Package leaflet: Information for the user

Linezolid Krka 2 mg/ml solution for infusion

Linezolid

Read all of this leaflet carefully before this medicinal product is given to you because it contains important information for you.

• Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist or nurse.

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Linezolid Krka is and what it is used for

2.    What you need to know before you are treated with Linezolid Krka

3.    How Linezolid Krka is given

4.    Possible side effects

5.    How to store Linezolid Krka

6.    Contents of the pack and other information

1.    What Linezolid Krka is and what it is used for

Linezolid Krka is an antibiotic of the oxazolidinones group that works by stopping the growth of certain bacteria (germs) that cause infections in adults. It is used to treat pneumonia and some infections in the skin or under the skin. Your doctor will have decided if Linezolid Krka is suitable to treat your infection.

2.    What you need to know before you are treated with Linezolid Krka

You should not be treated with Linezolid Krka:

•    if you are allergic to linezolid or any of the other ingredients of this medicine (listed in section 6).

•    if you are taking or have taken within the last 2 weeks any medicines known as monoamine oxidase inhibitors. (MAOIs: for example phenelzine, isocarboxazid, selegiline, moclobemide). These medications may be used to treat depression or Parkinson’s disease.

•    if you are breast-feeding. This is because Linezolid Krka passes into breast milk and could affect the baby.

Warnings and precautions

Talk to your doctor or pharmacist or nurse before you are treated with Linezolid Krka.

Linezolid Krka may not be suitable for you if you answer yes to any of the following questions. In this case tell your doctor as he/she will need to check your general health and your blood pressure before and during your treatment or may decide that another treatment is better for you.

Ask your doctor if you are not sure whether these categories apply to you.

•    Do you have high blood pressure, whether or not you are taking medicines for this?

•    Have you been diagnosed with an overactive thyroid?

•    Do you have a tumour of the adrenal glands (phaeochromocytoma) or carcinoid syndrome (caused by tumours of the hormone system with symptoms of diarrhoea, flushing of the skin, wheezing)?

•    Do you suffer from manic depression, schizoaffective disorder, mental confusion or other mental problems?

•    Are you taking any of the following medicines?

-    decongestant, cold or flu remedies containing pseudoephedrine or phenylpropanolamine

-    medicines used to treat asthma such as salbutamol, terbutaline, fenoterol

-    antidepressants known as tricyclics or SSRIs (selective serotonin reuptake inhibitors) for example amitriptyline, cipramil, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline

-    medicines used to treat migraine such as sumatriptan and zolmitriptan

-    medicines used to treat sudden, severe allergic reactions such as adrenaline (epinephrine)

-    medicines which increase your blood pressure, such as noradrenaline (norepinephrine), dopamine and dobutamine

-    medicines used to treat moderate to severe pain, such as pethidine

-    medicines used to treat anxiety disorders, such as buspirone

-    an antibiotic called rifampicin Take special care with Linezolid Krka

Tell your doctor before you are treated with this medicine if you:

•    bruise and bleed easily

•    are anaemic (have low red blood cells)

•    are prone to getting infections

•    have a history of seizures

•    have liver problems or kidney problems particularly if you are on dialysis

•    have diarrhoea

Tell your doctor immediately if during treatment you suffer from:

•    problems with your vision such as blurred vision, changes in colour vision, difficulty in seeing detail or if your field of vision becomes restricted.

•    loss of sensitivity in your arms or legs or a sensation of tingling or pricking in your arms or legs.

•    You may develop diarrhoea while taking or after taking antibiotics, including Linezolid Krka. If this becomes severe or persistent or you notice that your stools contains blood or mucus, you should stop taking Linezolid Krka immediately and consult your doctor. In this situation, you should not take medicines that stop or slow bowel movement.

•    recurrent nausea or vomiting, abdominal pain or rapid breathing.

Other medicines and Linezolid Krka

There is a risk that Linezolid Krka may sometimes interact with certain other medicines to cause side effects such as changes in blood pressure, temperature or heart rate.

Tell your doctor if you are taking or have taken within the last 2 weeks the following medicines as Linezolid Krka must not be taken if you are already taking these medicines or have taken them recently (see also Section 2 above You should not be treated with Linezolid Krka ’).

•    monoamine oxidase inhibitors (MAOIs; for example phenelzine, isocarboxazid, selegiline, moclobemide). These may be used to treat depression or Parkinson’s disease.

Also tell your doctor if you are taking the following medicines. Your doctor may still decide to give you Linezolid Krka, but will need to check your general health and your blood pressure before and during your treatment. In other cases, your doctor may decide that another treatment is better for you.

•    Decongestant cold or flu remedies containing pseudoephedrine or phenylpropanolamine.

•    Some medicines used to treat asthma such as salbutamol, terbutaline, fenoterol.

•    Certain antidepressants known as tricyclics or SSRIs (selective serotonin reuptake inhibitors). There are many of these, including amitriptyline, cipramil, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline.

•    Medicines used to treat migraine such as sumatriptan and zolmitriptan.

•    Medicines used to treat sudden, severe allergic reactions such as adrenaline (epinephrine).

•    Medicines which increase your blood pressure, such as noradrenaline (norepinephrine) dopamine and dobutamine.

•    Medicines used to treat moderate to severe pain, such as pethidine.

•    Medicines used to treat anxiety disorders, such as buspirone.

•    Medicines that stop blood clotting, such as warfarin.

Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines.

Linezolid Krka with food and drink

•    You can take Linezolid Krka either before, during or after a meal.

•    Avoid eating large amounts of mature cheese, yeast extracts, or soya bean extracts e.g. soy sauce and drinking alcohol, especially draught beers and wine. This is because Linezolid Krka may react with a substance called tyramine which is naturally present in some foods. This interaction may cause an increase in your blood pressure.

•    If you develop a throbbing headache after eating or drinking, tell your doctor or pharmacist immediately.

Pregnancy and breast-feeding and fertility

The effect of Linezolid Krka in pregnant women is not known. Therefore, it

should not be taken in pregnancy unless advised by your doctor. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

You should not breast-feed when taking Linezolid Krka because it passes into breast milk and could affect the baby.

Driving and using machines

Linezolid Krka may make you feel dizzy or experience problems with your vision. If this happens, do not drive or operate any machinery. Remember that if you are unwell your ability to drive or operate machinery may be affected.

Linezolid Krka contains glucose.

300 ml of solution for infusion contains 13.7 g glucose. This should be taken into account in patients with diabetes mellitus.

Linezolid Krka contains sodium.

300 ml of solution for infusion contains 114 mg sodium (5 mmol). To be taken into consideration by patients on a controlled sodium diet.

3.    How Linezolid Krka is given

Adults

This medicine will be given to you through a drip (by infusion into a vein) by a doctor or healthcare professional. The usual dose for adults (18 years and older) is 300 ml (600 mg linezolid) twice daily which is given directly into the blood stream (intravenously) by a drip over a period of 30 to 120 minutes.

If you are on kidney dialysis, you should be given Linezolid Krka after dialysis.

A course of treatment usually lasts 10 to 14 days, but can last up to 28 days. The safety and effectiveness of this medicine have not been established for treatment periods longer than 28 days. Your doctor will decide how long you should be treated.

While you are taking Linezolid Krka, your doctor should perform regular blood tests to monitor your blood count.

Your doctor should monitor your eyesight if you take Linezolid Krka for more than 28 days.

Use in children and adolescents

Linezolid Krka is not normally used to treat children and adolescents (under 18 years old).

If you receive more Linezolid Krka than you should

If you are concerned that you may have been given too much Linezolid Krka, tell your doctor or a nurse at once.

If you miss a dose of Linezolid Krka

As you will be given this medicine under close supervision, it is very unlikely that you will miss a dose. If you think that you have missed a dose of treatment, tell a doctor or nurse at once.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4.    Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor, nurse or pharmacist immediately if you notice any of these side effects during your treatment with Linezolid Krka:

•    skin reactions such as red sore skin and flaking (dermatitis), rash, itching, or swelling, particularly around the face and neck. This may be the sign of an allergic reaction and it may be necessary for you to stop taking Linezolid Krka.

•    problems with your vision such as blurred vision, changes in colour vision, difficulty in seeing detail or if your field of vision becomes restricted.

•    severe diarrhoea containing blood and/or mucus (antibiotic associated colitis including pseudomembranous colitis), which in rare circumstances may develop into complications that are life-threatening.

•    recurrent nausea or vomiting, abdominal pain or rapid breathing.

•    fits or seizures have been reported with Linezolid Krka. You should let your doctor know if you experience agitation, confusion, delirium, rigidity, tremor, incoordination and seizure while also taking antidepressants

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known as SSRI’s (see section 2).

Numbness, tingling or blurred vision have been reported by patients who have been given Linezolid Krka for more than 28 days. If you experience difficulties with your vision you should consult your doctor as soon as possible.

Other side effects include:

Common side effects (may affect up to 1 in 10 people):

•    Fungal infections especially vaginal or oral “thrush”

•    Headache

•    Metallic taste in the mouth

•    Diarrhoea, nausea or vomiting

•    Changes in some blood test results including those measuring your kidney or liver function or blood sugar levels

•    Unexplained bleeding or bruising, which may be due to changes in the numbers of certain cells in the blood which may affect blood clotting or lead to anaemia

•    Difficulty in sleeping

•    Increased blood pressure

•    Anaemia (low red blood cell)

•    Changes in numbers of certain cells in the blood which may affect your ability to fight infection

•    Skin rash

•    Itching skin

•    Dizziness

•    Localised or general abdominal pain

•    Constipation

•    Indigestion

•    Localised pain

•    Fever

Uncommon side effects (may affect up to 1 in 100 people):

•    Inflammation of the vagina or genital area in women

•    Sensations such as tingling or feeling numb

•    Blurred vision

•    “Ringing” in the ears (tinnitus)

•    Inflammation of the veins

•    Dry or sore mouth, swollen, sore, or discoloured tongue

•    Pain at and around the place where the infusion (drip) was given

•    Inflammation of the veins (including where the infusion (drip) was given)

•    A need to urinate more often

•    Chills

•    Feeling tired or thirsty

•    Inflammation of the pancreas

•    Increased sweating

•    Changes in proteins, salts or enzymes in the blood which measure kidney or liver function.

•    Convulsions

•    Hyponatraemia (low blood sodium levels)

•    Kidney failure

•    Reduction in platelets

•    Abdominal bloating

•    Transient ischaemic attacks (temporary disturbance of blood flow to the brain causing short term symptoms such as loss of vision, leg and arm weakness, slurring of speech and loss of consciousness).

•    Injection site pain

•    Inflammation of the skin

•    Increase in creatinine

•    Stomach pain

•    Changes in heart rate (e.g. increase rate)

Rare side effects (may affect up to 1 in 1000 people):

•    Restricted field of vision

•    Superficial tooth discolouration, removable with professional dental cleaning (manual descaling)

The following side effects have also been reported (frequency cannot be estimated from the available data):

•    Serotonin syndrome (symptoms include fast heart rate, confusion, abnormal sweating, hallucinations, involuntary movements chills and shivering)

•    Lactic acidosis (symptoms include recurrent nausea and vomiting, abdominal pain, rapid breathing)

•    Severe skin disorders

•    Sideroblastic anaemia (a type of anaemia (low red blood cells))

•    Alopecia (hair loss)

•    Changes in colour vision or difficulty in seeing detail

•    Decrease of the blood cell count

•    Weakness and/or sensory changes Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the safety of this medicine.

5.    How to store Linezolid Krka

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the packaging after EXP. The expiry date refers to the last day of that month. Do not store above 30°C.

Store in the original package in order to protect from light.

After opening: Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature in primary bag after removal of the secondary pack (pouch). From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Do not use this medicine if you notice that solution is not clear, colourless to yellow or to yellowish-brown.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6.    Contents of the pack and other information

What Linezolid Krka contains

•    The active substance is linezolid. 1 ml of solution for infusion contains 2 mg linezolid. Each 300 ml infusion bag contains 600 mg linezolid.

•    The other ingredients are glucose monohydrate, sodium citrate dihydrate, citric acid anhydrous, hydrochloric acid (for pH-adjustment), sodium hydroxide (for pH-adjustment) and water for injections. See section 2 “Linezolid Krka contains glucose and sodium.”

What Linezolid Krka looks like and contents of the pack

Clear colourless to yellow or to yellowish-brown solution (pH: 4.6 - 5.2, osmolality: 270 mOsmol/kg - 320 mOsmol/kg).

Linezolid solution for infusion:

Primary packaging:

multilayer polyolefin plastic bag (300 ml) with multilayer polyolefin plastic port tube and polyolefin twist off connector.

Secondary packaging:

Overpouch bag made of multilayer film. Film layers of bag from outside to inside: polyester, aluminium, polyester, propylene, 1 and 10 in a box.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

KRKA, d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto, Slovenia

This leaflet was last revised in

The following information is intended for healthcare professionals only:

Linezolid Krka 2 mg/ml solution for infusion

Linezolid

IMPORTANT: Refer to Summary of Product Characteristics before prescribing.

Linezolid is not active against infections caused by Gram negative pathogens. Specific therapy against Gram negative organisms must be initiated concomitantly if co-infection with a Gram negative pathogen is documented or suspected.

Description

For single use only. The bag holds 300 ml solution and is packaged in a box. Each box contains 1 or 10 infusion bags.

Linezolid Krka 2 mg/ml solution for infusion contains linezolid 2 mg/ml in a clear, colourless to yellow or to yellowish-brown solution. Other ingredients are glucose monohydrate, sodium citrate dihydrate, citric acid anhydrous, hydrochloric acid, sodium hydroxide and water for injection. Dosage and method of administration Linezolid should only be initiated in a hospital environment and after consultation with a relevant specialist such as a microbiologist or an infectious diseases specialist.

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 linezolid has an oral bioavailability of approximately 100 %.

The solution for infusion should be administered over a period of 30 to 120 minutes.

The recommended linezolid dosage should be administered IV twice daily.

Recommended dosage and duration 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 have not yet been established for treatment periods longer than 28 days.

No increase in the recommended dosage or duration of treatment is required for infections associated with concurrent bacteraemia. The dose recommendation for the solution for infusion and the tablets/granules for oral suspension are identical and are as follows:

Infections	Dosage and route for twice daily administration	Duration of treatment
Nosocomial pneumonia	600 mg twice daily	10-14 Consecutive Days
Community acquired pneumonia
Complicated skin and soft tissue infections	600 mg twice daily

Paediatric population: There are insufficient data on the pharmacokinetics, 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.

Elderly patients: No dose adjustment is required.

Patients with renal insufficiency: No dose adjustment is required. Patients with severe renal insufficiency (i.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 Krka 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. 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 (CAPD) or alternative treatments for renal failure (other than haemodialysis).

Patients with hepatic insufficiency: Patients with mild to moderate hepatic insufficiency (Child-Pugh class A or B): No dose adjustment is required.

Patients with severe hepatic insufficiency (Child-Pugh class C): As linezolid is metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism and, therefore, no dose adjustment is recommended. However, there are no pharmacokinetic data and limited clinical experience of linezolid in patients with severe hepatic insufficiency. Linezolid should be used with special caution in patients with severe hepatic insufficiency and only when the anticipated benefit is considered to outweigh the theoretical risk.

Contraindications

Hypersensitivity to linezolid or to any of the excipients.

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 drug.

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.

•    Patients taking any of the following medications: Serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), directly and indirectly acting sympathomimetic agents (including the adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressive agents (e.g. adrenaline / epinephrine, noradrenaline / norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), pethidine or buspirone.

Breast feeding should be discontinued prior to and throughout administration.

Special warnings and precautions for use

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. 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; 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.

Cases of sideroblastic anaemia have been reported post-marketing. Where time of onset was known, most patients had received linezolid therapy for more than 28 days. Most patients fully or partially recovered following discontinuation of linezolid with or without treatment for their anaemia.

Mortality imbalance in a clinical trial in patients with catheter-related Gram positive bloodstream infections

Excess mortality was seen in patients treated with linezolid, relative to vancomycin/dicloxacillin/oxacillin, in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs 58/363 (16.0%)]. The main factor influencing the mortality rate was the Gram positive infection status at baseline. Mortality rates were similar in