs theoretical risk.

Hepatic Impairment

No dosage adjustment is required in mild to moderate hepatic impairment. There is minimal information on the use of linezolid in severe hepatic impairment, special caution should be applied and should only be used when anticipated benefit outweighs theoretical risk.

• Baseline U&Es, CRP, LFTs and FBC (including haemoglobin, platelets, and total differentiated leucocyte counts). For patients started in the community on advice from a Microbiology or ID consultant of treatment duration <7 days, baseline monitoring may not be necessary if the patient has no underlying risk factors, such as pre-existing myelosuppression, severe renal impairment or receiving concomitant medicines that may affect blood counts.
• Baseline monitoring of blood pressure is required in patients where the concomitant administration of interacting drugs is considered necessary.
• There is a limited evidence base to support the use of TDM to optimise linezolid dosing in patients with renal impairment or extremes of body weight. The paediatric OPAT service may undertake or advise linezolid TDM on rare occasions.

Laboratory Monitoring

• Weekly FBC including haemoglobin, platelets and total differentiated leucocyte counts
• Weekly U&Es, LFTS and CRP

Visual Monitoring

• All patients should be advised to report any symptoms of visual impairment. These include changes in visual acuity, changes in colour vision, blurred vision or visual field defects.
• Any patient  experiencing  new  visual  symptoms  whilst  taking  linezolid  should  be  referred  to ophthalmology.
• Visual function should be monitored regularly if treatment is required for longer than 28 days.

Additional Monitoring

• Symptoms and signs of lactic acidosis e.g. recurrent nausea and/or vomiting, abdominal pain, a low bicarbonate level or hyperventilation. If the patient complains of increasing nausea and vomiting following initiation of linezolid measure a serum lactate concentration. Linezolid should be discontinued if signs/ symptoms observed or a raised lactate is reported.
• All patients should be advised to report any numbness or tingling in the extremities, as linezolid may cause peripheral neuropathy.
• Close monitoring of blood pressure is required in patients where the concomitant administration of interacting drugs is considered necessary.

More frequent monitoring is recommended in the following patients:

• Receiving longer than 10-14 days of treatment.
• With pre-existing myelosuppression.
• Receiving concomitant medicines that might affect their blood counts.
• With severe renal insufficiency

Please discuss all patients treated with linezolid in the RHC with the Infectious Diseases team. Patients on a course > 7 days will require referral to paediatric OPAT (OPAT referral - paediatric).

Please discuss all patients started on linezolid in the community with the Infectious Diseases team if treatment duration is likely to be >7days, to discuss monitoring arrangements.

For a full list of side effects please see the SPC

• Myelosuppression including anaemia, leucopenia, pancytopenia and thrombocytopenia has been reported in patients receiving linezolid.
• Peripheral neuropathy and optic neuropathy have been reported, particularly in patients receiving linezolid for more than 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. If any patients are taking linezolid for longer than the recommended 28 days, their visual function should be regularly monitored.
• Serotonin Syndrome may occur due to drug-drug interaction with SSRIs, tricyclic and serotonin 5-HT1 receptor agonist classes of antidepressants. Patients should be observed closely for signs of ‘serotonin syndrome’ which include confusion, delirium, restlessness, tremor or blushing.
• Lactic acidosis may occur, patients who develop signs and symptoms including: recurrent nausea or vomiting, abdominal pain, a low bicarbonate level or hyperventilation, should receive immediate medical attention.

See SPC or discuss with a clinical pharmacist for further information on drug interactions (the list below is not exhaustive).

Drug Interactions

• 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.
• Antiepileptic: Where possible linezolid should be avoided in patients with increased risk of seizure.
• Unless there are facilities available for close observation and monitoring of blood pressure, linezolid should not be administered to patients on the following types of concomitant medications due to the risk of serotonin syndrome:
  • Serotonin re-uptake inhibitors, 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), analgesics including oxycodone and serotonergic antiemetics e.g. ondansetron and metoclopramide.

Rifampicin Interaction

• Rifampicin reduces linezolid concentrations (AUC reduced by 30%).  This is not a CYP450-mediated interaction but is thought to be due to induction of a p-glycoprotein transporter and subsequent increased linezolid excretion. 
• If avoidance is not possible, monitor concurrent use closely to ensure that the antibacterial treatment is effective. The available evidence suggests that, where possible, linezolid concentrations should be monitored if both drugs are given. Note that the effect of rifampicin on linezolid might persist for 2 to 3 weeks after rifampicin is stopped.

Warfarin Interaction

• Linezolid may enhance the anticoagulant effect. Ensure follow up with the Anticoagulant Service for INR monitoring and any necessary dosage adjustments. Patients should also be counselled on signs of over anticoagulation (e.g. bruising, bleeding).

Levothyroxine Interaction

• Decreased linezolid exposure has been observed when co-administered with levothyroxine. Close observation for clinical efficacy and therapeutic drug monitoring is recommended.

Food Interactions

• Patients should be counselled to avoid food rich in tyramine (e.g. mature cheeses, soy sauce and yeast extract) due to the increased risk of hypertension.

Patients and their carers must be given the Paediatric Linezolid Patient Information Leaflet.

• Patients and their carers should be advised to report immediately any visual disturbances or impairment.
• Patients and their carers should be advised to avoid consuming excessive amounts of tyramine rich foods e.g. mature cheese, yeast extracts, soya bean extracts.
• Patients and their carers should be advised not to take any OTC medicines e.g. decongestant cold and flu remedies, without first consulting their medical team.