SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Celafexin 500 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

500 mg Cefalexin (as monohydrate)

For excipients, see 6.1

3    PHARMACEUTICAL FORM

Film-coated tablets

Round pink film coated tablets embossed ‘CHX 500’ on one side

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Cefalexin is a semi synthetic cephalosporin antibiotic for oral administration.

Cefalexin is indicated in the treatment of the following infections: Respiratory tract infections; otitis media; skin and soft tissue infections; bone and joint infections; genito-urinary infections, including acute prostatitis and dental infections.

Cefalexin is active against the following organisms: p-haemolytic streptococci; staphylococci, including coagulase-positive, coagulase-negative and penicillinase-producing strains; Streptococcus pneumoniae; Escherichia coli; Proteus mirabilis; Klebsiella species, Haemophilus influenzae; Branhamella catarrhalis.

Most strains of enterococci (Streptococcus faecalis) and a few strains of staphylococci are resistant to cefalexin. Cefalexin is inactive against most strains of enterobacter, morganella morganii, pr. Vulgaris, colstridium difficule, and the following species: legionella, campylobacter,,pseudomonas or herellea species. When tested by in vitro methods, staphylococci exhibit cross-resistance between cefalexin and methicillin-type antibiotics.

4.2 Posology and method of administration

Adults

1-4 g daily in divided doses; most infections will respond to a dosage of 500 mg every 8 hours.

For skin and soft tissue infections, streptococcal pharyngitis and mild, uncomplicated urinary tract infections, the usual dosage is 250 mg every 6 hours, or 500 mg every 12 hours.

More severe infections, or those caused by less susceptible organisms may need larger doses.

If daily doses greater than 4g are required other parenteral cephalosporins, in appropriate doses, should be considered.

Elderly and patients with impaired renal function:

As for adults although dosage should be reduced to a daily maximum of 500mg if renal function is severely impaired (glomerular filtration rate < 10ml/min).

Children

The recommended daily dosage for children is 25-50 mg/kg (10-20mg/lb) in divided doses.

For skin, soft tissue infections, streptococcal pharyngitis and mild, uncomplicated urinary tract infections, the total daily dose may be divided and administered every 12 hours.

For most infections the following schedule is suggested:

Children under 5 years: 125mg every 8 hours.

Children 5 years and over: 250 mg every 8 hours.

In severe infections, the dosage may be doubled.

In the therapy of otitis media, clinical studies have shown that a dosage of 75-100 mg/kg/day in 4 divided doses is required.

In the treatment of beta-haemolytic streptococcal infections, a therapeutic dose should be administered for at least 10 days.

Route of administration Oral

4.3 Contraindications

Cefalexin is contraindicated in patients with known allergy to the cephalosporins group of antibiotics.

Cefalexin should be given cautiously to patients who have shown hypersensitivity to other drugs. Cephalosporins should be given with caution to penicillin-sensitive patients, as there is some evidence of partial cross-allergenicity between the penicillins and the cephalosporins. Patients have had severe reactions (including anaphylaxis) to both drugs.

Cefalexin is contra-indicated in patients with porphyria.

4.4 Special warnings and precautions for use

Before instituting therapy with cefalexin, every effort should be made to determine whether the patient has had previous hypersensitivity reactions to the cephalosporins, penicillins or other drugs. Cefalexin should be given cautiously to penicillin-sensitive patients. There is some clinical and laboratory evidence of partial cross-allergenicity of the penicillins and cephalosporins. Patients have had severe reactions (including anaphylaxis) to both drugs.

If an allergic reaction to cefalexin occurs the drug should be discontinued and the patient treated with the appropriate agents. Prolonged use of cefalexin may result in the overgrowth of non-susceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Pseudomembranous colitis has been reported with virtually all broad -spectrum antibiotics, including macrolides, semisynthetic 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 of pseudomembranous colitis usually respond to drug discontinuance alone whilst in more severe cases, appropriate measures should be taken.

Cefalexin should be administered with caution in the presence of markedly impaired renal function. Careful clinical and laboratory studies should be made because safe dosage may be lower than that usually recommended.

Positive direct Coombs’ tests have been reported during treatment with cephalosporin antibiotics. In haematological studies, or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side, or in Coombs’ testing of newborn babies whose mothers have received cephalosporin antibiotics before parturition, it should be noted that a positive Coombs’ test may be due to the drug.

A false positive reaction for glucose in the urine may occur with Benedict’s or Fehling’s solutions or with copper sulphate test tablets.

4.5 Interaction with other medicinal products and other forms of interaction

Probenecid causes reduced excretion of cefalexin leading to increased plasma concentrations. Cephalosporins may have an increased risk of nephrotoxicity in the presence of amphotericin, loop diuretics, aminoglycosides, capreomycin or vancomycin.

In a single study of 12 healthy subjects given single 500mg doses of cefalexin and metformin, plasma metformin Cmax and AUC increased by an average of 34% and 24%, respectively, and metformin renal clearance decreased by an average of 14%. No side-effects were reported in the 12 healthy subjects in this study. No information is available about the interaction of cefalexin and metformin following multiple dose administration. The clinical significance of this study is unclear, particularly as no cases of “lactic acidosis” have been reported in association with concomitant metformin and cefalexin treatment.

Hypokalaemia has been described in patient taking cytotoxic drugs for leukaemia when they were given gentamicin and cefalexin.

4.6 Fertility, pregnancy and lactation

Fertility, pregnancy and lactation

Pregnancy: Although laboratory and clinical studies have shown no evidence of teratogenicity, caution should be exercised when prescribing for the pregnant patient.

Breastfeeding:The excretion of cefalexin in human breast milk increased up to 4 hours following a 500mg dose. The drug reached a maximum level of 4 micrograms/ml then decreased gradually and had disappeared 8 hours after administration. Caution should be exercised in administration to a nursing woman, possible effects to the infant include modification of bowel flora.

4.7 Effects on ability to drive and use machines

Not applicable

4.8 Undesirable effects

Gastro-intestinal: Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. Nausea and vomiting have been reported rarely. The most frequent side-effect has been diarrhoea. It was very rarely severe enough to warrant cessation of therapy. Dyspepsia and abdominal pain have also occurred

Hypersensitivity: Allergic reactions have been observed in the form of rash, urticaria, angioedema, and rarely erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. These reactions usually subside upon discontinuation of the drug, although in some cases supportive therapy may be necessary. Anaphylaxis has also been reported.

Haemic and Lymphatic System: Eosinophilia, neutropenia, thrombocytopenia, haemolytic anaemia and positive Coombs’ tests have been reported.

Hepatic: transient hepatitis and cholestatic jaundice have been reported rarely.

Other: These have included genital and anal pruritus, genital candidiasis, vaginitis and vaginal discharge, dizziness, fatigue, headache, agitation, confusion, hallucinations, arthralgia, arthritis and joint disorder. Reversible interstitial nephritis has been reported rarely. Slight elevations in AST and ALT have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product, Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms reported include nausea, vomiting, diarrhoea, epigastric distress and haematuria.

In the event of severe overdosage, general supportive care is recommended, including close clinical and laboratory monitoring of haematological, renal and hepatic functions, and coagulation status until the patient is stable. Forced diuresis, peritoneal dialysis, haemodialysis, or charcoal haemoperfusion have not been established as beneficial for an overdose of cefalexin. It would be extremely unlikely that one of these procedures would be indicated.

Unless 5 to 10 times the normal daily dose of cefalexin has been ingested, gastro-intestinal decontamination should not be necessary.

There have been reports of haematuria without impairment of renal function in children accidentally ingesting more than 3.5g of cefalexin in a day. Treatment has been supportive (fluids) and no sequelae have been reported.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Cefalexin is bactericidal and has antimicrobial activity similar to that of cephaloridine or cephalothin against both gram-positive and gram-negative organisms.

In vitro tests demonstrate that cephalosporins are bactericidal because of their inhibition of cell-wall synthesis.

Cefalexin is active against the following organisms in vitro:

Beta haemolytic streptococci

Staphylococci, including coagulase positive, coagulase negative and penicillinase producing strains.

Streptococcus pneumoniae

Escherichia coli

Proteus mirabilis

Klebsiella species

Haemophilus influenzae

Branhamella catarrhalis

Most strains of enterococci (Streptococcus faecalis) and a few strains of staphylococci are resistant to cefalexin. It is not active against most strains of Enterobacter species, Morganella morganii and Pr. vulgaris. It has no activity against Pseudomonas or Herellea species or Acinetobacter calcoaeticus. Penicillin-resistant Streptococcus pneumoniae is usually cross-resistant to beta-lactam antibiotics. When tested by in vitro methods, staphylococci exhibit cross resistance between cefalexin and methicillin type antibiotics

5.2 Pharmacokinetic properties

Cefalexin is acid stable and may be given without regard to meals. Cefalexin is rapidly absorbed from the gastro-intestinal tract and produces peak plasma concentrations about 1 hour after administration. Following doses of 250mg, 500mg and 1g, average peak serum levels of approximately 9, 18 and 32mg/L respectively were obtained at 1 hour. Measurable levels were present 6 hours after administration. Cefalexin is excreted in the urine by glomerular filtration and tubular secretion. Studies showed that over 90% of the drug was excreted unchanged in the urine within 8 hours. During this period peak urine concentrations following the 250mg, 500mg and 1g doses were approximately 1000, 2200 and 5000mg/L respectively.

Cefalexin is almost completely absorbed from the gastro-intestinal tract, and 75-100% is rapidly excreted in active form in the urine. If cefalexin is taken with food there is delayed and slightly reduced absorption and there may be delayed elimination from the plasma. The half-life is approximately 60 minutes in patients with normal renal function. The biological half-life has been reported to range from 0.6 to at least 1.2 hours and this increases with reduced renal function. About 10 to 15% of a dose is bound to plasma proteins. Haemodialysis and peritoneal dialysis will remove cefalexin from the blood.

Peak blood levels are achieved one hour after administration, and therapeutic levels are maintained for 6-8 hours. About 80% or more of a dose is excreted unchanged in the urine in the first 6 hours by glomerular filtration and tubular secretion; urinary concentrations greater than 1 mg per ml have been achieved after a dose of 500 mg. Probenecid delays urinary excretion and has been reported to increase biliary excretion. Cefalexin is widely distributed in the body but does not enter the cerebrospinal fluid in significant quantities unless the meninges are inflamed. It diffuses across the placenta and small quantities are found in the milk of nursing mothers. Therapeutically effective concentrations may be found in the bile.

No accumulation is seen with dosages above the therapeutic maximum of 4g/day.

The half-life may be increased in neonates due to their renal immaturity, but there is no accumulation when given at up to 50mg/kg/day.

5.3 Preclinical safety data

The daily oral administration of cefalexin to rats in doses of 250 or 500mg/kg prior to and during pregnancy, or to rats and mice during the period of organogenesis only, had no adverse effect on fertility, foetal viability, foetal weight, or litter size.

Cefalexin showed no enhanced toxicity in weanling and newborn rats as compared with adult animals.

The oral LD50 of cefalexin in rats is 5,000mg/kg.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Pregelatinised Starch Colloidal Anhydrous Silica Magnesium Stearate Microcrystalline Cellulose

Coating

Hydroxypropyl Methylcellulose Polyethylene Glycol Titanium Dioxide (E171) Erythrosine Lake (E127) Purified Water

6.2 Incompatibilities

None known

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C.

Keep the container tightly closed (for bottles). Store in the original package (for blisters).

6.5 Nature and contents of container

Polypropylene tubular container with an open end equipped to accept a polyethylene closure, with tamper evident strip containing 7, 14, 20, 21, 28, 30, 50,56, 60, 100 or 500 tablets or PVC/Aluminium blisters or PVdC coated PVC/Aluminium blisters (60g/m²PVdC on 250pm PVC/20pm Al) containing 7, 14, 20, 21, 28, 30, 50, 56, 60, 100 or 500 tablets. They come in bulk packs of 30, 50, 100 and 500 as well as blisters of 21 and 28 tablets. Not all packs are marketed.

6.6 Special precautions for disposal

No special instructions.

7 MARKETING AUTHORISATION HOLDER

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16363/0121

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/03/2009

DATE OF REVISION OF THE TEXT

27/11/2015