Klaricid or Clarithromycin 250 mg Tablets

250 mg/tablet

Active: Clarithromycin

A yellow, ovaloid fil m-coated tablet containing 250 mg of clarithromycin.

Clarithromycin 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.

Clarithromycin is appropriate for initial therapy in community acquired respiratory infections and has been shown to be active in vitro against common and atypical respiratory pathogens as listed in the microbiology section.

Clarithromycin is also indicated in skin and soft tissue infections of mild to moderate severity.

Clarithromycin in the presence of acid suppression effected by omeprazole or lansoprazole is also indicated for the eradication of H. pylori in patients with duodenal ulcers. See Dosage and Administration section.

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 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.

Anaerobes: Macrolide-susceptible Bacteroides fragilis; 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; H. pylori and Campylobacter spp.

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

Patients with respiratory tract/skin and soft tissue infections.

Adults: The usual dose is 250 mg twice daily for 7 days although this may be increased to 500mg twice daily for up to 14 days in severe infections.

Children older than 12 years: As for adults.

Children younger than 12 years: Use Clarithromycin Paediatric Suspension.

Eradication of H. pylori in patients with duodenal ulcers (Adults)

Triple Therapy (7 - 14 days)

Clarithromycin (500mg) twice daily and lansoprazole 30mg twice daily should be given with amoxycillin 1000mg twice daily for 7 - 14 days.

Triple Therapy (7 days)

Clarithromycin (500mg) twice daily and lansoprazole 30mg twice daily should be given with metronidazole 400mg twice daily for 7 days.

Triple Therapy (7 days)

Clarithromycin (500mg) twice daily and omeprazole 40mg daily should be given with amoxycillin 1000mg twice daily or metronidazole 400mg twice daily for 7 days.

Triple Therapy (10 days)

Clarithromycin (500mg) twice daily should be given with amoxycillin 1000mg twice daily and omeprazole 20mg daily for 10 days.

Dual Therapy (14 days)

The usual dose of Clarithromycin is 500 mg three times daily for 14 days. Clarithromycin should be administered with oral omeprazole 40 mg once daily. The pivotal study was conducted with omeprazole 40 mg once daily for 28 days. Supportive studies have been conducted with omeprazole 40 mg once daily for 14 days.

For further information on the dosage for omeprazole see the Astra data sheet.

Elderly: As for adults.

Renal impairment: Dosage adjustments are not usually required except in patients with severe renal impairment (creatinine clearance < 30 ml/min). If adjustment is necessary, the total daily dosage should be reduced by half, e.g. 250 mg once daily or 250 mg twice daily in more severe infections.

Clarithromycin may be given without regard to meals as food does not affect the extent of bioavailability.

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).

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

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.

H. pylori organisms may develop resistance to clarithromycin in a small number of patients.

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).

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, oral anticoagulants (eg warfarin), quinidine, sildenafil, ergot alkaloids, alprazolam, triazolam, midazolam, disopyramide, lovastatin, rifabutin, phenytoin ,cyclosporin vinblastine, valporate 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 Klaricid or Clarithromycin 250 mg Tablets. Monitoring of serum digoxin levels should be considered.

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

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV infected adult patients may result in decreased steady-state zidovudine levels. This can be largely avoided by staggering the doses of Clarithromycin and zidovudine by 1 -2 hours. No such reaction has been reported in children.

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, 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.

Although the plasma concentrations of clarithromycin and omeprazole may be increased when they are administered concurrently, no adjustment to the dosage is necessary. At the dosages recommended, there is no clinically significant interaction between clarithromycin and lansoprazole.Increased plasma concentrations of clarithromycin may also occur when it is co-administered with Maalox or ranitidine. No adjustment to the dosage is necessary.

There have been post-marketed reports of Torsade de Points 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 colchicines. Patients should be monitored for clinical symptoms of colchicine toxicity (see Section 4.4).

Postmarketing 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).

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.

None known.

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 and thrombocytopenia 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, hypokalemia and hypoxemia. 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 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.

Anaerobes: Macrolide-susceptible Bacteroides fragilis; 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, H. pylori and Campylobacter spp.

H. pylori is associated with acid peptic disease including duodenal ulcer and gastric ulcer in which about 95% and 80% of patients respectively are infected with the agent. H. pylori is also implicated as a major contribution factor in the development of gastric and ulcer recurrence in such patients.

Clarithromycin has been used in small numbers of patients in other treatment regimens. Possible kinetic interactions have not been fully investigated. These regimens include:

Clarithromycin plus tinidazole and omeprazole; clarithromycin plus tetracycline, bismuth subsalicylate and ranitidine; clarithromycin plus ranitidine alone.

Clinical studies using various different H. pylori eradication regimens have shown that eradication of H. pylori prevents ulcer recurrence.

Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral administration of Clarithromycin tablets. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first pass metabolism. Clarithromycin may be given without regard to meals as food does not affect the extent of bioavailability of Clarithromycin tablets. Food does slightly delay the onset of absorption of clarithromycin and formation of the 14-hydroxymetabolite. The pharmacokinetics of clarithromycin are non linear; however, steady-state is attained within 2 days of dosing. At 250 mg b.i.d. 15-20% of unchanged drug is excreted in the urine. With 500 mg b.i.d. daily dosing urinary excretion is greater (approximately 36%). The 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.

When clarithromycin 500 mg is given three times daily, the clarithromycin plasma concentrations are increased with respect to the 500 mg twice daily dosage.

Clarithromycin provides tissue concentrations that are several times higher than the circulating drug levels. Increased levels have been found in both tonsillar and lung tissue. Clarithromycin is 80% bound to plasma proteins at therapeutic levels.

Clarithromycin also penetrates the gastric mucus. Levels of clarithromycin in gastric mucus and gastric tissue are higher when clarithromycin is co-administered with omeprazole than when clarithromycin is administered alone.

In acute mouse and rat studies, the median lethal dose was greater than the highest feasible dose for administration (5g/kg).

In repeated dose studies, toxicity was related to dose, duration of treatment and species. Dogs were more sensitive than primates or rats. The major clinical signs at toxic doses included emesis, weakness, reduced food consumption and weight gain, salivation, dehydration and hyperactivity. In all species the liver was the primary target organ at toxic doses. Hepatotoxicity was detectable by early elevations of liver function tests. Discontinuation of the drug generally resulted in a return to or toward normal results. Other tissues less commonly affected included the stomach, thymus and other lymphoid tissues and the kidneys. At near therapeutic doses, conjunctival injection and lacrimation occurred only in dogs. At a massive dose of 400mg/kg/day, some dogs and monkeys developed corneal opacities and/or oedema.

Fertility and reproduction studies in rats have shown no adverse effects. Teratogenicity studies in rats (Wistar (p.o.) and Spraque-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 embryonic loss was seen in monkeys but only at dose levels which were clearly toxic to the mothers.

Croscarmellose sodium, starch pregelatinised, cellulose microcrystalline, silica gel, povidone, stearic acid, magnesium stearate, talc, hypromellose, hydroxypropylcellulose, propylene glycol, sorbitan monooleate, titanium dioxide, sorbic acid, vanillin, quinoline yellow E104.

None known.

The recommended shelf life is 24 months.

Protect from light. Store in a dry place.

2/14/56 tablets in a blister original pack. The blisters are packaged in a carton with a pack insert.

Not applicable

Abbott Laboratories Limited

Queenborough

Kent

ME11 5EL, UK

PL 0037/0211

09/04/91

September 2006