Levofloxacin 5mg/ml Solution for infusion,

Each ml of solution for infusion contains 5 mg levofloxacin (as 5.12 mg of levofloxacin hemihydrate).

100 ml of solution for infusion contains 500 mg of levofloxacin as levofloxacin hemihydrate

Excipient(s) with known effect:

This medicinal product contains 354 mg sodium per 100 ml of solution of infusion, equivalent to 17.7 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

For the full list of excipients, see section 6.1.

Solution for infusion

Levofloxacin 5 mg/ml Solution for infusion is a clear yellow to greenish-yellow solution with pH ranging from 3.80 to 5.80 and osmolality ranging from 270 to 340 mOsmol/kg

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

• 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).

In the below mentioned indications levofloxacin should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.

• Community-acquired pneumonia.

• Complicated skin and soft tissue infections

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

Levofloxacin solution for infusion is administered by slow intravenous infusion once or twice daily. The dosage depends on the type and severity of the infection and the susceptibility of the presumed causative pathogen. Treatment with Levofloxacin 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 dosage can be used.

Posology

The following dose recommendations can be given for levofloxacin

Special populations

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

Levofloxacin 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 levofloxacin solution for infusion (see section 4.4).

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

• Hypersensitivity to the active substance, any other quinolone and to any of the excipients listed in section 6.1,

• Patients with epilepsy,

• Patients with history of tendon disorders related to fluoroquinolone administration,

• Children or growing adolescents (up to age of 18),

• During pregnancy,

• Breast-feeding women.

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

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 pre-existing risk factors. Levofloxacin 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.

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 Levofloxacin 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.

Sodium content

This medicinal product contains 7.6 mmol (177 mg) sodium per 50 ml dose and 15.4 mmol (354 mg) per 100 ml dose. To be taken into consideration by patients on a controlled sodium diet.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as 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, patients receiving daily doses of 1000 mg, and those treated concurrently with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

At the first sign of tendinitis (e.g. painful swelling, inflammation) the treatment with levofloxacin 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 G-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 solution for infusion 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 photosensitization

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 drugs are given concomittantly (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 self-endangering 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.

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 drugs that are known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics).

- uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia)

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

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

(See section 4.2 Elderly, 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 levofloxacin 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 life threatening 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. Postmarketing 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 false-positive 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.

Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.

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 in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet's disease, hypertension, known atherosclerosis).

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

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 drugs 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 drugs 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 drugs: 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)

Drugs known to prolong QT interval

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs 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.

Pregnancy

There are 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 sections 4.3 and 5.3).

Breast-feeding

Levofloxacin 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 these 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 breast-feeding women (see sections 4.3 and 5.3).

Fertility

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

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).

The information given below is based on data from clinical studies in more than 5000 patients and on extensive post marketing experience.

Frequencies in this table are defined using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), 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).

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

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

According to toxicity studies in animals or clinical pharmacology studies performed with supra-therapeutic doses, the most important signs to be expected following acute overdosage of Levofloxacin Solution for infusion are central nervous system symptoms such as confusion, dizziness, impairment of consciousness, and convulsive seizures, increases in QT interval.

CNS effects including confusional state, convulsion, hallucination, and tremor have been observed in post marketing experience..

In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in removing levofloxacin from the body. No specific antidote exists.

Pharmacotherapeutic group: - Quinolone antibacterials - Fluoroquinolones

ATC code: J01MA12

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-) enantiomer of the racemic drug substance ofloxacin.

Mechanism of action

As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA-gyrase complex and topoisomerase IV.

PK/PD relationship

The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum concentration in serum (Cmax) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).

Mechanism of resistance

The main mechanism of resistance is due to a gyr-A mutation. In vitro there is a cross-resistance between levofloxacin and other fluoroquinolones.

Due to the mechanism of action, there is generally no cross-resistance between levofloxacin and other classes of antibacterial agents.

Breakpoints

The EUCAST recommended MIC breakpoints for levofloxacin, separating susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms are presented in the below table for MIC testing (mg/L).

EUCAST clinical MIC breakpoints for levofloxacin (2009-04-07):

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable

Absorption

Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma concentrations being obtained within 1-2h. The absolute bioavailability is 99-100 %.

Food has little effect on the absorption of levofloxacin.

Distribution

Approximately 30 - 40 % of levofloxacin is bound to serum protein. The mean volume of distribution of levofloxacin is approximately 100 l after single and repeated 500 mg doses, indicating widespread distribution into body tissues.

Penetration into tissues and body fluids:

Levofloxacin has been shown to penetrate into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostatic tissue and urine. However, levofloxacin has poor penetration intro cerebro-spinal fluid.

Biotransformation

Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for < 5 % of the dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

Following oral and intravenous administration of levofloxacin, it is eliminated relatively slowly from the plasma (t_½: 6 - 8 h). Excretion is primarily by the renal route (> 85 % of the administered dose).

There are no major differences in the pharmacokinetics of levofloxacin following intravenous and oral administration, suggesting that the oral and intravenous routes are interchangeable.

Linearity

Levofloxacin obeys linear pharmacokinetics over a range of 50 to 1000 mg.

Special populations

Subjects with renal insufficiency

The pharmacokinetics of levofloxacin are affected by renal impairment. With decreasing renal function renal elimination and clearance are decreased, and elimination half-lives increased as shown in the table below:

Elderly subjects

There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects, except those associated with differences in creatinine clearance.

Gender differences

Separate analysis for male and female subjects showed small to marginal gender differences in levofloxacin pharmacokinetics. There is no evidence that these gender differences are of clinical relevance.

Non-clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential and toxicity to reproduction and development.

Levofloxacin caused no impairment of fertility or reproductive performance in rats and its only effect on fetuses was delayed maturation as a result of maternal toxicity.

Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did induce chromosome aberrations in Chinese hamster lung cells in vitro. These effects can be attributed to inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid exchange, unscheduled DNA synthesis, dominant lethal tests) did not show any genotoxic potential.

Studies in the mouse showed levofloxacin to have phototoxic activity only at very high doses. Levofloxacin did not show any genotoxic potential in a photomutagenicity assay, and it reduced tumour development in a photocarcinogenity study.

In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats and dogs. These findings were more marked in young animals.

Sodium chloride

Sodium hydroxide (for pH adjustment)

Hydrochloric acid, (for pH adjustment)

Water for injection

Levofloxacin 5 mg/ml Solution for infusion should not be mixed with heparin or alkaline solutions (e.g. sodium hydrogen carbonate). This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Shelf life as packaged for sale: 2 years

Shelf life after removal of the outer carton/overwrap pouch – to be used immediately

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

From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Do not freeze.

Keep bottle/bag in the outer carton/over wrap pouch in order to protect from light (see section 6.3). Inspect visually prior to use. Only clear solutions without particles should be used.

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

100 ml type I glass bottle with aluminium cap, bromobutyl rubber stopper and flip off seal. Each bottle contains 100 ml of solution for infusion. Packs of 1, 5, and 10 x 100 ml bottles are available.

100 ml Non PVC bag consists of Non PVC Film, Non PVC Tube, Spike Port and EMP White Elastomer closure. Each bag contains 100 ml of solution for infusion. Packs of 1, 5, and 10 x 100 ml bags are available.

Not all pack sizes may be marketed.

Levofloxacin 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 infusion.

For single use only. Discard any unused solution.

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

Mixture with other solutions for infusion:

Levofloxacin Solution for infusion is compatible with the following solutions for infusion:

0.9 % sodium chloride solution USP.

5 % dextrose injection USP.

2.5 % dextrose in Ringer solution.

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

See section 6.2 for incompatibilities.

United Kingdom:

Baxter Healthcare Limited

Caxton Way

Thetford, Norfolk IP24 3SE,

United Kingdom

PL 00116/0677

18/07/2012

January 2020