LINEZOLID KRKA

Posology Linezolid Krka film-coated tablets may be used as initial therapy. Patients who commence treatment on the parenteral formulation may be switched to oral presentation when clinically indicated. In such circumstances, no dose adjustment is required as linezolid has an oral bioavailability of approximately 100%.

Recommended dosage and duration of treatment for adults:

The duration of treatment is dependent on the pathogen, the site of infection and its severity, and on the patient's clinical response. The following recommendations for duration of therapy reflect those used in the clinical trials.

Shorter treatment regimens may be suitable for some types of infection but have not been evaluated in clinical trials. 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.

4). No increase in the recommended dosage or duration of treatment is required for infections associated with concurrent bacteraemia.

The dose recommendation for the film-coated tablets are as follows:

Infections Dosage Duration of treatment Nosocomial pneumonia Community acquired pneumonia 600 mg twice daily Complicated skin and soft tissue infections 600 mg twice daily 10-14 Consecutive days Paediatric population The safety and efficacy of linezolid in children and adolescents (< 18 years old) has not been established.

2 but no recommendation on a posology can be made. Elderly patients No dose adjustment is required. 2). e.

CLCR < 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 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 3 hours of haemodialysis, linezolid should be given after dialysis in patients receiving such treatment. The primary metabolites of linezolid 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.

The table below provides a listing of adverse drug reactions with frequency based on all-causality data from clinical studies that enrolled more than 6,000 adult patients who received the recommended linezolid doses for up to 28 days.

2%). 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 because they experienced a drug- related adverse event.

Additional adverse reactions reported from post-marketing experience are included in the table with frequency category 'Not known', since the actual frequency cannot be estimated from the available data. The following undesirable effects have been observed and reported during treatment with linezolid with the following frequencies: - Very common (≥ 1/10) - Common (≥ 1/100 to < 1/10) - Uncommon (≥ 1/1,000 to < 1/100) - Rare (≥ 1/10,000 to < 1/1,000) - Very rare (< 1/10,000) - Not known (cannot be estimated from the available data) System Organ Class Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very Rare (<1/10 ,000) Frequency not known (cannot be estimated from available data) Infections and infestations candidiasis, oral candidiasis, vaginal candidiasis, fungal infections antibiotic- associated colitis, including pseudomemb ranous colitis*, vaginitis Blood and the lymphatic system disorders thrombocyt openia*, anaemia*† pancytopenia *, leucopenia*, neutropenia, eosinophilia sideroblastic anaemia* myelosuppressi on* Immune system disorders anaphylaxis Metabolism and nutrition disorders hyponatraem ia lactic acidosis* Psychiatric disorders insomnia Nervous system disorders headache, taste perversion (metallic taste), dizziness convulsions* , peripheral neuropathy*, hypoaesthesi a, paraesthesia serotonin syndrome**, Eye disorders optic neuropathy*, blurred vision* changes in visual field defect* optic neuritis*, loss of vision*, changes in visual acuity*, changes in colour vision* Ear and labyrinth disorders tinnitus Cardiac disorders arrhythmia (tachycardia) Vascular disorders hypertensio n transient ischaemic attacks, phlebitis, thrombophle bitis Gastrointest inal disorders diarrhoea, nausea, vomiting, localised or general abdominal pain, constipation , dyspepsia pancreatitis, gastritis, abdominal distention, dry mouth, glossitis, loose stools, stomatitis, tongue discolouratio n or disorder superficial tooth discolouratio n Hepato- biliary disorders abnormal liver function test; increased AST, ALT or alkaline phosphatase increased total bilirubin Skin and subcutaneo us tissue disorders pruritus, rash angioedema, urticaria, dermatitis, dermatitis bullous, diaphoresis toxic epidermal necrolysis#, Stevens- Johnson syndrome#, hypersensitiv ity vasculitis alopecia Musculoskel etal and connective tissue disorders rhabdomyoly sis* Renal and urinary disorders increased BUN renal failure, increased creatinine, polyuria Reproductiv e system and breast disorders vulvovaginal disorder General disorders and administrati on site conditions fever, localised pain chills, fatigue, injection site pain, increased thirst Investigatio ns Chemistry Increased LDH, creatine kinase, lipase, amylase or non fasting glucose.

Myelosuppression 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 haematologic parameters have risen toward pretreatment levels.

The risk of these effects appears to be related to the duration of treatment. Elderly patients treated with linezolid 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, and in patients with moderate to severe hepatic impairment.

Therefore, close monitoring of blood counts is recommended in patients who: have pre-existing anaemia, granulocytopenia 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 or moderate to severe hepatic impairment; receive more than 10-14 days of therapy.

Linezolid should be administered to such patients only when close monitoring of haemoglobin levels, blood counts and platelet counts is possible. 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 baseline blood count.

In compassionate use studies, a higher incidence of serious anaemia was reported in patients receiving linezolid for more than the maximum recommended duration of 28 days. These patients more often required blood transfusion. Cases of anaemia requiring blood transfusion have also been reported post marketing, with more cases occurring in patients who received linezolid therapy for more than 28 days.

1. g. phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of taking any such medicinal product. Unless there are facilities available for close observation and monitoring of blood pressure, linezolid should not be administered to patients with the following underlying clinical conditions or on the following types of concomitant medications: - Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute confusional states.

g. g. dopamine, dobutamine), pethidine or buspirone. 6).