CLABACT 250

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Description

CLABACT 250

COMPOSITION:

Clarithromycin ........................................................ 250 mg

Excipients q.s  ........................................................ 1 tablet

(Microcrystalline cellulose, croscarmellose sodium, HPMC, sepitrap 80, stearic acid, magnesium stearate, aerosil, PVP K30, copovidone, PEG 6000, titanium dioxide, quinoline color, talc).

DOSAGE FORM: Film coated tablet.

PRESENTATION: Box of 2 blisters x 10 film coated tablets.

PHARMACODYNAMICS:

Clabact contains the active ingredient clarithromycin, a semi-synthetic macrolide antibiotic. Clarithromycin is usually bacteriostatic against Gram-positive bacteria and some Gram-negative bacteria. It may be bactericidal in high concentrations or against highly susceptible organisms. Clarithromycin inhibits protein synthesis in susceptible organisms by binding the 50S ribosomal subunits, thereby inhibiting translocation of aminocyl transfer-RNA and inhibiting polypeptide synthesis. The site of action of clarithromycin appears to be the same as that of erythromycin, clindamycin, lincomycin, and chloramphenicol.

Spectrum:

Clarithromycin generally displays in vitro activity similar to or greater than that of erythromycin against erythromycin-sensitive organisms and also exhibits activity against some organisms (e.g., atypical Mycobacteria, Toxoplasma).

Susceptible bacteria:

Gram-positive aerobic bacteria: Clarithromycin in vitro has greater activity than erythromycin against susceptible bacteria of streptococci and staphylococci.

Clarithromycin is active against some gram-positive aerobic bacilli such as Listeria monocytogenes and some strains of Corynebacterium.

Gram-negative aerobic bacteria: Clarithromycin is active in vitro against some Gram-negative organisms, including Neisseria gonorrhoeae and Moraxella (Branhamella) catarrhalis, Haemophilus influenzae, H. parainfluenzae, Pasteurella multocida. Clarithromycin has greater activity than erythromycin against Legionella spp., Campylobacter spp., Bordetella pertussis in vitro. Clarithromycin is active against most strains of Helicobacter pylori. Clarithromycin exbibits greater activity than most other macrolides against Helicobacter pylori.

Clarithromycin has greater activity than erythromycin and azithromycin against Mycobacteria including Mycobacterium avium complex and M. leprae.

Other aerobic bacteria: Clarithromycin is active against Mycoplasma pneumonia, Ureaplasma urealyticum, Clamydia trachomatis and some strains of C. pneumoniae.

Anaerobic bacteria: Clarithromycin is active in vitro against most strains of Peptococcus, Peptostreptococcus, Clostridium perfringens, Propionibacterium acnes, strains of Prevotella spp., Bacteroides fragilis.

Clarithromycin reportedly has exhibited activity against Toxoplasma gondii, Gardnerella vaginalis, Borrelia burgdorferi and Cryptosporidis.

Resistance:

Resistance to macrolide antibiotics usually involves an alteration at the antibiotic target site, but resistance caused by modification and/or active efflux of the antibiotic also have been reported. Such resistance may be chromosomally or plasmid medicated. Bacteria resistant to macrolides produce an enzyme that leads to methylation of adenine residues in ribosomal RNA and subsequent inhibition of binding of the antibiotic to the ribosome.

Organisms resistant to erythromycin generally are resistant to all macrolides because all of these drugs induce the methylase enzyme.

Streptococcus pneumoniae resistant to erythromycin is cross-resistant to clarithromycin. Penicillin-resistant strains are also resistant to clarithromycin and had clarithromycin-resistant Helicobacter pylori isolates. Due to rapid development of resistance to M. avium when using clarithromycin alone, a combination therapy should be recommended.

Most of Enterococci such as Enterococcus faecalis were resistant both clarithromycin and erythromycin.

Oxacillin-resistant staphylococci, Staphylococcus coagulase-negative (S. epidermidis). Enterobacteriaceae (Salmonella enteriditis; Yersinia enterocolitica, Shigella and Vibrio spp. are resistant to clarithromycin.

Situation of resistance to macrolide antibiotics in Vietnam tends to increase rapidly. Erythromycin-resistant bacteria are usually resistant to macrolides including clarithromycin.

PHARMACOKINETICS:

Clarithromycin is absorbed rapidly from the GI tract and undergoes extensive first-pass metabolism. The absolute bioavailability of clarithromycin has been reported to be approximately 55%. Clarithromycin is unaffected by the presence of food. Peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Steady state is attained within 3-4 days; peak concentrations of clarithromycin and its metabolite 14-hydroxyclarithromycin are reported to be about 1 and 0.6 mcg per ml respectively following a single 250-mg dose every 12 hours by mouth.

Clarithromycin exhibits nonlinear, dose-dependent pharmacokinetics. Disproportionate increases in peak concentrations have been reported in patients receiving high doses. Such nonlinearity is slight at the usual dosages of 250 - 500 mg every 8 - 12 hours.

The principal metabolite is 14 - hydroxyclarithromycin, which also has activity and may strengthen the activity of clarithromycin in vitro.

Clarithromycin and 14 - hydroxyclarithromycin metabolite appear to be widely distributed. Because of high intracellular concentrations of the drug, tissue concentrations are higher than serum concentrations. Protein binding of clarithromycin has been reported to range from approximately 42 - 72%. At usual therapeutic concentrations, clarithromycin is found in human milk and CFS; however, there is no evidence that the drug would be effective in the treatment of meningitis. Clarithromycin is extensively metabolized in the liver and eliminated in the bile. A significant amount is excreted in urine. With oral administration of 250 or 500 mg of clarithromycin as tablets approximately 20 or 30% of the respective dose is excreted unchanged in urine. The principal metabolite found in urine is 14 - hydroxyclarithromycin, which accounts for approximately 10 - 15% of the dose. The elimination half-life of clarithromycin and 14 - hydroxyclarithromycin reportedly increased from 3 - 4 hours and 5 - 6 hours following a 250-mg dose every 12 hours; 5 - 7 hours and 7 - 9 hours following a 500-mg dose every 8 - 12 hours. The serum half-life is prolonged in patients with impaired renal function.

INDICATIONS:

Clabact 250 is indicated in adults and adolescents ≥ 12 years of age:

Treatment of respiratory tract infections, including tonsillitis, otitis media, acute sinusitis, acute exacerbations of chronic bronchitis, community-acquired pneumonia caused by Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae and Streptococcus pneumoniae; skin and soft tissue infections caused by susceptible bacteria.

Prevention and treatment of Mycobacterium avium complex (MAC) infections in patients with serious HIV infection.

Prevention of bacterial endocarditis in penicillin-allergic patients.

Conjunctional treatment of duodenal ulcer disease caused by Helicobacter pylori infection.

CONTRAINDICATIONS:

Clarithromycin is contraindicated in patients with known hypersensitivity to macrolides or any ingredients of the drug.

Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, pimozide and terfenadine, as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and Torsades de Pointes.

Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine) also is contraindicated because of potentially serious toxicity.

Concurrent use of clarithromycin and oral midazolam agent is contraindicated.

Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes.

Clarithromycin should not be given to patients with hypokalaemia (risk of prolongation of QT-time).

Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.

Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis.

As with other strong CYP3A4 inhibitors, clarithromycin should not be used in patients taking colchicine.

Concomitant administration with ticagrelor or ranolazine is contraindicated.

WARNINGS AND PRECAUTIONS:

The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy.

Long-term use may, as with other antibiotics, result in colonization with increased numbers of non-susceptible bacteria and fungi. If super-infection occurs, appropriate therapy should be instituted.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Clostridium difficile-associated diarrhea (CDAD) must be considered in all patients who present with diarrhea following antibiotic use. Exploitation of drug-use history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. Discontinue clarithromycin immediately if signs and symptoms of hepatitis, including anorrxia, jaundice, dark urine, pruritus, or tender abdomen occur.

Clarithromycin is principally excreted by the liver. Therefore, caution should be exercised in administering clarithromycin to patients with impaired hepatic function. Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment.

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. Concomitant administration of clarithromycin and colchicine is contraindicated.

Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam.

Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment.

Due to the risk for QT prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe cardiac insufficiency, hypomagnesaemia, bradycardia (<50 bpm), or when co-administered with other medicinal products associated with QT prolongation.

Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with additional appropriate antibiotics.

Skin and soft tissue infections:

These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, and DRESS, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme.

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

HMG-CoA reductase Inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated. Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered.

Oral hypoglycemic agents/Insulin

The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. Careful monitoring of glucose is recommended.

Oral anticoagulants

There is a risk of serious hemorrhage and significant elevations in International Normalized Ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.

PREGNANCY AND LACTATION:

Safety of clarithromycin in pregnant women and nursing mothers has not been determined. Do not administer clarithromycin to pregnant women, unless there is no alternative therapies and careful monitoring is required. Clarithromycin should be used with caution in nursing mothers.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES:

The potential for headache, dizziness, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

INTERACTIONS: The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects

Cisapride, pimozide, astemizole and terfenadine: Elevated levels have been reported in patients receiving clarithromycin and the drugs above concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes.

Ergotamine/dihydroergotamine: Postmarketing 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 extremities and other tissues including the central nervous system.

HMG-CoA reductase inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated, as these statins are extensively metabolized by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Effects of other medicinal products on clarithromycin

Drugs that are inducers of CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John's Wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A4 inducer, which could be increased owing to the inhibition of CYP3A4 by clarithromycin. Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.

The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required: efavirenz, nevirapine, rifampicin, rifabutin, rifapentine, etravirine, fluconazole, and ritonavir.

Effect of clarithromycin on other medicinal products

Antiarrhythmics

There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these drugs. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy.

There have been post marketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.

Oral hypoglycemic agents/Insulin

With certain hypoglycemic drugs such as nateglinide and repaglinide, inhibition of CYP3A4 enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Careful monitoring of glucose is recommended.

CYP3A4-based interactions

Co-administration

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