Linobact Fc 600 mg FC tablets

LINOBACT FC is indicated for the treatment of patients with the following infections, which are caused by susceptible strains of micro-organisms:

• 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). Combination therapy may be clinically indicated if the documented or presumptive pathogens include Gram-negative organisms.
• 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).
• Complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae. Combination therapy may be clinically indicated if the documented or presumptive pathogens include Gram-negative organisms.
• Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes.

1 MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as penicillin-resistant Streptococcus pneumoniae, and are strains resistant to two or more of the following antibiotics: penicillin, second generation cephalosporins, macrolides, tetracycline and trimethoprim/sulfamethoxazole.

LINOBACT FC tablets may be used as initial therapy. Patients who commence treatment on the parenteral solution may be switched to the tablet formulation when clinically indicated. No dose adjustment is required, as LINOBACT FC has an oral bioavailability of approximately 100%. LINOBACT FC tablets may be taken with or without food.

The recommended dosage schedule for LINOBACT FC is as follows:

Adult and adolescent (12 years and older) patients:

• Infections (including those associated with concurrent bacteraemia)

Dosage and route of administration:

• Community-acquired pneumonia, including concurrent bacteraemia: 600 mg orally every 12 hours for 10 u2013 14 consecutive days
• Nosocomial pneumonia, including concurrent bacteraemia: 600 mg orally every 12 hours, depending on clinical severity
• Skin and soft tissue infections, including concurrent bacteraemia: 600 mg orally every 12 hours, depending on clinical severity
• Enterococcal infections, including vancomycin-resistant infections, and those with concurrent bacteraemia: 600 mg orally every 12 hours for 14 u2013 28 consecutive days

For patients younger than 12 years, the recommended dose is 10 mg/kg every 8 hours. This product is not suitable for use in children, as LINOBACT FC cannot be divided; please refer to the dosage recommendations in professional information of infusion or oral suspension formulations of linezolid.

Elderly patients: No dose adjustment is necessary.

Patients with renal impairment:

• Patients with mild to moderate renal insufficiency, i.e. CL CR (creatinine clearance) > 30 mu2113/min.: No dosage adjustment is required.
• Patients with serious renal impairment (i.e. CL CR < 30 ml/min.): Dosage should not be reduced in these patients. However, evidence indicates that the primary metabolites of LINOBACT FC accumulate in patients with severe renal insufficiency. The clinical significance has not been established. LINOBACT FC should only be used with special care in these patients, when the expected benefit is considered to exceed the theoretical risk.
• Haemodialysis: LINOBACT FC should be given after dialysis in patients receiving such treatment.

Patients with hepatic impairment: No dose adjustment is required.

LINOBACT FC tablets are contraindicated for use:

• in patients who have known hypersensitivity to linezolid or any of the excipients in the formulation (see COMPOSITION);
• in patients taking any medicine which inhibits monoamine oxidases A or B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of taking any of these medicines.

Pseudomembranous colitis: Treatment with LINOBACT FC alters the normal flora of the colon, which may lead to excessive growth of non-susceptible organisms such as Candida and Clostridium difficile. Antibiotic-associated diarrhoea (AAD), Clostridium difficile u2013 associated diarrhoea (CDAD) and pseudomembranous colitis has been reported with linezolid (contained in LINOBACT FC) and may vary in seriousness from mild diarrhoea to fatal colitis. It is therefore important to consider this diagnosis in patients presenting with diarrhoea after administration of LINOBACT FC. Should superinfection occur during therapy, appropriate treatment should be instituted. The risk/benefit should be thoroughly considered in patients with worsening diarrhoea.

Lactic acidosis: Lactic acidosis has been reported with the use of LINOBACT FC. Immediate medical attention is required in patients who develop signs and symptoms of metabolic acidosis, including recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or hyperventilation while receiving LINOBACT FC. If lactic acidosis occurs, the benefits of continued use of LINOBACT FC should be weighed against the potential risks.

Mitochondrial dysfunction: Linezolid, contained in LINOBACT FC, inhibits mitochondrial protein synthesis. Adverse events, such as lactic acidosis, anaemia and neuropathy (optic and peripheral), may occur as a result of this inhibition; these events are more common when LINOBACT FC is used longer than 28 days.

Myelosuppression: Myelosuppression may occur. Anaemia, pure red blood cell aplasia, leukopenia, pancytopenia and thrombocytopenia have been reported in patients receiving LINOBACT FC (see SIDE EFFECTS). Patients particularly at risk are those who have received LINOBACT FC for more than 10 or 14 days, who are receiving other bone marrow suppressant medicines, patients with severe renal insufficiency, or who have pre-existing myelosuppression. The risk/benefit should be thoroughly considered in patients with worsening myelosuppression. Discontinuation of therapy with linezolid should be considered in patients who develop, or have worsening, myelosuppression. Monitoring of full blood counts should be done for patients exposed to an increased risk for bleeding, who have pre-existing myelosuppression, who received concomitant medications which may decrease haemoglobin levels or platelet count or platelet function, or who have received LINOBACT FC for longer than 2 weeks.

Antibacterial spectrum: LINOBACT FC has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections (see Pharmacodynamic properties and INDICATIONS). Patients with mixed (Gram-negative and Gram-positive) infections are at a higher risk of mortality when LINOBACT FC is given as monotherapy; LINOBACT FC must therefore be used with appropriate antibacterial cover for Gram-negative organisms in such patients. LINOBACT FC should be used with special caution in patients exposed to a high risk for life-threatening systemic infections, such as those with infections related to central venous catheters in intensive care units. LINOBACT FC is not intended for the treatment of patients with catheter-related infections of the blood stream.

Serotonin syndrome: Serotonin syndrome has been reported with concomitant administration of linezolid and serotonergic agents (such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants and serotonin 5-HT1 receptor agonists). Doctors should be alert to the possibility of signs and symptoms of serotonin syndrome (e.g., hyperpyrexia, incoordination and cognitive dysfunction) in patients receiving such concomitant therapy with LINOBACT FC (see INTERACTIONS, u201cSerotonergic interactionsu201d). If signs or symptoms occur, doctors should consider discontinuing either one or both agents. Should the concomitant serotonergic agent be withdrawn, discontinuation symptoms may occur.

Peripheral and optic neuropathy: Peripheral and optic neuropathy and optic neuritis, sometimes progressing to loss of vision have been reported with LINOBACT FC (see SIDE EFFECTS). These side effects mainly occurred in patients treated for longer than the maximum recommended duration of 28 days (see Treatment period). The continued use of LINOBACT FC should be weighed against the potential risks. If a patient is taking LINOBACT FC for longer than the recommended 28 days, their visual function should be regularly monitored. There may be an increased risk of neuropathies when LINOBACT FC is used in patients currently taking, or who have recently taken, antibacterial medicines for the treatment of tuberculosis (see INTERACTIONS). 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. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary.

Convulsions: Convulsions may occur in patients treated with LINOBACT FC (see SIDE EFFECTS), particularly in patients with a history of convulsions, or risk factors for convulsions.

Resistance: There have been reports of linezolid resistance in:

• enterococci
• staphylococci, such as methicillin-resistant Staphylococcus aureus, S. auricularis and S. epidermidis.

Treatment period: The safety and effectiveness of LINOBACT FC when administered for periods longer than 28 days have not been established. See also Mitochondrial dysfunction above.

Patient populations: Underlying clinical conditions: LINOBACT FC has not been studied in patients with uncontrolled hypertension, phaeochromocytoma, carcinoid syndrome, untreated hyperthyroidism, bipolar depression, schizoaffective disorder or acute confusional states. If LINOBACT FC is used at all in these patients, they should be carefully monitored for potential increases in blood pressure.

Porphyria: LINOBACT FC is possibly porphyrinogenic and should therefore only be used when no safer alternative is available and precautions should be considered in vulnerable patients.

Renal impairment: LINOBACT FC should be used with special care in patients with severe renal impairment and only when the expected benefit is considered to exceed the theoretical risk.

Hepatic impairment: It is recommended that LINOBACT FC should only be considered for treatment in patients with severe hepatic insufficiency only when the expected benefit is considered to exceed the theoretical risk.

LINOBACT FC is contraindicated in patients treated with monoamine oxidase inhibitors or within two weeks of taking such a medicine (see CONTRAINDICATIONS). LINOBACT FC is a reversible, non-selective monoamine oxidase inhibitor (MAOI). It produces a mild, reversible enhancement of the pressor responses induced by pseudoephedrine and phenylpropanolamine hydrochloride. The potential for interaction with sympathomimetic or adrenergic agents should therefore be considered (see WARNINGS AND SPECIAL PRECAUTIONS).

Doses of compounds, such as dopamine or epinephrine (adrenalin), should be titrated to achieve the desired response.

Cytochrome P450 interactions: LINOBACT FC 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 medicine interactions are expected. Phenytoin, which is a CYP2C9 substrate, may be given with LINOBACT FC without changes in dosage regimen. Also, no interactions have been observed with either aztreonam or gentamicin.

Tyramine-rich foods: Large amounts of food and beverages with high tyramine content (e.g. mature cheese, yeast extracts, undistilled alcoholic beverages and fermented soya bean products such as soy sauce) should be avoided to prevent a pressor response.

Serotonergic interactions: Serotonin syndrome, associated with the simultaneous administration of LINOBACT FC and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) has been reported (see CONTRAINDICATIONS and WARNINGS AND SPECIAL PRECAUTIONS). Although LINOBACT FC has the potential for interaction with serotonergic agents, no serotonin effects were observed in subjects receiving linezolid and dextromethorphan.

Opioid analgesics: Pethidine should not be given to patients receiving MAO inhibitors (including LINOBACT FC) or within 14 days of their discontinuation. Very severe reactions, including coma, severe respiratory depression, cyanosis and hypotension may occur.

Rifampicin: Concomitant administration of rifampicin with LINOBACT FC may cause a decrease of about 20% in linezolid Cmax and a decrease of about 30% in linezolid AUC. The mechanism of this interaction and the clinical significance thereof is not known.

The use of LINOBACT FC tablets in pregnancy and lactation is contraindicated, as safety has not been demonstrated. LINOBACT FC may be secreted into breast milk.

Fertility: Linezolid, as in LINOBACT FC, reversibly decreased fertility and induced abnormal sperm morphology in animals. The possible effect on the human male reproductive system has not been established.

Patients should be informed not to drive or handle machinery or tools if they experience dizziness or visual impairment (see SIDE EFFECTS).

Infections and infestations:

• Frequent: Oral and vaginal monoliasis, moniliasis or fungal infection.
• Less frequent: Antibiotic associated colitis, Clostridium difficile associated diarrhoea (CDAD), pseudomembranous colitis (may be fatal; see WARNINGS AND SPECIAL PRECAUTIONS), vaginitis.

Blood and the lymphatic system disorders:

• Less frequent: Myelosuppression* with anaemia*, eosinophilia, leukopenia*, neutropenia, thrombocytopenia*, pancytopenia*, sideroblastic anaemia.

Immune system disorders:

• Frequency not known: Hypersensitivity reactions, anaphylaxis, angioedema, bullous skin disorders such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Metabolism and nutrition disorders:

• Less frequent: Increased serum creatine phosphokinase, hyperglycaemia, lactic acidosis*, hyponatraemia.

Psychiatric disorders:

• Frequent: Insomnia.

Nervous system disorders:

• Frequent: Headache, taste alterations, metallic taste.
• Less frequent: Dizziness, hypoesthesia, paraesthesia, peripheral neuropathy*, convulsions*, serotonin syndrome.

Eye disorders:

• Less frequent: Blurred vision*, optical neuropathy*, optic neuritis*, loss of vision*, changes in visual acuity*, changes in colour vision*, changes in visual field defect.

Ear and labyrinth disorders:

• Less frequent: Tinnitus.

Cardiac disorders:

• Less frequent: Dysrhythmia (tachycardia).

Vascular disorders:

• Less frequent: Hypertension, hypotension, phlebitis, thrombophlebitis, transient ischaemic attacks.

Gastrointestinal disorders:

• Frequent: Diarrhoea, nausea, vomiting, abdominal pain, cramps or distension.
• Less frequent: Constipation, dry mouth, dyspepsia, gastritis, pancreatitis, stomatitis, tongue discolouration or disorder, localised or general abdominal pain, glossitis, loose stools.

Hepatobiliary disorders:

• Frequent: Abnormal liver function tests (see Investigations below).

Skin and subcutaneous tissue disorders:

• Less frequent: Dermatitis, diaphoresis, pruritus, rash, urticaria, alopecia.

Musculoskeletal, connective tissue and bone disorders:

• Less frequent: Superficial tooth discolouration.

Renal and urinary disorders:

• Less frequent: Polyuria, increased creatinine, renal failure.

Reproductive system and breast disorders:

• Less frequent: Vulvovaginal disorder.

General disorders and administration site conditions:

• Less frequent: Chills, fatigue, fever, increased thirst.

Investigations:

• Frequent: Increased total bilirubin, AST, ALT, LDH, alkaline phosphatase, blood urea, creatine kinase, lipase, amylase or non-fasting glucose; decreased total protein, albumin, sodium, calcium, increased or decreased potassium or bicarbonate.
• Blood: Increased neutrophils or eosinophils, decreased haemoglobin, haematocrit or red blood cell count, increased or decreased platelet or white blood cell counts.

Less frequent: Increased creatinine, sodium, calcium; decreased non-fasting glucose, increased or decreased chloride.

Blood: Increased reticulocyte count, decreased neutrophils.

* See WARNINGS AND SPECIAL PRECAUTIONS.

**See CONTRAINDICATIONS and INTERACTIONS.

In the event of overdosage, supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a LINOBACT FC dose is removed during 3 hours of haemodialysis, but no data are available for the removal of LINOBACT FC by peritoneal dialysis or haemoperfusion.