Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension

Activemg/5ml

Clarithromycin 250

White to off - white granules for oral suspension.

Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension is indicated for the treatment of infections caused by susceptible organisms. Indications include:

Lower respiratory tract infections.

Upper respiratory tract infections.

Skin and skin structure infections.

Acute otitis media.

Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension is usually active against the following organisms in vitro:

Gram-positive Bacteria:Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-haemolytic streptococci); alpha-haemolytic streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.

Gram-negative Bacteria: Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Helicobacter pylori; Campylobacter jejuni.

Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.

Other Organisms:Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae; Chlamydia pneumoniae.

Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.

Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension has bactericidal activity against several bacterial strains. These organisms include H. influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter species.

The activity of clarithromycin against H. pylori is greater at neutral pH than at acid pH.

Recommended doses and dosage schedules:

The usual duration of treatment is for 5 to 10 days depending on the pathogen involved and the severity of the condition. The recommended daily dosage of Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension in children is given in the following table and is based on a 7.5mg/kg twice a day dosage regimen. Doses up to 500mg twice a day have been used in the treatment of severe infections.

KLARICID PAEDIATRIC SUSPENSION 250MG/5ML OR CLARITHROMYCIN 250MG/5ML GRANULES FOR ORAL SUSPENSION

DOSAGE IN CHILDREN

* Children < 8 kg should be dosed on a per kg basis (approx. 7.5 mg/kg twice a day)

Preparation for use:140ml bottle: 74ml of water should be added to the granules in the bottle and shaken to yield 140ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 250mg per 5ml.

100 ml bottle:

70 ml bottle:

50 ml bottle:

Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension is contra-indicated in patients with known hypersensitivity to macrolide antibiotic drugs and other ingredients.

Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension and ergot derivatives should not be co-administered (see section 4.5).

Concomitant administration of clarithromycin and any of the following drugs is contraindicated: cisapride, pimozide and terfenadine. Elevated cisapride, pimozide and terfenadine levels have been reported in patients receiving either of these drugs and clarithromycin concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes. Similar effects have been observed with concomitant administration of astemizole and other macrolides.

Clarithromycin is principally excreted by the liver and kidneys. This antibiotic should not be administered to paediatric patients with hepatic or renal failure.

Prolonged or repeated use of clarithromycin may result in an overgrowth of non-susceptible bacteria or fungi. If super-infection occurs, clarithromycin should be discontinued and appropriate therapy instituted.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5).

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

As with other macrolide antibiotics the use of clarithromycin in patients concurrently taking drugs metabolised by the cytochrome P450 system (eg. cilostazol, methylprednisolone, oral anticoagulants (e.g warfarin), quinidine, ergot alkaloids, alprazolam, triazolam, midazolam, disopyramide, lovastatin, rifabutin,phenytoin, cyclosporin, vinblastine, valproate and tacrolimus) may be associated with elevations in serum levels of these other drugs. Rhabdomyolysis, co-incident with the co- administration of clarithromycin, and HMG-CoA reductase inhibitors, such as lovastatin and simvastatin has been reported.

The administration of clarithromycin to patients who are receiving theophylline has been associated with an increase of serum theophylline levels and potential theophylline toxicity.

The use of Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension in patients receiving digoxin, warfarin and carbamazepine may result in potentiation of their effects due to a reduction in the rate of excretion. Prothrombin time should be frequently monitored in patients receiving warfarin. Monitoring of serum digoxin levels should be considered.

Ritonavir increases the AUC (area under the curve) of clarithromycin when administered concurrently. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 ml/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR<30ml/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1g/day should not be coadministered with ritonavir.

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine levels. To date, this interaction does not appear to occur in paediatric HIV-infected patients taking Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension with zidovudine or dideoxyinosine.

There have been postmarketed reports of Torsade de Points occurring with the concurrent use of clarithrtomycin and quinidine or disopyramide. Levels of these medications should be monitored during clarithromycin therapy.

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.4).

Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischemia of the extremeties and other tissues including the central nervous system (see section 4.3, Contraindications)

The safety of clarithromycin during pregnancy and breast feeding of infants has not been established. Some animal studies have suggested an embryotoxic effect but only at dose levels which are clearly toxic to mothers. Therefore, if a patient of post-pubertal age becomes pregnant, clarithromycin should not be used during pregnancy or lactation unless the benefit outweighs the risk. Clarithromycin has been found in the milk of lactating animals and in human breast milk.

None known.

Clarithromycin is generally well tolerated. Side effects reported include nausea, dyspepsia, diarrhoea, vomiting and abdominal pain and paraesthesia. Stomatitis, glossitis and oral monilia and tongue discolouration have been reported. Other side-effects include headache, arthralgia, myalgia and allergic reactions ranging from urticaria, mild skin eruptions and angioedema to anaphylaxis have been reported. There have been reports of Stevens-Johnson syndrome / toxic epidermal necrolysis with orally administered clarithromycin.

Reports of alteration of the sense of smell, usually in conjunction with taste perversion have also been received. There have been reports of tooth discolouration in patients treated with clarithromycin. Tooth discolouration is usually reversible with professional dental cleaning.

There have been reports of transient central nervous system side-effects including dizziness, vertigo, anxiety, insomnia, bad dreams, tinnitus, confusion, disorientation, hallucinations, psychosis and depersonalisation. There have been reports of hearing loss with clarithromycin which is usually reversible upon withdrawal of therapy. Pseudomembranous colitis has been reported rarely with clarithromycin, and may range in severity from mild to life threatening. There have been rare reports of hypoglycaemia, some of which have occurred in patients on concomitant oral hypoglycaemic agents or insulin. There have been very rare reports of uveitis mainly in patients treated with concomitant rifabutin, most of these were reversible. Isolated cases of leukopenia andthrombocytopenia have been reported.

As with other macrolides, hepatic dysfunction (which is usually reversible) including altered liver function tests, hepatitis and cholestasis with or without jaundice, has been reported. Dysfunction may be severe and very rarely fatal hepatic failure has been reported.

Cases of increased serum creatinine, interstitial nephritis, renal failure, pancreatitis and convulsions have been reported rarely.

As with other macrolides, QT prolongation, ventricular tachycardia and Torsade de Pointes have been rarely reported with clarithromycin.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see sections 4.4 and 4.5).

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastro-intestinal symptoms. Adverse reactions accompanying overdosage should be treated by gastric lavage and general supportive measures. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxaemia. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.

Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its anti-bacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. Clarithromycin demonstrates excellent in-vitro activity against standard strains of clinical isolates. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than the MICs of erythromycin.

The 14-(R)-hydroxy metabolite of clarithromycin formed in man by first pass metabolism also has anti-microbial activity. The MICs of this metabolite are equal or two-fold higher than the MICs of the parent compound, except for H.influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound. Clarithromycin is also bactericidal against several bacterial strains.

Clarithromycin is usually active against the following organisms in vitro:-

Gram-positive Bacteria:Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-haemolytic streptococci); alpha-haemolytic streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.

Gram-negative Bacteria: Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Helicobacter pylori; Campylobacter jejuni.

Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.

Other Organisms:Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae; Chlamydia pneumoniae.

Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.

Clarithromycin also has bactericidal activity against several bacterial strains. These organisms include H. influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter species.

Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral administration. The microbiologically active 14(R)-hydroxyclarithromycin is formed by first pass metabolism. Clarithromycin may be given without regard to meals as food does not affect the extent of bioavailability. Food does slightly delay the onset of absorption of clarithromycin and formation of the 14-hydroxy metabolite. Although the pharmacokinetics of clarithromycin are non linear, steady state is attained within 2 days of dosing. 14-Hydroxyclarithromycin is the major urinary metabolite and accounts for 10-15% of the dose. Most of the remainder of the dose is eliminated in the faeces, primarily via the bile. 5-10% of the parent drug is recovered from the faeces.

Clarithromycin provides tissue concentrations that are several times higher than circulating drug level. Increased levels of clarithromycin have been found in both tonsillar and lung tissue. Clarithromycin penetrates into the middle ear fluid at concentrations greater than in the serum. Clarithromycin is 80% bound to plasma proteins at therapeutic levels.

Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension does not contain tartrazine or other azo dyes, lactose or gluten.

In both mice and rats, body weight was reduced or its increase suppressed and suckling behaviour and spontaneous movements were depressed for the first few days following drug administration. Necropsy of animals that died disclosed dark-reddish lungs in mice and about 25% of the rats; rats treated with 2197 mg/kg or more of a clarithromycin suspension were also noted to have a reddish - black substance in the intestines, probably because of bleeding. Deaths of these animals were considered due to debilitation resulting from depressed suckling behaviour or bleeding from the intestines.

Pre-weaning rats (5 days old) were administered a clarithromycin suspension formulation for two weeks at doses of 0, 15, 55 and 200 mg/kg/day. Animals from the 200 mg/kg/day group had decreased body-weight gains, decreased mean haemoglobin and haematocrit values, and increased mean relative kidney weights compared to animals from the control group. Treatment-related minimal to mild multifocal vacuolar degeneration of the intrahepatic bile duct epithelium and an increased incidence of nephritic lesions were also observed in animals from this treatment group. The "no-toxic effect" dosage for this study was 55 mg/kg/day.

An oral toxicity study was conducted in which immature rats were administered a clarithromycin suspension (granules for suspension) for 6 weeks at daily dosages of 0, 15, 50 and 150 mg base/kg/day. No deaths occurred and the only clinical sign observed was excessive salivation for some of the animals at the highest dosage from 1 to 2 hours after administration during the last 3 weeks of treatment. Rats from the 150 mg/kg dose group had lower mean body weights during the first three weeks, and were observed to have decreased mean serum albumin values and increased mean relative liver weight compared to the controls. No treatment-related gross or microscopic histopathological changes were found. A dosage of 150 mg/kg/day produced slight toxicity in the treated rats and the "no effect dosage" was considered to be 50 mg/kg/day.

Juvenile beagle dogs, 3 weeks of age, were treated orally daily for four weeks with 0, 30, 100, or 300 mg/kg of clarithromycin, followed by a 4-week recovery period. No deaths occurred and no changes in the general condition of the animals were observed. Necropsy revealed no abnormalities. Upon histological examination, fatty deposition of centrilobular hepatocytes and cell infiltration of portal areas were observed by light microscopy and an increase in hepatocellular fat droplets was noted by electron

microscopy in the 300 mg/kg dose group. The toxic dose in juvenile beagle dogs was considered to be greater than 300 mg/kg and the "no effect dose" 100 mg/kg.

Fertility, Reproduction and Teratogenicity

Fertility and reproduction studies have shown daily dosages of 150-160 mg/kg/day to male and female rats caused no adverse effects on the oestrus cycle, fertility, parturition and number and viability of offspring. Two teratogenicity studies in both Wistar (p.o.) and Sprague-Dawley (p.o. and i.v.) rats, one study in New Zealand white rabbits and one study in cynomolgus monkeys failed to demonstrate any teratogenicity from clarithromycin.

Carbopol 974P, povidone K90, water purified, hypromellose phthalate (HP-55), castor oil, silicon dioxide, sucrose, xanthan gum, flavour - fruit punch, potassium sorbate, citric acid, titanium dioxide and maltodextrin.

None known.

The recommended shelf life of the dry granule is 24 months.

Once reconstituted, Klaricid Paediatric Suspension 250mg/5ml or Clarithromycin 250mg/5ml Granules for Oral Suspension should be used within 14 days.

Do not store above 30ºC. Do not refrigerate or freeze.

Granules for reconstitution in a HDPE bottle. Pack sizes of 50, 70, 100 and 140ml are available.

Not applicable.

Abbott Laboratories Limited

Queenborough

Kent

ME11 5EL

0037/0277

19^th May 1999

14 September 2006