Dosage in patients with normal renal function (creatinine clearance > 50 ml/min) Indication

Daily dose regimen (according to severity)

Total duration of treatment(according to severity)

Community-acquired pneumonia

500 mg once or twice daily

7 - 14 days

Acute Pyelonephritis

500 mg once daily

7 - 10 days

Complicated urinary tract infections

500 mg once daily

7 - 14 days

Chronic bacterial prostatitis

500 mg once daily

28 days

Complicated skin and soft tissue infections

500 mg once or twice daily

7 - 14 days

Inhalation anthrax

500 mg once daily

8 weeks

Impaired renal function (creatinine clearance <50 ml/min) Dose regimen

250 mg/24h

500 mg/24h

500 mg/12 h

Creatinine clearance

first dose:

250 mg

first dose:

500 mg

first dose:

500 mg

50 - 20 ml/min

then:

125 mg/24 h

then:

250 mg/24 h

then:

250 mg/12 h

19-10 ml/min

then:

125 mg/48 h

then:

125 mg/24 h

then:

125 mg/12 h

<10 ml/min

(including haemodialysis and CAPD) 

then:

125 mg/48 h

then:

125 mg/24 h

then:

125 mg/24 h

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.

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 photosensitization.

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).

System organ class

Common

(≥1/100 to <1/10 )

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Not known (cannot be estimated from available data)

Infections and infestations

Fungal infection including Candida infection

Pathogen resistance

Blood and the lymphatic system disorders

Leukopenia

Eosinophilia

Thrombocytopenia

Neutropenia

Pancytopenia

Agranulocytosis

Haemolytic anaemia

Immune system Disorders

Angioedema

Hypersensitivity(see section 4.4)

Anaphylactic shock ^a

Anaphylactoid shock ^a

(see section 4.4)

Endocrine disorders

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

Metabolism and nutrition disorders

Anorexia

Hypoglycaemia particularly in diabetic patients

Hyperglycaemia

Hypoglycaemic coma

(see section 4.4)

Psychiatric Disorders*

Insomnia

Anxiety

Confusional state

Nervousness

Psychotic reactions (with e.g. hallucination, paranoia)

Depression Agitation Abnormal dreams Nightmares

Psychotic disorders with self-endangering behaviour including suicidal ideation or suicide attempt

(see section 4.4)

Nervous system Disorders*

Headache

Dizziness

Somnolence

Tremor

Dysgeusia

Convulsion (see sections 4.3 and 4.4) Paraesthesia

Peripheral sensory neuropathy (see section 4.4) Peripheral sensory motor neuropathy (see section 4.4)

Parosmia including anosmia

Dyskinesia

Extrapyramidal disorder

Ageusia

Syncope

Benign intracranial hypertension

Eye disorders*

Visual disturbances such as blurred vision (see section 4.4)

Transient vision loss (see section 4.4)

Ear and Labyrinth disorders*

Vertigo

Tinnitus

Hearing loss

Hearing impaired

Cardiac disorders

Tachycardia,

Palpitation

Ventricular tachycardia, which may result in cardiac arrest

Ventricular arrhythmia and torsade de pointes (reported predominantly in patients with risk factors of QT prolongation),

Vascular disorders

Applies to iv form only:

Hypotension

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Bronchospasm

Pneumonitis allergic

Gastro-intestinal disorders

Diarrhoea

Vomiting

Nausea

Abdominal pain

Dyspepsia Flatulence Constipation

Diarrhoea – haemorrhagic which in very rare cases may be indicative of enterocolitis, including pseudomembranous colitis (see section 4.4)

Pancreatitis

Hepatobiliary disorders

Hepatic enzyme increased (ALT/AST, alkaline phosphatase, GGT)

Blood bilirubin increased

Jaundice and severe liver injury, including fatal cases with acute liver failure, primarily in patients with severe underlying diseases (see section 4.4)

Hepatitis

Skin and subcutaneous tissue disorders ^b

Rash
Pruritus
Urticaria
Hyperhidrosis

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (see section 4.4), Fixed drug eruption

Toxic epidermal necrolysis

Stevens-Johnson syndrome Erythema multiforme Photosensitivity reaction (see section 4.4)

Leukocytoclastic vasculitis

Stomatitis

Musculoskeletal and connective tissue disorders*

Arthralgia

Myalgia

Tendon disorders (see sections 4.3 and 4.4) including tendinitis (e.g. Achilles tendon)

Muscular

Rhabdomyolysis

Tendon rupture (e.g. Achilles tendon) (see sections 4.3 and

4.4)

Ligament rupture Muscle rupture Arthritis

Renal and Urinary disorders

Blood creatinine increased

Renal failure acute (e.g. due to interstitial nephritis)

General disorders and administration site conditions*

Applies to iv form only:

Infusion site reaction (pain, reddening)

Asthenia

Pyrexia

Pain (including pain in back, chest, and extremities)

The National Pharmacovigilance Centre (NPC):

- Fax: +966-11-205-7662

- Call NPC at +966-11-2038222, Ext: 2317-2356-2340

- TOLL FREE : 8002490000

- E-mail: npc.drug@sfda.gov.sa

- Website: https://ade.sfda.gov.sa/

Please contact the relevant competent authority.

Pathogen

Susceptible

Resistant

Enterobacteriacae

≤1 mg/L

>2 mg/L

Pseudomonas spp.

≤1 mg/L

>2 mg/L

Acinetobacter spp.

≤1 mg/L

>2 mg/L

Staphylococcus spp.

≤1 mg/L

>2 mg/L

Streptococcus A,B,C,G

≤1 mg/L

>2 mg/L

S.pneumoniae ¹

≤2 mg/L

>2 mg/L

H.influenzae^{2, 3}

≤1 mg/L

>1 mg/L

M.catarrhalis³

≤1 mg/L

>1 mg/L

Non-species related breakpoints⁴

≤1 mg/L

>2 mg/L

1. The breakpoints for levofloxacin relate to high dose therapy.

2. Low-level fluoroquinolone resistance (ciprofloxacin MICs of 0.12-0.5 mg/l) may occur but there is no evidence that this resistance is of clinical importance in respiratory tract infections with H. influenzae.

3.Strains with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.

4. Breakpoints apply to an oral dose of 500 mg x 1 to 500 mg x 2 and an intravenous dose of 500 mg x 1 to 500 mg x 2

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

Clcr [ml/min]

< 20

20 - 49

50 - 80

ClR [ml/min]

13

26

57

t1/2 [h]

35

27

9