Levofloxacin 250 mg Film-coated Tablets

1. Name Of The Medicinal Product

Levofloxacin 250 mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each film coated tablet contains 250 mg of levofloxacin as active substance corresponding to 256.23 mg of levofloxacin hemihydrate.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet

For 250 mg tablets: Pink coloured, capsule shaped, biconvex, film coated tablet with break line on both sides. Debossed 'L' and 'F' either side of the break line on one face.

The tablets can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

In adults with infections of mild or moderate severity, Levofloxacin Tablets are indicated for the treatment of the following infections when due to levofloxacin-susceptible microorganisms: (see section 5.1)

• Acute sinusitis (adequately diagnosed according to national and/or local guidelines on the treatment of respiratory tract infections, and when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of this infection or when these have failed to resolve the infection),

• Acute exacerbations of chronic bronchitis (adequately diagnosed according to national and/or local guidelines on the treatment of respiratory tract infections, and when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of this infection or when these have failed to resolve the infection),

• Community-acquired pneumonia (when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of this infection),

• For 250mg only: Uncomplicated urinary tract infections

• Complicated urinary tract infections (including pyelonephritis)

• Chronic bacterial prostatitis.

• Skin and soft tissue infections.

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

4.2 Posology And Method Of Administration

Levofloxacin Tablets are administered once or twice daily. The dosage depends on the type and severity of the infection and the sensitivity of the presumed causative pathogen.

Treatment time

The duration of therapy varies according to the course of the disease (see table below). As with antibiotic therapy in general, administration of Levofloxacin Tablets should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.

Method of administration

Levofloxacin Tablets should be swallowed whole and with sufficient amount of liquid. The tablets may be taken during meals or between meals. Levofloxacin Tablets should be taken at least two hours before iron salts, antacids and sucralfate administration since reduction of absorption can occur (see section 4.5).

The following dose recommendations can be given for Levofloxacin Tablets:

Dosage in patients with normal renal function

(creatinine clearance > 50 ml/min)

Indication	Daily dose regimen (according to severity)	Duration of treatment
Acute sinusitis	500 mg once daily	10 - 14 days
Acute exacerbations of chronic bronchitis	250 to 500 mg once daily	7 - 10 days
Community-acquired pneumonia	500 mg once or twice daily	7 - 14 days
Uncomplicated urinary tract infections	250 mg once daily	3 days
Complicated urinary tract infections including pyelonephritis	250 mg once daily1	7 - 10 days
Chronic bacterial prostatitis	500 mg once daily	28 days
Skin and soft tissue infections	250 mg once daily or 500 mg once or twice daily2	7 - 14 days

^1,2 Consideration should be given to increasing the dose in cases of severe infection and special attention should be paid to available information on resistance to levofloxacin before commencing therapy.

¹ Because of the increasing E.coli resistance the dose 500 mg/day should be considered.

² Because of the increasing Staphylococcus resistance the dose 500 mg twice daily should be considered.

Special Populations

Impaired renal function (creatinine clearance

Creatinine clearance	Dosage regimen
250 mg/24 h	500 mg/24 h	500 mg/12 h
First dose: 250 mg	First dose: 500 mg	First dose: 500 mg
50-20 ml/min	Then:125 mg/24h	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)1	Then: 125 mg/48 h	Then: 125 mg/24 h	Then:125 mg/24 h

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

Impaired liver function

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

Dosage in elderly

No adjustment of dosage is required in the elderly, other than that imposed by consideration of renal function (see section 4.4 QT interval prolongation).

In children

Levofloxacin is contraindicated in children and growing adolescents (less than 18 years of age) (see section 4.3).

4.3 Contraindications

Levofloxacin Tablets must not be used:

• in patients hypersensitive to levofloxacin or other quinolones or any of the excipients,

• 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

In the most severe cases of pneumococcal pneumonia Levofloxacin Tablets may not be the optimal therapy.

Nosocomial infections due to P. aeruginosa may require combination therapy.

Methicillin-resistant Staphylococcus aureus (MRSA)

Levofloxacin is not effective against infections caused by MRSA (see section 5.1). In infections suspicious for MRSA levofloxacin should be combined with an agent approved to treat MRSA infections.

Tendinitis and tendon rupture

Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to tendon rupture. The risk of tendinitis and tendon rupture is increased in the elderly and in patients using corticosteroids. Close monitoring of these patients is therefore necessary if they are prescribed Levofloxacin Tablets. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with Levofloxacin Tablets must be halted immediately, and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon.

Clostridium difficile-associated disease

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with Levofloxacin Tablets, may be symptomatic of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous enterocolitis. If pseudomembranous enterocolitis is suspected, Levofloxacin Tablets must be stopped immediately and patients should be treated with supportive measures and specific therapy without delay (e.g. oral metronidazole or vancomycin). Products inhibiting the peristalsis are contraindicated in this clinical situation.

Patients predisposed to seizures

Levofloxacin Tablets are contraindicated in patients with a history of epilepsy and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures, such as patients with pre-existing central nervous system damage; concomitant treatment with fenbufen and similar non-steroidal anti-inflammatory drugs or with drugs which lower the cerebral seizure threshold, such as theophylline (see section 4.5). In case of convulsive seizures, 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, and so levofloxacin should be used with caution.

Patients with renal impairment

Since levofloxacin is excreted mainly by the kidneys, the dose of Levofloxacin Tablets 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 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.

Hypoglycemia

As with all quinolones, hypoglycemia has been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glibenclamide) or with insulin. In these diabetic patients, careful monitoring of blood glucose is recommended. (see section 4.8).

Prevention of photosensitisation

Although photosensitisation is very rare with levofloxacin, it is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp, solarium), 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 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 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 a history of psychiatric disease.

Cardiac disorders

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).

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

- elderly

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

(see section 4.2 Elderly, section 4.5, section 4.8, section 4.9).

Peripheral neuropathy

Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving fluoroquinolones, including levofloxacin, which can be rapid in its onset. Levofloxacin should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition.

Opiates

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 a more specific method.

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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effect of other medicinal products on levofloxacin

Iron salts, magnesium- or aluminium-containing antacids

Levofloxacin absorption is significantly reduced when iron salts, or magnesium- or aluminium-containing antacids are administered concomitantly. It is recommended that preparations containing divalent or trivalent cations such as iron salts, or magnesium- or aluminium-containing antacids should not be taken 2 hours before or after Levofloxacin Tablets administration (see section 4.2). No interaction was found with calcium carbonate.

Sucralfate

The bioavailability of Levofloxacin Tablets is significantly reduced when administered together with sucralfate. If the patient is to receive both sucralfate and Levofloxacin Tablets, it is best to administer sucralfate 2 hours after the Levofloxacin Tablets administration (see section 4.2).

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 effect the tubular renal secretion such as probenecid and cimetidine, especially in renally impaired patients.

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 the 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, antipsychotic). (See section 4.4 ).

Other forms of interactions

Meals

There is no clinically relevant interaction with food. Levofloxacin Tablets may therefore be administered regardless of food intake.

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.

4.6 Pregnancy And Lactation

Pregnancy

There are no data with respect to 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). In juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been observed; thus, it cannot be excluded that the drug could cause damage to articular cartilage in the human immature organism / fetus (see section 5.3). The product is therefore contraindicated during pregnancy.

Lactation

There is insufficient information with respect to the excretion of levofloxacin in human and/or animal milk. In the absence of these data and given the potential risk of articular damage, levofloxacin is contraindicated during breast-feeding.

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 5000 patients and on extensive post marketing experience.

The adverse reactions are described according to the MedDRA system organ class below.

Frequencies are defined using the following convention: very common (

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

Cardiac disorders

Rare: Tachycardia

Not Known: ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), Electrocardiogram QT prolonged (see section 4.4 and section 4.9)

Blood and lymphatic system disorders

Uncommon : Leukopenia, eosinophilia

Rare : Thrombocytopenia, neutropenia

Very rare : Agranulocytosis

Not Known : Pancytopenia, haemolytic anaemia

Nervous system disorders

Uncommon : Dizziness, headache, somnolence

Rare : Convulsion, tremor, paraesthesia,

Very rare: sensory or sensorimotor peripheral neuropathy, dysgeusia including ageusia, parosmia including anosmia

Eye disorders

Very rare: Visual disturbance

Ear and Labyrinth disorders

Uncommon: Vertigo

Very rare: Hearing impaired

Not known: Tinnitus

Respiratory, thoracic and mediastinal disorders

Rare: Bronchospasm, dyspnoea

Very rare: Pneumonitis allergic

Gastrointestinal disorders

Common: Diarrhoea, nausea

Uncommon: Vomiting, abdominal pain, dyspepsia, flatulence, constipation

Rare: Diarrhoea –haemorrhagic which in very rare cases may be indicative of enterocolitis, including pseudomembranous colitis

Renal and urinary disorders

Uncommon: Blood creatinine increased

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

Skin and subcutaneous tissue disorders

Uncommon: Rash, pruritus

Rare: Urticaria

Very rare: Angioneurotic oedema, photosensitivity reaction

Not Known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, hyperhidrosis

Mucocutaneous reactions may sometimes occur even after the first dose

Musculoskeletal and Connective tissue disorders

Rare: Tendon disorder (see section 4.4) including tendinitis (e.g. Achilles tendon), arthralgia, myalgia

Very rare: Tendon rupture (see section 4.4). This undesirable effect may occur within 48 hours of starting treatment and may be bilateral, muscular weakness which may be of special importance in patients with myasthenia gravis

Not Known: Rhabdomyolysis

Metabolism and nutrition disorders

Uncommon: Anorexia

Very rare: Hypoglycemia, particularly in diabetic patients (see section 4.4)

Infections and infestations

Uncommon: Fungal infection (and proliferation of other resistant microorganisms)

Vascular disorders

Rare: Hypotension

General disorders and administration site conditions

Uncommon: Asthenia

Very rare: Pyrexia

Not known: Pain (including pain in back, chest, and extremities)

Immune system disorders

Very rare: Anaphylactic shock (see section 4.4)

Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose

Not known: Hypersensitivity (see section 4.4)

Hepatobiliary disorders

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

Uncommon: Blood bilirubin increased

Very rare: Hepatitis

Not known: Jaundice and severe liver injury, including cases with acute liver failure, have been reported with levofloxacin, primarily in patients with severe underlying diseases (see section 4.4).

Psychiatric disorders

Uncommon: Insomnia, nervousness

Rare: Psychotic disorder, Depression, confusional state, agitation, anxiety

Very rare: Psychotic reactions with self-endangering behaviour including suicidal ideation or acts (see section 4.4), hallucination

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

• extrapyramidal symptoms and other disorders of muscular coordination,

• hypersensitivity vasculitis,

• attacks of porphyria in patients with porphyria.

4.9 Overdose

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 are central nervous system symptoms such as confusion, dizziness, impairment of consciousness, and convulsive seizures, increases in QT interval as well as gastro-intestinal reactions such as nausea and mucosal erosions.

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

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiifectives for systemic use – Antibacterials for systemic use – Quinolone antibasterials – 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 releationship

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

Mechanism(s) of resisance

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 (2006-06-20):

Pathogen	Susceptible	Resistant
Enterobacteriacae		>2 mg/L
Pseudomonas spp.		>2 mg/L
Acinetobacter spp.		>2 mg/L
Staphylococcus spp.		>2 mg/L
S.pneumoniae1		>2 mg/L
Streptococcus A,B,C,G		>2 mg/L
H.influenzae M.catarrhalis2		>1 mg/L
Non-species related breakpoints 3		>2 mg/L

¹ the S/I-breakpoint was increased from 1.0 to 2.0 to avoid dividing the wild type MIC distribution. The breakpoints relate to high dose therapy.

² Strains with MIC values above the S/I 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 sent to a reference laboratory.

³ Non-species related breakpoints have been determined mainly on the basis of pharmacokinetic/pharmacodynamic data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and are not for use with species where susceptibility testing is not recommended or for which there is insufficient evidence that the species in question is a good target (Enterococcus, Neisseria, Gram negative anaerobes)

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.

Commonly susceptible species

Aerobic Gram-positive bacteria

Staphylococcus aureus* methicillin-susceptible Coagulase negative meticillin-susceptible Staphylococcus, including staphylococcus saprophyticus Streptococci

Aerobic Gram- negative bacteria

Eikenella corrodens Haemophilus influenzae * Haemophilus para-influenzae * Klebsiella oxytoca Klebsiella pneumoniae * Legionella pneumophila* Moraxella catarrhalis * Pasteurella multocida Proteus vulgaris Providencia rettgeri

Anaerobic bacteria

Clostridium perfringens Fusobacterium Prevotella($), Propionibacterium

Other

Chlamydophila pneumoniae * Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae * Mycoplasma hominis Ureaplasma urealyticum

Species for which acquired resistance may be a problem

Aerobic Gram-positive bacteria

Enterococcus faecalis* Staphylococcus aureus methicillin-resistant Staphylococcus coagulase negative methicillin-resistant

Aerobic Gram- negative bacteria

Acinetobacter baumannii * Citrobacter freundii * Enterobacter aerogenes Enterobacter agglomerans Enterobacter cloacae * Escherichia coli * Morganella morganii * Proteus mirabilis * Providencia stuartii Pseudomonas aeruginosa* Serratia marcescens *

Anaerobic bacteria

Peptostreptococcus

Naturally resistant species

Aerobic Gram-positive bacteria

Enterococcus faecium

Aerobic Gram-negative bacteria

Burkholderia cepacia

Anaerobic bacteria

Bacteroides Clostridium difficile

* Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical indications.

$ natural intermediate susceptibility

Other information

Nosocomial infections due to P. aeruginosa may require combination therapy.

5.2 Pharmacokinetic Properties

Absorption

Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma concentrations being obtained within 1 h. The absolute bioavailability is approximately 100 %. Food has little effect on the absorption of levofloxacin.

Distribution

Approximately 30 - 40 % of levofloxacin is bound to serum protein. 500 mg once daily multiple dosing with levofloxacin showed negligible accumulation. There is modest but predictable accumulation of levofloxacin after doses of 500 mg twice daily. Steady-state is achieved within 3 days.

Penetration into tissues and body fluids:

Penetration into Bronchial Mucosa, Epithelial Lining Fluid (ELF)

Maximum levofloxacin concentrations in bronchial mucosa and epithelial lining fluid after 500 mg p.o. were 8.3 μg/g and 10.8 μg/ml respectively. These were reached approximately one hour after administration.

Penetration into Lung Tissue

Maximum levofloxacin concentrations in lung tissue after 500 mg p.o. were approximately 11.3 μg/g and were reached between 4 and 6 hours after administration. The concentrations in the lungs consistently exceeded those in plasma.

Penetration into Blister Fluid

Maximum levofloxacin concentrations of about 4.0 and 6.7 μg/ml in the blister fluid were reached 2 - 4 hours after administration following 3 days dosing at 500 mg once or twice daily, respectively.

Penetration into Cerebro-Spinal Fluid

Levofloxacin has poor penetration into cerebro-spinal fluid.

Penetration into prostatic tissue

After administration of oral 500mg levofloxacin once a day for three days, the mean concentrations in prostatic tissue were 8.7 µg/g, 8.2 µg/g and 2.0 µg/g respectively after 2 hours, 6 hours and 24 hours; the mean prostate/plasma concentration ratio was 1.84.

Concentration in urine

The mean urine concentrations 8 - 12 hours after a single oral dose of 150 mg, 300 mg or 500 mg levofloxacin were 44 mg/L, 91 mg/L and 200 mg/L, respectively.

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 600 mg.

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:

Clcr [ml/min]	< 20	20 - 40	50 - 80
ClR [ml/min]	13	26	57
t1/2 [h]	35	27	9

Elderly subjects

There are no significant differences in levofloxacin kinetics 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.

5.3 Preclinical Safety Data

During repeat-dose studies, common observations included reduced food consumption and minor alterations in haematological and biochemical parameters at 200 mg/kg/day in the rat and reduced body weight, salivation, diarrhoea and decreased urinary pH at 100 mg/kg/day in the monkey.

Levofloxacin had no effect on fertility or reproductive performance and was not teratogenic in the rat. In the

Hydroquinone/Vitamin A

Pronunciation: HYE-droe-kwin-one/VYE-ta-min A
Generic Name: Hydroquinone/Vitamin A
Brand Name: Alustra

Hydroquinone/Vitamin A is used for:

Bleaching freckles, age spots, and other skin discolorations that may occur due to pregnancy, skin trauma, use of birth control pills, or other hormone replacement therapy. It may also be used for other conditions as determined by your doctor.

Hydroquinone/Vitamin A is a combination depigmenting agent and vitamin A. It works by lightening the skin.

Do NOT use Hydroquinone/Vitamin A if:

• you are allergic to any ingredient in Hydroquinone/Vitamin A

Contact your doctor or health care provider right away if any of these apply to you.

Before using Hydroquinone/Vitamin A:

Some medical conditions may interact with Hydroquinone/Vitamin A. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have asthma or damaged or irritated skin


• if you are unusually sensitive to sunlight or must be outside for prolonged periods of time

Some MEDICINES MAY INTERACT with Hydroquinone/Vitamin A. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Products that contain benzoyl peroxide or hydrogen peroxide because side effects, such as a dark staining of the skin, may occur


• Medicines that contain phenol, resorcinol, or salicylic acid because the risk of side effects may be increased


• Fluoroquinolones (eg, levofloxacin), phenothiazines (eg, chlorpromazine), sulfonamides (eg, glipizide, sulfamethoxazole), tetracyclines (eg, doxycycline), or thiazide diuretics (eg, hydrochlorothiazide) because the risk of sunburn may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Hydroquinone/Vitamin A may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Hydroquinone/Vitamin A:

Use Hydroquinone/Vitamin A as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Hydroquinone/Vitamin A comes with an additional patient leaflet. Read it carefully and reread it each time you get Hydroquinone/Vitamin A refilled.


• Hydroquinone/Vitamin A is for external use only.


• Before using Hydroquinone/Vitamin A for the first time, apply a small amount to an unbroken patch of skin and check in 24 hours for itching, blistering, or excessive redness or irritation. If these side effects develop, contact your doctor.


• Wash your hands before and after using Hydroquinone/Vitamin A, unless your hands are a part of the treated area.


• Remove all cosmetics with a mild soap before applying Hydroquinone/Vitamin A. Gently dry the area.


• Apply enough medicine to cover the affected area and gently rub it in until it is evenly distributed.


• If you miss a dose of Hydroquinone/Vitamin A, use it as soon as possible. If it is almost time for you next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Hydroquinone/Vitamin A.

Important safety information:

• Some of these products contain sulfites, which can cause allergic reactions in certain individuals (eg, asthma patients). If you have previously had allergic reactions to sulfites, contact your pharmacist to determine if the product you are using contains sulfites.


• Hydroquinone/Vitamin A may cause increased sensitivity to the sun. Avoid exposure to the sun, sunlamps, or tanning booths until you know how you react to Hydroquinone/Vitamin A. Use a sunscreen and wear protective clothing if you must be outside for a prolonged period.


• If your symptoms do not improve within 2 months or if they become worse, check with your doctor.


• Do not use products containing benzoyl peroxide or hydrogen peroxide with Hydroquinone/Vitamin A because your skin may become darkly stained. The stain can be removed by stopping use of the peroxide product and washing your skin with soap and water.


• Do not use other medicines or products on your skin, especially products that dry or irritate the skin, without first discussing it with your doctor.


• Avoid getting Hydroquinone/Vitamin A in your eyes, nose, or mouth. If you get Hydroquinone/Vitamin A in your eyes, rinse thoroughly with water.


• Do not exceed the recommended dose or use Hydroquinone/Vitamin A for longer than prescribed without checking with your doctor.


• Hydroquinone/Vitamin A may be harmful if swallowed. If you or someone you know may have taken Hydroquinone/Vitamin A by mouth, contact your local poison control center or emergency room immediately.


• Use Hydroquinone/Vitamin A with extreme caution in CHILDREN younger than 12 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant while using Hydroquinone/Vitamin A, discuss with your doctor the benefits and risks of using Hydroquinone/Vitamin A during pregnancy. It is unknown if Hydroquinone/Vitamin A is excreted in breast milk. If you are or will be breast-feeding while you are using Hydroquinone/Vitamin A, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Hydroquinone/Vitamin A:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Mild burning or redness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blistering; blue-black darkening of the skin; cracking or excessive dryness, redness, stinging, or irritation.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Hydroquinone/Vitamin A side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blurred vision; bone pain; change in texture of hair or nails; drowsiness; dry, scaly skin; headache; itching; nausea; vomiting.

Proper storage of Hydroquinone/Vitamin A:

Store Hydroquinone/Vitamin A at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Hydroquinone/Vitamin A out of the reach of children and away from pets.

General information:

• If you have any questions about Hydroquinone/Vitamin A, please talk with your doctor, pharmacist, or other health care provider.


• Hydroquinone/Vitamin A is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Hydroquinone/Vitamin A. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Hydroquinone/Vitamin A resources

• Hydroquinone/Vitamin A Side Effects (in more detail)
• Hydroquinone/Vitamin A Use in Pregnancy & Breastfeeding
• Hydroquinone/Vitamin A Support Group
• 2 Reviews for Hydroquinone/Vitamin A - Add your own review/rating

Compare Hydroquinone/Vitamin A with other medications

• Dermatological Disorders

Colocort

hydrocortisone

Dosage Form: rectal suspension
Colocort® 

Hydrocortisone Rectal

Suspension, USP

(Retention)

100 mg/60 mL

Disposable Unit for Rectal Use Only

Colocort Description

Hydrocortisone is a white to practically white, odorless, crystalline powder, very slightly soluble in water. It has the chemical name Pregn-4-ene-3,20-dione, 11,17,21-trihydroxy-,(11β)- and the following structural formula:

Colocort® is a convenient disposable single-dose hydrocortisone enema designed for ease of self-administration.

Each disposable unit (60 mL) contains: Hydrocortisone, 100 mg in an aqueous solution containing carbomer 934P, polysorbate 80, purified water, sodium hydroxide and methylparaben, 0.18% as a preservative.

Colocort - Clinical Pharmacology

Hydrocortisone is a naturally occurring glucocorticoid (adrenal corticosteroid), similar to its acetate and sodium hemisuccinate derivatives, is partially absorbed following rectal administration. Absorption studies in ulcerative colitis patients have shown up to 50% absorption of hydrocortisone administered as hydrocortisone rectal suspension and up to 30% of hydrocortisone acetate administered in an identical vehicle.

Colocort® provides the potent anti-inflammatory effect of hydrocortisone. Because this drug is absorbed from the colon, it acts both topically and systemically. Although rectal hydrocortisone, used as recommended for hydrocortisone rectal suspension, has a low incidence of reported adverse reactions, prolonged use presumably may cause systemic reactions associated with oral dosage forms.

Indications and Usage for Colocort

Colocort® is indicated as adjunctive therapy in the treatment of ulcerative colitis, especially distal forms, including ulcerative proctitis, ulcerative proctosigmoiditis, and left-sided ulcerative colitis. It has proved useful also in some cases involving the transverse and ascending colons.

Contraindications

Systemic fungal infections; and ileocolostomy during the immediate or early post-operative period.

Warnings

In severe ulcerative colitis, it is hazardous to delay needed surgery while awaiting response to medical treatment.

Damage to the rectal wall can result from careless or improper insertion of an enema tip.

In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.

Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.

Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

Usage in pregnancy:

Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of child-bearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Neonates born of mothers who have received substantial doses of corticosteroid during pregnancy should be carefully observed for signs of hypoadrenalism.

Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

While on corticosteroid therapy, patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response.

Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in non-immune pediatric patients or adults on corticosteroids. In such pediatric patients or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Precautions

General:

Colocort® Hydrocortisone Rectal Suspension, USP should be used with caution where there is a probability of impending perforation, abscess or other pyogenic infection; fresh intestinal anastomoses; obstruction; or extensive fistulas and sinus tracts. Use with caution in presence of active or latent peptic ulcer; diverticulitis; renal insufficiency; hypertension; osteoporosis; and myasthenia gravis.

Steroid therapy might impair prognosis in surgery by increasing the hazard of infection. If infection is suspected, appropriate antibiotic therapy must be administered, usually in larger than ordinary doses.

Drug-induced secondary adrenocortical insufficiency may occur with prolonged Colocort® therapy. This is minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis.

Corticosteroid should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation.

The lowest possible dose of corticosteroid should be used to control the conditions under treatment, and when reduction in dosage is possible, the reduction should be gradual.

Psychic derangement may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

Growth and development of pediatric patients on prolonged corticosteroid therapy should be carefully observed.

Information for Patients:

Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Adverse Reactions

Local pain or burning, and rectal bleeding attributed to hydrocortisone rectal suspension have been reported rarely. Apparent exacerbations or sensitivity reactions also occur rarely. The following adverse reactions should be kept in mind whenever corticosteroids are given by rectal administration.

Fluid and Electrolyte Disturbances: Sodium retention; fluid retention; congestive heart failure in susceptible patients; potassium loss; hypokalemic alkalosis; hypertension. Musculoskeletal: Muscle weakness; steroid myopathy; loss of muscle mass; osteoporosis; vertebral compression fractures; asceptic necrosis of femoral and humeral heads; pathologic fracture of long bones. Gastrointestinal: Peptic ulcer with possible perforation and hemorrhage; pancreatitis; abdominal distention; ulcerative esophagitis. Dermatologic: Impaired wound healing; thin fragile skin; petechiae and ecchymoses; facial erythema; increased sweating; may suppress reactions to skin tests. Neurological: Convulsions; increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment; vertigo; headache. Endocrine: Menstrual irregularities; development of Cushingoid state; suppression of growth in pediatric patients; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness, decreased carbohydrate tolerance; manifestations of latent diabetes requirements for insulin or oral hypoglycemic agents in diabetics. Ophthalmic: Posterior subcapsular cataracts; increased intraocular pressure; glaucoma; exophthalmos. Metabolic: Negative nitrogen balance due to protein catabolism.

Colocort Dosage and Administration

The use of Colocort® Hydrocortisone Rectal Suspension, USP is predicated upon the concomitant use of modern supportive measures such as rational dietary control, sedatives, antidiarrheal agents, antibacterial therapy, blood replacement if necessary, etc.

The usual course of therapy is one Colocort® nightly for 21 days, or until the patient comes into remission both clinically and proctologically. Clinical symptoms usually subside promptly within 3 to 5 days. Improvement in the appearance of the mucosa, as seen by sigmoidoscopic examination, may lag somewhat behind clinical improvement. Difficult cases may require as long as 2 or 3 months of Colocort® treatment. Where the course of therapy extends beyond 21 days, Colocort® should be discontinued gradually by reducing administration to every other night for 2 or 3 weeks.

If clinical or proctologic improvement fails to occur within 2 or 3 weeks after starting Colocort®, discontinue its use.

Symptomatic improvement, evidenced by decreased diarrhea and bleeding; weight gain; improved appetite; lessened fever; and decrease in leukocytosis, may be misleading and should not be used as the sole criterion in judging efficacy. Sigmoidoscopic examination and X-ray visualization are essential for adequate monitoring of ulcerative colitis. Biopsy is useful for differential diagnosis.

Patient instructions for administering Colocort® are printed on this carton. It is recommended that the patient lie on their left side during administration and for 30 minutes thereafter, so that the fluid will distribute throughout the left colon. Every effort should be made to retain the enema for at least an hour and preferably, all night. This may be facilitated by prior sedation and/or antidiarrheal medication, especially early in therapy when the urge to evacuate is great.

How is Colocort Supplied

Colocort®, Hydrocortisone Rectal Suspension, USP, (Retention) 100 mg/60 mL, is supplied as disposable single-dose bottles with lubricated rectal applicator tips, in boxes of seven × 60 mL (NDC 0574-2020-07) and boxes of one × 60 mL (NDC 0574-2020-01).

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]

Paddock Laboratories, Inc.

Minneapolis, MN 55427

(08-08)

PATIENT INSTRUCTIONS

How to use the retention enema:

Best results are achieved if the bowel is emptied immediately before the enema is given.

1

Preparing the Medication for Administration

a

Shake the bottle well to make sure that the suspension is homogeneous.

b

Remove the protective sheath from the applicator tip. Hold the bottle at the neck so as not to cause any of the medication to be discharged.

2

Assuming the Correct Body Position

a

Best results are obtained by lying on the left side with the left leg extended and the right leg flexed forward for balance.

b

An alternative to lying on the left side is the "knee-chest" position as shown here.

3

Administering the Retention Enema

a

Gently insert the lubricated applicator tip into the rectum, pointed slightly toward the navel (umbilicus).

b

Grasp the bottle firmly, then tilt slightly so that the nozzle is aimed toward the back, and squeeze slowly to instill the medication. Steady hand pressure will discharge most of the solution. After administering, withdraw and discard the used unit.

c

Remain in position for at least 30 minutes to allow thorough distribution of the medication internally. Retain the enema all night, if possible.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]

PRINCIPAL DISPLAY PANEL - 7 × 60 mL Bottle Carton

NDC 0574-2020-07

Colocort®

Hydrocortisone Rectal Suspension, USP (Retention)

100 mg/60 mL

Rx ONLY

SHAKE WELL BEFORE USE

FOR RECTAL USE ONLY

7 X 60 mL UNIT DOSE

Paddock

Laboratories, Inc.

LIFT THIS

PANEL FOR

PRODUCT

INFORMATION

Colocort  hydrocortisone  suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0574-2020 Route of Administration RECTAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HYDROCORTISONE (HYDROCORTISONE) HYDROCORTISONE 100 mg  in 60 mL

Inactive Ingredients Ingredient Name Strength METHYLPARABEN 10.8 g  in 60 mL CARBOMER 934   POLYSORBATE 80   WATER   SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0574-2020-01 1 BOTTLE In 1 BOX contains a BOTTLE, DISPENSING 1 60 mL In 1 BOTTLE, DISPENSING This package is contained within the BOX (0574-2020-01) 2 0574-2020-07 7 BOTTLE In 1 BOX contains a BOTTLE, DISPENSING 2 60 mL In 1 BOTTLE, DISPENSING This package is contained within the BOX (0574-2020-07)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA075172	12/31/1999

Labeler - Paddock Laboratories, Inc. (086116803)

Establishment
Name	Address	ID/FEI	Operations
Paddock Laboratories, Inc.		086116803	MANUFACTURE

Revised: 01/2010Paddock Laboratories, Inc.

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• Inflammatory Bowel Disease
• Ulcerative Colitis
• Ulcerative Proctitis

Iodure de Potassium Pharmacie centrale des armées

Iodure de Potassium Pharmacie centrale des armées may be available in the countries listed below.

Ingredient matches for Iodure de Potassium Pharmacie centrale des armées

Potassium Iodide

Potassium Iodide is reported as an ingredient of Iodure de Potassium Pharmacie centrale des armées in the following countries:

• France

International Drug Name Search

Augmentin 375mg Tablets

1. Name Of The Medicinal Product

Augmentin® 375 mg Tablets

2. Qualitative And Quantitative Composition

Augmentin 375 mg Tablets: Each tablet contains co-amoxiclav 250/125.

The amoxicillin is present as amoxicillin trihydrate and the clavulanic acid is present as potassium clavulanate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Augmentin 375 mg Tablets: White to off-white, oval film-coated tablets engraved Augmentin on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Augmentin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1).

• Acute bacterial sinusitis (adequately diagnosed)

• Cystitis

• Pyelonephritis

• Cellulitis

• Animal bites

• Severe dental abscess with spreading cellulitis.

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

4.2 Posology And Method Of Administration

Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component.

The dose of Augmentin that is selected to treat an individual infection should take into account:

• The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)

• The severity and the site of the infection

• The age, weight and renal function of the patient as shown below.

The use of alternative presentations of Augmentin (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1).

For adults and children

Treatment should not be extended beyond 14 days without review.

Adults and children

One 250 mg/125 mg tablet taken three times a day.

Children < 40 kg

Augmentin 250 mg/125 mg film-coated tablets are not recommended in children < 40 kg.

Elderly

No dose adjustment is considered necessary.

Renal impairment

Dose adjustments are based on the maximum recommended level of amoxicillin.

No adjustment in dose is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.

Adults and children

CrCl: 10-30 ml/min	250 mg/125 mg twice daily
CrCl < 10 ml /min	250 mg/125 mg once daily
Haemodialysis	Two doses of 250 mg/125 mg every 24 hours, plus two doses of 250 mg/125 mg during dialysis, to be repeated at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased)

Children < 40 kg

In children < 40 kg with creatinine clearance less than 30 ml/min, the use of Augmentin presentations with an amoxicillin to clavulanic acid ratio of 2:1 is not recommended, as no dose adjustments are available. In such patients, Augmentin formulations with an amoxicillin to clavulanic acid ratio of 4:1 are recommended.

Hepatic impairment

Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4).

Method of administration

Augmentin is for oral use.

Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid.

4.3 Contraindications

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.

History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).

History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8).

4.4 Special Warnings And Precautions For Use

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents.

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted.

In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.

This presentation of Augmentin is not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid (e.g. penicillin-insusceptible S. pneumoniae).

Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).

Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.

Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see Section 4.8). This reaction requires Augmentin discontinuation and contra-indicates any subsequent administration of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8).

Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and, in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8).

Antibiotic-associated colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation.

Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.

Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8).

In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2).

In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9).

During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods.

The presence of clavulanic acid in Augmentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see section 4.4 and 4.8).

Methotrexate

Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.

4.6 Pregnancy And Lactation

Pregnancy

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.

Lactation

Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. The possibility of sensitisation should be taken into account. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).

4.8 Undesirable Effects

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting.

The ADRs derived from clinical studies and post-marketing surveillance with Augmentin, sorted by MedDRA System Organ Class are listed below.

The following terminologies have been used in order to classify the occurrence of undesirable effects.

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Infections and infestations
Mucocutaneous candidosis	Common
Overgrowth of non-susceptible organisms	Not known
Blood and lymphatic system disorders
Reversible leucopenia (including neutropenia)	Rare
Thrombocytopenia	Rare
Reversible agranulocytosis	Not known
Haemolytic anaemia	Not known
Prolongation of bleeding time and prothrombin time1	Not known
Immune system disorders10
Angioneurotic oedema	Not known
Anaphylaxis	Not known
Serum sickness-like syndrome	Not known
Hypersensitivity vasculitis	Not known
Nervous system disorders
Dizziness	Uncommon
Headache	Uncommon
Reversible hyperactivity	Not known
Convulsions2	Not known
Gastrointestinal disorders
Diarrhoea	Very common
Nausea3	Common
Vomiting	Common
Indigestion	Uncommon
Antibiotic-associated colitis4	Not known
Black hairy tongue	Not known
Hepatobiliary disorders
Rises in AST and/or ALT5	Uncommon
Hepatitis6	Not known
Cholestatic jaundice6	Not known
Skin and subcutaneous tissue disorders 7
Skin rash	Uncommon
Pruritus	Uncommon
Urticaria	Uncommon
Erythema multiforme	Rare
Stevens-Johnson syndrome	Not known
Toxic epidermal necrolysis	Not known
Bullous exfoliative-dermatitis	Not known
Acute generalised exanthemous pustulosis (AGEP)9	Not known
Renal and urinary disorders
Interstitial nephritis	Not known
Crystalluria8	Not known
1 See section 4.4 2 See section 4.4. 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking amoxicillin/clavulanic acid at the start of a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See sections 4.3 and 4.4

4.9 Overdose

Symptoms and signs of overdose

Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).

Convulsions may occur in patients with impaired renal function or in those receiving high doses.

Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4)

Treatment of intoxication

Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.

Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.

Mode of action

Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.

PK/PD relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.

Mechanisms of resistance

The two main mechanisms of resistance to amoxicillin/clavulanic acid are:

• Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class B, C and D.

• Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints

MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Organism	Susceptibility Breakpoints (μg/ml)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae1		-	> 1
Moraxella catarrhalis1		-	> 1
Staphylococcus aureus 2		-	> 2
Coagulase-negative staphylococci 2			> 0.25
Enterococcus1		8	> 8
Streptococcus A, B, C, G5		-	> 0.25
Streptococcus pneumoniae3		1-2	> 2
Enterobacteriaceae1,4	-	-	> 8
Gram-negative Anaerobes1		8	> 8
Gram-positive Anaerobes1		8	> 8
Non-species related breakpoints1		4-8	> 8
1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l. 2 The reported values are Oxacillin concentrations. 3 Breakpoint values in the table are based on Ampicillin breakpoints. 4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant. 5 Breakpoint values in the table are based on Benzylpenicillin breakpoints.

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.

Commonly susceptible species

Aerobic Gram-positive micro-organisms Enterococcus faecalis Staphylococcus aureus ( methicillin-susceptible)£ Streptococcus agalactiae Streptococcus pneumoniae1 Streptococcus pyogenes and other beta-hemolytic streptococci Streptococcus viridans group Aerobic Gram-negative micro-organisms Capnocytophaga spp. Eikenella corrodens Haemophilus influenzae2 Moraxella catarrhalis Pasteurella multocida Anaerobic micro-organisms Bacteroides fragilis Fusobacterium nucleatum Prevotella spp.

Species for which acquired resistance may be a problem

Aerobic Gram-positive micro-organisms Enterococcus faecium $ Aerobic Gram-negative micro-organisms Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Proteus vulgaris

Inherently resistant organisms

Aerobic Gram-negative micro-organisms Acinetobacter sp. Citrobacter freundii Enterobacter sp. Morganella morganii Providencia spp. Pseudomonas sp. Serratia sp. Stenotrophomonas maltophilia

$ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid 1Streptococcus pneumoniae that is fully susceptible to penicillin may be treated with this presentation of amoxicillin/clavulanic acid. Organisms that show any degree of reduced susceptibility to penicillin should not be treated with this presentation (see sections 4.2 and 4.4). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%.

5.2 Pharmacokinetic Properties

Absorption

Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (T_max) in each case is approximately one hour.

The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (250 mg/125 mg tablets three times daily) was administered in the fasting state to groups of healthy volunteers are presented below.

Mean (± SD) pharmacokinetic parameters
Active substance(s) administered	Dose	Cmax	Tmax *	AUC (0-24h)	T 1/2
(mg)	(μg/ml)	(h)	((μg.h/ml)	(h)
Amoxicillin
AMX/CA 250 mg/125 mg	250	3.3 ± 1.12	1.5 (1.0-2.0)	26.7±4.56	1.36 ± 0.56
Clavulanic acid
AMX/CA 250 mg/125 mg	125	1.5 ± 0.70	1.2 (1.0-2.0)	12.6 ± 3.25	1.01 ± 0.11
AMX – amoxicillin, CA – clavulanic acid * Median (range)

Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone.

Distribution

About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid.

Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.

From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6).

Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6).

Biotransformation

Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air.

Elimination

The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms.

Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single Augmentin 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration.

Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5).

Age

The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Gender

Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid.

Renal impairment

The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2).

Hepatic impairment

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

5.3 Preclinical Safety Data

Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction.

Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue.

Carcinogenicity studies have not been conducted with amoxicillin/clavulanic acid or its components.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Augmentin 375 mg tablets:

Each tablet contains magnesium stearate, sodium starch glycollate, colloidal silica, microcrystalline cellulose, titanium dioxide (E171), hydroxypropyl methylcellulose, polyethylene glycol and silicone oil.

6.2 Incompatibilities

None

6.3 Shelf Life

Augmentin 375 mg Tablets

Blister enclosed in pouch 24M, Glass Bottles 24M

6.4 Special Precautions For Storage

Augmentin 375 mg Tablets should be stored in a dry place at 25°C or below.

6.5 Nature And Contents Of Container

Augmentin 375 mg Tablets: Aluminium PVC/PVdC blister enlcosed within an aluminium laminate pouch containing a desiccant sachet. Each pouch contains a plaque of 7 tablets. 3 pouches are enclosed within a carton to provide a pack of 21 tablets. Tablets are also supplied in amber glass bottles of 50 and 100*.

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data

7. Marketing Authorisation Holder

Beecham Group plc

980 Great West Road

Brentford

Middlesex TW8 9GS

Trading as:

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex UB11 1BT

8. Marketing Authorisation Number(S)

PL 00038/0270

9. Date Of First Authorisation/Renewal Of The Authorisation

27 July 2002

10. Date Of Revision Of The Text

01 June 2010