SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Cefaclor for Oral Suspension 125 mg/5 mL.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 mL of the constituted suspension contains Cefaclor monohydrate 131.1 mg equivalent to anhydrous Cefaclor 125 mg.

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Granules for oral suspension.

White to off-white granular powder forming a red suspension on constitution with water having a strawberry flavour.

4.    CLINICAL PARTICULARS

4.1    Therapeutic Indications

Cefaclor is used in the treatment of the following mild or moderately-severe infections caused by susceptible microorganisms.

Respiratory tract infections, namely pneumonia (community acquired), acute exacerbations of chronic bronchitis, pharyngitis and tonsillitis and sinusitis. Otitis media

Skin and soft tissue infections Urinary tract infections, namely cystitis

Penicillin is the usual drug of choice for the treatment of streptococcal infections.

Cefaclor should not be used in the treatment of meningitis.

Consideration should be given to local guidance regarding the appropriate use of antibacterial agents.

4.2 Posology and Method of Administration

Cefaclor is administered orally. The spoon provided with the package dispenses a volume of 5 mL.

Adults: The usual adult dosage for mild to moderately-severe infections is 250 mg every eight hours. For more severe infections or those caused by less susceptible organisms, doses may be doubled to 500 mg every eight hours. Doses of 4 g per day have been administered safely to normal subjects for 28 days but the total daily dosage should not exceed this amount.

Cefaclor may be administered in the presence of impaired renal function. Under such conditions dosage adjustment may be necessary (see Precautions).

Patients undergoing haemodialysis: Haemodialysis shortens serum half-life by 25-30%. In patients undergoing regular haemodialysis, a loading dose of 250 mg - 1g administered prior to dialysis and a therapeutic dose of 250 - 500 mg every six to eight hours maintained during interdialytic periods is recommended.

The elderly: As for adults

Children: The usual recommended daily dosage for mild to moderately-severe infections in children is 20 mg/kg/day in divided doses every eight hours. For bronchitis and pneumonia, the dosage is 20 mg/kg/day in divided doses administered three times daily. Safety and efficacy have not been established for use in infants aged less than one month.

Cefaclor for oral Suspension	125 mg/5 ml	250 mg/5 ml
< 1 year (9 kg)	2.5 ml tid
1-5 years (9-18 kg)	5.0 ml tid
Over 5 years		5.0 ml tid

In more serious infections, otitis media, sinusitis and infections caused by less susceptible organisms, 40 mg/kg/day in divided doses is recommended up to a daily maximum of 1 g.

In the treatment of beta-haemolytic streptococcal infections, therapy should be continued for at least 10 days.

4.3 Contra-Indications

Cefaclor is contra-indicated in patients with hypersensitivity to the cephalosporin group of antibiotics or any of its ingredients (see section 6.1 List of excipients).

4.4 Special Warnings and Special Precautions for Use

Precautions: Cefaclor should be administered with caution in the presence of markedly impaired renal function. The half-life of cefaclor in anuric patients is 2.3 to 2.8 hours (compared to 0.6-0.9 hours in normal subjects). Dosage adjustments for patients with moderate or severe renal impairment may be necessary. Clinical experience with cefaclor under such conditions is limited, therefore careful clinical observation and laboratory studies should be made.

Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastro-intestinal disease, particularly colitis.

Prolonged use of cefaclor may result in the overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Positive direct Coombs' tests have been reported during treatment with the cephalosporin antibiotics. In haematological studies or in transfusion crossmatching procedures when anti-globulin tests are performed on the minor side, or in Coombs' testing of newborns whose mothers have received cephalosporin antibiotics before parturition, it should be recognised that a positive Coombs' test may be due to the drug.

A false-positive reactions for glucose in the urine may occur with Benedict's or Fehling's solutions or with Copper sulphate test tablets.

Warnings: Before instituting therapy with cefaclor, every effort should be made to determine whether the patient has had previous hypersensitivity reactions to cefaclor, cephalosporins, penicillins or other drugs. Cefaclor should be given cautiously to penicillin-sensitive patients because crosshypersensitivity, including anaphylaxis, among beta-lactam antibiotics has been clearly documented.

If an allergic reaction to cefaclor occurs, the drug should be discontinued and the patient treated with the appropriate agents.

Pseudomembranous colitis has been reported with virtually all broad-spectrum antibiotics including macrolides, semi-synthetic penicillins and cephalosporins. It is important, therefore, to consider its diagnosis in patients who develop diarrhoea in association with the use of antibiotics. Such colitis may range in severity from mild to life-threatening. Mild cases usually respond to drug discontinuance alone. In moderate to severe cases, appropriate measures should be taken. Use of peristalsis-inhibiting preparations are contra-indicated in such situations.

4.5    Interaction with other medicinal products and other forms of interaction

There have been rare reports of increased prothrombin time, with or without clinical bleeding, in patients receiving cefaclor and warfarin concomitantly. It is recommended that in such patients, regular monitoring of prothrombin time should be considered with adjustment of dosage if necessary.

A combination with oral contraceptives may require dose adjustment.

The absorption of cefaclor may be reduced by antacids.

The renal excretion of Cefaclor is inhibited by probenecid.

4.6    Pregnancy and Lactation

Animal studies have shown no evidence of impaired fertility or teratogenicity. However, since there are no adequate or well-controlled studies in pregnant women, caution should be exercised when prescribing for the pregnant patient.

Small amounts of cefaclor have been detected in breast milk following administration of single 500 mg doses. Average levels of about 0.2 micrograms/ml or less were detected up to five hours later. Trace amounts were detected at one hour. As the effect on nursing infants is not known, caution should be exercised when cefaclor is administered to a nursing woman.

4.7 Effects on Ability to Drive and Use Machines

No effect has been reported.

4.8 Undesirable effects

Gastro-intestinal: The most frequent side-effect has been diarrhoea. It is rarely severe enough to warrant cessation of therapy. Colitis, including rare instances of pseudomembranous colitis,has been reported. Nausea and vomiting have also occurred.

Hypersensitivity: Allergic reactions such as morbiliform eruptions, pruritus and urticaria have been observed. These reactions usually subside upon discontinuation of therapy. Serum sickness-like reactions (erythema multiforme minor, rashes or other skin manifestations accompanied by arthritis/arthralgia, with or without fever) have been reported. Lymphadenopathy and proteinuria are infrequent, there are no circulating immune complexes and no evidence of sequelae. Serum sickness-like reactions are apparently due to hypersensitivity and have usually occurred during or following a second (or subsequent) course of therapy with cefaclor.

Such reactions have been reported more frequently in children than in adults. Signs and symptoms usually occur a few days after initiation of therapy and usually subside within a few days of cessation of therapy. Antihistamines and corticosteroids appear to enhance resolution of the syndrome. No serious sequelae have been reported.

Anaphylactoid events may be solitary symptoms, including angioedema, asthenia, oedema (including face and limbs), dyspnea, paresthesia, syncope, hypotension or vasodilation.

There are rare reports of erythema multiforme major (Stevens-Johnson syndrome), toxic epidermal necrolysis and anaphylaxis. Anaphylaxis may be more common in patients with a history of penicillin allergy.

Rarely, hypersensitivity symptoms may persist for several months.

Haematological: Eosinophilia, positive Coombs' tests and, rarely, thrombocytopenia have been reported. Transient lymphocytosis, leucopenia and, rarely, haemolytic anaemia, aplastic anaemia, agranulocytosis and reversible neutropenia of possible clinical significance have also been reported. See 'Drug Interactions'.

Hepatic: Transient hepatitis and cholestatic jaundice have been reported rarely, slight elevations in AST, ALT or alkaline phosphatase values.

Renal: Reversible interstitial nephritis has occurred rarely, also slight elevations in blood urea or serum creatinine or abnormal urinalysis.

Toxic nephropathy has been observed with other beta-lactam antibiotics.

Central Nervous System: Reversible hyperactivity, nervousness, insomnia, confusion, hypertonia, dizziness, hallucinations and somnolence have been reported rarely.

Beta lactam antibiotics may trigger seizures.

Miscellaneous: Genital pruritus, vaginitis and vaginal moniliasis.

4.9 Overdose

Symptoms of nausea, vomiting, epigastric distress and diarrhoea would be anticipated.

Treatment: Unless five times the normal total daily dose has been ingested, gastro-intestinal decontamination will be not necessary.

General management may consist of supportive therapy.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

ATC-code: JO1DA General properties

Cefaclor is a semi-synthetic, orally active, 2nd generation cephalosporin antibiotic. Like other P-lactam antibiotics cefaclor owes its antibacterial activity to its ability to bind to and inhibit the action of certain bacterial cell wall synthetic enzymes, namely the penicillin binding proteins. The results of inhibition of one or more of essential penicillin binding proteins is the interruption of cell wall (peptidoglycan) biosynthesis which leads, through the activity of the cell’s autolytic enzymes, to lysis and death.

Breakpoints

The preliminary MIC breakpoints for sensitive, intermediately sensitive or resistant organisms are as follows:

MIC (mg/mL)    Interpretation

< 8    Sensitive

8-16    Intermediately    sensitive

>_ 32    Resistant

Sensitivity

Sensitive: this category includes bacterial species which are fully sensitive to cefaclor i.e. they are inhibited by usually achievable concentrations of cefaclor in blood.

Intermediate sensitive: this category includes bacterisl species which have natural intermediate sensitivity to cefaclor as demonstrated by moderate in vitro activity. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high doses of the drug can be used.

Resistant: this category includes bacterial species which are naturally resistant to the antibiotic or with acquired resistance precluding antibiotic treatment with this medicinal product.

The following table gives the antibacterial spectrum of cefaclor. 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 probabilities whether microorganisms will be susceptible to cefaclor or not.

Micro-organisms	European range of acquired resistance*
	(%)
Sensitive (anaerobes are generally not sensitive)
Staphylococcus aureus	9
Streptoccocus pneumoniae	4.5
Streptococcus pyogenes	0.9
E. coli	1.5 (hospital isolates) 1.4 (community isolates)
H. influenza	3.7
Klebsiella pneumoniae	8.2
Moraxella catarrhalis	1.7
Proteus. Mirabilis	14.4
Resistant
Enterococcus faecalis	-
Methicillin resistant S. aureus	-
Providencia rettgeri	-
Pseudomonas aeruginosa	-
Serratia marcescens	-

* consideration should be given to local guidance regarding information on acquired resistance

Other information

Mechanisms of bacterial resistance to Cefaclor:

Bacteria may be resistant to cefaclor due to production of those beta lactamases which can hydrolyse cephalosporins due to alterations in penicillin binding proteins, due to impermeability to the drug or due to drug efflux pumps. One or more of these mechanisms may coexist in the same organism, leading to variable and unpredictable cross-resistance to other beta-lactams and to antibacterial drugs of other classes.

5.2. Pharmacokinetic Properties

Cefaclor is well absorbed after oral administration to fasting subjects. Total absorption is the same whether the drug is given with or without food. However, when it is taken with food, the peak concentration achieved is 50% to 75% of that observed when the drug is administered to fasting subjects and generally appears from 45 to 60 minutes later. Following administration of 250 mg, 500 mg and 1 g doses to fasting subjects, average peak serum levels

of approximately 7, 13 and 23 pg/l, respectively, were obtained within 30 to 60 minutes. Approximately 60% to 85% of the drug is excreted unchanged in the urine within eight hours, the greater portion being excreted within the first two hours. During the eight hour period, peak urine concentrations following the 250 mg, 500 mg and 1 g doses were approximately 600, 900 and 1900 pg/l respectively. The serum half-life in normal subjects is 0.6 to 0.9 hours. In patients with reduced renal function, the serum half-life of cefaclor is slightly prolonged. In those with complete absence of renal function, the plasma halflife of the intact molecules is 2.3 to 2.8 hours. Excretion pathways in patients with markedly impaired renal function have not been determined. Haemodialysis shortens the half-life by 25% to 30%.

The Cefaclor plasma concentrations for various doses are shown in the table below:

Cefaclor plasma concentrations for doses of 250 mg, 500 mg and 1000 mg.

N=10
Time (h)	250 mg	500 mg	1000 mg
0.5	4.38 ± 1.32	8.22±2.66	8.82 ±2.85
1.0	6.31 ±0.95	15.22 ±2.39	25.44 ± 3.70
2.0	1.94 ± 0.47	6.99 ± 1.49	12.74 ± 4.50
4.0	0.20 ± 0.18	1.83 ± 0.90	1.94 ± 0.28
6.0	0	0	0

Protein binding of cefaclor is 25%.

5.3 Pre-clinical Safety Data

Cefaclor is well established for its pharmacological and toxicological properties. There are no preclinical data of clinical concern.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Xanthan gum Sodium benzoate Sucrose

Colloidal anhydrous silica

Allura Red (FD & C Red No 40,E129)

Strawberry flavour

Sodium citrate

Citric acid (anhydrous)

Simethicone emulsion 30% w/w

6.2. Incompatibilities

No incompatibilities have been reported with cefaclor.

6.3. Shelf-Life

Shelf life as packaged for sale: two years Shelf life following constitution: 14 days

6.4. Special Precautions for Storage

Store in well closed containers at a temperature not exceeding 25°C protected from light and moisture.

After constitution the suspension should be stored in a refrigerator (2-8°C) and used within 14 days.

6.5. Nature and Content of Container

HDPE bottle with polypropylene child resistant closure containing 60 or 100 ml of suspension when constituted.

6.6. Instructions for Use, Handling and Disposal

Directions for mixing:

100 mL

Measure 70 mL of water using a measuring cup. Add this volume of water in two portions to the dry mixture in the bottle. Shake well after each addition.

60 mL

Measure 42 mL of water using a measuring cup. Add this volume of water in two portions to the dry mixture in the bottle. Shake well after each addition.

The spoon provided with the package dispenses a volume of 5 mL.

7 Marketing authorisation holder

Ranbaxy (UK) Limited 20 Balderton Street London W1K 6TL United Kingdom

8. MARKETING AUTHORISATION NUMBER

Cefaclor Oral Suspension 125mg/5mL 14894/0003

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/08/2006

10    DATE OF REVISION OF THE TEXT

20/08/2006