Risk Management Plan Linezolid solution for infusion

Transcription

1 VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology Linezolid is used to treat pneumonia and some infections in the skin or under the skin, caused by a group of bacteria called the Gram positive bacteria. Linezolid is an antibiotic drug and belongs to the group of medical products called oxazolidinones. Linezolid works by stopping the growth of certain bacteria that cause infections 11. It stops the growth of bacteria by disrupting their production of proteins. Linezolid is unique since it blocks the start of the protein production in contrast to other antibiotics 16. Pneumonia is an inflammation of the lung, usually caused by an infection. Three common causes are bacteria, viruses and fungi. People can also get pneumonia by accidentally inhaling a liquid or chemical. People most at risk are older than 65 or younger than two years, or already have health problems. Patients with pneumonia have difficulty breathing and have cough and fever. A physical exam and history can help determine if it is pneumonia. Chest x-rays and blood tests can help determine what is wrong. Treatment depends on what made the patient sick. If bacteria are the cause, antibiotics should help while viral pneumonia may get better with rest and drinking liquids 9. Nosocomial pneumonia (Hospital-acquired pneumonia) is a respiratory infection developing more than 48 h after hospital admission and affects 0.5% to 1.7% of patients. Hospital-acquired pneumonia is the most common healthcare-acquired infection contributing to death and is estimated to increase hospital stay by 7 9 days. Mortality increases to 76% if infection is caused by multidrug-resistant pathogens 8. Community-acquired pneumonia is common, although precise figures are not available for most European countries, because appropriate studies have not been performed. Studies in Spain, Finland and England have suggested frequencies of 1.6, 2.6, 4.7 and 9 cases per 1000 of the general adult population per year. The frequency of the condition is age-related with the highest rates in the very young and very old. A study from Finland found rates of 36 of 1000 in those aged <5 yrs falling to 4.4 of 1000 in the age group and rising again to 34.2 of 1000 in those aged >74 yrs. Of those in the community, between 8% and 51% are admitted to hospital and between 4% and 15 % of such patients will die. Its frequency, morbidity and mortality are the reasons why hospital-acquired pneumonia and community-acquired pneumonia are such important diseases 19. Skin and soft tissue infections include infections of skin, subcutaneous tissue, fascia, and muscle, encompass a wide spectrum of clinical presentations, ranging from simple cellulitis to rapidly progressive necrotizing fasciitis. Diagnosing the exact extent of the disease is critical for successful management of a patient of soft tissue infection 10. In the United States, The United States had just over 1 million skin and soft tissue infections in Over the forecast period, the greatest amount of growth, 2.3% per year, on average, is expected in the United States. Among the Europe, Germany had the most skin and soft tissue infections in 2010 with about 222,000 and Spain had the fewest with roughly 115,000. The average annual growth rates ranged from 1.7% in Italy to 2.2% in France and the United Kingdom. In both the United States and Europe, the clear majority of skin and soft tissue infections are caused by Staphylococcus aureus, accounting for nearly 52% of skin and soft tissue infections in the United States and about 40% of infections in Europe 4. Document number (version): RMP.NUS (2.0).2870_E01.01 Page 77 of 90

2 VI.2.2 Summary of treatment benefits As the golden standard compound for vancomycin-resistant Gram-positive cocci in multiple clinical situation 7, linezolid is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms, e.g. nosocomial pneumonia, community acquired pneumonia and complicated skin and soft tissue infections as mentioned in the SmPC 3. Nosocomial pneumonia (Hospital-acquired pneumonia) In a clinical trial, involving patients throughout the world, 203 patients with nosocomial pneumonia were given linezolid with aztreonam and 193 patients with nosocomial pneumonia were given vancomycin with aztreonam. About the same amount of patients in both groups were cured after treatment 12. These studies were performed in patients with pneumonia suspected to be caused by (bacteria). The patients were treated with linezolid or with another group of antibiotics i.e. glycopeptide antibiotics 17. In this study it was found that superiority of linezolid over glycopeptides antibiotics was not proved. Linezolid and glycopeptide antibiotics ( a class of antibiotic drugs) were also compared in another study 6, but than in patients with nosocomial pneumonia. Also in this group of patients, linezolid was not clinical superior compared to glycopeptide antibiotics. In addition, patients treated with linezolid had a significant two-fold increase in the risk of thrombocytopenia and gastrointestinal events. Community acquired pneumonia (pneumonia in these who have not recently been hospitalized) In a clinical study 13, linezolid was compared with the antibiotic ceftriaxone/cefpodoxime in patients with pneumonia. Three hundred eighty-one patients were treated with linezolid and 366 with ceftriaxone/cefpodoxime. More patients treated with linezolid were cured (83%) compared to 76.4% of the patients treated with ceftriaxone/cefpodoxime. In patients who were infected with the Streptococcus pneumoniae bacteria, linezolid cured even more patients (93.1%) compared to 68.2% of the patients treated with ceftriaxone/cefpodoxime. However, more side effects were reported in the patients treated with linezolid. The study investigators concluded that linezolid was more effective than ceftriaxone/cefpodoxime in patients hospitalized with community acquired pneumonia, with comparable cure rates in Streptococcus pneumoniae pneumonia and higher cure rates in pneumonia complicated by bacteremia. Linezolid is indicated for the treatment of community acquired pneumonia and nosocomial pneumonia when known or suspected to be caused by susceptible Gram positive bacteria. In determining whether linezolid is an appropriate treatment, the results of microbiological tests or information on the prevalence of resistance to antibacterial agents among Gram positive bacteria should be taken into consideration. Linezolid is not active against infections caused by Gram negative pathogens. Specific therapy against Gram negative organisms must be initiated concomitantly if a Gram negative pathogen is documented or suspected. Complicated skin and soft tissue infections In a study with patients with complicated skin and soft tissue infections 14, 819 patients received linezolid or oxacillin. The cure rates were 69.8% in patients who received linezolid and 64.9% in the patients who received oxacillin. Among the 298 clinical evaluable patients, the cure rates were 88.6% for linezolid treated patients and 85.8% in the oxacillin group. None of the patients treated with linezolid reported serious side effects. Nine clinical trials about the treatment of patients with gram Document number (version): RMP.NUS (2.0).2870_E01.01 Page 78 of 90

3 positive bacterial infections were compared 1. Those studies included 2,489 patients who were treated with linezolid or vancomycin (another antibiotic). It was concluded that linezolid was as effective as vancomycin in patients with gram positive infections but that linezolid is superior in the treatment of complicated skin and soft tissue infections caused by the bacteria Staphylococcus aureus. The efficacy of linezolid was also compared with teicoplanin in a study with 430 patients with Gram positive infection 18. The investigator concluded that the cure rate was better in the linezolid treated patients (95.5%) compared to teicoplanin treated patients (87.6%) and the article author concluded that linezolid was clinical superior compared to teicoplanin in gram positive infections. Linezolid is indicated for the treatment of complicated skin and soft tissue infections only when microbiological testing has established that the infection is known to be caused by susceptible Gram positive bacteria. Linezolid is not active against infections caused by Gram negative pathogens. Linezolid should only be used in patients with complicated skin and soft tissue infections with known or possible coinfection with Gram negative organisms if there are no alternative treatment options available. In these circumstances treatment against Gram negative organisms must be initiated concomitantly. Linezolid should only be initiated in a hospital environment and after consultation with a relevant specialist such as a microbiologist or infectious diseases specialist. VI.2.3 Unknowns relating to treatment benefits Paediatric population In an open study with the paediatric population 15, the efficacy of linezolid (10 mg/kg every eight hours) was compared to vancomycin (10-15mg/kg every 6-24 hours) in treating infections due to suspected or proven resistant gram-positive pathogens (including nosocomial pneumonia, complicated skin and skin structure infections, catheter related bacteraemia, bacteraemia of unknown source, and other infections), in children from birth to 11 years. Clinical cure rates in the clinically evaluable population were 89.3% (134/150) and 84.5 % (60/71) for linezolid and vancomycin, respectively. Pharmacokinetic studies indicate that after single and multiple doses in children (1 week to 12 years), linezolid clearance (based on kg body weight) was greater in paediatric patients than in adults, but decreased with increasing age. In children 1 week to 12 years old, administration of 10 mg/kg every 8 hours daily gave exposure approximating to that achieved with 600 mg twice daily in adults. In neonates up to 1 week of age, the systemic clearance of linezolid (based on kg body weight) increases rapidly in the first week of life. Therefore, neonates given 10 mg/kg every 8 hours daily will have the greatest systemic exposure on the first day after delivery. However, excessive accumulation is not expected with this dosage regimen during the first week of life as clearance increases rapidly over that period. In adolescents (12 to 17 years old), linezolid pharmacokinetics were similar to that in adults following a 600mg dose. Therefore, adolescents administered 600 mg every 12 hours daily will have similar exposure to that observed in adults receiving the same dosage. In paediatric patients with ventriculoperitoneal shunts who were administered linezolid 10mg/kg either 12 hourly or 8 hourly, variable cerebrospinal fluid (CSF) linezolid concentrations were observed Document number (version): RMP.NUS (2.0).2870_E01.01 Page 79 of 90

4 following either single or multiple dosing of linezolid. Therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empirical treatment of paediatric patients with central nervous system infections is not recommended. There are insufficient data on the safety and efficacy of linezolid in children and adolescents (< 18 years old) and therefore, use of linezolid in this age group is not recommended. Further studies are needed to establish safe and effective dosage recommendations. Patients with renal insufficiency: After single doses of 600 mg, there was a 7-8 fold increase in exposure to the two primary metabolites of linezolid in the plasma of patients with severe renal insufficiency (i.e. creatinine clearance < 30 ml/min). However, there was no increase in AUC of parent drug. Although there is some removal of the major metabolites of linezolid by haemodialysis, metabolite plasma levels after single 600 mg doses were still considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency. In 24 patients with severe renal insufficiency, 21 of whom were on regular haemodialysis, peak plasma concentrations of the two major metabolites after several days dosing were about 10 fold those seen in patients with normal renal function. Peak plasma levels of linezolid were not affected. The clinical significance of these observations has not been established as limited safety data are currently available. VI.2.4 Summary of safety concerns The most commonly reported side effects which led to discontinuation of treatment were headache, diarrhoea, nausea and vomiting. About 3% of patients discontinued treatment because they experienced a side effect. Common side effects with linezolid (occurring in less than 1 in 10 patients) are candidiasis, oral candidiasis, vaginal candidiasis, fungal infections, headache, taste perversion, diarrhoea, nausea, vomiting, abnormal liver function test (increased AST, ALT or alkaline phosphatise), increased BUN, increased lactic acid dehydrogenase (LDH), increased creatine kinase, increased lipase, increased amylase or non fasting glucose, decreased total protein, decreased albumin, decreased sodium or decreased calcium, increased or decreased potassium or bicarbonate, increased neutrophils or eosinophils, decreased haemoglobin, decreased haematocrit or red blood cell count and increased or decreased platelet or white blood cell counts. Uncommon side effects (occurring in less than 1 in 100 treated patients) are vaginitis, leucopenia, neutropenia, thrombocytopenia, eosinophilia, insomnia, dizziness, hypoaesthesia, paraesthesia, blurred vision, tinnitus, hypertension, phlebitis, thrombophlebitis, pancreatitis, gastritis, localised or general abdominal pain, constipation, dry mouth, dyspepsia, glossitis, loose stools, stomatitis, tongue discolouration or disorder, increased total bilirubin, urticaria, dermatitis, diaphoresis, pruritus, rash, polyuria, increased creatinine, vulvovaginal disorder, chills, fatigue, fever, injection site pain, increased thirst, localised pain, increased sodium or calcium, decreased non fasting glucose, increased or decreased chloride, increased reticulocyte count and decreased neutrophils. Rare side effects (occurring in less than 1 in 1000 treated patients) are arrhythmia, transient ischaemic attacks and renal failure. Document number (version): RMP.NUS (2.0).2870_E01.01 Page 80 of 90

5 The following side effects have also been reported (frequency not known): antibiotic-associated colitis, including pseudomembranous colitis, Myelosuppression, pancytopenia, anaemia, sideroblastic anaemia, anaphylaxis, lactic acidosis, hyponatraemia, serotonin syndrome, convulsions, peripheral neuropathy, optic neuropathy, optic neuritis, loss of vision, changes in visual acuity, changes in colour vision, changes in visual field defect, superficial tooth discolouration, bullous disorders such as those described as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema and alopecia. See below summaries of what is known about each important identified risk, important potential risks and important missing information associated with the use of linezolid. Important identified risk Risk What is known Preventability Antibiotic-associated diarrhoea and colitis (including pseudomembranous colitis and Clostridium difficile associated diarrhea) Convulsions Food-drug interactiontyramine-rich foods (e.g. mature cheese, yeast extracts,. soy sauce, draught beers and wine) Lactic acidosis Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile (bacteria) associated diarrhoea, has been reported in association with the use of nearly all antibiotics including linezolid (with unknown frequency). Patients treated with linezolid may experience nausea, vomiting, diarrhea, fever, and abdominal pain. The symptoms 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 antibioticassociated colitis is suspected or confirmed, ongoing treatment with antibacterial agents, including linezolid, should be discontinued and adequate therapeutic measures should be initiated immediately. Convulsion is a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure. Convulsion has been observed previously in patients treated with linezolid (unknown frequency). 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. Linezolid may react with a substance called tyramine which is naturally present in some foods to cause an increase in your blood pressure. Patients are advised against consuming large amounts of tyramine-rich foods, including mature cheese, yeast extracts, or soya bean extracts e.g. soy sauce, draught beers and wine. Patients experiencing a throbbing headache after eating or drinking should tell their doctors or pharmacists. Lactic acidosis (low ph in body tissues and blood) has been reported with the use of linezolid (unknown frequency). Patients may experienc recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or Yes, by monitoring for early symptoms. Yes, by not using linezolid in patients with a history of seizures or risk factors for convulsion. Yes, by not using excessive amounts of tyramine-rich foods during linezolid treatment. Yes, 1) by monitoring for early symptoms and bicarbonate level, 2) by not using linezolid more than 28 Document number (version): RMP.NUS (2.0).2870_E01.01 Page 81 of 90

6 Risk What is known Preventability overbreathing while receiving linezolid. These events are more common when the drug is used longer than 28 days. If lactic acidosis occurs, the benefits of continued use of linezolid should be weighed against the potential risks. day. Mitochondrial toxicity Mitochondrial toxicity is a condition in which the Yes, 1) by monitoring for mitochondria of a body's cells become damaged or early symptoms, 2) by not decline significantly in number; it occurs as a side effect of linezolid. The commonly observed symptoms are using linezolid more than 28 day. lactic acidosis, anaemia and neuropathy (optic and peripheral). These events are more common when the drug is used longer than 28 days. Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) (bone marrow suppression) Myelosuppression, (including anaemia, leucopenia, pancytopenia and thrombocytopenia) also known as bone marrow suppression, a reduction of bone marrow activity, that leads to a lower concentration of platelets, red blood cells and white blood cells. This condition can rapidly lead to life-threatening infection, as the body cannot produce leukocytes in response to invading bacteria and viruses, as well as leading to anaemia due to a lack of red blood cells and spontaneous severe bleeding due to deficiency of platelets. Myelosuppression has been reported in patients receiving linezolid. The risk of these effects is more common when the drug is used longer than 28 days. Elderly patients may be at greater risk. Thrombocytopenia (decrease of platelets in blood may) occur more commonly in patients with severe renal insufficiency. Therefore, close monitoring of blood counts is recommended in patients who: have preexisting anaemia, granulocytopenia (low concentration of certain white blood cells) 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 days of therapy. 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 Yes, 1) by close monitoring of blood counts in patients with linezolid treatment who: have pre-existing anaemia, granulocytopenia (low concentration of certain white blood cells) 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 days of therapy. 2) by monitoring blood counts weekly in patients with linezolid treatment. Document number (version): RMP.NUS (2.0).2870_E01.01 Page 82 of 90

7 Risk What is known Preventability baseline blood count. Optic neuropathy Optic neuropathy is damage to nerves of the optic nerve. optic neuropathy have been reported in patients treated with linezolid; these reports have primarily been in Yes, by monitoring for early symptoms. patients treated for longer than the maximum recommended duration of 28 days. Patients treated with linezolid may experience reduced sensation, or abnormal sensation, and visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. If 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. Peripheral neuropathy Peripheral neuropathy is damage to nerves of the peripheral nervous system and the optic nerve. Peripheral neuropathy has 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. Patients treated with linezolid may experience reduced sensation or abnormal sensation If peripheral 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. Renal failure Renal (Kidney) failure is a serious event of rare frequency (may affect up to 1 in 1000 people) associated with linezolid use. Kidney failure is typically detected by an elevated serum creatinine level, abnormal levels of potassium, calcium, and anemia. Serotonin syndrome associated with the coadministration of linezolid and serotonergic agents (e.g. serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants, serotonin 5- HT1 receptor agonists) Serotonin syndrome is a serious event of unknow frequency associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs). The excess serotonin activity produces a spectrum of specific symptoms including cognitive dysfunction, fever and incoordination. If signs or symptoms occur physicians should consider discontinuing either one or both agents; if the concomitant serotonergic agent is withdrawn, symptoms can disappear. Yes, by monitoring for early symptoms. Yes, by monitoring creatinine, potassium, calcium level and blood count. Yes, by not concomitantly using linezolid with serotonergic agents. Skin and subcutaneous tissue Bullous disorders described as Stevens-Johnson Doctors and patients are Document number (version): RMP.NUS (2.0).2870_E01.01 Page 83 of 90

8 Risk What is known Preventability disorders (bullous disorders described as Stevens-Johnson syndrome and toxic epidermal necrolysis, and angioedema) syndrome and toxic epidermal necrolysis affect the skin and the mucous membranes, which are serious events of unknown frequency associated with linezolid use. informed about these risks. Superinfection (candidiasis and fungal infections) Use in patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder and acute confusional states Important potential risks Risk Hypoglycemia Impairment of fertility Increased fatal outcome in subsets of patients with catheter related infections, especially, those with Gramnegative organisms The use of antibiotics may occasionally result in an overgrowth of non-susceptible organisms. For example, approximately 3% of patients receiving the recommended linezolid doses experienced drug-related candidiasis during clinical trials. Most candidial infections result in minimal complications such as redness, itching and discomfort, though complications may be severe or fatal if left untreated in certain populations. If superinfection occurs during linezolid therapy, appropriate measures should be taken by doctors. Increased blood pressure has been associated with linezolid use, especially in patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder and acute confusional states. Unless there are facilities available for close observation and monitoring of blood pressure, linezolid should not be administered to the above mentioned patients. Doctors and patients are informed about this risk. What is known (Including reason why it is considered a potential risk) Yes, by not using linezolid in patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder and acute confusional states, or close observation and monitoring of blood pressure. Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid 2. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be cautioned of potential hypoglycemic reactions when treated with linezolid. If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required. 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. Excess mortality was seen in patients with intravascular catheter-related infections during linezolid treatment. More patients with linezolid treatment acquired Gram negative pathogens during the study and died from infection caused by Gram negative pathogens and polymicrobial infections. Therefore, in complicated skin and soft tissue infections 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 Document number (version): RMP.NUS (2.0).2870_E01.01 Page 84 of 90

9 Use in patients with severe hepatic insufficiency Use in patients with severe renal insufficiency Use in patients taking any medicinal product which inhibits monoamine oxidases A or B Use in pregnant and lactating women these circumstances treatment against Gram negative organisms must be initiated concomitantly. The pharmacokinetics of linezolid in patients with severe hepatic (liver) insufficiency (i.e. Child-Pugh class C) has not been evaluated. However, as linezolid is metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism. Since there are limited clinical data and it is recommended that linezolid should be used in such patients only when the anticipated benefit is considered to outweigh the theoretical risk. 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 three hours of haemodialysis, linezolid should be given after dialysis in patients receiving such treatment. 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 or alternative treatments for renal failure (other than haemodialysis). In 24 patients with severe renal insufficiency, 21 of whom were on regular haemodialysis, peak plasma concentrations of the two major metabolites after several days dosing were about 10 fold those seen in patients with normal renal function. Peak plasma levels of linezolid were not affected. The clinical significance of these observations has not been established as limited safety data are currently available. Linezolid is a reversible, non-selective inhibitor of monoamine oxidase. Therefore, 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 products (used to treat depression or Parkinson s disease). Studies in animals have shown reproductive toxicity. A potential risk for humans exists. There are no adequate data from the use of linezolid in pregnant women. 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. Important missing information Risk Long-term treatment (more than 28 days) Overdose What is known (Including reason why it is considered a potential risk) Linezolid inhibits mitochondrial protein synthesis. Side effects, 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. The maximum treatment duration is 28 days. The safety and effectiveness of linezolid when administered for periods longer than 28 days have not been established. No specific antidote is known. No cases of overdose have been reported. However, the following information may prove Document number (version): RMP.NUS (2.0).2870_E01.01 Page 85 of 90

10 Risk Use in children and adolescents (under 18 years old) Use in patients with diabetic foot lesions, decubitus or ischaemic lesions and severe burns or gangrene What is known (Including reason why it is considered a potential risk) useful: Supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis, but no data are available for the removal of linezolid by peritoneal dialysis or haemoperfusion. The two primary metabolites of linezolid are also removed to some extent by haemodialysis. Signs of toxicity in rats following doses of 3000 mg/kg/day linezolid were decreased activity and ataxia whilst dogs treated with 2000 mg/kg/day experienced vomiting and tremors. There are insufficient data on the safety and efficacy of linezolid in children and adolescents (< 18 years old) to establish dosage recommendations. Therefore, until further data are available, use of linezolid in this age group is not recommended. Controlled clinical trials did not include patients with diabetic foot lesions, decubitus or ischaemic lesions, severe burns or gangrene. Therefore, experience in the use of linezolid in the treatment of these conditions is limited. VI.2.5 Summary of additional risk minimisation measures by safety concern No additional risk minimisation measures have been proposed. VI.2.6 Planned post authorisation development plan (if applicable) No post--authorization development is planned. VI.2.7 Summary of changes to the risk management plan over time Since this is the s the first RMP for the Applicant s, this sections is currently not applicable. Document number (version): RMP.NUS (2.0).2870_E01.01 Page 86 of 90