EVOXIL 5 MG / ML SOLUTION FOR INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Evoxil 5 mg/mL solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution for infusion contains 5 mg of levofloxacin (as hemihydrate). Each 50 mL vial of solution for infusion contains 250 mg of levofloxacin (as hemihydrate).

Each 100 mL vial of solution for infusion contains 500 mg of levofloxacin (as hemihydrate).

Excipients with known effect:

Each ml of solution for infusion contains 0.15 mmol (3.54 mg) sodium (as chloride) 50 mL of solution for infusion contains 7.70 mmol (177.10 mg) sodium (as chloride) 100 mL of solution for infusion contains 15.40 mmol (354.20 mg) sodium (as chloride)

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for infusion.

A clear greenish-yellow solution, free from foreign particles.

pH: 4.5 – 5.1

Osmolality: 290 mOsmol/Kg ± 5%

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Evoxil solution for infusion is indicated in adults for the treatment of the following infections (see sections 4.4 and 5.1):

Community-acquired pneumonia

Complicated skin and soft tissue infections

For the above-mentioned infections Evoxil should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections.

Acute pyelonephritis and complicated urinary tract infections (see section 4.4)

Chronic bacterial prostatitis

Inhalation Anthrax: post-exposure prophylaxis and curative treatment (see section 4.4)

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Evoxil solution for infusion is administered by slow intravenous infusion once or twice daily. The dose depends on the type and severity of the infection and the susceptibility of the presumed causative pathogen. Treatment with Evoxil after initial use of the intravenous preparation may be completed with an appropriate oral presentation according to the SPC for the film-coated tablets and as considered appropriate for the individual patient. Given the bioequivalence of the parenteral and oral forms, the same dose can be used.

Posology

The following dose recommendations can be given for Evoxil:

Dose in patients with normal renal function (creatinine clearance > 50 mL/min)

1Treatment duration includes intravenous plus oral treatment. The time to switch from intravenous to oral

treatment depends on the clinical situation but is normally 2 to 4 days.

Special populations

Impaired renal function (creatinine clearance < 50 mL/min)

1 No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

Impaired liver function

No adjustment of dose is required since levofloxacin is not metabolised to any relevant extent by the liver and is mainly excreted by the kidneys.

Elderly population

No adjustment of dose is required in the elderly, other than that imposed by consideration of renal function (see section 4.4 „Tendinitis and tendon rupture“ and „QT interval prolongation“).

Paediatric population

Levofloxacin is contraindicated in children and growing adolescents (see section 4.3).

Method of administration

Evoxil solution for infusion is only intended for slow intravenous infusion; it is administered once or twice daily. The infusion time must be at least 30 minutes for 250 mg or 60 minutes for 500 mg Evoxil solution for infusion (see section 4.4).

For incompatibilities, see section 6.2 and compatibility with other infusion solutions, see section 6.6.

4.3 Contraindications

Evoxil solution for infusion must not be used:

in patients hypersensitive to the active substance, any other quinolones or to any of the excipients listed in section 6.1,

in patients with epilepsy,

in patients with history of tendon disorders related to fluoroquinolone administration,

in children or growing adolescents (up to age of 18),

during pregnancy,

in breast-feeding women.

4.4 Special warnings and precautions for use

The use of Evoxil should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolones containing products (see section 4.8). Treatment of these patients with Evoxil should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3)

Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to levofloxacin (and commonly recommended antibacterial agents for the treatment of MRSA-infections are considered inappropriate).

Resistance to fluoroquinolones of E. coli – the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.

Inhalation Anthrax: Use in humans is based on in vitro Bacillus anthracis susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.

Infusion time

The recommended infusion time of at least 30 minutes for 250 mg or 60 minutes for 500 mg Evoxil solution for infusion should be observed. It is known for ofloxacin that during infusion tachycardia and a temporary decrease in blood pressure may develop. In rare cases, as a consequence of a profound drop in blood pressure, circulatory collapse may occur. Should a conspicuous drop in blood pressure occur during infusion of levofloxacin, (l-isomer of ofloxacin) the infusion must be halted immediately.

Prolonged, disabling and potentially irreversible serious adverse drug reactions

Very rare cases of prolonged (continuing months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and preexisting risk factors. Evoxil should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (especially but not limited to Achilles tendon). sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, in patients receiving daily doses of 1,000 mg of levofloxacin and those treated concurrently with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided. The daily dose should be adjusted in elderly patients based on creatinine clearance (see section 4.2). Close monitoring of these patients is therefore necessary if they are prescribed levofloxacin. At the first sign of tendinitis (e.g. painful swelling, inflammation) the treatment with Evoxil should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g. immobilisation). Corticosteroids should not be used if signs of tendinopathy occur.

Clostridium difficile -associated disease

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with levofloxacin (including several weeks after treatment), may be symptomatic of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life-threatening, the most severe form of which is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with levofloxacin. If CDAD is suspected or confirmed, levofloxacin should be stopped immediately and appropriate treatment initiated without delay. Anti-peristaltic medicinal products are contraindicated in this clinical situation.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and may trigger seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section 4.3) and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures or concomitant treatment with active substances that lower the cerebral seizure threshold, such as theophylline (see section 4.5). In case of convulsive seizures (see section 4.8), treatment with levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity may be prone to haemolytic reactions when treated with quinolone antibacterial agents. Therefore, if levofloxacin has to be used in these patients, potential occurrence of haemolysis should be monitored.

Patients with renal impairment

Since levofloxacin is excreted mainly by the kidneys, the dose of levofloxacin should be adjusted in patients with renal impairment (see section 4.2).

Hypersensitivity reactions

Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema up to anaphylactic shock), occasionally following the initial dose (see section 4.8). Patients should discontinue treatment immediately and contact their physician or an emergency physician, who will initiate appropriate emergency measures.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN: also known as Lyell's syndrome), Stevens Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with levofloxacin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. If signs and symptoms suggestive of these reactions appear, levofloxacin should be discontinued immediately and an alternative treatment should be considered. If the patient has developed a serious reaction such as SJS, TEN or DRESS with the use of levofloxacin, treatment with levofloxacin must not be restarted in this patient at any time.

Dysglycaemia

As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g. glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).

Prevention of photosensitisation

Photosensitisation has been reported with levofloxacin (see section 4.8). It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp, solarium), during treatment and for 48

hours following treatment discontinuation in order to prevent photosensitisation.

Patients treated with Vitamin K antagonists

Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these medicinal products are given concomitantly (see section 4.5).

Psychotic reactions

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare cases these have progressed to suicidal thoughts and selfendangering behaviour – sometimes after only a single dose of levofloxacin (see section 4.8). In the event that the patient develops these reactions, levofloxacin should be discontinued and appropriate measures instituted. Caution is recommended if levofloxacin is to be used in psychotic patients or in patients with history of psychiatric disease.

Aortic aneurysm and dissection, and heart valve regurgitation/in­competence

Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/in­competence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.8).

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease or congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection or heart valve disease, or in presence of other risk factors or conditions predisposing

> for both aortic aneurysm and dissection and heart valve regurgitation/in­competence (e.g. connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behcet’s disease, hypertension, rheumatoid arthritis) or additionally

> for aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjogren’s syndrome) or additionally

> for heart valve regurgitation/in­competence (e.g. infective endocarditis).

The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.

In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Patients should be advised to seek immediate medical attention in case of acute dyspnoea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities.

QT interval prolongation

Caution should be taken when using fluoroquinolones, including levofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example: – congenital long QT syndrome

– concomitant use of medicinal products that are known to prolong the QT interval (e.g.

Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)

– uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesemia)

– cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)

Elderly patients and women may be more sensitive to QTc-prolonging medicinal products. Therefore, caution should be taken when using fluoroquinolones, including levofloxacin, in these populations.

(See sections 4.2 “Elderly population”, 4.5, 4.8 and 4.9).

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with Evoxil should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially irreversible condition. (see section 4.8)

Hepatobiliary disorders

Cases of hepatic necrosis up to fatal hepatic failure have been reported with levofloxacin, primarily in patients with severe underlying diseases, e.g. sepsis (see section 4.8). Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post-marketing serious adverse reactions, including deaths and the requirement for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended in patients with a known history of myasthenia gravis.

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).

Superinfection

The use of levofloxacin, especially if prolonged, may result in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Interference with laboratory test

In patients treated with levofloxacin, determination of opiates in urine may give falsepositive results. It may be necessary to confirm positive opiate screens by more specific method.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and, therefore, may give false-negative results in the bacteriological diagnosis of tuberculosis.

Sodium content

This medicinal product contains 177.10 mg sodium per 250 mg dose and 354.20 mg sodium per 500 mg dose, equivalent to 8.85 % and 17.71 % of the WHO recommended maximum daily intake for sodium, respectively.

The maximum daily dose of this product is equivalent to 35.42 % of the WHO recommended maximum daily intake for sodium.

Evoxil is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on levofloxacin

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs

No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. However, a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs, or other agents which lower the seizure threshold.

Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone.

Probenecid and cimetidine

Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). This is because both medicinal products are capable of blocking the renal tubular secretion of levofloxacin. However, at the tested doses in the study, the statistically significant kinetic differences are unlikely to be of clinical relevance.

Caution should be exercised when levofloxacin is coadministered with medicinal products that affect the tubular renal secretion such as probenecid and cimetidine, especially in renally impaired patients.

Other relevant information

Clinical pharmacology studies have shown that the pharmacokinetics of levofloxacin were not affected to any clinically relevant extent when levofloxacin was administered together with the following medicinal products: calcium carbonate, digoxin, glibenclamide, ranitidine.

Effect of levofloxacin on other medicinal products

Ciclosporin

The half-life of ciclosporin was increased by 33% when coadministered with levofloxacin.

Vitamin K antagonists

Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin). Coagulation tests, therefore, should be monitored in patients treated with vitamin K antagonists (see section 4.4).

Medicinal products known to prolong QT interval

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4 “QT interval prolongation”).

Other relevant information

In a pharmacokinetic interaction study, levofloxacin did not affect the pharmacokinetics of theophylline (which is a probe substrate for CYP1A2), indicating that levofloxacin is not a CYP1A2 inhibitor.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited amount of data from the use of levofloxacin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). However, in the absence of human data and due to that experimental data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in pregnant women (see section 4.2 and 5.3).

Breast-feeding

The product is contraindicated in breast-feeding women. There is insufficient information on the excretion of levofloxacin in human milk; however other fluoroquinolones are excreted in breast milk. In the absence of human data and due to the experimental data suggests risk of damage by fluoroquinolones to the weightbearing cartilage of the growing organism, levofloxacin must not be used in breastfeeding women (see sections 4.3 and 5.3).

Fertility

Levofloxacin caused no impairment of fertility or reproductive performance in rats.

4.7 Effects on ability to drive and use machines

Some undesirable effects (e.g. dizziness/vertigo, drowsiness, visual disturbances) may impair the patient’s ability to concentrate and react, and therefore may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

4.8 Undesirable effects

The information given below is based on data from clinical studies in more than 8,300 patients and on extensive post-marketing experience.

Frequencies in this table are defined using the following convention:

Very common (>1/10) Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100) Rare (>1/10,000

to <1/1,000) Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

a Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose. b Mucocutaneous reactions may sometimes occur even after the first dose.

*Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors (see section 4.4) ** Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/in­competence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.4).

Other undesirable effects which have been associated with fluoroquinolone administration include:

attacks of porphyria in patients with porphyria.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can

help provide more information on the safety of this medicine.

4.9 Overdose

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Hydrochloric acid 5N (for pH adjustment)

Water for injection

6.2 Incompatibilities

Evoxil solution for infusion must not be mixed with heparin or alkaline solutions (e.g. sodium bicarbonate).

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

3 years

Shelf life after removal of the outer packaging:   3 days (under indoor light

conditions)

Shelf life after perforation of the rubber stopper: immediate use (see section 6.6)

After first opening:

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Keep the container in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

50 mL, type I transparent glass vial sealed with bromobutyl rubber stopper and an aluminium cap. Each vial contains 50 mL solution. Packs of 1 and 5 and 20 vials are available.

100 mL, type I transparent glass vial sealed with bromobutyl rubber stopper and an aluminium cap. Each vial contains 100 mL solution. Packs of 1, 5 and 20 vials are available.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

For single use only. Discard any unused solution.

The product should be inspected visually for particles and discoloration prior to administration. Only clear, greenish-yellow solution, free from particles must be used.

Evoxil solution for infusion should be used immediately (within 3 hours) after perforation of the rubber stopper in order to prevent any bacterial contamination. No protection from light is necessary during the infusion.

Mixture with other solutions for infusion

Evoxil solution for infusion is compatible with the following solutions for infusion: 0.9% sodium chloride solution

5% dextrose injection

2.5% dextrose in Ringer’s solution

Combination solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes)

Chemical and physical compatibility of Evoxil solution for infusion with the above solutions have been demonstrated for 4 hours at room conditions.

See section 6.2 for incompatibilities.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.