ZYVOXID Tablet / Solution for Infusion / Granules for suspension Ref.[51027] Active ingredients: Linezolid

Pseudomembranous colitis has been reported with ZYVOXID and may range in severity from mild to lifethreatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of this antibacterial agent.

Clostridium difficile associated diarrhoea (CDAD) has been reported with ZYVOXID, and may range in severity from mild diarrhoea to fatal colitis. Treatment with ZYVOXID alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Reversible myelosuppression (anaemia, thrombocytopenia, leukopenia, and pancytopenia) that may be dependent on duration of therapy has been reported in some patients receiving ZYVOXID. Monitoring of complete blood counts should be considered for patients who are at increased risk for bleeding, who have pre-existing myelosuppression, who receive concomitant medications that may decrease haemoglobin levels or platelet count or function, or who receive ZYVOXID for more than 2 weeks.

Peripheral neuropathy and optic neuropathy have been reported in patients treated with ZYVOXID. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with ZYVOXID for less than 28 days.

If symptoms of visual impairment appear, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking ZYVOXID for extended periods (greater than or equal to 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with ZYVOXID. If peripheral or optic neuropathy occurs, the continued use of ZYVOXID in these patients should be weighed against the potential risks.

Lactic acidosis has been reported with the use of ZYVOXID. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving ZYVOXID should receive immediate medical attention.

Convulsions have been reported to occur in patients when treated with ZYVOXID. In some of these cases, a history of seizures or risk factors for seizures were reported.

ZYVOXID has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. Specific Gram-negative therapy is required if a concomitant Gram-negative pathogen is documented or suspected. ZYVOXID should be used with special caution in patients at high risk for life threatening systemic infections, such as those with infections related to central venous catheters in intensive care units. ZYVOXID is not approved for the treatment of patients with catheter-related bloodstream infections.

The use of antibiotics may result in an overgrowth of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

The safety and effectiveness of ZYVOXID when administered for periods longer than 28 days have not been established.

ZYVOXID has not been studied in patients with uncontrolled hypertension, phaeochromocytoma, carcinoid syndrome, or untreated hyperthyroidism.

ZYVOXID 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.

It is recommended that ZYVOXID should be used in patients with severe hepatic insufficiency only when the anticipated benefit is considered to outweigh the theoretical risk.

ZYVOXID is not detectably metabolised by the cytochrome P450 (CYP) enzyme system and it does not induce or inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-induced drug interactions are expected. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with ZYVOXID without changes in dosage regimen.

No interactions have been observed in pharmacokinetic studies with either aztreonam or gentamicin.

ZYVOXID is a reversible, non-selective monoamine oxidase inhibitor (MAOI). Clinical studies have shown that it produces a mild, reversible enhancement of the pressor responses induced by pseudoephedrine and phenylpropanolamine hydrochloride. Thus, the potential for interaction with sympathomimetic or adrenergic agents should be considered and doses of compounds, such as dopamine or adrenalin, should be titrated to achieve the desired response.

No significant pressor response was observed in subjects receiving both ZYVOXID and less than 100 mg tyramine. This suggests that it is only necessary to avoid ingesting large 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).

Although ZYVOXID has the potential for interaction with serotonergic agents, no serotonin effects (e.g. confusion, delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia) were observed in subjects receiving linezolid and dextromethorphan.

Spontaneous reports of serotonin syndrome associated with the co-administration of ZYVOXID and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported.

Where administration of ZYVOXID and concomitant serotonergic agents is clinically appropriate, 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 discontinuation of either one or both agents. If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can be observed.

In healthy volunteers, co-administration of rifampin with ZYVOXID resulted in a 21% decrease in linezolid C_max and a 32% decrease in linezolid AUC. The mechanism of this interaction and its clinical significance are unknown.

The use of ZYVOXID formulations in pregnancy and lactation is contraindicated, as safety has not been demonstrated.

No effects on the ability to drive and use machines have been observed.

Approximately 22% of patients experienced adverse reactions. Those most commonly reported were headache, diarrhoea, nausea, vomiting, metallic taste, abnormal liver function tests and vaginal moniliasis.

Adverse events considered drug-related in controlled clinical trials with an incidence of at least 1% were:

Gastrointestinal Disorders: Abdominal pain/cramps/distension, diarrhoea, nausea, vomiting

Infections and Infestations: Moniliasis

Investigations: Abnormal hematology tests, abnormal liver function tests

Nervous System Disorders: Headache, taste alteration

Adverse drug events occurring at frequencies greater than 0,1% include:

(Common: ≥1/100 and <1/10 or ≥1% and <10%
Uncommon: ≥1/1 000 and <1/100 or ≥0,1% and <1%)

General body

Common: headache, moniliasis or fungal infection

Uncommon: chills, fatigue, fever, injection site pain, phlebitis/thrombophlebitis, localised pain, angioedema, anaphylaxis

Blood and the lymphatic system disorders

Uncommon: reversible anaemia, eosinophilia, leukopenia, neutropenia, thrombocytopenia, pancytopenia

Metabolism and nutrition disorders

Uncommon: increased serum creatine phosphokinase, hyperglycaemia, lactic acidosis

Nervous system disorders

Uncommon: dizziness, hypoaesthesia, insomnia, paraesthesia, peripheral neuropathy, convulsions

Special senses

Common: metallic taste

Uncommon: blurred vision, tinnitus, optic neuropathy

Cardiovascular disorders

Uncommon: hypertension, hypotension

Gastro-intestinal disorders

Common: abdominal pain, cramps or distension, diarrhoea, nausea, vomiting

Uncommon: constipation, dry mouth, dyspepsia, gastritis, increased thirst, pancreatitis, stomatitis, tongue discolouration or disorder, superficial tooth discolouration

Skin and subcutaneous tissue disorders

Uncommon: dermatitis, diaphoresis, pruritus, rash, urticaria, angioedema, bullous skin disorders such described as Stevens Johnson syndrome

Urogenital disorders

Common: vaginal moniliasis

Uncommon: vulvovaginal disorder, polyuria, vaginitis

Laboratory abnormalities: Chemistry

Common: increased total bilirubin, AST, ALT, LDH, alkaline phosphatase, BUN, creatine kinase, lipase, amylase or non-fasting glucose, decreased total protein, albumin, sodium, calcium, increased or decreased potassium or bicarbonate

Uncommon: increased creatinine, sodium, calcium; decreased non-fasting glucose, increased or decreased chloride

Laboratory abnormalities: Haematology

Common: increased neutrophils or eosinophils, decreased haemoglobin, haematocrit or red blood cell count, increased or decreased platelet or white blood cell counts

Uncommon: increased reticulocyte count; decreased neutrophils