Pharmaniaga Clarithromycin

Clarithromycin.

Each tablet f/c contains Clarithromycin 250 mg and 500 mg.

Pharmacology: Clarithromycin is an antibiotic of the macrolide family. Clarithromycin exerts its antibacterial activity by inhibiting synthesis of proteins, by means of a link with the 50S sub-unit of the cellular ribosome. Clarithromycin has demonstrated excellent in-vitro activity against both standard strains of bacteria and clinical isolates. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The in-vitro antibacterial spectrum of clarithromycin is as follows: Usually Sensitive Bacteria: Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus viridans, Streptococcus pneumoniae, Heamophilus influenzae, Haemophilus parainfluenzae, Neisseria gonorrheae, Listeria monocytogenes, Legionella pneumophila, Pasteurella multocida, Mycoplasma pneumoniae, Helicobacter (Campylobacter) pylori, Campylobacter jejuni, Chlamydia trachomatis, Chlamydia pneumoniae (TWAR), Moraxella (Branhamella) catarrhalis, Bordetella pertussis, Borrelia burgdorferi, Staphylococcus aureus, Clostridium perfringens, Peptococcus niger, Propionibacterium acnes, Bacteroides melaninogenicus, Mycobacterium avium, Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium intracellulare.
Non-Sensitive Bacteria: Enterobacteriaceae, Pseudomonas spp.
Pharmacokinetics: The principal metabolite of clarithromycin in man and other primates is a microbiologically-active metabolite, 14-OH-clarithromycin. This metabolite is as active or 1- to 2-fold less active than the parent compound for most organisms, except for H. influenzae against which it is twice as active. The parent compound and the 14-OH metabolite exert either an additive or synergistic effect on H. influenzae in vitro and in vivo, depending on bacterial strains.
Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin was approximately 50%. Food slightly delays both the onset of clarithromycin absorption and the formation of the antimicrobially active metabolite, 14-OH clarithromycin, but does not affect the extent of bioavailability. Therefore, Clarithromycin tablets may be given without regard to food.
In fasting healthy human subjects, peak serum concentrations were attained within 2 hours after oral dosing. Steady state peak serum clarithromycin concentrations were attained in 2 to 3 days and were approximately 1 μg/mL with a 250 mg dose administered every 12 hours, 2 to 3 μg/mL with a 500 mg dose administered every 12 hours and 3 to 4 μg/mL with a 500 mg dose administered every 8 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours.
The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH clarithromycin, attains a peak steady-state concentration of about 0.6 μg/mL and has an elimination half life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 μg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of the metabolite is generally attained within 2 to 3 days.
After a 250-mg tab every 12 hrs, approximately 20% of the dose is excreted in the urine as clarithromycin while after a 500-mg tab every 12 hrs, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL) suspension every 12 hrs, approximately 40% is excreted in urine as clarithromycin. 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 10-15% of the dose with either a 250- or 500-mg tab administered every 12 hrs.
Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500-mg doses of clarithromycin every 12 hrs to adult patients with HIV infection were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500- or 1000-mg doses of clarithromycin every 12 hrs, steady-state clarithromycin C_max values ranged from 2-4 mg/mL and 5-10 mg/mL, respectively.
The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.
The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function. Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intracellular concentrations, tissues concentrations are higher than serum concentrations.

Treatment of infection caused by pathogens sensitive to Clarithromycin. Infections of nasopharynx tract (tonsillitis, pharyngitis), and of paranasal sinuses. Infections of lower respiratory tract; bronchitis, bacterial pneumonia and atypical pneumonia. Skin infections eg, impetigo, erysipelas, folliculitis, furunculosis and septic wounds.

Tablet: Clarithromycin recommended dosage in adults is one 250mg tablet every 12 hours. In cases of severe infections, dosage can be increased up to 500 mg every 12 hours.
Administration must be continued, according to severity of infection, up to 6-14 days.
In patients with renal impairment with creatinine clearance less than 30 mL/min, the dosage should be reduced by one-half. (Dosage should not be continued beyond 14 days in these patients).
Route of Administration: Oral.

Reports indicate that the digestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested 8 g of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxemia. Allergic reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures.
As with other macrolides, clarithromycin plasma levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.

Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin or any of the macrolide antibiotics.
Concomitant administration of clarithromycin with cisapride, pimozide or terfenadine is contraindicated. Clarithromycin and ergot derivatives should not be administered.
Clarithromycin should not be used in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If pregnancy occurs while taking this drug, the patient should be appraised of the potential hazard to the fetus. Clarithromycin has demonstrated adverse effects of pregnancy outcome and/or embryo-fetal development in monkeys, rats, mice and rabbits at doses that produced plasma levels 2-17 times the serum levels achieved in humans treated at the maximum recommended human doses.
There have been reports of an interaction between erythromycin and astemizole resulting in QT prolongation and torsade de pointes. Concomitant administration of erythromycin and astemizole is contraindicated. Because clarithromycin is also metabolised by cytochrome P450, concomitant administration of clarithromycin with astemizole is not recommended.
Concomitant administration of clarithromycin and the following drugs is contraindicated: Domperidone as this may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (See Interactions.)

The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.
Clarithromycin is principally excreted by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal failure. Attention should also be paid to the possibility of cross-resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with creatinine clearance less than25 mL/min.
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCARs) [e.g. Steven-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) & acute generalised exanthematous pustulosis (AGEP)], clarithromycin should be discontinued immediately and appropriate treatment should be urgently initiated.
Effects on ability to drive and operate machines: There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.
Use in pregnancy: See Contraindication.
Use in lactation: It is not known whether clarithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clarithromycin is administered to a nursing woman.
Use in children: Safety and effectiveness of clarithromycin in pediatric patients under 6 months of age have not been established.
Use in the elderly: Kidney function declines progressively with age. This condition can affect pharmacokinetics profile. Therefore, dosage adjustment should be considered in elderly patients with severe renal impairment.

Pregnancy: See Contraindication.
Lactation: It is not known whether clarithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clarithromycin is administered to a nursing woman.

After oral administration of clarithromycin, some cases of G.I disturbances have been reported (nausea, vomiting, heartburns, abdominal pain, diarrhoea), headache and skin rashes. Other adverse reactions reported include stomatitis, glossitis, oral monilia, taste perversion, pseudomembranous colitis.
Transient CNS events including anxiety, behavioural changes, confusional states, depersonalisation, disorientation, hallucinations, insomnia, manic behaviour, nightmares, psychosis, tinnitus, tremor, and vertigo have been reported during post-marketing surveillance. Events usually resolve with discontinuation ofthe drug.
Hepatic dysfunction, including increased liver enzymes and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.
There have been rare reports of hypoglycaemia, some of which have occurred in patients taking oral hypoglycaemic agents or insulin. Rarely, erythromycin and clarithromycin have been associated with ventricular arrhythmias including ventricular tachycardia and Torsade de pointes, in individuals with prolonged QTc intervals.
Skin and subcutaneous Tissue Disorders: Frequency not known: severe cutaneous adverse reactions (SCARs) including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) & acute generalised exanthematous pustulosis (AGEP).
Immunocompromised Pediatric Patients: In AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it is often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness.
The most frequently reported adverse events excluding those due to the patient's concurrent condition, were tinnitus, deafness, vomiting, nausea, abdominal pain, purpuric rash, pancreatitis and increased amylase.
Evaluations of laboratory values for these patients were made by analysing those values outside the seriously abdominal level (eg, the extreme high or low limit) for the specified test. Based on these criteria, one paediatric AIDS patient receiving <15 mg/kg/day of clarithromycin had seriously abnormal (elevated) total bilirubin; of the patients receiving 15 to <25 mg/kg/day of clarithromycin, there was one each reported as seriously abnormal SGPT, BUN, and seriously decreased platelet count. None of these seriously abnormal values for these laboratory parameters were reported for patients received the highest dosage (≥25 mg/kg/day) of clarithromycin.

Theophylline: Clarithromycin use in patients who are 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.
Carbamazepine: Concomitant administration 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 threefold higher, on average, than the values observed when terfenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-hydroxy-clarithromycin were not significantly affected by co-administration of terfenadine once clarithromycin reached steady-state conditions. Concomitant administration of clarithromycin with terfenadine is contraindicated.
Omeprazole: Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased by the concomitant administration of clarithromycin.
Zidovudine: Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients resulted in decreased steady-state zidovudine concentrations.
Oral anticoagulants: Concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously.
Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin levels should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.
The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg, warfarin), pimozide, quinidine, rifabutin, simvastatin, tacrolimus, terfenadine and triazolam.
Co-administration of clarithromycin, known to inhibit CYP3A4, and a drug primarily metabolized by CYP3A4 may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.
The following drugs or drug classes are known to be known or suspected to be metabolized by CYP3A isozyme: Domperidone.
Use of clarithromycin in patients concurrently taking drugs metabolized by the cytochrome P450 system (eg, Warfarin, ergot alkaloids, midazolam, lovastatin, phenytoin, ciclosporin) may be associated with an increase in the serum levels of these drugs.
Quinidine/disopyramide have been reported to cause torsade de pointes when taken in combination with clarithromycin.

Store below 30°. Protect from light.

Macrolides

J01FA09 - clarithromycin ; Belongs to the class of macrolides. Used in the systemic treatment of infections.

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