Klaricid XL or Clarithromycin 500 mg Modified Release Tablets

A yellow, ovaloid tablet containing 500mg clarithromycin in a modified-release preparation.

Klaricid XL or Clarithromycin 500 mg Modified Release Tablets is indicated for treatment of infections caused by susceptible organisms. Indications include:

Lower respiratory tract infections for example, acute and chronic bronchitis, and pneumonia.

Upper respiratory tract infections for example, sinusitis and pharyngitis.

Klaricid XL or Clarithromycin 500 mg Modified Release Tablets is also indicated in skin and soft tissue infections of mild to moderate severity, for example folliculitis, cellulitis and erysipelas.

Adults: The usual recommended dosage of Klaricid XL or Clarithromycin 500 mg Modified Release Tablets in adults is one 500mg modified-release tablet daily to be taken with food.

In more severe infections, the dosage can be increased to two 500mg modified-release tablets daily. The usual duration of treatment is 7 to 14 days.

Children older than 12 years: As for adults.

Children younger than 12 years: Use Klaricid Paediatric Suspension or Clarithromycin 125 mg/5ml Granules for Oral Suspension.

Klaricid XL or Clarithromycin 500 mg Modified Release Tablets should not be used in patients with renal impairment (creatinine clearance less than 30 mL/min). Clarithromycin immediate release tablets may be used in this patient population. (See 4.3 Contra-indications).

Clarithromycin is contra-indicated in patients with known hypersensitivity to macrolide antibiotic drugs.

Clarithromycin and ergot derivatives should not be co-administered (see section 4.5).

As the dose cannot be reduced from 500mg daily, Klaricid XL or Clarithromycin 500 mg Modified Release Tablets is contraindicated in patients with creatinine clearance less than 30 mL/min.

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 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 kidney. Caution should be exercised in administering this antibiotic to patients with impaired hepatic and renal function.

Prolonged or repeated used 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 ins ome 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.

Clarithromycin has been shown not to interact with oral contraceptives.

As with other macrolide antibiotics the use of clarithromycin in patients concurrently taking drugs metabolised by the cytochrome P450 system (eg. Cilostazol, methylprednisolone, anticoagulants (eg warfarin) quinidine, sildenafil, 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 in serum theophylline levels and potential theophylline toxicity.

The use of clarithromycin in patients receiving warfarin may result in potentiation of the effects of warfarin. Prothrombin time should be frequently monitored in these patients.

The effects of digoxin may be potentiated with concomitant administration of clarithromycin. Monitoring of serum digoxin levels should be considered.

Clarithromycin may potentiate the effects of carbamazepine due to a reduction in the rate of excretion.

Interaction studies have not been conducted with Klaricid XL or Clarithromycin 500 mg Modified Release Tablets and zidovudine. If concomitant administration of clarithromycin and zidovudine is required, then an immediate release formulation of clarithromycin should be used.

There have been post-marketed reports of Torsade de Pointes occurring with the concurrent use of clarithromycin 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 ischaemia of the extremities and other tissues including the central nervous system (see section 4.3 Contra-indications).

Ritonavir increases the area under the curve (AUC), C_max and C_min 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 an immediate release form of clarithromycin should be used. Doses of clarithromycin greater than 1g/day should not be coadministered with ritonavir.

The safety of clarithromycin during pregnancy and breast feeding of infants has not been established. Clarithromycin should thus not be used during pregnancy or lactation unless the benefit is considered to outweigh the risk. Some animal studies have suggested an embryotoxic effect, but only at dose levels which are clearly toxic to mothers. Clarithromycin has been found in the milk of lactating animals and in human breast milk.

The medicine is unlikely to produce an effect.

Clarithromycin is generally well tolerated. Side effects include nausea, dyspepsia, diarrhoea, vomiting, abdominal pain and paraesthesia. Stomatitis, glossitis, 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 on 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. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxaemia. Adverse reactions accompanying overdosage should be treated by gastric lavage and supportive measures. 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 antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. 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-hydroxy metabolite of clarithromycin also has antimicrobial 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 usually active against the following organisms in vitro:

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

Gram-negative Bacteria: Haemophilus influenza; Haemophilus parainfluenza; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Campylobacter jejuni.

Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.

Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae; Mycobacterium kansasii; Mycobacterium chelonae; Mycobacterium fortuitum; Mycobacterium intracellularis; Chlamydia pneumoniae.

Anaerobes: Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.

Clarithromycin has bactericidal activity against several bacterial strains. The organisms include Haemophilus influenzae; Streptococcus pneumoniae; Streptococcus pyogenes; Streptococcus agalactiae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae and Campylobacter spp.

The kinetics of orally administered modified-release clarithromycin have been studied in adult humans and compared with clarithromycin 250mg and 500mg immediate release tablets. The extent of absorption was found to be equivalent when equal total daily doses were administered. The absolute bioavailability is approximately 50%. Little or no unpredicted accumulation was found and the metabolic disposition did not change in any species following multiple dosing. Based upon the finding of equivalent absorption the following in vitro and in vivo data are applicable to the modified-release formulation.

In vitro: Results of in vitro studies showed that the protein binding of clarithromycin in human plasma averaged about 70 % at concentrations of 0.45 - 4.5μg/mL. A decrease in binding to 41% at 45.0μg/mL suggested that the binding sites might become saturated, but this only occurred at concentrations far in excess of therapeutic drug levels.

In vivo: Clarithromycin levels in all tissues, except the central nervous system, were several times higher than the circulating drug levels. The highest concentrations were found in the liver and lung tissue, where the tissue to plasma ratios reached 10 to 20.

The pharmacokinetic behaviour of clarithromycin is non-linear. In fed patients given 500mg clarithromycin modified-release daily, the peak steady state plasma concentration of clarithromycin and 14 hydroxy clarithromycin were 1.3 and 0.48μg/mL, respectively. When the dosage was increased to 1000mg daily, these steady-state values were 2.4μg/mL and 0.67μg/mL respectively. Elimination half-lives of the parent drug and metabolite were approximately 5.3 and 7.7 hours respectively. The apparent half-lives of both clarithromycin and its hydroxylated metabolite tended to be longer at higher doses.

Urinary excretion accounted for approximately 40% of the clarithromycin dose. Faecal elimination accounts for approximately 30%.

In repeated dose studies, clarithromycin toxicity was related to dose and duration of treatment. The primary target organ was the liver in all species, with hepatic lesions seen after 14 days in dogs and monkeys. Systemic exposure levels associated with this toxicity are not known but toxic mg/kg doses were higher than the dose recommended for patient treatment.

No evidence of mutagenic potential of clarithromycin was seen during a range of in vitro and in vivo tests.

Fertility and reproduction studies in rats have shown no adverse effects. Teratogenicity studies in rats (Wistar (p.o.) and Sprague-Dawley (p.o. and i.v.)), New Zealand White rabbits and cynomolgous monkeys failed to demonstrate any teratogenicity from clarithromycin. However, a further similar study in Sprague-Dawley rats indicated a low (6%) incidence of cardiovascular abnormalities which appeared to be due to spontaneous expression of genetic changes. Two mouse studies revealed a variable incidence (3-30%) of cleft palate and in monkeys embryonic loss was seen but only at dose levels which were clearly toxic to the mothers.

No other toxicological findings considered to be of relevance to the dose level recommended for patient treatment have been reported.

Citric acid anhydrous, sodium alginate, sodium calcium alginate, lactose, povidone K30, talc, stearic acid, magnesium stearate, methyl hydroxypropylcellulose 6cps, polyethylene glycol 400, macrogol 8000, titanium dioxide (E171), sorbic acid, quinoline yellow (dye) aluminium lake (E104).

None known.

The shelf-life is 18 months when stored in HDPE or glass bottles and 36 months when stored in PVC/PVdC blisters.

Do not store above 30°C Store in the original package.

1,4,5,6,7 or 14 tablets in a blister original pack or in bottles. The blisters, of PVC/PVdC, are heat sealed with 20 micron hard tempered aluminium foil and packaged in a cardboard carton with a pack insert. The bottles, of HDPE or glass, are packaged in a cardboard carton with a pack insert.

Not applicable.

Abbott Laboratories Limited

Queenborough

Kent

ME11 5EL

PL00037/0275

December 1996

September 2007