Zyvoxid

Package leaflet: Information for the user

ZYVOXID 2 mg/ml solution for infusion

Linezolid
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

1. What Zyvoxid is and what it is used for
2. What you need to know before taking Zyvoxid
3. How to take Zyvoxid
4. Possible side effects
5. How to store Zyvoxid
6. Contents of the pack and other information

1. What Zyvoxid is and what it is used for

Zyvoxid is an antibiotic belonging to the oxazolidinone class, which works by inhibiting the growth of certain bacteria causing infections. It is used to treat pneumonia and certain skin or soft tissue infections. Your doctor will decide whether Zyvoxid is suitable for treating your type of infection.

2. What you need to know before taking Zyvoxid

Do not take Zyvoxid:

• if you are allergic to linezolid or to 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 of the medicines called monoamine oxidase inhibitors (MAOIs, for example phenelzine, isocarboxazid, selegiline, moclobemide). These are medicines generally used to treat depression or Parkinson's disease.
• if you are breastfeeding. Zyvoxid passes into breast milk and may affect the baby.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Zyvoxid.
Zyvoxid may not be suitable for you if you answer yes to any of the following questions. In this case,
inform your doctor, who should check your general health and blood pressure before and during treatment,
or who may decide that an alternative therapy is better for you.
Ask your doctor if you are unsure whether any of these conditions apply to you.

• Do you have high blood pressure, whether or not you are taking medicines for this condition?
• Have you been diagnosed with hyperthyroidism (overactive thyroid)?
• Do you have a tumour of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumours of the hormonal system with symptoms such as diarrhoea, skin flushing, wheezing)?
• Do you suffer from manic depression, schizoaffective disorder, confusion or any other mental disorder?
• Do you have a history of hyponatraemia (low levels of sodium in the blood) or are you taking medicines that lower sodium levels in the blood, e.g. certain diuretics (also called "water pills") such as hydrochlorothiazide?
• Are you taking opioids?

The use of certain medicines, including antidepressants and opioids, together with Zyvoxid may lead to
the development of serotonin syndrome, a potentially life-threatening condition (see section 2
"Other medicines and Zyvoxid" and section 4).
Take special care with Zyvoxid
Tell your doctor before taking this medicine if:

• you are elderly
• you are prone to bruising or bleeding episodes
• you are anaemic (have low red blood cell count)
• you are prone to infections
• you have a history of seizures
• you have liver or kidney problems, especially if you are on dialysis
• you have diarrhoea

Tell your doctor immediately if, during treatment, you experience:

• vision problems such as blurred vision, changes in colour vision, difficulty seeing details, or narrowing of the visual field.
• loss of sensation in the arms or legs or tingling or prickling sensations in the arms or legs.
• during or after antibiotic treatment, including Zyvoxid, you may develop diarrhoea. If diarrhoea becomes severe or persistent, or if you notice blood or mucus in your stools, stop taking Zyvoxid immediately and consult your doctor. In such cases, do not take medicines that stop or slow down intestinal movements.
• recurrent nausea or vomiting, abdominal pain or rapid breathing.
• unexplained muscle pain, tenderness or weakness and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage.
• feeling unwell with muscle weakness, headache, confusion and memory problems, which may indicate hyponatraemia (low sodium levels in the blood).

Other medicines and Zyvoxid
There is a risk that Zyvoxid may sometimes interact with other medicines, causing unwanted effects
such as changes in blood pressure, body temperature or heart rate.
Tell your doctor or pharmacist if you are taking or have recently taken any other medicine.
Tell your doctor if you are taking or have taken any of the following medicines within the last 2 weeks,
since Zyvoxid must not be taken if you are already taking these medicines or have recently taken them
(see also section 2 above "Do not take Zyvoxid").

• monoamine oxidase inhibitors (MAOIs), for example phenelzine, isocarboxazid, selegiline, moclobemide. These are medicines generally used to treat depression or Parkinson's disease.

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

• Decongestants, cold or flu remedies containing pseudoephedrine or phenylpropanolamine.
• Certain medicines used to treat asthma such as salbutamol, terbutaline, fenoterol.
• Certain antidepressants such as tricyclics or SSRIs (selective serotonin reuptake inhibitors). There are many, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline.
• Medicines used to treat migraine such as sumatriptan and zolmitriptan.
• Medicines used to treat severe and sudden allergic reactions such as adrenaline (epinephrine).
• Medicines that raise blood pressure, such as noradrenaline (norepinephrine), dopamine and dobutamine.
• Opioids, for example meperidine (pethidine), used to treat moderate to severe pain.
• Medicines used to treat anxiety disorders, such as buspirone.
• Medicines that prevent blood clotting, such as warfarin.
• An antibiotic called rifampicin.

Zyvoxid with food, drinks and alcohol

• Zyvoxid can be taken before, during or after meals.
• Avoid eating large amounts of aged cheeses, yeast extracts or soybean products, e.g. soy sauce, and avoid drinking alcohol, especially draught beer and wine. This is because Zyvoxid can react with a substance called tyramine, which is naturally present in certain foods. This interaction may cause a rise in blood pressure.
• If you develop a throbbing headache after eating or drinking, inform your doctor, pharmacist or nurse immediately.

Pregnancy, breastfeeding and fertility
The effect of Zyvoxid in pregnant women is unknown. Therefore, the medicine should not be taken during
pregnancy unless specifically prescribed by your doctor. If you are pregnant, think you may be pregnant,
are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking
this medicine.
While taking Zyvoxid, you must not breastfeed, as the medicine passes into breast milk and may affect
the baby.
Driving and using machines
Zyvoxid may cause mild dizziness or vision problems. If this occurs, do not drive or operate machinery.
Remember that your ability to drive or operate machinery may be impaired if you do not feel well.

Zyvoxid contains
Glucose
1 ml of Zyvoxid solution contains 45.7 mg of glucose (13.7 g of glucose in a bag).
Inform your doctor if you are diabetic.
Sodium
1 ml of Zyvoxid solution contains 0.38 mg of sodium (main component of table salt) (114 mg of sodium in a bag). The sodium content in one bag corresponds to 5.7% of the maximum recommended daily dietary sodium intake for an adult.
Inform your doctor or nurse if you are on a low-sodium diet.

3. How to take Zyvoxid

Adults
Take this medicine exactly as described in this leaflet or as directed by your doctor, pharmacist, or nurse. If you are in doubt, consult your doctor, pharmacist, or nurse.
This medicine will be administered to you as a slow intravenous infusion (drip) by a doctor or healthcare professional. The recommended dose for adults (over 18 years of age) is 300 ml (600 mg of linezolid) twice daily, administered directly into the bloodstream via slow intravenous infusion over a period of 30 to 120 minutes.
If you are undergoing renal dialysis, you must take Zyvoxid after dialysis.
A treatment course usually lasts from 10 to 14 days, but may last up to 28 days. The safety and efficacy of this medicine for periods longer than 28 days have not been established. Your doctor will decide how long your treatment should last.
While you are taking Zyvoxid, your doctor should regularly perform blood tests to monitor your blood cell counts.
If you take Zyvoxid for longer than 28 days, your doctor should monitor your vision.

Use in children and adolescents
Zyvoxid is not normally used to treat children and adolescents (under 18 years of age).

If you take more Zyvoxid than you should
If you think you have been given too much Zyvoxid, inform your doctor or nurse immediately.

If you forget to take Zyvoxid
Since this medicine will be administered under careful supervision, it is very unlikely that a dose will be missed. If you think a dose has been missed, inform your doctor or nurse immediately. Do not take a double dose to make up for a forgotten dose.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Immediately inform your doctor, nurse or pharmacist if you notice any of the following side effects during treatment with Zyvoxid:
The serious side effects (with frequency indicated in parentheses) of Zyvoxid are:

• severe skin reactions (uncommon), swelling, especially of the face and neck (uncommon), breathlessness and/or difficulty breathing (rare). These may be signs of an allergic reaction, and treatment with Zyvoxid may need to be stopped. Skin reactions such as raised, purple rash due to inflammation of blood vessels (rare), skin ulceration and peeling (dermatitis) (uncommon), rash (common), itching (common).

• vision disturbances (uncommon) such as blurred vision (uncommon), changes in colour vision (frequency not known), difficulty seeing details (frequency not known), or narrowing of the visual field (rare).

• severe diarrhoea containing blood and/or mucus (antibiotic-associated colitis, including pseudomembranous colitis), which in rare cases may lead to life-threatening complications (uncommon).

• recurrent nausea or vomiting, abdominal pain or rapid breathing (rare).

• seizures or convulsions have been reported with Zyvoxid (uncommon).

• Serotonin syndrome (frequency not known): if you experience agitation, confusion, delirium, muscle rigidity, tremor, lack of coordination, seizures, rapid heartbeat, severe breathing problems and diarrhoea (suggestive of serotonin syndrome) while also taking antidepressant medicines called SSRIs or opioids (see section 2), you must inform your doctor.

• unexplained bleeding or bruising, possibly due to changes in the number of certain blood cells affecting blood clotting or leading to anaemia (common).

• changes in the number of certain blood cells affecting the ability to fight infections (uncommon); signs of infection may include: fever (common), sore throat (uncommon), mouth ulcers (uncommon) and fatigue (uncommon).

• rhabdomyolysis (rare): symptoms include unexplained muscle pain, tenderness or weakness and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage.

• inflammation of the pancreas (uncommon).

• convulsions (uncommon).

• transient ischaemic attacks (temporary disruption of blood flow to the brain causing short-lived symptoms such as loss of vision, weakness in arms and legs, difficulty speaking and loss of consciousness) (uncommon).

• ringing in the ears (tinnitus) (uncommon).

Numbness, tingling sensations or blurred vision have been reported in patients treated with Zyvoxid for more than 28 days. If you have any vision problems, consult your doctor as soon as possible.
Other side effects include:
Common (may affect up to 1 in 10 people):

• fungal infections, especially vaginal or oral candidiasis
• headache
• metallic taste in the mouth
• diarrhoea, nausea or vomiting
• changes in certain blood test results, including values used to monitor proteins, salts or enzymes measuring kidney or liver function, or blood sugar levels
• difficulty sleeping
• increased blood pressure
• anaemia (low red blood cell count)
• dizziness
• localized or general abdominal pain
• constipation
• indigestion
• localized pain
• reduced platelet count

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

• inflammation of the vagina or genital area in women
• sensations such as tingling or numbness
• swelling, pain or discolouration of the tongue
• dry mouth
• pain at the infusion site
• inflammation of veins (including at the infusion site)
• need to urinate more frequently
• chills
• feeling thirsty
• increased sweating
• hyponatraemia (low sodium levels in the blood)
• kidney failure
• abdominal swelling
• injection site pain
• increased creatinine
• stomach ache
• changes in heart rate (e.g. increased heart rate)
• reduced number of blood cells
• weakness and/or sensory disturbances

Rare (may affect up to 1 in 1,000 people):

• superficial tooth discolouration, removable with professional dental cleaning (manual removal)

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

• alopecia (hair loss)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zyvoxid

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton, on the bags, and on the outer packaging following "EXP".
The expiry date refers to the last day of that month.
Hospital staff must ensure that Zyvoxid solution is not used beyond the expiry date printed on the bag and that it is administered immediately after opening. They will also perform a visual inspection of the solution before use and will only use a clear solution free from particles. The responsible staff will also ensure that the solution is properly stored in its packaging and within the protective outer pouch to protect it from light and to keep it out of the sight and reach of children, for the required duration.

After opening:
From a microbiological standpoint, the product should be used immediately, unless the method of opening excludes any risk of contamination. If not used immediately, the duration and conditions of storage are the responsibility of the user.

Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Contents of the pack and other information

What Zyvoxid contains

• The active substance is linezolid. 1 ml of solution contains 2 mg of linezolid. Each 300 ml infusion bag contains 600 mg of linezolid.
• The other components are monohydrate glucose (a type of sugar; see section 2 “Zyvoxid contains glucose”), disodium citrate dihydrate (E331) (see section 2 “Zyvoxid contains sodium”), anhydrous citric acid (E330), hydrochloric acid (E507) or sodium hydroxide (E524), and water for injections.

Description of the appearance of Zyvoxid and contents of the pack
Zyvoxid is supplied as a crystalline solution in single-use infusion bags, each containing 300 ml of solution.
The bags are packaged in packs containing 1, 2, 5, 10, 20 or 25 bags.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Pfizer Italia S.r.l. - Via Isonzo, 71 - 04100 Latina

Manufacturer
HP Halden Pharma AS: Svinesundveien 80, 1788 Halden, Norway

This medicinal product is authorised in the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:
Austria Zyvoxid
Belgium Zyvoxid
Cyprus Zyvoxid
Czech Republic Zyvoxid
Denmark Zyvoxid
Estonia Zyvoxid
Finland Zyvoxid
France Zyvoxid
Germany Zyvoxid
Greece Zyvoxid
Iceland Zyvoxid
Ireland Zyvox
Italy Zyvoxid
Latvia Zyvoxid
Lithuania Zyvoxid
Luxembourg Zyvoxid
Malta Zyvox
Netherlands Zyvoxid
Norway Zyvoxid
Poland Zyvoxid
Portugal Zyvoxid
Slovakia Zyvoxid
Slovenia Zyvoxid
Spain Zyvoxid
Sweden Zyvoxid
United Kingdom (Northern Ireland) Zyvox

The following information is intended for healthcare professionals only:
Zyvoxid 2 mg/ml infusion solution
Linezolid
IMPORTANT: Refer to the Summary of Product Characteristics before prescribing.
Linezolid is not active against infections caused by Gram-negative pathogens. When co-infection with Gram-negative pathogens is suspected or confirmed, appropriate concomitant therapy directed against Gram-negative organisms should be initiated.

Description
Single-use, ready-to-use infusion bags made of non-latex, multilayer polyolefin film ( Excel or Freeflex ), sealed within a laminated overwrap.
The bags contain 300 ml of solution and are packed in a carton. Each carton contains 1, 2, 5, 10*, 20 or 25 infusion bags.
Note:
*Only cartons containing 10 bags are currently marketed.
Zyvoxid 2 mg/ml infusion solution contains linezolid 2 mg/ml in an isotonic, clear, colourless to yellow solution. The excipients are: monohydrate glucose, disodium citrate dihydrate (E331), anhydrous citric acid (E330), hydrochloric acid (E507) or sodium hydroxide (E524), water for injections.

Dosage and method of administration
Treatment with linezolid should only be initiated in a hospital setting and after consultation with a qualified specialist, such as a microbiologist or infectious disease specialist.
Patients starting treatment with the parenteral formulation may be switched to oral formulations when clinically appropriate. In such cases, no dose adjustment is required, as the oral bioavailability of linezolid is approximately 100%.
The infusion solution must be administered over a period of 30 to 120 minutes.
The recommended dose of linezolid should be administered intravenously twice daily.

Recommended dosage and duration of treatment in adults
The duration of treatment depends on the causative pathogen, the site and severity of infection, and the patient's clinical response.
The following recommendations on treatment duration reflect those used in clinical trials.
Shorter treatment regimens may be appropriate for certain types of infection but have not been evaluated in clinical trials.
The maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for periods longer than 28 days have not been established.
No increase in dose or duration of treatment is required for infections associated with concomitant bacteraemia.
The recommended dosage for the infusion solution, tablets, and oral granules for suspension is the same and is as follows:

Paediatric population: The safety and efficacy of linezolid in children (< 18 years) have not
been established. The currently available data are reported in sections 4.8, 5.1, and 5.2 of the SmPC, but
no dosage recommendations can be made.
Elderly: no dose adjustment is required.
Renal impairment: no dose adjustment is required.
Severe renal impairment (i.e., creatinine clearance < 30 ml/min): no dose adjustment is required.
Since the clinical significance of higher exposure (up to 10-fold) to the two main metabolites of linezolid
in patients with severe renal impairment is unknown, linezolid should be used with particular caution
in these patients and only when the expected benefit outweighs the theoretical risk.
As approximately 30% of a dose of linezolid is removed during 3 hours of haemodialysis, linezolid
should be administered after dialysis in patients undergoing this treatment. The main metabolites of
linezolid are partially eliminated by haemodialysis, but their concentrations remain substantially
higher after dialysis compared to those observed in patients with normal or mild to moderate renal
function. Linezolid should therefore be used with particular caution in patients with severe renal
impairment undergoing dialysis, and only when the expected benefit outweighs the theoretical risk.
There are currently no data on the administration of linezolid in patients undergoing continuous
ambulatory peritoneal dialysis (CAPD) or other alternative treatments for renal failure (other than
haemodialysis).
Hepatic impairment: Patients with mild to moderate hepatic impairment (i.e., Child-Pugh class A or
B): no dose adjustment is required.
Severe hepatic impairment (i.e., Child-Pugh class C): Since linezolid is metabolized via a non-enzymatic process, altered hepatic function is not expected to significantly affect its metabolism; therefore, no dose adjustment is recommended. However, clinical data are limited, and linezolid should be used in such patients only when the expected benefits outweigh the theoretical risks (see sections 4.4 and 5.2).
Contraindications
Patients with hypersensitivity to linezolid or any of the excipients.
Linezolid must not be used in patients receiving medications that inhibit monoamine oxidase A or B (e.g., phenelzine, isocarboxazide, selegiline, moclobemide) or within two weeks of discontinuing such medications.
Linezolid must not be administered to patients who have the following clinical conditions or who are taking the following types of concomitant medications unless facilities for close patient observation and blood pressure monitoring are available:

• Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorders, acute confusional states.
• Patients taking the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5HT receptor agonists (triptans), direct or indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, and phenylpropanolamine), vasopressor substances (e.g., adrenaline, noradrenaline), dopaminergic substances (e.g., dopamine), dobutamine, pethidine, or buspirone.

Breastfeeding must be discontinued before or during administration (see section 4.6 of the SmPC).
Special warnings and precautions for use
Myelosuppression
Cases of myelosuppression (including anaemia, leucopenia, pancytopenia, and thrombocytopenia) have been reported in patients treated with linezolid. In cases with known outcome, haematological parameters returned towards pre-treatment values after discontinuation of linezolid. The risk of these effects appears to be related to the duration of treatment. Elderly patients receiving linezolid may be at greater risk of haematological disorders compared to younger patients. Thrombocytopenia may occur more commonly in patients with severe renal impairment, whether or not on dialysis, and in patients with moderate or severe hepatic impairment. Careful monitoring of blood cell counts is therefore recommended in patients with pre-existing anaemia, granulocytopenia, or thrombocytopenia; in patients receiving concomitant medications that may reduce haemoglobin levels, depress blood cell counts, or have adverse effects on platelet count or function; in patients with severe renal impairment or moderate to severe hepatic impairment; and in patients receiving linezolid for more than 10–14 days. In such patients, linezolid should be administered only if haemoglobin levels can be closely monitored or if blood cell and platelet counts can be performed.
If significant myelosuppression occurs during treatment with linezolid, administration should be discontinued unless continuation of therapy is considered absolutely necessary; in such cases, intensive monitoring of blood cell counts and appropriate therapeutic measures should be initiated.
Furthermore, complete weekly monitoring of blood cell counts (including haemoglobin levels, platelets, and total and differential leucocyte counts) is recommended in all patients receiving linezolid, regardless of baseline values.
In compassionate use studies, a higher incidence of severe anaemia has been reported in patients treated with linezolid for periods exceeding the maximum recommended duration of 28 days. In these patients, the need for blood transfusion was more frequent. Cases of anaemia requiring transfusion have also been reported in post-marketing experience, with a higher incidence in patients treated with linezolid for more than 28 days.
In post-marketing experience, cases of sideroblastic anaemia have been reported. In cases where onset time was known, most patients had received linezolid treatment for more than 28 days. Most patients showed complete or partial recovery after discontinuation of linezolid therapy, with or without treatment for anaemia.
Imbalance in mortality rate in a clinical study on patients with Gram-positive catheter-related bloodstream infections
In an open-label clinical study in critically ill patients with intravascular catheter-related infections, a higher mortality rate was observed in patients treated with linezolid compared to vancomycin, dicloxacillin, or oxacillin [78/363 (21.5%) vs. 58/363 (16.0%)].
The main factor influencing mortality rate was the baseline severity of Gram-positive infection. Mortality was similar in patients with infections caused exclusively by Gram-positive bacteria (odds ratio 0.96; 95% confidence interval: 0.58–1.59), but significantly higher (p=0.0162) in the linezolid treatment group among patients who had any other pathogen or no pathogen at baseline (odds ratio 2.48; 95% confidence interval: 1.38–4.46). The greatest difference occurred during treatment and within 7 days after discontinuation of therapy. A greater number of patients in the linezolid treatment group developed infections with Gram-negative pathogens during the study, and patients died from Gram-negative and polymicrobial infections.
Therefore, in complicated skin and soft tissue infections, linezolid should be used in patients with confirmed or suspected concomitant Gram-negative pathogen infections only when no other therapeutic alternatives are available. In these circumstances, concomitant treatment against Gram-negative pathogens should be initiated.
Antibiotic-associated diarrhoea and colitis
Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, have been reported with the use of nearly all antibiotics, including linezolid, with severity ranging from mild diarrhoea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop severe diarrhoea during or after treatment with linezolid. If antibiotic-associated diarrhoea or colitis is suspected or confirmed, ongoing antibacterial therapy, including linezolid, should be discontinued and appropriate therapeutic measures initiated immediately. In this situation, antiperistaltic agents are contraindicated.
Lactic acidosis
Cases of lactic acidosis have been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis during linezolid therapy—including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation—should receive immediate medical attention. If lactic acidosis occurs, the benefits of continuing linezolid therapy should be weighed against the potential risks.
Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. As a consequence of this inhibition, adverse events such as lactic acidosis, anaemia, and neuropathy (optic and peripheral) may occur; these events are more common when the drug is used for more than 28 days.
Serotonin syndrome
Spontaneous reports of serotonin syndrome associated with concomitant administration of linezolid and serotonergic drugs, including selective serotonin re-uptake inhibitors (SSRIs) and opioids, have been reported (see section 4.5 of the SmPC). Concomitant administration of linezolid and serotonergic drugs is therefore contraindicated (see section 4.3 of the SmPC), except when concomitant administration of linezolid and serotonergic drugs is essential.
In such cases, patients must be closely monitored for signs and symptoms of serotonin syndrome, such as cognitive dysfunction, hyperthermia, hyperreflexia, and lack of coordination. If these signs and symptoms occur, the physician should consider discontinuing one or both concomitant treatments; if the serotonergic drug is discontinued, withdrawal symptoms may occur.
Rhabdomyolysis
Cases of rhabdomyolysis have been reported with the use of linezolid. Linezolid should be used with caution in patients with predisposing factors for rhabdomyolysis. If signs or symptoms of rhabdomyolysis occur, linezolid should be discontinued and appropriate therapy initiated.
Hyponatraemia and SIADH
Hyponatraemia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in some patients treated with linezolid. Regular monitoring of serum sodium levels is recommended in patients at risk of hyponatraemia, such as elderly patients or patients taking medications that may lower blood sodium levels (e.g., thiazide diuretics such as hydrochlorothiazide).
Peripheral and optic neuropathy
Peripheral neuropathy, as well as optic neuropathy and optic neuritis, have been reported in patients receiving linezolid therapy, sometimes progressing to vision loss. These cases occurred primarily in patients treated for periods exceeding the maximum recommended duration of 28 days.
All patients should be advised to report symptoms of visual disturbances, such as changes in visual acuity, altered colour vision, blurred vision, or visual field defects. In such cases, timely ophthalmological evaluation is recommended, and referral to an ophthalmologist may be necessary. In cases of linezolid administration for periods exceeding the maximum recommended duration of 28 days, regular monitoring of visual function should be performed in all patients.
If peripheral or optic neuropathy develops, continuation of linezolid therapy in these patients should be evaluated considering the potential risks.
The risk of neuropathy may increase when linezolid is used in patients who are concomitantly receiving or have recently received antimycobacterial agents for the treatment of tuberculosis.
Seizures
Cases of seizures have been reported in patients treated with Zyvoxid. In most cases, a positive history of seizures or risk factors for seizures was reported.
In patients with a history of seizures, they should be advised to inform their physician.
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective monoamine oxidase (MAO) inhibitor; however, at doses used for antibacterial therapy, it does not exert an antidepressant effect. Very limited data are available from drug interaction studies and on the safety of linezolid administered to patients with pre-existing clinical conditions and/or concomitant therapies that may pose a risk due to MAO inhibition. Therefore, the use of linezolid is not recommended in these circumstances unless close patient monitoring and surveillance are possible.
Use with tyramine-rich foods
Patients should be advised not to consume large quantities of tyramine-rich foods.
Superinfections
Clinical studies have not evaluated the effects of linezolid therapy on normal flora.
The use of antibiotics may occasionally lead to overgrowth of non-susceptible microorganisms. For example, approximately 3% of patients treated with the recommended dose of linezolid developed drug-related candidiasis during clinical trials. Appropriate measures should be taken if superinfection occurs during therapy.
Special populations
Linezolid should be used with particular caution in patients with severe renal impairment and only when the expected benefit outweighs the theoretical risk (see sections 4.2 and 5.2 of the SmPC).
Linezolid should be administered in patients with severe hepatic impairment only when the expected benefit outweighs the theoretical risk.
Impairment of fertility
Linezolid reversibly reduced fertility and induced morphological abnormalities in sperm of adult male rats at exposure levels equivalent to those expected in humans; possible effects of linezolid on the male reproductive system in humans are unknown.
Clinical studies
The safety and efficacy of linezolid administered for periods exceeding 28 days have not been established.
Controlled studies did not include patients with diabetic foot lesions, pressure ulcers, ischaemic wounds, severe burns, or gangrene. Therefore, experience with the use of linezolid in the treatment of such lesions is limited.
Excipients
Glucose
Each ml of solution contains 45.7 mg (i.e., 13.7 g/300 ml) of glucose. This should be taken into account in patients with diabetes mellitus or other conditions associated with glucose intolerance.
Sodium
Each ml of solution also contains 0.38 mg (114 mg/300 ml) of sodium, equivalent to 0.02% of the maximum recommended daily intake (RDI) from diet for an adult as defined by the WHO, corresponding to 2 g. The sodium content should be considered in patients on sodium-restricted diets.
Zyvoxid infusion solution may be further prepared for administration with sodium-containing solutions (see sections 4.2, 6.2, and 6.6), and this should be taken into account regarding the total amount of sodium from all sources to be administered to the patient.
Interactions
Monoamine oxidase inhibitors
Linezolid is a reversible, non-selective monoamine oxidase (MAO) inhibitor. Very limited data are available from pharmacological interaction studies and on the safety of linezolid administered to patients receiving concomitant medications that may pose a risk due to MAO inhibition. Therefore, the use of linezolid is not recommended in these circumstances unless close monitoring and careful surveillance of the recipient are possible.
Potential interactions causing increases in blood pressure
In healthy normotensive volunteers, linezolid potentiated the blood pressure increase induced by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid with pseudoephedrine and phenylpropanolamine resulted in mean increases in systolic blood pressure of 30–40 mmHg, compared to increases of 11–15 mmHg with linezolid alone, 14–18 mmHg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mmHg with placebo. Similar studies have not been conducted in hypertensive subjects. Careful titration of the dosage of vasopressor medications, including dopaminergic agents, is recommended to achieve the desired response when administered concomitantly with linezolid.
Potential serotonergic interactions
The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were treated with dextromethorphan (two 20 mg doses 4 hours apart), with or without linezolid. In normal subjects treated with linezolid and dextromethorphan, no effects of serotonin syndrome (confusion, delirium, restlessness, tremors, erythema, diaphoresis, and hyperthermia) were observed.
Post-marketing experience: one case report described a patient who developed symptoms suggestive of serotonin syndrome during concomitant use of linezolid and dextromethorphan, which resolved upon discontinuation of both treatments.
In clinical experience with concomitant use of linezolid and serotonergic drugs, including selective serotonin re-uptake inhibitors (SSRIs) and opioids, cases of serotonin syndrome have been reported. Concomitant administration is therefore contraindicated (see section 4.3 of the SmPC), but management of patients for whom treatment with linezolid and serotonergic drugs is essential is described in the section "Special warnings and precautions for use."
Use with tyramine-rich foods
Subjects treated with linezolid and less than 100 mg of tyramine did not exhibit any significant pressor response. This indicates that only excessive consumption of foods and beverages high in tyramine (e.g., aged cheese, yeast extracts, non-distilled alcoholic beverages, and fermented soy products such as soy sauce) should be avoided.
Drugs metabolised by cytochrome P450
Linezolid is not significantly metabolised by the cytochrome P450 (CYP) enzyme system and does not inhibit any of the clinically significant isoforms of human CYP (1A2, 2C9, 2C19, 2D6, 2E1, and 3A4). Similarly, linezolid does not induce P450 isoenzymes in rats. Therefore, no CYP450-mediated drug interactions with linezolid are expected.
Rifampicin
The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers who received linezolid 600 mg twice daily for 2.5 days with and without rifampicin 600 mg once daily for 8 days. Rifampicin reduced the Cmax and AUC of linezolid by a mean of 21% [90% CI, 15, 27] and 32% [90% CI, 27, 37], respectively. The mechanism of this interaction and its clinical significance are unknown.
Warfarin
When warfarin was co-administered with linezolid under steady-state conditions, a 10% reduction in mean maximum INR (International Normalized Ratio) was observed during concomitant administration, with a 5% reduction in INR AUC. The clinical significance of these findings, if any, cannot be determined due to insufficient data from patients treated with warfarin and linezolid.
Fertility, pregnancy and lactation
Pregnancy
Limited data are available on the use of linezolid in pregnant women. Animal studies have shown toxic effects on reproduction. A potential risk to humans exists.
Zyvoxid must not be used during pregnancy unless strictly necessary, i.e., only when the expected benefits outweigh the theoretical risk.
Lactation
Animal data indicate that linezolid and its metabolites may pass into breast milk; therefore, breastfeeding must be discontinued before and during administration.
Fertility
In animal studies, linezolid caused a reduction in fertility.
Effects on ability to drive and use machines
Patients should be informed of the potential occurrence of dizziness or visual impairment symptoms during treatment with Zyvoxid and should therefore be advised not to drive or operate machinery if any of these symptoms occur.
Undesirable effects
The table below lists adverse reactions by frequency based on all randomized data from clinical trials involving over 6,000 adult patients treated for up to 28 days with the recommended doses of linezolid. The most commonly reported were diarrhoea (8.9%), nausea (6.9%), vomiting (4.3%), and headache (4.2%).
The most commonly reported drug-related adverse events leading to treatment discontinuation were headache, diarrhoea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to a drug-related adverse event.
Additional adverse reactions reported during post-marketing experience are included in the table.
The following undesirable effects have been observed and reported during treatment with linezolid at the following frequencies: Very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).

* See section Special warnings and precautions for use
** See sections Contraindications and Interactions
Estimated ADR frequency using “The rule of 3”
† See information below
The following adverse reactions to linezolid have been considered severe in rare cases: localized
abdominal pain, transient ischaemic attacks and hypertension.
†In controlled clinical studies in which linezolid was administered for up to 28 days of
treatment, reported cases of anaemia were 2.0% of patients. During a compassionate use programme in patients with potentially fatal infections and concomitant underlying conditions, the percentage of patients who developed anaemia during treatment with
linezolid for ≤ 28 days was 2.5% (33/1,326), compared to 12.3% (53/430) in cases where
therapy lasted >28 days. The percentage of cases in which severe drug-related anaemia requiring blood transfusion was reported was 9% (3/33) in patients treated for ≤ 28
days and 15% (8/53) in those treated for >28 days.
Paediatric population
Safety data from clinical studies conducted in over 500 paediatric patients (from birth
up to 17 years) do not indicate that the safety profile of linezolid in paediatric patients
differs from that in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorisation is important, as it allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via
adverse.
Overdose
No specific antidote is known.
Cases of overdose have not been reported. The following information may nevertheless be
useful:
Supportive treatment is recommended, together with maintenance of glomerular filtration.
Approximately 30% of a dose of linezolid is removed during 3 hours of haemodialysis, but no data are available on the elimination of linezolid by peritoneal dialysis or haemoperfusion.
Instructions for use and handling
For single use only. Remove the overwrap only immediately before use, then check for leaks by firmly squeezing the bag. If leaks are present, discard the bag, as sterility may be compromised. The solution should be inspected visually prior to use and only clear solution free from particles should be used. Do not use these bags in series connections. Any unused solution must be discarded. Do not reconnect partially used bags.
Zyvoxid infusion solution is compatible with the following solutions: glucose 5% for intravenous infusion, sodium chloride 0.9% for intravenous infusion, Ringer lactate solution for injection (Hartmann's solution for injection).
Incompatibilities
No additives should be added to this solution. If linezolid is to be administered in combination with another medicinal product, each medicinal product must be administered separately in accordance with their respective instructions for use. Similarly, if the same intravenous line is used for sequential infusion of different medicinal products, the line must be flushed with a compatible infusion solution before and after administration of linezolid.
Zyvoxid infusion solution is physically incompatible with the following substances: amphotericin
B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, erythromycin lactobionate, sodium phenytoin and sulfamethoxazole/trimethoprim. In addition, it is chemically incompatible with ceftriaxone sodium.
Shelf life
Before opening: 3 years
After opening: From a microbiological standpoint, the product should be used immediately, except when in-use storage conditions preclude the risk of contamination. If not used immediately, the times and conditions of storage are the responsibility of the user.
Special precautions for storage
Store in the original packaging (overwrap and carton) until the time of use.

Package leaflet: information for the user

Zyvoxid 100 mg/5 ml granules for oral suspension

Linezolid
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

1. What Zyvoxid is and what it is used for
2. What you need to know before taking Zyvoxid
3. How to take Zyvoxid
4. Possible side effects
5. How to store Zyvoxid
6. Contents of the pack and other information

1. What Zyvoxid is and what it is used for

Zyvoxid is an antibiotic belonging to the oxazolidinone class, which works by inhibiting the growth of certain bacteria that cause infections. It is used to treat pneumonia and certain skin or soft tissue infections. Your doctor will decide whether Zyvoxid is suitable for treating your type of infection.

2. What you should know before taking Zyvoxid

Do not take Zyvoxid

• if you are allergic to linezolid or to 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 called monoamine oxidase inhibitors (MAOIs), for example phenelzine, isocarboxazid, selegiline, moclobemide. These are medicines generally used to treat depression or Parkinson’s disease;
• if you are breastfeeding. Zyvoxid passes into breast milk and may affect the baby.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Zyvoxid.
Zyvoxid may not be suitable for you if you answer yes to any of the following questions. In such cases, inform your doctor, who may need to monitor your general health and blood pressure before and during treatment, or who may decide that an alternative therapy is more appropriate for you.
Ask your doctor if you are unsure whether any of these conditions apply to you.

• Do you have high blood pressure, whether or not you are taking medication for this condition?
• Have you been diagnosed with hyperthyroidism (overactive thyroid)?
• Do you have a tumor of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumors of the hormonal system, with symptoms such as diarrhea, skin flushing, and wheezing)?
• Do you suffer from manic depression, schizoaffective disorder, mental confusion, or any other mental disorder?
• Do you have a history of hyponatremia (low sodium levels in the blood), or are you taking medicines that lower sodium levels in the blood, for example certain diuretics (also called “medicines that increase urine production”) such as hydrochlorothiazide?
• Are you taking opioids?

The use of certain medicines, including antidepressants and opioids, together with Zyvoxid may lead to the development of serotonin syndrome, a potentially life-threatening condition (see section 2 “Other medicines and Zyvoxid” and section 4).
Exercise particular caution with Zyvoxid
Inform your doctor before this medicine is administered to you if:

• you are elderly;
• you are prone to bruising or bleeding episodes;
• you are anemic (have low red blood cell count);
• you are prone to infections;
• you have a history of seizures;
• you have liver or kidney problems, especially if you are on dialysis;
• you have diarrhea.

Inform your doctor immediately if, during treatment, you experience:

• vision problems such as blurred vision, changes in color vision, difficulty seeing details, or narrowing of the visual field;
• loss of sensation in the arms or legs, or tingling or prickling sensations in the arms or legs;
• during or after antibiotic treatment, including treatment with Zyvoxid, you develop diarrhea. If diarrhea becomes severe or persistent, or if you notice blood or mucus in your stools, stop taking Zyvoxid immediately and contact your doctor. In such cases, do not take medicines that stop or slow down intestinal movements;
• nausea or recurrent vomiting, abdominal pain, or rapid breathing;
• unexplained muscle pain, tenderness, or weakness and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage;
• feeling unwell with muscle weakness, headache, confusion, and memory problems, which may indicate hyponatremia (low sodium levels in the blood).

Other medicines and Zyvoxid
There is a risk that Zyvoxid may sometimes interact with other medicines, causing unwanted effects such as changes in blood pressure, body temperature, or heart rate.
Inform your doctor or pharmacist if you are taking or have recently taken any other medicine.
Inform your doctor if you are taking or have taken within the last 2 weeks the following medicines, as Zyvoxid must not be taken if you are already taking these medicines or have recently taken them (see also the section 2 above “Do not take Zyvoxid”).

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

Also inform your doctor if you are taking any of the following medicines. Your doctor may still decide to prescribe Zyvoxid, but will need to monitor your general health and blood pressure before and during treatment. In other cases, your doctor may decide that another treatment is more suitable for you.

• Decongestants, cold or flu remedies containing pseudoephedrine or phenylpropanolamine;
• Certain medicines used to treat asthma, such as salbutamol, terbutaline, fenoterol;
• Certain antidepressants such as tricyclics or SSRIs (selective serotonin reuptake inhibitors). There are many, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline;
• Medicines used to treat migraine, such as sumatriptan and zolmitriptan;
• Medicines used to treat severe and sudden allergic reactions, such as adrenaline (epinephrine);
• Medicines that raise blood pressure, such as noradrenaline (norepinephrine), dopamine, and dobutamine;
• Opioids, for example meperidine, used to treat moderate to severe pain;
• Medicines used to treat anxiety disorders, such as buspirone;
• Medicines that prevent blood clotting, such as warfarin;
• An antibiotic called rifampicin.

Zyvoxid with food, drinks, and alcohol

• You may take Zyvoxid before, during, or after meals.
• Avoid eating large amounts of aged cheeses, yeast extracts or soybean products (e.g. soy sauce), and avoid drinking alcoholic beverages, especially draft beer and wine. This is because Zyvoxid can react with a substance called tyramine, which is naturally present in certain foods. This interaction may cause a rise in blood pressure.
• If you develop a throbbing headache after eating or drinking, inform your doctor, pharmacist, or nurse immediately.

Pregnancy, breastfeeding, and fertility
The effect of Zyvoxid in pregnant women is unknown. Therefore, this medicine should not be taken during pregnancy unless specifically prescribed by your doctor. If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
While taking Zyvoxid, you must not breastfeed, as the medicine passes into breast milk and may affect the baby.

Driving and using machines
Zyvoxid may cause mild dizziness or vision problems. If this occurs, do not drive or operate machinery. Remember that your ability to drive or operate machinery may be impaired if you do not feel well.

Zyvoxid contains

Aspartame
This medicine, in the suspension formulation, contains 210 mg of aspartame per dose, equivalent to 35 mg/5 ml. Aspartame is a source of phenylalanine. Phenylalanine may be harmful if you have phenylketonuria, a rare genetic disorder causing accumulation of phenylalanine due to the body’s inability to properly metabolize it.

Sucrose, sorbitol, mannitol, and fructose
This medicine contains sucrose, mannitol, sorbitol, and fructose.
This medicine, in the suspension formulation, contains up to 100.8 mg of fructose per dose, equivalent to 16.8 mg/5 ml.
This medicine, in the suspension formulation, contains up to 262.8 mg of sorbitol per dose, equivalent to 43.8 mg/5 ml. Sorbitol is a source of fructose.
If your doctor has informed you (or the child) that you have an intolerance to certain sugars, or if you have been diagnosed with hereditary fructose intolerance, a rare genetic disorder in which patients cannot metabolize fructose, speak with your doctor before taking this medicine.
Frequent or prolonged use (e.g. for 2 or more weeks) of fructose may damage teeth.
Due to its content of mannitol and sorbitol, the oral suspension may have a mild laxative effect.

Sodium
When reconstituted as a suspension, this medicine contains 68.43 mg of sodium (a main component of table salt) per dose, equivalent to 11.4 mg of sodium per 5 ml. The amount of sodium per dose is equivalent to 3.4% of the maximum daily sodium intake recommended in an adult diet. This should be taken into account in patients on a sodium-controlled diet.

Sodium benzoate
This medicine, in the suspension formulation, contains 60 mg of sodium benzoate per dose, equivalent to 10 mg/5 ml. Sodium benzoate may increase levels of a substance called bilirubin. High bilirubin levels may lead to jaundice (yellowing of the skin and eyes) and brain damage (encephalopathy) in newborns (up to 4 weeks of age).

Alcohol (ethanol)
This medicine, in the suspension formulation, contains no more than 6 mg of alcohol (ethanol) per dose, equivalent to 1 mg/5 ml (0.02% w/v). The amount of alcohol in each dose is equivalent to less than 0.15 ml of beer or 0.06 ml of wine.
The small amount of alcohol in this medicine will not produce any significant effects.

3. How to take Zyvoxid

Adults
Take this medicine exactly as stated in this leaflet or as instructed by your doctor, pharmacist, or nurse. If you have any doubts, consult your doctor, pharmacist, or nurse.
Zyvoxid is supplied as a granulate, which will be reconstituted exclusively by a healthcare professional into a ready-to-use suspension.
The recommended dose of Zyvoxid suspension is six 5 ml spoons (linezolid 600 mg) twice daily (every 12 hours).
Before use, gently invert the bottle several times. DO NOT SHAKE.
If you are undergoing renal dialysis, you must take Zyvoxid after dialysis.
A treatment course usually lasts from 10 to 14 days, but may last up to 28 days. The safety and efficacy of this medicine for periods longer than 28 days have not been established.
Your doctor will decide how long your treatment should last.
While taking Zyvoxid, your doctor should regularly perform blood tests to monitor your blood cell counts.
If you take Zyvoxid for longer than 28 days, your doctor should monitor your vision.

Use in children and adolescents
Zyvoxid is not normally used to treat children and adolescents (under 18 years of age).

If you take more Zyvoxid than you should
Inform your doctor or pharmacist immediately.

If you forget to take Zyvoxid
Take the missed dose as soon as you remember. Then take the next dose 12 hours after the missed dose, and continue taking the medicine every 12 hours. Do not take a double dose to make up for a forgotten dose.

If you stop taking Zyvoxid
Unless your doctor specifically tells you to stop treatment, it is important to continue taking Zyvoxid.
If you stop treatment and the original symptoms return, inform your doctor or pharmacist immediately.

If you have any questions about 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 everyone experiences them.
Immediately inform your doctor, nurse, or pharmacist if you notice any of the following side effects during treatment with Zyvoxid:
The serious side effects (with frequency indicated in parentheses) of Zyvoxid are:

• Severe skin reactions (uncommon), swelling, especially of the face and neck (uncommon), shortness of breath and/or difficulty breathing (rare). These may be signs of an allergic reaction, and treatment with Zyvoxid may need to be stopped. Skin reactions such as raised purple rash due to inflammation of blood vessels (rare), skin ulceration and peeling (dermatitis) (uncommon), rash (common), itching (common).
• Vision disorders (uncommon), such as blurred vision (uncommon), changes in colour vision (not known), difficulty seeing details (not known), or narrowing of the visual field (rare).
• Severe diarrhoea containing blood and/or mucus (antibiotic-associated colitis, including pseudomembranous colitis), which in rare cases may lead to life-threatening complications (uncommon).
• Recurrent nausea or vomiting, abdominal pain, or rapid breathing (rare).
• Seizures or convulsions have been reported with Zyvoxid (uncommon).
• Serotonin syndrome (not known): if you experience agitation, confusion, delirium, rigidity, tremor, lack of coordination, seizures, rapid heartbeat, severe breathing problems, or diarrhoea (suggestive of serotonin syndrome) while also taking antidepressant medicines called SSRIs or opioids (see section 2), you must inform your doctor.
  • Unexplained bleeding or bruising, probably due to changes in the number of certain blood cells that may affect blood clotting or lead to anaemia (common).
  • Changes in the number of certain blood cells that may affect the ability to fight infections (uncommon); some signs of infection include: fever (common), sore throat (uncommon), mouth ulcers (uncommon), and fatigue (uncommon).
  • Rhabdomyolysis (rare): signs and symptoms include unexplained muscle pain, tenderness or weakness, and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which may lead to kidney damage.
  • Inflammation of the pancreas (uncommon).
  • Convulsions (uncommon).
  • Transient ischaemic attacks (temporary disruption of blood flow to the brain causing short-term symptoms such as loss of vision, weakness in arms and legs, difficulty speaking, and loss of consciousness) (uncommon).
  • Ringing in the ears (tinnitus) (uncommon).

Numbness, tingling sensations, or blurred vision have been reported in patients who received Zyvoxid for more than 28 days. If you have vision problems, consult your doctor as soon as possible.
Other side effects include:
Common (may affect up to 1 in 10 people):

• Fungal infections, especially vaginal or oral candidiasis
• Headache
• Metallic taste in the mouth
• Diarrhoea, nausea, or vomiting
• Changes in certain blood test results, including values used to monitor proteins, salts, or enzymes measuring kidney or liver function, or blood sugar levels
• Difficulty sleeping
• Increased blood pressure
• Anaemia (low red blood cells)
• Dizziness
• Localised or general abdominal pain
• Constipation
• Indigestion
• Localised pain
• Reduced platelet count

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

• Inflammation of the vagina or genital area in women
• Sensations such as tingling or numbness
• Swelling, pain, or discolouration of the tongue
• Dry mouth
• Need to urinate more frequently
• Chills
• Thirst sensation
• Increased sweating
• Hyponatraemia (low sodium levels in the blood)
• Kidney failure
• Abdominal distension
• Increased creatinine
• Stomach discomfort
• Changes in heart rate (e.g. increased rate)
• Reduction in blood cell count
• Weakness and/or sensory disturbances

Rare (may affect up to 1 in 1,000 people):

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

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

• Alopecia (hair loss)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report side effects directly via the Italian Medicines Agency website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zyvoxid

Keep this medicine out of the sight and reach of children.
Store the bottle in the original packaging to protect it from light.
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.
Any unused reconstituted suspension must be discarded within 21 days of reconstitution.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures will help protect the environment.

6. Package contents and other information

What Zyvoxid contains

• The active substance in this medicine is linezolid. After reconstitution, 5 ml of suspension contains 100 mg of linezolid.
• The other components are sucrose, mannitol, microcrystalline cellulose (E460), sodium carmellose (E466), aspartame, anhydrous colloidal silica (E 551), sodium citrate, xanthan gum, sodium benzoate, anhydrous citric acid, sodium chloride, ethanol, and sweeteners (fructose, maltodextrin (maize-derived), monoammonium glycyrrhizinate, sorbitol). The flavourings are orange flavour, peppermint flavour, vanilla flavour, and orange cream flavour (see section 2 “Zyvoxid contains aspartame; sucrose, sorbitol, mannitol and fructose; sodium; sodium benzoate and alcohol (ethanol)”).

Description of the appearance of Zyvoxid and contents of the pack
Zyvoxid granules for oral suspension are supplied in an amber glass bottle containing granules/powder ranging in colour from white to orange-yellow, which may contain lumps ranging in colour from white to orange-yellow or from white to orange-yellow-brown. The reconstituted orange-flavoured liquid (suspension) appears white to orange-yellow after reconstitution with water. Each bottle is packaged in a box together with a 2.5 ml/5 ml dosing spoon.
Marketing Authorisation Holder
Pfizer Italia S.r.l. - Via Isonzo, 71 - 04100 Latina
Manufacturer
Pfizer Service Company BV, Hoge Wei 10, 1930 Zaventem, Belgium
This medicinal product is authorised in the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:
Austria Zyvoxid
Belgium Zyvoxid
Cyprus Zyvoxid
Czech Republic Zyvoxid
Denmark Zyvoxid
Estonia Zyvoxid
Finland Zyvoxid
France Zyvoxid
Germany Zyvoxid
Greece Zyvoxid
Iceland Zyvoxid
Ireland Zyvox
Italy Zyvoxid
Latvia Zyvoxid
Lithuania Zyvoxid
Luxembourg Zyvoxid
Malta Zyvox
Netherlands Zyvoxid
Norway Zyvoxid
Poland Zyvoxid
Portugal Zyvoxid
Slovakia Zyvoxid
Slovenia Zyvoxid
Spain Zyvoxid
Sweden Zyvoxid
United Kingdom (Northern Ireland) Zyvox
The following information is intended exclusively for physicians or healthcare professionals:
Instructions for preparation of the oral suspension:
Linezolid is supplied as granules, which must be reconstituted exclusively by a healthcare professional.
Dissolve the granules and reconstitute with 123 ml of water in two approximately equal portions to obtain 150 ml of oral suspension. The suspension must be shaken vigorously between each addition of water. The appearance after reconstitution is a white to orange-yellow suspension.
Before use, gently invert the bottle several times. DO NOT SHAKE.
The usual dose of Zyvoxid suspension is six 5 ml spoons (600 mg of linezolid) twice daily (every 12 hours).
Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.
See also section 3 above “How to take Zyvoxid”.

Package leaflet: Information for the user

Zyvoxid 600 mg film-coated tablets

Linezolid
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Zyvoxid is and what it is used for
2. What you need to know before taking Zyvoxid
3. How to take Zyvoxid
4. Possible side effects
5. How to store Zyvoxid
6. Contents of the pack and other information

1. What Zyvoxid is and what it is used for

Zyvoxid is an antibiotic belonging to the oxazolidinone class, which works by inhibiting the growth of certain bacteria causing infections. It is used to treat pneumonia and certain skin or soft tissue infections. Your doctor will decide whether Zyvoxid is appropriate for treating your type of infection.

2. What you need to know before taking Zyvoxid

Do not take Zyvoxid

• if you are allergic to linezolid or to 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 called monoamine oxidase inhibitors (MAOIs), for example phenelzine, isocarboxazid, selegiline, moclobemide. These are medicines generally used to treat depression or Parkinson’s disease;
• if you are breastfeeding. Zyvoxid passes into breast milk and may affect the baby.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Zyvoxid.
Zyvoxid may not be suitable for you if you answer yes to any of the following questions. In such cases,
inform your doctor, who may need to monitor your general health and blood pressure before and
during treatment, or who may decide that an alternative therapy is more appropriate for you.
Ask your doctor if you are unsure whether any of the following conditions apply to you.

• Do you have high blood pressure, whether or not you are taking medication for it?
• Have you been diagnosed with hyperthyroidism (overactive thyroid)?
• Do you have a tumour of the adrenal glands (pheochromocytoma) or carcinoid syndrome (caused by tumours of the hormonal system, with symptoms such as diarrhoea, skin flushing, and wheezing)?
• Do you suffer from manic depression, schizoaffective disorder, mental confusion, or any other mental disorder?
• Do you have a history of hyponatraemia (low sodium levels in the blood), or are you taking medicines that lower sodium levels in the blood, such as certain diuretics (also known as “medicines that increase urine production”), for example hydrochlorothiazide?
• Are you taking opioids?

The use of certain medicines, including antidepressants and opioids, together with Zyvoxid may lead to the
development of serotonin syndrome, a potentially life-threatening condition (see section 2
“Other medicines and Zyvoxid” and section 4).
Take special care with Zyvoxid
Inform your doctor before taking this medicine if:

• you are elderly
• you are prone to bruising or episodes of bleeding
• you are anaemic (have low red blood cell count)
• you are susceptible to infections
• you have a history of seizures
• you have liver or kidney problems, especially if you are on dialysis
• you have diarrhoea

Inform your doctor immediately if, during treatment, you experience:

• vision problems such as blurred vision, changes in colour vision, difficulty seeing details, or narrowing of the visual field.
• loss of sensation in arms or legs, or tingling or prickling sensations in arms or legs.
• during or after antibiotic treatment, including Zyvoxid, you may develop diarrhoea. If diarrhoea becomes severe or persistent, or if you notice blood or mucus in your stools, stop taking Zyvoxid immediately and contact your doctor. In such cases, do not take medicines that stop or slow down intestinal movements.
• recurrent nausea or vomiting, abdominal pain, or rapid breathing.
• unexplained muscle pain, tenderness or weakness and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage.
• feeling unwell with muscle weakness, headache, confusion, and memory problems, which may indicate hyponatraemia (low sodium levels in the blood).

Other medicines and Zyvoxid
There is a risk that Zyvoxid may sometimes interact with other medicines, causing unwanted effects
such as changes in blood pressure, body temperature, or heart rate.
Tell your doctor or pharmacist if you are taking or have recently taken any other
medicine.
Inform your doctor if you are taking or have taken within the last 2 weeks the following
medicines, as Zyvoxid must not be taken if you are already taking these medicines or have recently taken them (see also section 2 above “Do not take Zyvoxid”).

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

Also inform your doctor if you are taking any of the following medicines. Your doctor may still decide to
prescribe Zyvoxid, but will need to monitor your general health and blood pressure before and during treatment. In other cases, your doctor may decide that another treatment is better for you.

• Decongestants, cold or flu remedies containing pseudoephedrine or phenylpropanolamine.
• Certain medicines used to treat asthma, such as salbutamol, terbutaline, fenoterol.
• Certain antidepressants such as tricyclics or SSRIs (selective serotonin reuptake inhibitors). There are many, including amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine, imipramine, lofepramine, paroxetine, sertraline.
• Medicines used to treat migraine, such as sumatriptan and zolmitriptan.
• Medicines used to treat severe, sudden allergic reactions, such as adrenaline (epinephrine).
• Medicines that raise blood pressure, such as noradrenaline (norepinephrine), dopamine, and dobutamine.
• Opioids, for example meperidine (pethidine), used to treat moderate to severe pain.
• Medicines used to treat anxiety disorders, such as buspirone.
• Medicines that prevent blood clotting, such as warfarin.
• An antibiotic called rifampicin.

Zyvoxid with food, drinks, and alcohol

• You may take Zyvoxid before, during, or after meals.
• Avoid eating large amounts of aged cheeses, yeast extracts, or soybean products (e.g. soy sauce), and avoid drinking alcohol, especially draught beer and wine. This is because Zyvoxid can react with a substance called tyramine, naturally present in certain foods. This interaction may cause a rise in blood pressure.
• If you develop a throbbing headache after eating or drinking, inform your doctor, pharmacist, or nurse immediately.

Pregnancy, breastfeeding, and fertility
The effect of Zyvoxid in pregnant women is unknown. Therefore, this medicine should not be taken during pregnancy unless specifically prescribed by your doctor. If you are pregnant, think you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
While taking Zyvoxid, you must not breastfeed, as the medicine passes into breast milk and may affect the baby.
Driving and using machines
Zyvoxid may cause mild dizziness or vision problems. If this occurs, do not drive or operate machinery. Remember that your ability to drive or operate machinery may be impaired if you do not feel well.
Zyvoxid contains sodium
Zyvoxid contains less than 1 mmol (23 mg) of sodium per 600 mg tablet, i.e. it is essentially “sodium-free”.

3. How to take Zyvoxid

Adults
Always take this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has told you. If you are unsure, consult your doctor, pharmacist or nurse.
The recommended dose is one film-coated tablet (linezolid 600 mg) twice daily (every 12 hours). Swallow the film-coated tablet whole with some water.
If you are undergoing renal dialysis, you must take Zyvoxid after dialysis.
A treatment course usually lasts from 10 to 14 days, but may last up to 28 days. The safety and efficacy of this medicine for periods longer than 28 days have not been established.
Your doctor will decide how long your treatment should last.
While you are taking Zyvoxid, your doctor should regularly perform blood tests to monitor your blood cell counts.
If you take Zyvoxid for longer than 28 days, your doctor should monitor your vision.

Use in children and adolescents
Zyvoxid is not normally used to treat children and adolescents (under 18 years of age).

If you take more Zyvoxid than you should
Inform your doctor or pharmacist immediately.

If you forget to take Zyvoxid
Take the missed tablet as soon as you remember. Then take the next film-coated tablet 12 hours after the missed dose, and continue taking the tablets every 12 hours. Do not take a double dose to make up for the forgotten tablet.

If you stop taking Zyvoxid
Unless your doctor specifically tells you to stop treatment, it is important to continue taking Zyvoxid.
If you stop treatment and the original symptoms return, inform your doctor or pharmacist immediately.

If you have any questions about how to use this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Immediately inform your doctor, nurse or pharmacist if you notice any of the following side effects during treatment with Zyvoxid:
The serious side effects (with frequency indicated in brackets) of Zyvoxid are:

• Severe skin reactions (uncommon), swelling, especially of the face and neck (uncommon), breathlessness and/or difficulty breathing (rare). These may be signs of an allergic reaction and treatment with Zyvoxid may need to be stopped. Skin reactions such as raised purple rash due to inflammation of blood vessels (rare), skin ulceration and peeling (dermatitis) (uncommon), rash (common), itching (common).

• Vision disorders (uncommon), such as blurred vision (uncommon), changes in colour vision (not known), difficulty seeing details (not known), or narrowing of the visual field (rare).

• Severe diarrhoea containing blood and/or mucus (antibiotic-associated colitis, including pseudomembranous colitis), which in rare cases may lead to life-threatening complications (uncommon).

• Recurrent nausea or vomiting, abdominal pain or rapid breathing (rare).

• Seizures or convulsions have been reported with Zyvoxid (uncommon).

• Serotonin syndrome (not known): if you experience agitation, confusion, delirium, muscle rigidity, tremor, lack of coordination, convulsions, rapid heartbeat, severe breathing problems or diarrhoea (suggestive of serotonin syndrome) while taking antidepressant medicines called SSRIs or opioids (see section 2), you must inform your doctor.

• Unexplained bleeding or bruising, possibly due to changes in the number of certain blood cells which may affect blood clotting or lead to anaemia (common).

• Changes in the number of certain blood cells which may affect the ability to fight infections (uncommon); some signs of infection include: fever (common), sore throat (uncommon), mouth ulcers (uncommon) and fatigue (uncommon).

• Rhabdomyolysis (rare): signs and symptoms include unexplained muscle pain, tenderness or weakness and/or dark urine. These may be signs of a serious condition called rhabdomyolysis (muscle breakdown), which can lead to kidney damage.

• Inflammation of the pancreas (uncommon).

• Convulsions (uncommon).

• Transient ischaemic attacks (temporary disruption of blood flow to the brain causing short-lived symptoms such as loss of vision, weakness in arms and legs, difficulty speaking and loss of consciousness) (uncommon).

• Ringing in the ears (tinnitus) (uncommon).

Numbness, tingling sensations or blurred vision have been reported in patients treated with Zyvoxid for more than 28 days. If you have any vision problems, consult your doctor as soon as possible.

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

• Fungal infections, especially vaginal or oral candidiasis
• Headache
• Metallic taste in the mouth
• Diarrhoea, nausea or vomiting
• Changes in certain blood test results, including values used to monitor proteins, salts or enzymes measuring kidney or liver function, or blood sugar levels
• Difficulty sleeping
• Increased blood pressure
• Anaemia (low red blood cells)
• Dizziness
• Localised or general abdominal pain
• Constipation
• Indigestion
• Localised pain
• Reduced platelet count

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

• Inflammation of the vagina or genital area in women
• Sensations such as tingling or numbness
• Swelling, pain or discolouration of the tongue
• Dry mouth
• Need to urinate more frequently
• Chills
• Thirst
• Increased sweating
• Hyponatraemia (low sodium levels in the blood)
• Kidney failure
• Abdominal distension
• Increased creatinine
• Stomach discomfort
• Changes in heart rate (e.g. increased heart rate)
• Reduced number of blood cells
• Weakness and/or sensory disturbances

Rare (may affect up to 1 in 1,000 people):

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

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

• Alopecia (hair loss)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report side effects directly via the Italian Medicines Agency website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Zyvoxid

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the pack or blister after "EXP". The expiry date refers to the last day of that month. This medicine does not require any special storage conditions.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Zyvoxid contains

• The active substance in this medicine is called linezolid. Each film-coated tablet contains 600 mg of linezolid.
• The other ingredients are corn starch (derived from maize), microcrystalline cellulose (E 460), hydroxypropylcellulose (E 463), sodium carboxymethylstarch (type A) (see section 2 “Zyvoxid contains sodium”), and magnesium stearate (E 572). The film coating contains: hypromellose (E 464), titanium dioxide (E 171), macrogol 400, and carnauba wax (E 903).

Description of the appearance of Zyvoxid and package contents
Zyvoxid 600 mg film-coated tablets are oval-shaped, white tablets, with the code
“ZYV” engraved on one side and “600” on the other.
Zyvoxid film-coated tablets are available in blisters of 10 tablets packed in a
carton. Each carton contains 10, 20, 30, 50, 60 or 100 film-coated tablets. It is also available in white HDPE bottles with a polypropylene screw cap containing 10, 14, 20, 24,
30, 50, 60 or 100 (for hospital use only) film-coated tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Pfizer Italia S.r.l. – Via Isonzo 71, 04100 Latina, Italy
Manufacturer
Pfizer Service Company BVBA, Hoge Wei 10, 1930 Zaventem, Belgium
or
Pfizer Manufacturing Deutschland GmbH, Betriebsstätte Freiburg, Mooswaldallee 1, D-79090 Freiburg,
Germany
This medicinal product is authorised in the European Economic Area and in the United Kingdom (Northern Ireland)
under the following names:
Austria Zyvoxid
Belgium Zyvoxid
Cyprus Zyvoxid
Czech Republic Zyvoxid
Denmark Zyvoxid
Estonia Zyvoxid
Finland Zyvoxid
France Zyvoxid
Germany Zyvoxid
Greece Zyvoxid
Iceland Zyvoxid
Ireland Zyvox
Italy Zyvoxid
Latvia Zyvoxid
Lithuania Zyvoxid
Luxembourg Zyvoxid
Malta Zyvox
Netherlands Zyvoxid
Norway Zyvoxid
Poland Zyvoxid
Portugal Zyvoxid
Slovakia Zyvoxid
Slovenia Zyvoxid
Spain Zyvoxid
Sweden Zyvoxid
United Kingdom (Northern Ireland) Zyvox