Clarithrocid

CLARITHROMYCIN

250 mg Film-Coated Tablet
500 mg Film-Coated Tablet

ANTIBACTERIAL

Category:

Description

DESCRIPTION

Clarithromycin, a semisynthetic macrolide antibiotic derived from erythromycin, inhibits bacterial protein synthesis by binding to the bacterial 50S ribosomal subunit. The binding inhibits peptidyl transferase activity and interferes with amino acid translocation during the translation and protein assembly process. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump. Clarithromycin may be bacteriostatic or bactericidal depending on the organism and drug concentration.

PHARMACOLOGY

The spectrum of activity of clarithromycin includes many gram-positive (Staphylococcus aureus, S. pneumoniae, and S. pyogenes) and gram-negative aerobic bacteria (Haemophilus influenzae, H. parainfluenzae, and Moraxella catarrhalis), many anaerobic bacteria, some mycobacteria, and some other organisms including Mycoplasma, Ureaplasma, Chlamydia, Toxoplasma, and Borrelia. Other aerobic bacteria that clarithromycin has activity against include C. pneumoniae and M. pneumoniae. Clarithromycin has an in-vitro activity that is similar or greater than that of erythromycin against erythromycin-susceptible organisms. Clarithromycin is usually bacteriostatic, but may be bactericidal depending on the organism and the drug concentration.

PHARMACOKINETICS

Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration and undergoes first-pass metabolism. The absolute bioavailability of 250 mg Clarithromycin tablets was approximately 50%. For a single 500 mg dose of Clarithromycin, food slightly delays the onset of Clarithromycin absorption, increasing the peak time from approximately 2 to 2.5 hours. Food also increases the Clarithromycin peak plasma concentration by about 24%, but does not affect the extent of Clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH Clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, Clarithromycin tablets may be given without regard to food.

Clarithromycin and its principal metabolite are widely distributed, and tissue concentrations exceed those found in serum, partly due to intracellular intake. It is extensively metabolized in the liver. It is excreted in feces via the bile. Substantial amounts are also excreted via urine.

After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as Clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of Clarithromycin is somewhat greater, approximately 30%. The renal clearance of Clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH Clarithromycin, which accounts for an additional 10% to 15% of the dose with either a 250 mg or a 500 mg tablet administered every 12 hours.

INDICATIONS

Clarithromycin Film – Coated Tablet is indicated for the treatment of mild to moderate infections caused by susceptible organisms in the conditions as listed below:

  • Pharyngitis/Tonsillitis due to Streptococcus pyogenes
  • Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae
  • Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae
  • Community-Acquired Pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR)
  • Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus pyogenes (Abscesses usually require surgical drainage.)
  • Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare

DOSAGE AND ADMINISTRATION

Clarithromycin is given orally. The usual recommended dosage in adults is 250 mg twice daily. Dosage may be increased to 500 mg twice daily if necessary in cases of severe infection. Antibiotic course usually lasting for 7 to 14 days.

Dosage disseminated infection due to Mycobacterium avium complex

Prophylaxis and Treatment

Adult: Clarithromycin 500 mg twice daily by mouth

Children: The recommended dose is 7.5 mg/kg twice daily up to 500 mg twice daily.

Clarithromycin may be given in combination with other antimycobacterials for treatment.

Leprosy

Clarithromycin 500 mg daily by mouth, as part of an alternative multidrug therapy regimen.

Eradication of Helicobacter pylori associated peptic ulcer disease

Clarithromycin 500 mg twice daily, given concomitantly with other antibacterial and either a proton pump inhibitor or a histamine H2-receptor antagonist for 7-14 days.

CONTRAINDICATIONS

Clarithromycin is contraindicated in patients with known hypersensitivity to any macrolide antibiotics. Patients who are on Clarithrocid therapy should not take astemizole, cisapride or terfenadine concomitantly.

WARNINGS AND PRECAUTIONS

Attention should be considered to the possibility of cross resistance between cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.

Pseudomembranous colitis has been reported with nearly all antibacterial agents including clarithromycin, and may range severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who represent with diarrhea subsequent to the administration of clarithromycin and other antibacterial agents.

Overdosage of clarithromycin can cause gastrointestinal symptoms including abdominal pain, vomiting, nausea and diarrhea. Adverse reactions accompanying overdosage should be treated by the prompt elimination of the unabsorbed drug and through supportive measures. Serum concentrations of clarithromycin are not expected to be appreciably affected via hemodialysis or peritoneal dialysis.

ADVERSE EFFECTS

Gastrointestinal disturbances (e.g. nausea, dyspepsia, abdominal pain, vomiting and diarrhea) are the most frequent adverse effects of clarithromycin but are usually mild and less frequent than with erythromycin.

Other adverse effects are taste disturbances, stomatitis, glossitis and tooth discoloration, hypoglycaemia and thrombocytopenia. Interstitial nephritis and renal failure have been reported rarely.

Transient elevations of liver enzyme values, cholestatic jaundice, and hepatitis have been reported. Headache and rashes from mild skin eruptions to, rarely, Steven Johnson syndrome have occurred.

There also have been reports of transient CNS effects such as anxiety, dizziness, insomnia, hallucinations and confusion. Hearing loss has been reported occasionally and is usually reversible.

Thrombocytopenia purpura, corneal opacities which is usually reversible upon discontinuation of the treatment, pseudomonas colitis associated with clostridium difficile developed in a child receiving clarithromycin, acute psychosis, pancreatitis, QT prolongation and torsade de pointes, fever associated with clarithromycin and leukocytoclastic vasculitis have also been reported.

DRUG INTERACTIONS

  • Rifabutin. Increased rifabutin toxicity has been reported in patients receiving clarithromycin and rifabutin. There has also been a report of delirium following the concurrent use with fluoxetine.
  • Antiretrovirals
  • Concomitant administration of the HIV-protease inhibitor ritonavir inhibits the metabolism of clarithromycin producing elevated plasma concentrations and a prolonged half-life. It has been suggested that other HIV-protease inhibitors and non-nucleoside reverse trascriptase inhibitors may also affect the metabolism of clarithromycin.
  • Concurrent use of efavirenz with clarithromycin has resulted in a decrease in clarithromycin plasma concentrations and an increase in its hydroxyl metabolite. This combination has been associated with a high incidence of skin rashes.
  • Decreased concentrations of zidovudine have been reported in patients also taking clarithromycin. It is recommended that the administration of the two medications to be separated by 1 to 2 hours.
  • Administration of cimetidine with clarithromycin may alter some of the pharmacokinetic parameters of clarithromycin. The clinical significance of such changes is unknown.
  • Omeprazole. Concomitant administration of omeprazole with clarithromycin resulted in increased concentrations of clarithromycin and its active metabolite. There is also an increased and prolonged plasma concentration of omeprazole present. This interaction should account for the synergistic action with the combination when used in the eradication of Helicobacter pylori.
  • Other antimycobacterials. Clarithromycin has been reported to enhance the activity of a number of antimycobacterials including ethambutol, isoniazid, pyrazinamide, and rifampicin against mycobacterium tuberculosis.
  • Theophylline. The use of clarithromycin in patients receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
  • The concurrent use of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered.
  • Terfenadine, When clarithromycin and terfenadine were co-administered, plasma concentrations of the active acid metabolite of terfenadine were threefolds higher, on average, than the values observed when terfenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-hydroxyclarithromycin were not significantly affected by the co-administration of terfenadine once clarithromycin reached steady-state conditions.
  • Co-administration of fluconazole and clarithromycin increased the mean steady state of clarithromycin Cmin of 33% and AUC of 18%. Steady-state concentrations of 14-hydroxyclarithromycin were not significantly affected by the concomitant administration of fluconazole.
  • Other anticoagulants. Concurrent use of clarithromycin and oral anticoagulants may potentiate the effect of the oral anticoagulant. Prothrombin time should be carefully monitored.
  • There have been reports indicating increased in digoxin serum concentrations when clarithromycin is co-administered with digoxin. Serum levels of digoxin should be monitored.
  • Colchicine toxicity have been reported with the concomitant use of clarithromycin and colchicine, particularly in the elderly, some of which occurred in patients with renal insufficiency.

Clarithromycin is a substrate and inhibitor of the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A). Co-administration of clarithromycin and a drug primarily metabolized by CYP3A may be associated with an elevation in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the drug taken concomitantly. The following are examples of clinically significant CYP3A based drug interactions observed with clarithromycin:

Anti-arrhythmics. There have been post marketing reports of torsade de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum concentrations of these medications should also be monitored.

Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin with ergotamine or dihydroergotamine is contraindicated.

Drug interactions and CNS effects (e.g. somnolence and confusion) have been reported with the concomitant use of clarithromycin and triazolobenzodiazepines (such as triazolam and alprazolam) and other related benzodiazepines (such as midazolam).

Clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin). There have been rare reports of rhabdomyolysis in patients taking these drugs concomitantly.

Clarithromycin has been reported to increase the systematic exposure (AUC) of sildenafil. Reduction of sildenafil dosage should be considered.

There have been published reports of CYP3A based interaction of clarithromycin with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methylprednisolone, cilostazol, and bromocriptine. In addition, there also have been reports of interactions of clarithromycin with drugs not thought to be metabolized via CYP3A, including hexobarbital, phenytoin and valproate.

PREGNANCY AND LACTATION

Clarithromycin should not be used in pregnant women except during clinical circumstances when no alternative therapy is appropriate because high doses of clarithromycin have been associated with embryotoxicity in animal studies with clarithromycin. It is not known whether clarithromycin is excreted in breast milk. Exercise caution when administering to nursing women.

AVAILABILITY

Clarithromycin 250 mg and 500 mg Film – Coated Tablet x 30’s

STORAGE

Store at temperatures not exceeding 30°C.

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