Cefuroxime 1500 mg powder for solution for injection / infusion

1. Name Of The Medicinal Product

Cefuroxime 1500 mg powder for solution for injection/infusion

2. Qualitative And Quantitative Composition

1 vial contains 1500 mg of cefuroxime as 1578 mg of cefuroxime sodium.

1 infusion bottle contains 1500 mg of cefuroxime as 1578 mg of cefuroxime sodium.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Powder for solution for injection/infusion.

White to yellowish powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Cefuroxime is indicated in the parenteral treatment of the following infections caused by sensitive pathogens:

• respiratory tract infections: e.g. acute and chronic bronchitis, bacterial pneumonia

• infections of the ear, nose and throat,

• urinary tract infections

• infections of skin and soft tissue

• bone and joint infections

• obstetric and gynaecological infections

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

4.2 Posology And Method Of Administration

Route of Administration:

By intravenous injection or infusion.

Usual dosage for Adults and the Elderly:

Most infections will respond to cefuroxime 750 mg three times a day. For more severe infections, the dose may be increased to 1.5 g three times a day by intravenous injection.

The intramuscular method of administration is reserved to exceptional clinical situations and should undergo a risk-benefit assessment.

Special advice for intramuscular injection has to be regarded (please refer to section 6.6).

If necessary, the frequency of administration of cefuroxime can be increased to four times a day up to total daily doses of 3 g to 6 g.

Infants, toddlers and Children:

The daily dosage range is 30 to 100 mg/kg/day given as three or four divided doses. Most infections will respond to a dose of 60 mg/kg/day.

Neonates ( see section 5.2):

The daily dosage range is 30 to 100 mg/kg/day given as two or three divided doses. In the first weeks of life the serum half-life of cefuroxime can be three to five times that in adults.

For impaired renal function:

It is not necessary to reduce the dose if creatinine clearance is more than 20 ml/min. The recommended maintenance doses in impaired renal function are as follows:

Creatinine clearance (ml/min)	Recommended dosage of cefuroxime (mg)	Frequency of dosage (hours)
> 20	normal dosage
10-20	750	12
< 10	750	24
CAPD patients	750	12
Patients on CAVH/CAVHD	750	12

Special precautions are required if creatinine clearance is <10 ml/minute under appropriate expert supervision.

Patients undergoing haemodialysis will require a further 750 mg dose of cefuroxime at the end of each dialysis treatment. A suitable dosage for patients on continuous peritoneal dialysis is usually 750 mg twice daily.

A dosage of 750 mg twice daily is recommended for patients in renal failure on continuous arteriovenous haemodialysis or high flux haemofiltration in intensive therapy units. For low flux haemofiltration follow the dosage recommended under impaired renal function.

Cefuroxime is usually effective as a single therapy in the treatment of the above infections.

4.3 Contraindications

Hypersensitivity to Cefuroxime or to any other cephalosporin antibiotics.

Previous immediate and/or severe hypersensitivity reaction to penicillin or any beta-lactam drug.

4.4 Special Warnings And Precautions For Use

Special care is indicated in patients who have experienced an allergic reaction to a penicillin or to any other type of beta-lactam drug.

If after administration of cefuroxime sodium sensitivity reactions occur, the use should be discontinued immediately and an appropriate treatment should be established.

Special care should be taken in patients with hepatic dysfunction.

Renal function should be monitored in the elderly, and those with pre-existing renal impairment (see section 4.2). Clinical experience with cefuroxime sodium has shown that this is not likely to be a problem at the recommended dose levels.

There may be some variation on the results of biochemical tests of renal function, but these do not appear to be of clinical importance. As a precaution, renal function should be monitored if this is already impaired.

As with other broad spectrum antibiotics, prolonged use of cefuroxime sodium may result in the overgrowth of non-susceptible organisms (e.g. candida, enterococci and clostridium dificile) which may require interruption of treatment.

In patients who develop severe diarrhoea during or after use of cefuroxime sodium, the risk of life threatening pseudo-membranous colitis should be taken into account. The use of cefuroxime sodium should be discontinued and the appropriate treatment established. The use of preparations inhibiting intestinal peristalsis is contra-indicated (see section 4.8).

Long term use of cefuroxime sodium may lead to an excess of pathogens resistant to cefuroxime sodium. It is of high importance that the patient is carefully checked. If a super-infection occurs during treatment, appropriate measures should be taken (see section 4.8).

Either the glucose oxidase or the hexokinase methods are recommended to determine the blood and plasma glucose levels in patients receiving cefuroxime sodium. Cefuroxime does not interfere in the alkaline picrate assay for creatinine (see section 4.5).

Cefuroxime is excreted via the kidneys. Therefore a dosage adjustment is required in patients with impaired renal function (see section 4.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Cephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with potent diuretics such as furosemide, aminoglycosides and amphotericin as concomitant use increases the risk of nephrotoxicity.Renal function should be monitored in these patients.

Concomitant therapy with probenecid can reduce the renal excretion of cephalosporins. Plasma concentrations are enhanced if probenecid is given concomitantly.

Since bacteriostatic drugs may interfere with the bactericidal action of cephalosporins, it is advisable to avoid giving tetracyclines, macrolides, or chloramphenicol in conjunction with cefuroxime.

Urine sugar tests using reduction methods may show false positive reactions, therefore enzymatic methods should be used (see section 4.4).Cefuroxime sodium does not interfere in enzyme-based tests for glycosuria. Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed. However, this should not lead to false-positive results, as may be experienced with some other cephalosporins (see section 4.4).

During intravenous administration admixture with other medications in solution should be avoided.

Sodium bicarbonate is not recommended for the dilution of Cefuroxime.

The use of cefuroxime sodium may be accompanied by a false positive Coombs test. This may interfere with the performance of cross matching tests with blood (see section 4.8 ).

4.6 Pregnancy And Lactation

Use in pregnancy

There are not sufficient data on the use of cefuroxime sodium during pregnancy to assess its possible harmfulness. So far, animal tests have not yielded evidence of harmfulness. Cefuroxime crosses the placenta. Cefuroxime sodium should not be used during pregnancy unless considered essential by the physician

Use during lactation

Cefuroxime is excreted to a small degree in human milk; breast feeding should be avoided in women using cefuroxime sodium.

4.7 Effects On Ability To Drive And Use Machines

Cefuroxime may sometimes be associated with side effects, such as dizziness, that may impair the ability to drive a vehicle, to operate machinery or to work safely (see section 4.8).

4.8 Undesirable Effects

Common (

Uncommon (

Rare (

Very rare (<1/10,000), not known (cannot be extimated from the available data)

Infections and infestations:

Rare

As with other antibiotics prolonged use may lead to secondary superinfections caused by insusceptible organisms, e.g. Candida, Enterococci and Clostridium difficile

Blood and the lymphatic system disorders

Common

Neutropenia, eosinophilia

Uncommon

Leukopenia, decreased haemoglobin concentration, positive Coomb´s test

Rare

Thrombocytopenia

Very rare

Haemolytic anemia

Cephalosporins as a class tend to be absorbed onto the surface of red cell membranes and react with antibodies directed against the drug to produce a positive Coomb´s test (which can interfere with cross matching of blood) and very rarely haemolytic anaemia.

Immune system disorders:

Hypersensitivity reactions including

Uncommon

Skin rash, urticaria and pruritus

Rare

Drug fever, serum sickness

Very rare

Anaphylaxis, cutaneous vasculitis

See also “Skin and subcutaneous tissue disorders” and “Renal and urinary disorders”.

Nervous system disorders:

Uncommon

Headache, dizziness

Very rare

Vertigo, restlessness, nervousness, confusion

Ear and labyrinth disorders:

Mild to moderate hearing loss has been reported in some children treated for meningitis with cefuroxime.

Gastrointestinal disorders:

Uncommon

Gastrointestinal disturbance s such as diarrhoea, nausea and vomiting have been reported.

Very rare

Pseudomembranous colitis

Hepato-biliary disorders:

Common

Transient rise in liver enzymes.Uncommon

Transient rise in bilirubin.

Very rare

Jaundice

Transient rises in serum liver enzymes or bilirubin occur, particulary in patients with preexisting liver disease, but there is no evidence of harm to the liver.

Skin and subcutaneous tissue disorders:

Very rare

Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

See also “Immune system disorders”.

Renal and urinary disorders

Uncommon

Acute interstitial nephritis.

Nephrotoxicity has been reported. Acute renal tubular necrosis has followed excessive dosage and has also been associated with its use in older patients or those with pre-existing renal impairment.

Very rare

Elevations in serum creatinine, elevations in blood urea nitrogen and decreased creatinine clearance (see section 4.4).

See also “Immune system disorders”.

General disorders and administration site conditions:

Common

Injection site reactions which may include pain and thrombophlebitis.

Pain at the intramuscular injection site is more likely at higher doses.

However, this is unlikely to be a cause for discontinuation of treatment. After rapid intravenous administration of cefuroxime heat sensations or nausea may occur.

4.9 Overdose

Overdosage of cephalosporins can cause cerebral irritation leading to convulsions. Serum levels of cefuroxime can be reduced by haemodialysis or peritoneal dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

General properties:

ATC classification

Pharmacotherapeutic group: cephalosporins and related substances.

ATC-Code: J01D A06

Mode of action

All cephalosporins (β-lactam antibiotics) inhibit cell wall production and are selective inhibitors of peptidoglycan synthesis. The initial step in drug action consists of binding of the drug to cell receptors, called Penicillin-Binding Proteins. After a β-lactam antibiotic has bound to these receptors, the transpeptidation reaction is inhibited and peptidoglycan synthesis is blocked. Bacterial lysis is the end result.

Mechanism of resistance:

Bacterial resistance to cefuroxime may be due to one or more of the following mechanisms:

• hydrolysis by beta-lactamases. Cefuroxime may be efficiently hydrolysed by certain of the extended-spectrum beta-lactamases (ESBLs) and by the chromosomally-encoded (AmpC) enzyme that may be induced or stably derepressed in certain aerobic gram-negative bacterial species

• reduced affinity of penicillin-binding proteins for cefuroxime

• outer membrane impermeability, which restricts access of cefuroxime to penicillin binding proteins in gram-negative organisms

• drug efflux pumps

Methicillin-resistant staphylococci (MRS) are resistant to all currently available β-lactam antibiotics including cefuroxime.

Penicillin-resistant Streptococcus pneumoniae are cross-resistant to cephalosporins such as cefuroxime through alteration of penicillin binding proteins.

Beta-lactamase negative, ampicillin resistant (BLNAR) strains of H. influenzae should be considered resistant to cefuroxime despite apparent in vitro susceptibility.

Strains of Enterobacteriaceae, in particular Klebsiella spp. and Escherichia coli that produce ESBLs (extended spectrum β-lactamase) may be clinically resistant to therapy with cephalosporins despite apparent in vitro susceptibility and should be considered as resistant.

Breakpoints :

The following MIC breakpoints separating susceptible from intermediately susceptible organism and intermediately susceptible from resistant organisms are used.

Table 1: EUCAST (European Committee on Antimicrobial Susceptibility Testing)

Susceptibility breakpoints.

Organism	susceptible	resistant > (mg/l)
EnterobacteriaceaeA	8	8
Staphylococcus spp B .	-*	-*
Streptococcus (group A, B, C, G)C	-	-
Streptococcus pneumoniae	0.5	1
Haemophilus influenzae	1	2
Moraxella catarrhalis	1	2
Non species-related breakpointsD	4	8

A The breakpoints relate to a dosage of 1.5 g three times per day and to Escherichia coli, Proteus mirabilis and Klebsiella spp. only.

B The susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility.

C The susceptibility of streptococcus groups A, B, C and G can be inferred from their susceptibility to benzylpenicillin.

D Generally based on serum pharmacokinetics.

Susceptibility :

The prevalence of resistance may vary geographically and with time for selected species and local information 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

Aerobes, Gram positive : Staphylococcus aureus (methicillin-susceptible) Coagulase-negative staphylococci (methicillin-susceptible) Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes

Aerobes, Gram negative : Haemophilus influenzae Moraxella catarrhalis Proteus mirabilis Proteus rettgeri

Anaerobes Peptococcus species Peptostreptococcus species

Other organisms: Borrelia burgdorferi

Species for which resistance may be a problem

Citrobacter species Escherichia coli Enterobacter species Klebsiella species

Resistant Acinetobacter species Bacteroides fragilis Clostridium difficile Enterococci Listeria monocytogenes Morganella morganii Proteus vulgaris Pseudomonas species Serratia species

5.2 Pharmacokinetic Properties

Absorption

Cefuroxime is poorly absorbed from the gastro-intestinal tract and is given by intramuscular or intravenous injection or infusion as the sodium salt. Peak plasma concentration of 27 μg per ml have been achieved about 45 minutes after an intramuscular dose of 750 mg with measurable amounts present 8 hours after a dose.

Distribution

Cefuroxime is widely distributed in the body including pleural fluid, sputum, bone, synovial fluid, and aqueous humour, but only achieves therapeutic concentrations in the CSF when the meninges are inflamed. About 50% of cefuroxime in the circulation is bound to plasma proteins. It diffuses across the placenta and has been detected in breast milk.

Metabolism

Cefuroxime is not metabolized.

Elimination

Most of the dose of cefuroxime is excreted unchanged. About 50% is excreted by glomerular filtration and about 50% through renal tubular secretion within 24 hours, with the majority being eliminated within 6 hours; high concentrations are achieved in the urine. Small amounts of cefuroxime are excreted in bile.

Probenecid competes with cefuroxime for renal tubular secretion resulting in higher and more prolonged plasma concentrations of cefuroxime. The plasma half-life is about 70 minutes after either intramuscular, or intravenous injection and is prolonged in patients with renal impairment and in neonates.

5.3 Preclinical Safety Data

Cefuroxime sodium has a very low order of toxicity as demonstrated by acute toxicity studies. Investigations of chronic toxicity in several animal species (rat, dog and monkey) yielded no indications of drug related toxicological effects. The most prominent treatment-related effect was tissue damage at the injection sites.

A cefuroxime ester did not show clinically relevant effects when tested in vitro and in vivo for genotoxic potential.

Preclinical nephrotoxicity studies showed the product can cause renal damage in some species when administered in very high doses. Its nephrotoxicity increases when administered in combination with glycerol and furosemide.

No long-term investigations for determination of tumorigenic potential were performed.

Investigations in rabbits and mice did not demonstrate reproductive toxicity or teratogenic-effects. Cefuroxime has been shown to pass the placenta.

Gamma-glutamyl transpeptidase activity in rat urine is inhibited by various cephalosporins, however, the level of inhibition is less with cefuroxime. This may have significance in the interference in clinical laboratory tests in humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None.

6.2 Incompatibilities

Cefuroxime should not be mixed in the syringe with aminoglycoside antibiotics.

Mixing of cefuroxime with sodium bicarbonate solutions significantly affects the colour of the solution. Therefore, this solution is not recommended for the dilution of cefuroxime. If required, the cefuroxime solution in water for injections can be introduced into the tubing of the giving set in patients receiving sodium bicarbonate solution by infusion.

6.3 Shelf Life

24 months.

Do not store above 25°C.

Reconstituted solution: Chemical and physical stability has been demonstrated for 2 hours at 25°C and for 24 hours at 2°C – 8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally be no longer than 24 hours at 2°C – 8 °C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Keep the vial/infusion bottle in the outer carton in order to protect from light.

Reconstituted solution: The product should be used immediately. Keep the vial/infusion bottle in outer carton in order to protect from light.

6.5 Nature And Contents Of Container

30 ml vials of clear glass type III (Ph. Eur.) closed with rubber stopper and flip-off bordered caps.

100 ml infusion bottles of clear glass type II (Ph. Eur.) closed with rubber stopper and flipp-off bordered caps.

Pack sizes: 1, 5, 10, 25, 50, 100 vials/infusion bottles.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Compatibility with intravenous solutions

Cefuroxime remains stable for 2 hours at room temperature and 24 h at 2 °C – 8 °C, if dissolved in:

− water for injections

− 0.9 % sodium chloride solution

− 5 % glucose solution

Instructions for reconstitution

Cefuroxime 1500 mg powder for solution for injection/infusion should NOT be administered intramuscularly.

Cefuroxime 1500 mg powder for solution for injection/infusion as intravenous injection:

Dissolve Cefuroxime 1500 mg powder for solution for injection/infusion in at least 15 ml of water for injections, 0.9 % sodium chloride solution or 5 % glucose solution. Shake gently to produce a clear solution.

Cefuroxime 1500 mg powder for solution for injection/infusion as short intravenous infusion:

For short intravenous infusion (e.g. up to 30 minutes) Cefuroxime 1500 mg powder for solution for injection/infusion may be dissolved in 50 ml of water for injection, 0.9 % sodium chloride solution or 5 % glucose solution. These solutions may be given directly into the vein or introduced into the tubing of the giving set. Shake gently to produce a clear solution.

The contents and concentrations of cefuroxime as solution/suspension are shown in the table below:

mg cefuroxime per vial	addition of ml solvent	volume ml of final solution / suspension	Concentration mg/ml
250 750 1500 1500	2 6 15 50	2.2 6.8 16.5 51.5	114 110 91 29

Note: Antibiotics should not be added to routine infusion fluids. Most infusion fluids are given over 6 to 8 hours and this is impractical for antibiotic therapy. Cefuroxime should be given over short periods (30 minutes).

When reconstituted for intravenous injection, the white to yellowish powder gives a colourless to brownish-yellow solution respectively.

As for all parenteral medicinal products, inspect the reconstituted solution / suspension visually for particulate matter and discoloration prior to administration. The reconstituted solution is clear. For single use only. Any remaining solution should be discarded.

7. Marketing Authorisation Holder

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Marketing Authorisation Number(S)

PL 04416/0620

9. Date Of First Authorisation/Renewal Of The Authorisation

20^th July 2005

10. Date Of Revision Of The Text

November 2010

Cefotaxime 2g Powder for solution for injection or infusion (Wockhardt UK Ltd)

1. Name Of The Medicinal Product

Cefotaxime 2g Powder for solution for injection or infusion

2. Qualitative And Quantitative Composition

Each vial contains cefotaxime sodium equivalent to 2g of cefotaxime.

Each gram of cefotaxime contains approximately 48mg (2.09mmol) of sodium.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for injection or infusion (Powder for injection or infusion).

White to slightly yellow powder.

4. Clinical Particulars

4.1 Therapeutic Indications

1. Cefotaxime is indicated in the treatment of serious infections, either before the infecting organism has been identified or when caused by bacteria of established sensitivity, including

osteomyelitis,

septicaemia,

bacterial endocarditis,

meningitis, and

peritonitis.

and other serious bacterial infections suitable for parenteral antibiotic therapy.

2. Cefotaxime may be used for pre-operative prophylaxis in patients undergoing surgical procedures, that may be classified as contaminated or potentially so.

4.2 Posology And Method Of Administration

Cefotaxime may be administered intravenously, by bolus injection or by infusion, or by intramuscular injection. The dosage, route and frequency of administration should be determined by the severity of infection, the sensitivity of causative organisms and condition of the patient. Therapy may be initiated before the results of sensitivity tests are known.

Adults:

The recommended dosage for mild to moderate infections is 1g 12 hourly. However, dosage may be varied according to the severity of the infection, sensitivity of causative organisms and condition of the patient. Therapy may be initiated before the results of sensitivity tests are known.

In severe infections dosage may be increased up to 12g daily given in three or four divided doses. For infections caused by sensitive Pseudomonas species daily doses of greater than 6g will usually be required.

Children:

The usual dosage range is 100-150mg/kg/day in two to four divided doses. However, in very severe infection doses of up to 200mg/kg/day may be required.

Neonates: The recommended dosage is 50mg/kg/day in two to four divided doses. In severe infections 150-200mg/kg/day, in divided doses, have been given.

Dosage in renal impairment: Because of extra-renal elimination, it is only necessary to reduce the dosage of cefotaxime in severe renal failure (GFR <5ml/min = serum creatinine approximately 751 micromol/litre). After an initial loading dose of 1g, daily dose should be halved without change in the frequency of dosing, i.e. 1g twelve hourly becomes 0.5g twelve hourly, 1g eight hourly becomes 0.5g eight hourly, 2g eight hourly becomes 1g eight hourly etc. As in all other patients, dosage may require further adjustment according to the course of the infection and the general condition of the patient.

Dosage in hepatic impairment: No dosage adjustment is required.

Intravenous and Intramuscular Administration: Reconstitute cefotaxime with Water for Injections PhEur as directed in Section 6.6 (Instructions for use/handling). Shake well until dissolved and then withdraw the entire contents of the vial into the syringe.

Intravenous Infusion: Cefotaxime may be administered by intravenous infusion using the fluids stated in Section 6.6 (Instructions for use/handling). The prepared infusion may be administered over 20-60 minutes.

4.3 Contraindications

Known or suspected allergy to cephalosporins.

Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta-lactam drug.

Cefotaxime constituted with Lidocaine Injection BP must never be used:

- by the intravenous route

- in infants under 30 months

- in subjects with a previous history of hypersensitivity to Lidocaine Injection BP

- in patients who have an unpaced heart block

- in patients with severe heart failure.

4.4 Special Warnings And Precautions For Use

Preliminary enquiry about hypersensitivity to penicillin and other β-Lactam antibiotics is necessary before prescribing cephalosporins since cross allergy occurs in 5–10% of cases. Cefotaxime is contraindicated in patients who have had a previous hypersensitivity reaction to any cephalosporin. It is also contraindicated in patients who have had a previous immediate and/or any severe hypersensitivity reaction to any penicillin or to any other beta

Patients with severe renal dysfunction should be placed on the dosage schedule recommended under “Posology and Method of Administration”.

Since haematological abnormalities may develop during treatment with cefotaxime, blood count should be monitored if treatment lasts for longer than 7 days. In case of neutropenia (<1400 neutrophils/mm³), treatment should be interrupted.

As with other antibiotics, the use of cefotaxime, especially if prolonged, may result in overgrowth of non susceptible organisms, such as Enterococcus spp, candida, Pseudomonas aeruginosa. Repeated evaluation of the condition of the patient is essential. If superinfection occurs during treatment with cefotaxime, specific anti-microbial therapy should be instituted if considered clinically necessary.

The sodium content of cefotaxime (2.09mmol/g) should be taken into account when prescribing to patients requiring sodium restriction.

Cefotaxime may predispose patients to pseudomembranous colitis. Although any antibiotic may predispose to pseudomembranous colitis, the risk is higher with broad spectrum drugs, such as cephalosporins. This side effect, which may occur more frequently in patients receiving higher doses for prolonged periods, should be considered as potentially serious. The presence of C. difficile toxin should be investigated, and treatment with cefotaxime stopped in cases of suspected colitis. Diagnosis can be confirmed by toxin detection and specific antibiotic therapy (e.g. oral vancomycin or metronidazole) should be initiated if considered clinically necessary. The administration of products which cause faecal stasis should be avoided.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Aminoglycoside antibiotics and diuretics: Cephalosporin antibiotics at high dosage should be given with caution to patients receiving aminoglycoside antibiotics or potent diuretics such as frusemide as these combinations are suspected to adversely affect renal function. However, at the recommended doses, enhancement of nephrotoxicity is unlikely to be a problem with cefotaxime.

Uricosurics: Probenecid interferes with renal tubular transfer of cefotaxime delaying its excretion and increasing the plasma concentration.

Interference with Laboratory Tests:

A false positive Coombs test may be seen during treatment with cephalosporins. This phenomenon may occur during treatment with cefotaxime and can interfere with blood cross-matching.

A false positive reaction to urinary glucose may occur with copper reduction methods (Benedict's, Fehling's or Clinitest) but not with the use of specific glucose oxidase methods.

4.6 Pregnancy And Lactation

Pregnancy: It is known that cefotaxime crosses the placental barrier. Although studies in animals have not shown an adverse effect on the developing foetus, the safety of cefotaxime in human pregnancy has not been established. Consequently, cefotaxime should not be administered during pregnancy especially during the first trimester, without carefully weighing the expected benefit against possible risks.

Lactation: Cefotaxime is excreted in the milk in small amounts and is usually compatible with breast feeding, but careful monitoring of the infant is recommended. Consequently caution should be exercised when cefotaxime is administered to a nursing woman.

.

4.7 Effects On Ability To Drive And Use Machines

Cefotaxime has been associated with dizziness, which may affect the ability to drive or operate machinery.

4.8 Undesirable Effects

Adverse reactions to cefotaxime have occurred relatively infrequently and have generally been mild and transient. Effects reported include the following;

Genito Candidiasis.

Gastrointestinal: Nausea, vomiting, abdominal pain, diarrhoea (diarrhoea may sometimes be a symptom of pseudomembranous colitis see 4.4, Special Warnings and precautions for use).

Hepatobiliary: Transient rises in liver transaminases, alkaline phosphatase and/or bilirubin, transient hepatitis and cholestatic jaundice.

Renal: As with other cephalosporins, changes in renal function have been rarely observed with high doses of cefotaxime, particularly when co-prescribed with aminoglycosides. Rare cases of interstitial nephritis have been reported in patients treated with cefotaxime.

Nervous system: Headache, dizziness. Administration of high doses of cephalosporins, particularly in patients with renal insufficiency, may result in encephalopathy (e.g. impairment of consciousness, abnormal movements and convulsions).

Hypersensitivity: Hypersensitivity reactions have been reported. These include skin rashes, pruritus and less frequently urticaria, drug fever and very rarely anaphylaxis (e.g. angioedema and bronchospasm possibly culminating in shock). As with other cephalosporins, occasional cases of bullous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have also been reported.

Blood and lymphatic system: As with other beta-lactam antibiotics, granulocytopenia and more rarely agranulocytosis may develop during treatment with cefotaxime, particularly if given over long periods. A few cases of eosinophilia and neutropenia have been observed, reversible when treatment is ceased. Some cases of rapidly reversible eosinophilia and thrombocytopenia on stopping treatment, have been reported. Rare cases of haemolytic anaemia have been reported. For cases of treatment lasting longer than 10 days, blood count should therefore be monitored.

Cardiac: Avery small number of cases of arrhythmias have occurred following rapid bolus infusion through a central venous catheter.

Local effects: Transient pain may be experienced at the site of injection. This is more likely to occur with higher doses. Occasionally, phlebitis has been reported in patients receiving intravenous cefotaxime. However, this has rarely been a cause for discontinuation of treatment.

The following symptoms have occurred after several weeks of treatment for borreliosis (Lyme's Disease): skin rash, itching, fever, leucopenia, increases in liver enzymes, difficulty of breathing, joint discomfort. To some extent these manifestations are consistent with the symptoms of the underlying disease, for which the patient is being treated.

4.9 Overdose

Serum levels of cefotaxime may be reduced by peritoneal dialysis or haemodialysis. In the case of overdosage, particularly in renal insufficiency, there is a risk of reversible encephalopathy.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

General Properties

ATC Classification

Pharmacotherapeutic group: Beta-lactam antibiotics, cephalosporins.

ATC Code: J01D A10

Mode of action

Cefotaxime is a third generation broad spectrum bactericidal cephalosporin antibiotic. The bactericidal properties are due to the inhibitory effect of cefotaxime on bacterial cell wall synthesis.

Mechanisms of resistance

Resistance to Cefotaxime may be due to production of extended-spectrum beta-lactamases that can efficiently hydrolyse the drug, to the induction and/or constitutive expression of AmpC enzymes, to impermeability or to efflux pump mechanisms. More than one of these possible mechanisms may co-exist in a single bacterium.

Breakpoints:

Current MIC breakpoints used to interpret cefotaxime susceptibility data are shown below.

European Committee on Antimicrobial Susceptibility Testing (EUCAST) Clinical MIC Breakpoints (V1.1, 31/03/2006)

	Susceptible (< )/ Resistant (> )
Enterobacteriaceae2	1/2
Pseudomonas	--
Acinetobacter	--
Staphylococcus 3	Note3
Enterococcus	--
Streptococcus A, B, C, G	0.5/0.54
Streptococcus pneumoniae	0.5/24
Haemophilus influenzae Moraxella Catarrhalis	0.12/0.124
Neisseria gonorrhoea	0.12/0.124
Neisseria Meningitidis	0.12/0.124
Gram-negative, anaerobes	--
Non-species related breakpoints1 S< />R	1/2

1. Non-species related breakpoints have been determined mainly on the basis of PK/PD 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 not for those species where susceptibility testing is not recommended (marked with -- or IE in the table).

2. The cephalosporin breakpoints for Enterobacteriaceae will detect resistance mediated by most ESBLs and other clinically important beta-lactamases in Enterobacteriaceae. However, some ESBL-producing strains may appear susceptible or intermediate with these breakpoints. Laboratories may want to use a test which specifically screens for the presence of ESBL.

3. Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility (except ceftazidime which should not be used for staphylococcal infections).

4. 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. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported resistant.

-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug.

IE = There is insufficient evidence that the species in question is a good target for therapy with the drug.

RD = rationale document listing data used by EUCAST for determining breakpoints.

Susceptibility

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. This information gives only an approximate guidance on the probabilities whether micro-organisms will be susceptible to cefotaxime or not.

Species	Frequency of resistance ranges in EU (if > 10%) (extreme values)
Susceptible
Gram-positive aerobes
Staphylococcus aureus
(Methicillin-susceptible) *
Group A Streptococci (including Streptococcus pyogenes ) *
Group B Streptococci
β-hemolytic Streptococci (Group C, F, G)
Streptococcus pneumoniae *	12.7%
Viridans Group Streptococci
Gram-negative aerobes
Citrobacter spp. *
Escherichia coli*
Haemophilus influenzae*
Haemophilus parainfluenzae *
Klebsiella spp. *
Moraxella catarrhalis*
Neisseria gonorrhoeae *
Neisseria meningitides *
Proteus spp. *
Providencia spp. *
Yersinia enterocolitica
Anaerobes
Clostridium spp. (not Clostridium difficile)
Peptostreptococcus spp.
Propionibacterium spp.
Others
Borrelia spp.
Resistant
Gram-positive aerobes
Enterococcus spp.
Enterococcus faecalis
Enterococcus faecium
Listeria spp.
Staphylococcus aureus (MRSA)
Staphylococcus epidermidis (MRSE)
Gram-negative aerobes
Acinetobacter spp.
Citrobacter spp.
Enterobacter spp.
Morganella morganii
Pseudomonas spp.
Serratia spp.
Xanthomonas maltophilia
Anaerobes
Bacteroides spp.
Clostridium difficile Others Clamydiae Mycoplasma spp. Legionella pneumophilia

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

Methicillin-(oxacillin) resistant staphylococci (MRSA) are resistant to all currently available β-lactam antibiotics including cefotaxime.

Penicillin-resistant Streptococcus pneumoniae show a variable degree of cross-resistance to cephalosporins such as cefotaxime.

5.2 Pharmacokinetic Properties

After a 1000mg intravenous bolus, mean peak plasma concentrations of cefotaxime usually range between 81 and 102 microgram/ml. Doses of 500mg and 2000mg produce plasma concentrations of 38 and 200 microgram/ml, respectively. There is no accumulation following administration of 1000mg intravenously or 500mg intramuscularly for 10 or 14 days.

The apparent volume of distribution at steady-state of cefotaxime is 21.6 litres/1.73m² after 1g intravenous 30 minute infusion.

Concentrations of cefotaxime (usually determined by non-selective assay) have been studied in a wide range of human body tissues and fluids. Cerebrospinal fluid concentrations are low when the meninges are not inflamed, but are between 3 and 30 microgram/ml in children with meningitis. Cefotaxime usually passes the blood-brain barrier in levels above the minimum inhibitory concentration of common sensitive pathogens when the meninges are inflamed. Concentrations (0.2-5.4 microgram/ml), inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1 or 2g. Concentrations likely to be effective against most sensitive organisms are similarly attained in female reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid, renal tissue, peritoneal fluid and gall bladder wall, after usual therapeutic doses. High concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile.

Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390ml/minute and renal clearance 145 to 217 ml/minute.

After intravenous administration of cefotaxime to healthy adults, the elimination half-life of the parent compound is 0.9 to 1.14 hours and that of the desacetyl metabolite, about 1.3 hours.

In neonates the pharmacokinetics are influenced by gestational and chronological age, the half-life being prolonged in premature and low birth weight neonates of the same age.

In severe renal dysfunction the elimination half-life of cefotaxime itself is increased minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime is increased to about 10 hours. Total urinary recovery of cefotaxime and its principal metabolite decreases with reduction in renal function.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber that are additional to those included in other sections.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None.

6.2 Incompatibilities

Cefotaxime sodium should not be mixed with alkaline solutions such as sodium bicarbonate injection or solutions containing aminophylline.

Cefotaxime should not be admixed with aminoglycosides. If they are used concurrently they should be administered in separate sites.

Cefotaxime should not be mixed with other medicinal products except those listed in section 6.6.

6.3 Shelf Life

Unopened: 2 years.

For the reconstituted solution, chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C. From a microbiological point of view, once opened, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Unopened: Do not store above 25°C. Keep the vials in the outer carton.

For storage times following reconstitution, see section 6.3.

6.5 Nature And Contents Of Container

Cefotaxime is supplied in Type III 10ml glass vials, closed with a Type I rubber stopper coated in Omniflex and sealed with an aluminium cap fitted with a detachable flip top.

The vials are boxed individually and in packs of 10, 25 or 50 vials.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For single use only. Discard any unused contents.

When dissolved in Water for Injections PhEur, cefotaxime forms a straw-coloured solution suitable for intravenous and intramuscular injection. Variations in the intensity of colour of the freshly prepared solutions do not indicate a change in potency or safety.

Dilution table (Intramuscular and Intravenous administration):

Vial size	Diluent to be added	Approx available volume	Approx displacement volume
2g	10ml	11.2ml	1.2ml

Reconstituted solution: Whilst it is preferable to use only freshly prepared solutions for both intravenous and intramuscular injection, cefotaxime is compatible with several commonly used intravenous infusion fluids and will retain satisfactory potency for up to 24 hours refrigerated in the following:

Water for Injections Ph Eur

Sodium Chloride Intravenous Infusion BP

5% Glucose Intravenous Infusion BP

Sodium Chloride and Glucose Intravenous Infusion BP

Compound Sodium Lactate Intravenous Infusion BP (Ringer-lactate solution for injection)

Intravenous Infusion:

1-2g cefotaxime are dissolved in 40-100ml of infusion fluid.

After 24 hours any unused solution should be discarded.

Cefotaxime is compatible with 1% lidocaine; however freshly prepared solutions should be used.

Cefotaxime is also compatible with metronidazole infusion (500mg/100ml) and both will maintain potency when refrigerated (2º-8ºC) for up to 24 hours. Some increase in colour of prepared solutions may occur on storage. However, provided the recommended storage conditions are observed, this does not indicate change in potency or safety.

7. Marketing Authorisation Holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing Authorisation Number(S)

PL 29831/0029

PA 1339/2/3

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 13 October 2007 (UK)

19 December 2007 (Ireland)

10. Date Of Revision Of The Text

Catapres Tablets

Catapres Tablets 100 micrograms and 300 micrograms

(clonidine hydrochloride)

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets troublesome or serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What CATAPRES Tablets are and what they are used for


• 2. Before you take CATAPRES Tablets


• 3. How to take CATAPRES Tablets


• 4. Possible side effects


• 5. How to store CATAPRES Tablets


• 6. Further information

What Catapres Tablets Are And What They Are Used For

CATAPRES Tablets contain a medicine called clonidine. This belongs to a group of medicines called antihypertensives.

CATAPRES is used to lower high blood pressure (to treat hypertension).

Before You Take Catapres Tablets

Do not take CATAPRES if:

• You are pregnant, likely to get pregnant or are breast-feeding


• You are allergic (hypersensitive) to clonidine or any of the other ingredients of CATAPRES (see section 6: Further information)


• You have a slow heart rate due to heart problems

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before using CATAPRES.

Take special care with CATAPRES

Check with your doctor or pharmacist before taking CATAPRES if:

• You have Raynaud’s disease (a problem with circulation to the fingers and toes) or other blood circulation problems, including circulation to the brain


• You have heart or kidney problems


• You have or have ever had depression


• You have constipation


• You have a nerve disorder that causes your hands and feet to feel different (‘altered sensation’) or low blood pressure when you stand up

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking CATAPRES.

As you may get dry eyes whilst taking this medicine, this may be a problem if you wear contact lenses.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines that you buy without a prescription and herbal medicines. This is because CATAPRES can affect the way some other medicines work. Also some other medicines can affect the way CATAPRES works.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

• Other medicines that make you drowsy


• Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) such as ibuprofen


• Medicines for depression such as imipramine or mirtazapine


• Medicines for severe mental illness such as schizophrenia. These are also known as ‘antipsychotics’ and include chlorpromazine

Please also tell your doctor or pharmacist if you are taking any of the following medicines for high blood pressure or other heart problems:

• Beta blockers such as atenolol


• Water tablets (‘diuretics’) such as frusemide


• Alpha blockers such as prazosin or doxazosin. These can also be used for prostate problems in men


• Vasodilators such as diazoxide or sodium nitroprusside


• Calcium antagonists such as verapamil or diltiazem hydrochloride


• ACE inhibitors such as captopril or lisinopril


• Digitalis glycosides such as digoxin

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking CATAPRES.

Tests

If you are having any blood tests, tell the person giving the test that you are taking this medicine. This is because CATAPRES can affect results relating to your liver.

Operations

If you are going to have an operation, keep taking your CATAPRES Tablets. If you need to go into hospital, take the tablets with you.

Taking CATAPRES with food and drink

You may feel drowsy while taking CATAPRES. Drinking alcohol while taking CATAPRES can make this worse.

Pregnancy and breast-feeding

Do not take CATAPRES if you are pregnant, likely to get pregnant or are breast-feeding.

Driving or using machines

You may feel drowsy while taking CATAPRES, especially if you have been drinking alcohol. If this happens do not drive or use any tools or machines.

Important information about some of the ingredients of CATAPRES

CATAPRES contains lactose (a type of sugar). If you have been told by your doctor that you cannot tolerate or digest some sugars, talk to your doctor before taking this medicine.

How To Take Catapres Tablets

Always take CATAPRES exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Your doctor will start you on a low dose and gradually increase it. This will depend on how well your medicine works to control your blood pressure.

Taking this medicine

• Take this medicine by mouth


• The usual starting dose is between 50 micrograms and 100 micrograms, three times a day


• If necessary, your doctor will gradually increase the dose


• Most people’s blood pressure is controlled by taking between 300 micrograms and 1200 micrograms

CATAPRES is not recommended for children.

If you take more CATAPRES than you should

If you take more CATAPRES than you should, talk to a doctor or go to a hospital straight away. Take the medicine pack with you, even if there are no tablets left.

If you forget to take CATAPRES

If you forget a dose, take it as soon as you remember it. However, if it is nearly time for the next dose, skip the missed dose. Do not take a double dose to make up for a forgotten dose.

If you stop taking CATAPRES

Do not stop taking CATAPRES without first talking to your doctor. If you have been using this medicine for a long time, you may feel agitated when you stop taking it. This is called a ‘withdrawal effect’.

If you have any further questions on the use of CATAPRES, ask your doctor or pharmacist.

Catapres Tablets Side Effects

Like all medicines, CATAPRES can cause side effects, although not everybody gets them.

The side effects described below have been experienced by people taking CATAPRES. They are listed as either very common, common, uncommon, rare or not known.

Very common (affects more than 1 in 10 people)

• Dizziness, feeling tired and more relaxed than usual (sedation)


• Feeling dizzy when you stand up (because your blood pressure has fallen sharply)


• Dry mouth

Common (affects less than in 1 in 10 people, more than 1 in 100 people)

• Depression, sleeping problems


• Headache


• Constipation, feeling sick (nausea), pain below the ear (from the salivary gland), being sick (vomiting)


• Erectile dysfunction


• Fatigue

Uncommon (affects less than 1 in 100 people, more than 1 in 1,000 people)

• Problems with understanding what is happening around you, hallucinations, nightmares


• Your hands and feet feeling different (‘altered sensation’)


• Regular unusually slow heart beat


• Raynaud’s phenomenon (a problem with circulation to the fingers and toes)


• Itching, rash, urticaria (nettle rash)


• A feeling of discomfort and fatigue (‘malaise’)

Rare (affects less than 1 in 1,000 people, more than 1 in 10,000 people)

• Breast growth (‘gynaecomastia’) in men


• Dry eyes


• Irregular heartbeat


• Drying out of the lining of the nose


• Pseudo-obstruction of the large bowel, which causes colicky pain, vomiting and constipation. Contact your doctor straight away if you have all these side effects.


• Hair loss


• Increase in your blood sugar

Not known

• Confusion, loss of libido


• Blurred vision


• Abnormally slow heart beat

Two cases of hepatitis (inflammation of the liver) have also been reported. This might show up in some blood tests. Your body may hold onto more water than usual (fluid retention).

If any of the side effects gets troublesome or serious, or if you notice any side effects not listed in the leaflet, tell your doctor or pharmacist.

How To Store Catapres Tablets

Keep out of the reach and sight of children.

The tablets should not be stored above 30°C and the blister strips should be kept in the outer carton.

Do not use CATAPRES after the expiry date which is stated on the packaging. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

Further Information

What CATAPRES contains

• The active substance is clonidine hydrochloride. Each tablet contains either 100 micrograms or 300 micrograms.


• The other ingredients are: lactose monohydrate, calcium hydrogen phosphate (anhydrous), maize starch, colloidal silica (anhydrous), povidone, soluble starch and stearic acid.

What CATAPRES looks like and contents of the pack

• CATAPRES 100 microgram tablets are white, round and flat with a bevelled edge. They have the Boehringer Ingelheim company logo on one side and the code 01C written either side of the breakline on the other.


• CATAPRES 300 microgram tablets are white, round and flat with a bevelled edge. They have the Boehringer Ingelheim company logo on one side and the code 03C written either side of the breakline on the other.

CATAPRES tablets are available in blister packs of 100 tablets.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisations for CATAPRES are held by:

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

and the tablets are manufactured at:

Delpharm Reims S.A.S.

10 Rue Colonel Charbonneaux

51100 Reims

France

This leaflet was revised in October 2009.

© Boehringer Ingelheim Limited 2009

311450-006

20081008