Zyvoxid

ZYVOXID formulations are indicated for the treatment of patients with the following infections caused by susceptible strains of the designated Gram-positive microorganisms (see section 5). ZYVOXID is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy must be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected (see section 4.4).

• Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteraemia.
• Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), or Streptococcus pneumoniae (including multi-drug resistant S. pneumoniae (MDRSP) strains).
• Complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae. ZYVOXID has not been studied in the treatment of decubitus ulcers.
• Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes.
• Community-acquired pneumonia caused by Streptococcus pneumoniae (including multi-drug resistant S. pneumoniae (MDRSP) strains), including cases with concurrent bacteraemia, or Staphylococcus aureus (methicillin-susceptible and -resistant strains).

Due to concern about inappropriate use of antibiotics leading to an increase in resistant organisms, prescribers should carefully consider alternatives before initiating treatment with ZYVOXID in the outpatient setting. Prescribers should adhere to the principles of antibiotic stewardship. Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to ZYVOXID. Therapy may be instituted empirically while awaiting results of these tests. Once these results become available, antimicrobial therapy should be adjusted accordingly.

Posology ZYVOXID tablets, oral suspension or solution for infusion 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 ZYVOXID has an oral bioavailability of approximately 100 %. The solution for infusion should be administered over a period of 30 to 120 minutes.

The film-coated tablets or oral suspension may be taken with or without food. The recommended ZYVOXID dosage should be administered IV or orally as described in the tables below. In the treatment of beta-haemolytic streptococcal infections, a therapeutic dose should be administered for at least 10 days.

Adult and adolescent (12 years and older) patients

Infections (including those associated with concurrent bacteraemia) Dosage and route of administration Recommended duration of treatment

• Community-acquired pneumonia, including concurrent bacteraemia 600 mg IV or orally* every 12 hours 10 u2013 14 consecutive days
• Nosocomial pneumonia, including concurrent bacteraemia Skin and soft tissue infections, including concurrent bacteraemia 400 mg to 600 mg orally* every 12 hours or 600 mg IV every 12 hours depending on clinical severity
• Enterococcus infections, including vancomycin-resistant infections, and those with concurrent bacteraemia 600 mg IV or orally* every 12 hours 14 u2013 28 consecutive days

* Oral dosing either ZYVOXID tablets or oral suspension

Paediatric patients (birth* through to 11 years)

Infections (including those associated with concurrent bacteraemia) Dosage and route of administration Recommended duration of treatment

• Community-acquired pneumonia, including concurrent bacteraemia 10 mg/kg IV or oral uf064 every 8 hours 10 u2013 14 consecutive days
• Nosocomial pneumonia, including concurrent bacteraemia Skin and soft tissue infections, including concurrent bacteraemia Enterococcus infections, including vancomycin-resistant infections, and those with concurrent bacteraemia 10 mg/kg IV or oral uf064 every 8 hours 14 u2013 28 consecutive days

* Pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have lower systemic ZYVOXID clearance values and larger AUC values than many full-term neonates and older infants. By day 7 of age, ZYVOXID clearance and AUC values are similar to those of full-term neonates and older infants.

uf064 Oral dosing using either ZYVOXID tablets or oral suspension

Special populations

Elderly patients No dose adjustment is required. Patients with renal insufficiency No dose adjustment is required (see section 5.2). Patients with severe renal insufficiency (i.e. CL CR < 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 ZYVOXID in patients with severe renal insufficiency, ZYVOXID 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 ZYVOXID dose is removed during 3 hours of haemodialysis, ZYVOXID should be given after dialysis in patients receiving such treatment. The primary metabolites of ZYVOXID 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, ZYVOXID 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.

There is no experience of ZYVOXID 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 ZYVOXID should be used in such patients only when the anticipated benefit is considered to outweigh the theoretical risk (see section 5.2).

Method of administration Instructions for use/handling Intravenous administration: ZYVOXID solution for infusion must be used immediately after the seal is first broken. ZYVOXID solution for infusion is supplied in single-use, ready-to-use infusion bags. Parenteral medicines should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Administer ZYVOXID solution for infusion over a period of 30 to 120 minutes. Do not use the intravenous infusion bag in series connections. Do not introduce additives into the intravenous solution. If ZYVOXID solution for infusion is to be given concomitantly with another medicine, each medicine should be given separately, in accordance with the recommended dosage and route of administration for each medicine.

ZYVOXID solution for infusion was physically incompatible with the following medicines when combined in simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isethionate, phenytoin sodium, erythromycin lactobionate and trimethoprim-sulfamethoxazole. ZYVOXID solution for infusion was chemically incompatible when combined with ceftriaxone sodium.

Compatible infusion solutions 0,9 % Sodium Chloride Injection 5 % Dextrose Injection Lactated Ringeru2019s Injection For instructions on constitution of ZYVOXID granules for suspension before administration, see section 6.6.

ZYVOXID formulations are contraindicated for use in patients with known hypersensitivity to linezolid or any excipients listed in section 6.1. Monoamine oxidase inhibitors ZYVOXID should not be used in patients taking any medicine which inhibits monoamine oxidases A or B (e.g. phenelzine, isocarboxazid) or within two weeks of taking any such medicine. Potential interactions producing elevation of blood pressure Unless patients are monitored for potential increases in blood pressure, ZYVOXID should not be administered to patients with uncontrolled hypertension, pheochromocytoma, hyperthyroidism and/or patients taking any of the following types of medicines: directly and indirectly acting sympathomimetic medicines (e.g., pseudoephedrine, phenylpropanolamine), vasopressive medicines (e.g., epinephrine, norepinephrine), dopaminergic medicines (e.g., dopamine, dobutamine) (see section 4.5). Potential serotonergic interactions Unless patients are carefully observed for signs and/or symptoms of serotonin syndrome, ZYVOXID should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medicines: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5 - HT1 receptor agonists (triptans), meperidine or buspirone (see section 4.5).

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. Pseudomembranous colitis has been reported with ZYVOXID and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of this antibacterial medicine. 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 medicines. Peripheral neuropathy and optic neuropathy have been reported in patients treated with ZYVOXID, primarily those patients treated for longer than the maximum recommended duration of 28 days. 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 treatment with ZYVOXID should be discontinued. 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 most 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. Pharmacokinetic information generated in paediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of paediatric patients with central nervous system infections is not recommended. Fructose/sucrose ZYVOXID granules for suspension contain fructose. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take ZYVOXID granules for suspension. ZYVOXID granules for suspension contain sucrose. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take ZYVOXID granules for suspension. Contains sucrose, dextrose and fructose which may have an effect on the glycaemic control of patients with diabetes mellitus. ZYVOXID Infusion contains glucose which may have an effect on the control of your blood sugar if you have diabetes mellitus.

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. Medicines such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with ZYVOXID without changes in dosage regimen. ZYVOXID is a reversible, non-selective monoamine oxidase inhibitor (MAOI). Therefore, some patients receiving ZYVOXID may experience a reversible enhancement of the pressor response induced by pseudoephedrine HCl or phenylpropanolamine HCl. Thus, the potential for interaction with sympathomimetic or adrenergic medicines should be considered and initial doses of compounds, such as dopamine or adrenaline, should be reduced and titrated to achieve the desired response (see section 4.3).

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 medicines, 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 medicines, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported. Where administration of ZYVOXID and concomitant serotonergic medicines 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 medical practitioners should consider discontinuation of either one or both medicines. If the concomitant serotonergic medicine is withdrawn, discontinuation symptoms can be observed. In healthy volunteers, co-administration of rifampicin 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. Spontaneous reports of serotonin syndrome with co-administration of ZYVOXID and serotonergic medicines have been reported (see section 4.4). Antibiotics The pharmacokinetics of ZYVOXID were not altered when administered together with either aztreonam or gentamicin. The effect of rifampicin on the pharmacokinetics of ZYVOXID was studied in sixteen healthy adult male volunteers administered ZYVOXID 600 mg twice daily for 2,5 days with and without rifampicin 600 mg once daily for 8 days. Rifampicin decreased the linezolid C max 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 (see section 4.4).

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

Fertility In animal studies, ZYVOXID caused a reduction in fertility (see section 5.3).

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

Approximately 22 % of patients experienced adverse reactions. Frequency terminology: Very common ( u2265 1/10); Common ( u2265 1/100 to <1/10); Uncommon ( u2265 1/1 000 to <1/100); Rare ( u2265 1/10 000 to <1/1 000); Very rare (<1/10 000), including isolated reports.

Table 1: Side effects reported in clinical trials

System organ class Frequency Side effect

• Infections and infestations Common Moniliasis + or fungal infections
• Blood and lymphatic system disorders Uncommon Eosinophilia, neutropenia
• Metabolism and nutrition disorders Uncommon Increased serum creatine phosphokinase, hyperglycaemia
• Nervous system disorders Common Headache + , taste alteration + Uncommon Dizziness, hypoaesthesia, insomnia, paraesthesia
• Special senses Common Metallic taste Uncommon Blurred vision, tinnitus
• Cardiac disorders Uncommon Hypertension, hypotension
• Gastrointestinal disorders Common Abdominal pain + , cramps + or distension + , diarrhoea + , nausea + , vomiting + Uncommon Constipation, dry mouth, dyspepsia, gastritis, increased thirst, pancreatitis, stomatitis
• Skin and subcutaneous tissue disorders Uncommon Dermatitis, diaphoresis, pruritus, urticaria
• Urogenital disorders Common Vaginal moniliasis Uncommon Vulvovaginal disorder, polyuria, vaginitis
• General disorders and administration site conditions Uncommon Chills, fatigue, fever, injection site pain, phlebitis/thrombophlebitis, localised pain
• Investigations Common Chemistry: 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. 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 creatinine, sodium, calcium, decreased non-fasting glucose, increased or decreased chloride. Haematology: Increased reticulocyte count, decreased neutrophils + Events considered medicine-related in controlled clinical trials with an incidence of at least 1 %.

Table 2: Side effects reported during post-marketing use:

Blood and lymphatic system disorders Pancytopenia ^ , leukopenia ^ , thrombocytopenia ^ , anaemia ^ , sideroblastic anaemia u2021 Immune system disorders Anaphylaxis Metabolism and nutrition disorders Lactic acidosis ^ Nervous system disorders Convulsions ^, peripheral neuropathy ^ Eye disorders Optic neuropathy ^ a Gastrointestinal disorders Tongue discolouration or disorder, superficial tooth discolouration b Skin and subcutaneous tissue disorders Bullous skin disorders including severe cutaneous adverse reactions (such as toxic epidermal necrolysis, Stevens-Johnson syndrome), angioedema, rash

u2021 Primarily reported in patients receiving ZYVOXID for more than the maximum recommended duration of 28 days ^ See section 4.4 a Sometimes progressing to loss of vision, have been reported in patients treated with ZYVOXID. These reports have primarily been in patients treated for longer than the maximum recommended durations of 28 days b The discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

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 ZYVOXID dose is removed during 3 hours of haemodialysis, but no data are available for the removal of ZYVOXID by peritoneal dialysis or haemoperfusion.