Instructions Fromilid Uno modified-release tablets 500 mg No. 7
Composition
active ingredient: clarithromycin;
1 tablet contains 500 mg of clarithromycin;
excipients: sodium alginate, sodium calcium alginate, lactose monohydrate, povidone, polysorbate 80, colloidal anhydrous silica, magnesium stearate, talc, hypromellose, yellow iron oxide (E 172), titanium dioxide (E 171), propylene glycol.
Dosage form
Modified-release tablets.
Main physicochemical properties: oval biconvex tablets, film-coated, brownish-yellow in color with the letter "U" embossed on one side.
Pharmacotherapeutic group
Antibacterial agents for systemic use.
Macrolides, lincosamides and streptogramins. Clarithromycin. ATC code J01F A09.
Pharmacological properties
Pharmacodynamics
Clarithromycin is a semi-synthetic macrolide antibiotic. The antibacterial effect of clarithromycin is determined by its binding to the 5OS ribosomal subunit of sensitive bacteria and inhibition of protein biosynthesis. Modified-release tablets are a homogeneous crystalline base, which, when passing through the gastrointestinal tract, provides a prolonged release of the active substance.
The drug exhibits high in vitro activity against a wide range of aerobic and anaerobic Gram-positive and Gram-negative microorganisms, including hospital strains. The minimum inhibitory concentrations (MICs) of clarithromycin are usually half the MICs of erythromycin.
Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as gram-negative bacteria that do not ferment lactose, are insensitive to clarithromycin.
Microbiology
Clarithromycin is active in vitro and in clinical practice against most strains of the following microorganisms:
Aerobic gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes.
Aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhlis, Neisseria gonorrhоeae, Legionella pneumophila.
Other microorganisms: Mycoplasma pneumonia, Chlamydia pneumonia (TWAR).
Mycobacteria: Mycobacterium leprae, Mycobacterium kansaii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium сomplex (MAC), which include Mycobacterium avium, Mycobacterium intracellueare.
Beta-lactamases of microorganisms do not affect the effectiveness of clarithromycin.
Most methicillin- and oxacillin-resistant staphylococcal strains are insensitive to clarithromycin.
Clarithromycin is active in vitro against most strains of such microorganisms, however, clinical efficacy and safety have not been established.
Aerobic Gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groups C, F, G), Viridans group streptococci.
Aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida.
Anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.
Anaerobic Gram-negative microorganisms: Bacteriodes melaninogenicus.
Spirochetes: Borrelia burgdorferi, Treponemsa pallidum.
Campylobacter: Campylobacter jejuri.
Clarithromycin has bactericidal activity against several strains of bacteria: Haemophilus influenzae, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Campylobacter spp. and Helicobacter pylori.
The main metabolite of clarithromycin in humans is the microbiologically active 14-OH-clarithromycin. For most microorganisms, the microbiological activity of the metabolite is equal to or 1-2 times weaker than the parent substance, with the exception of Haemophilus influenzae, against which the effectiveness of the metabolite is twice as high. In vitro and in vivo, the parent substance and its main metabolite exhibit either an additive or synergistic effect against Haemophilus influenzae, depending on the strain of the microorganism.
Pharmacokinetics
The kinetics of clarithromycin extended-release tablets were compared with those of 250 and 500 mg immediate-release tablets. The extent of absorption was equivalent when equivalent doses were used. Absolute bioavailability is approximately 50%. No accumulation was observed with multiple dosing and the pattern of metabolism in humans was unchanged.
Healthy subjects
After administration of clarithromycin, extended-release tablets, orally after meals at 500 mg per day, the steady-state maximum plasma concentrations (Cmax) of clarithromycin and 14-OH-clarithromycin were 1.3 and 0.48 μg/mL, respectively. The half-lives of the drug and its metabolite were 5.3 and 7.7 hours, respectively. After administration of 1000 mg of clarithromycin extended-release tablets per day (2 tablets of 500 mg), the steady-state maximum plasma concentrations of clarithromycin and 14-OH-clarithromycin averaged 2.4 μg/mL and 0.67 μg/mL, respectively. The half-lives of the drug and its major metabolite were 5.8 and 8.9 hours, respectively. Tmax was reached after 6 hours for doses of 500 mg and 1000 mg per day. The steady-state concentrations of 14-OH-clarithromycin do not increase proportionally with the dose of clarithromycin, and the half-lives of clarithromycin and its major metabolite increase with increasing dose. The nonlinear nature of the pharmacokinetics of clarithromycin is associated with a decrease in the formation of the 14-hydroxylated and N-demethylated metabolites at higher doses. About 40% of the clarithromycin dose is excreted in the urine, and 30% through the intestines.
Clarithromycin and its metabolite are widely distributed in body tissues and fluids. After oral administration, clarithromycin concentrations in cerebrospinal fluid remain low (1-2% of serum levels with a normal blood-brain barrier). Clarithromycin concentrations in tissues are usually several times higher than in serum.
Liver dysfunction.
In patients with moderate to severe hepatic impairment but with preserved renal function, no dose adjustment of clarithromycin is required.
Kidney dysfunction.
In renal impairment, the minimum and maximum plasma concentrations, half-life and area under the concentration/time curve of clarithromycin and 14-OH-clarithromycin increase. The elimination constant and urinary excretion decrease. The degree of change in these parameters depends on the degree of renal impairment - the more severe the impairment, the more pronounced the changes in the parameters.
Elderly patients.
In elderly patients, blood levels of clarithromycin and 14-OH-clarithromycin were higher and elimination was slower compared to younger subjects. The change in pharmacokinetics in elderly patients is primarily due to impaired renal function, rather than to the patient's age.
Indication
Treatment of infections caused by microorganisms sensitive to clarithromycin.
Lower respiratory tract infections (bronchitis, pneumonia, etc.); Upper respiratory tract infections (sinusitis, pharyngitis, etc.); Skin and soft tissue infections (folliculitis, erysipelas, etc.).
Contraindication
hypersensitivity to clarithromycin or other macrolide antibiotics or to any of the ingredients of the drug;
Concomitant use with any of the following drugs: astemizole, cisapride, pimozide, terfenadine (as this may lead to QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes); ergot alkaloids such as ergotamine, dihydroergotamine (as this may lead to ergotoxicity); HMG-CoA reductase inhibitors (statins) extensively metabolised by CYP3A4 (lovastatin or simvastatin) due to increased risk of myopathy including rhabdomyolysis (see sections 4.4 and 4.5);
simultaneous use of clarithromycin and oral midazolam (see sections "Special instructions for use" and "Interaction with other medicinal products and other types of interactions");
congenital or established acquired prolongation of the QT interval or history of ventricular cardiac arrhythmias, including torsade de pointes (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other types of interactions");
hypokalemia (risk of QT prolongation); severe hepatic insufficiency and concomitant renal insufficiency;
simultaneous use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine in patients with renal or hepatic insufficiency (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other types of interactions");
concomitant use of clarithromycin with ticagrelor or ranolazine; creatinine clearance less than 30 ml/min (since this form does not allow the dose to be reduced below 500 mg per day).
Interaction with other medicinal products and other types of interactions
Clarithromycin does not interact with oral contraceptives.
The use of the following drugs is strictly contraindicated due to the possible development of severe interaction effects:
Cisapride, pimozide, astemizole, and terfenadine
Increased serum levels of cisapride have been observed with concomitant use with clarithromycin, which may lead to QT prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes. Similar effects have been observed with concomitant use of pimozide and clarithromycin (see Contraindications).
Macrolides have been reported to alter the metabolism of terfenadine, leading to increased serum levels of terfenadine, which have sometimes been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsade de pointes (see Contraindications). In a study of 14 volunteers, concomitant administration of terfenadine and clarithromycin resulted in a 2- to 3-fold increase in the acid metabolite of terfenadine and a prolongation of the QT interval, without clinically significant effects. Similar effects have been observed with the concomitant administration of astemizole and other macrolides.
Ergotamine/dihydroergotamine
Postmarketing reports indicate that concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with the development of signs of acute ergotism, characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system. Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see section 4.3).
When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 7-fold after oral administration of midazolam. Concomitant use of oral midazolam and clarithromycin is contraindicated (see Contraindications).
HMG-CoA reductase inhibitors (statins)
The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"), since these statins are extensively metabolized by CYP3A4 and concomitant use with clarithromycin increases their plasma concentrations, which in turn increases the risk of myopathy, including rhabdomyolysis. Rhabdomyolysis has been reported in patients receiving concomitant treatment with clarithromycin and these statins. If treatment with clarithromycin cannot be avoided, lovastatin or simvastatin should be discontinued during the course of treatment.
Caution should be exercised when prescribing clarithromycin concomitantly with other statins. In situations where concomitant use of clarithromycin with a statin cannot be avoided, it is recommended to use the lowest approved dose of the statin. A statin that is not metabolized by CYP3A (e.g. fluvastatin) may be used. Patients should be monitored for signs and symptoms of myopathy.
Effect of other drugs on the pharmacokinetics of clarithromycin
Medicinal products that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may lead to subtherapeutic levels of clarithromycin and reduced efficacy. In addition, monitoring of plasma levels of the CYP3A inducer, which may be increased due to inhibition of CYP3A by clarithromycin, may be necessary (see also the Summary of Product Characteristics of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has been shown to increase rifabutin levels and decrease clarithromycin serum levels, with a concomitant increase in the risk of uveitis.
The following drugs are known or expected to affect clarithromycin blood concentrations and may require dose adjustment or alternative therapy.
Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine
Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, may accelerate the metabolism of clarithromycin, reducing its plasma concentration but increasing the concentration of 14-OH-clarithromycin, the microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin is different against different bacteria, the expected therapeutic effect may not be achieved due to the simultaneous use of clarithromycin and inducers of cytochrome P450 enzymes.
Etravirine
Clarithromycin activity was attenuated by etravirine; however, concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Therefore, alternative agents to clarithromycin should be considered for the treatment of MAC.
Fluconazole
The steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered by co-administration with fluconazole. No dose adjustment of clarithromycin is required.
Ritonavir
Ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. Clarithromycin Cmax increased by 31%, Cmin by 182%, and AUC by 77% with concomitant ritonavir. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the large therapeutic window, no dose reduction of clarithromycin is necessary in patients with normal renal function. Dosage adjustment is required in patients with renal impairment: for CLCR 30-60 mL/min, the dose of clarithromycin should be reduced by 50%; for CLCR < 30 mL/min, the dose should be reduced by 75%. Doses of clarithromycin exceeding 1 g/day should not be co-administered with ritonavir.
Similar dose adjustments should be made for patients with impaired renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir.
Effect of clarithromycin on the pharmacokinetics of other drugs.
Antiarrhythmic drugs
There have been postmarketing reports of torsades de pointes associated with concomitant use of clarithromycin with quinidine or disopyramide. ECG monitoring is recommended for early detection of QT prolongation. Serum concentrations of these drugs should be monitored during clarithromycin therapy.
Hypoglycemia has been reported with concomitant use of clarithromycin and disopyramide, therefore blood glucose monitoring is necessary when these agents are used concomitantly.
Oral hypoglycemic agents/insulin
When used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide, clarithromycin may inhibit the CYP3A enzyme, which may cause hypoglycemia. Close monitoring of glucose levels is recommended.
Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, and a drug that is primarily metabolized by CYP3A may result in increased plasma concentrations of the latter, which in turn may increase or prolong its therapeutic effect and the risk of adverse reactions. Caution should be exercised when administering clarithromycin to patients receiving therapy with drugs that are CYP3A substrates, especially if the CYP3A substrate has a narrow therapeutic index (e.g. carbamazepine) and/or is extensively metabolized by this enzyme.
Dose adjustment may be necessary and, if possible, close monitoring of serum concentrations of a drug metabolized by CYP3A in patients receiving concomitant clarithromycin.
The following drugs or drug classes are known (or suspected) to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not exhaustive. A similar mechanism of interaction has been observed with phenytoin, theophylline and valproate, which are metabolized by a different cytochrome P450 isoenzyme.
Omeprazole
The use of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers resulted in an increase in the equilibrium concentrations of omeprazole (Cmax, AUC0-24, t1/2 increased by 30%, 89% and 34%, respectively). When omeprazole was used alone, the mean pH of gastric juice measured over 24 hours was 5.2, when omeprazole was used together with clarithromycin - 5.7.
Sildenafil, tadalafil and vardenafil
Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil, which are at least partially metabolized by CYP3A, is likely to result in increased exposure to the phosphodiesterase inhibitor, which may require a reduction in the dose of the phosphodiesterase inhibitor.
Theophylline, carbamazepine
Clinical trial results have shown that there is a small but statistically significant (p ≤0.05) increase in plasma concentrations of theophylline or carbamazepine when co-administered with clarithromycin.
Tolterodine
Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoform (CYP2D6). However, in a population of patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A results in significantly increased plasma concentrations of tolterodine. In such patients, a reduction in the dose of tolterodine may be necessary when administered with CYP3A inhibitors such as clarithromycin.
Triazolebenzodiazepines (e.g. alprazolam, midazolam, triazolam)
When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous administration and 7-fold after oral administration of midazolam. The combined use of oral midazolam and clarithromycin should be avoided. When intravenous midazolam is administered with clarithromycin, the patient should be closely monitored for timely dose adjustment.
The same precautions should be observed when using other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), the development of clinically significant interactions with clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and central nervous system adverse events (such as drowsiness and confusion) with concomitant use of clarithromycin and triazolam. The patient should be monitored for the potential for potentiation of central nervous system pharmacological effects.
Other types of interactions
Colchicine
Colchicine is a substrate of CYP3A and P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are coadministered, inhibition of Pgp and CYP3A by clarithromycin may lead to increased exposure to colchicine. Concomitant use of clarithromycin with colchicine is contraindicated in patients with renal or hepatic impairment (see sections 4.3 and 4.4).
Digoxin
Digoxin is considered a substrate for P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When used concomitantly, inhibition of Pgp may result in increased digoxin exposure. Increased serum digoxin concentrations have been reported in patients receiving clarithromycin concomitantly with digoxin. Some patients have developed signs of digitalis toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be closely monitored in patients receiving clarithromycin.
Concomitant use of clarithromycin immediate-release tablets and zidovudine in HIV-infected patients may result in decreased steady-state serum concentrations of zidovudine. Clarithromycin may interfere with the absorption of oral zidovudine when administered concomitantly; this can be largely avoided by separating the doses of clarithromycin and zidovudine by 4 hours. No such interaction has been reported in children with clarithromycin suspension and zidovudine or dideoxyinosine. Such an interaction is unlikely with intravenous clarithromycin.
Phenytoin and valproate
There have been spontaneous or published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). It is recommended that serum levels of these drugs be monitored when co-administered with clarithromycin. Increased serum levels have been reported.
Bidirectional drug interactions
Atazanavir
Coadministration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), which are CYP3A substrates and inhibitors, resulted in a 2-fold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, no dose reduction is necessary in patients with normal renal function. The clarithromycin dose should be reduced by 50% for patients with creatinine clearance 30-60 mL/min and by 75% for patients with creatinine clearance < 30 mL/min. Clarithromycin doses greater than 1 mg/day should not be administered with protease inhibitors.
Calcium channel blockers
Due to the risk of hypotension, caution should be exercised when administering clarithromycin concomitantly with calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem). The interaction may result in increased plasma concentrations of both clarithromycin and the calcium channel blocker.
Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving clarithromycin with verapamil.
Itraconazole
Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, and therefore clarithromycin may increase plasma levels of itraconazole and vice versa. When itraconazole is used concomitantly with clarithromycin, patients should be closely monitored for signs or symptoms of increased or prolonged effects.
Saquinavir
The use of clarithromycin with saquinavir (soft gelatin capsules 3 times daily), which are substrates and inhibitors of CYP3A, resulted in an increase in steady-state AUC by 177% and Cmax by 187% compared to the use of saquinavir alone. At the same time, the AUC and Cmax of clarithromycin increased by approximately 40% compared to the use of clarithromycin alone. No dose adjustment is necessary if both drugs are used simultaneously for a limited period of time and at the above doses and dosage forms. The results of a drug interaction study with the use of soft gelatin capsules may not correspond to the effects observed with the use of saquinavir in the form of hard gelatin capsules. The results of a drug interaction study with saquinavir alone may not correspond to the effects observed with saquinavir/ritonavir therapy. If saquinavir is used with ritonavir, the possible effect of ritonavir on clarithromycin should be considered (see above).
Application features
Clarithromycin should not be administered to pregnant women without careful benefit/risk assessment, especially during the first trimester of pregnancy (see section “Use during pregnancy or lactation”).
Prolonged or repeated use of antibiotics may result in overgrowth of nonsusceptible bacteria and fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy initiated.
The drug should be used with caution in patients with severe renal insufficiency (see section "Contraindications").
Clostridium difficile-associated diarrhea, ranging from mild to fatal, has been reported with the use of nearly all antibacterial agents, including clarithromycin. The possibility of Clostridium difficile-associated diarrhea should be kept in mind in all patients presenting with diarrhea following antibiotic therapy. In addition, a careful history should be taken, as Clostridium difficile-associated diarrhea has been reported up to 2 months after the use of antibacterial agents. If pseudomembranous colitis occurs, clarithromycin should be discontinued regardless of the indication for which it was prescribed. Microbiological investigation should be performed and appropriate treatment initiated. Drugs that inhibit peristalsis should be avoided.
The drug is excreted by the liver and kidneys. Caution should be exercised when using the drug in patients with impaired liver function, moderate or severe renal impairment.
Colchicine
Colchicine toxicity (including fatal outcomes) has been reported with concomitant use of clarithromycin and colchicine, particularly in elderly patients, including those with renal insufficiency. Concomitant use of clarithromycin with colchicine is contraindicated in patients with renal or hepatic insufficiency (see Contraindications).
Caution should be exercised when clarithromycin is administered concomitantly with triazolebenzodiazepines, e.g. triazolam, intravenous midazolam (see section 4.5).
Clarithromycin should be used with caution in combination with other ototoxic agents, especially aminoglycosides. Vestibular and auditory function should be monitored during and after treatment.
Cardiovascular events
Prolongation of cardiac repolarization and QT interval, indicating a risk of cardiac arrhythmia and torsades de pointes, has been observed with macrolides, including clarithromycin (see section 4.8). Since the following situations may lead to an increased risk of ventricular arrhythmias (including torsades de pointes), clarithromycin should be used with caution in the following patient groups:
patients with ischemic heart disease, severe heart failure, conduction disorders or clinically significant bradycardia;
patients with electrolyte imbalances such as hypomagnesemia. Clarithromycin should not be used in patients with hypokalemia (see section "Contraindications");
patients who are simultaneously taking other drugs that prolong the QT interval (see section "Interaction with other medicinal products and other types of interactions").
Concomitant use of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated (see section "Contraindications").
Clarithromycin should not be used in patients with congenital or established acquired QT prolongation or a history of ventricular arrhythmia (see section "Contraindications").
Epidemiological studies on the risk of adverse cardiovascular events with macrolides have been mixed. Some studies have reported a rare short-term risk of arrhythmia, myocardial infarction, and fatal cardiovascular events associated with macrolides, including clarithromycin. Consideration of these findings when prescribing clarithromycin should be balanced against the benefits of treatment.
Pneumonia
Since Streptococcus pneumoniae may be resistant to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin for the treatment of community-acquired pneumonia. In the case of nosocomial pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.
Mild to moderate skin and soft tissue infections
These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Susceptibility testing is therefore important. In cases where beta-lactam antibiotics are not suitable (e.g. allergy), other antibiotics such as clindamycin may be used as first-line agents. Macrolides currently have a role only in the treatment of certain skin and soft tissue infections, such as: infections caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, erysipelas; and in situations where penicillin treatment is not appropriate.
In the event of severe acute hypersensitivity reactions such as anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, Henoch-Schonlein-Schönlein disease, clarithromycin therapy should be discontinued immediately and appropriate treatment should be initiated immediately.
Clarithromycin should be used with caution when co-administered with inducers of the cytochrome CYP3A4 enzyme (see section “Interaction with other medicinal products and other types of interactions”).
Attention should be paid to the possibility of cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.
The use of any antimicrobial therapy, including clarithromycin, for the treatment of Helicobacter pylori infection may lead to the emergence of microbial resistance.
Concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulphonylureas) and/or insulin may result in severe hypoglycaemia. Close monitoring of glucose levels is recommended (see section 4.5).
Oral anticoagulants
Concomitant use of clarithromycin with warfarin carries a risk of serious bleeding, significant elevations in INR (international normalized ratio) and prothrombin time. MNR and prothrombin time should be monitored frequently while patients are receiving concomitant clarithromycin and oral anticoagulants.
HMG-CoA reductase inhibitors
The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). Caution should be exercised when clarithromycin is administered concomitantly with other statins. Rhabdomyolysis has been reported in patients receiving concomitant clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. If concomitant use of clarithromycin with statins cannot be avoided, it is recommended that the lowest registered dose of the statin be used. A statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) may be used (see section "Interaction with other medicinal products and other forms of interaction").
Excipients
The drug contains lactose, therefore patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not use the drug.
Ability to influence reaction speed when driving vehicles or other mechanisms
There are no data on the effects. However, before driving or operating machinery, it is necessary to take into account the possible occurrence of adverse reactions from the nervous system, such as seizures, dizziness, vertigo, confusion, hallucinations.
Use during pregnancy or breastfeeding
The safety of clarithromycin during pregnancy or breastfeeding has not been established. Clarithromycin should be used only if the expected benefit to the mother outweighs the potential risk to the fetus, especially during the first three months of pregnancy.
Clarithromycin is contraindicated in women who are breastfeeding.
Method of administration and doses
Take orally during meals, without chewing and with water.
The recommended dose of clarithromycin for adults and children aged 12 years and over is 500 mg (1 tablet) every 24 hours; for severe infections, the dose may be increased to 1000 mg (2 tablets) every 24 hours.
The usual duration of treatment is 5 to 14 days, except for the treatment of community-acquired pneumonia and sinusitis, which require 6-14 days of therapy.
Use in patients with renal impairment: This formulation should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min) as it does not allow for adequate dose reduction. Clarithromycin immediate-release tablets (Fromilid, film-coated tablets 250 mg or 500 mg) should be used in such patients. For patients with moderate renal impairment (creatinine clearance 30-60 ml/min), the dose should be reduced by 50% to the maximum dose of clarithromycin – 1 prolonged-release tablet per day.
Children
Clarithromycin tablets have not been studied in children under 12 years of age. Clarithromycin suspension should be used in these patients.
Overdose
Symptoms: There have been reports that clarithromycin overdose may cause gastrointestinal symptoms. One patient with a history of bipolar disorder who took 8 grams of clarithromycin developed altered mental status, paranoid behavior, hypokalemia, and hypoxemia.
Treatment: Adverse reactions associated with overdose should be treated with immediate gastric lavage and symptomatic therapy. As with other macrolides, hemodialysis or peritoneal dialysis is unlikely to significantly alter serum levels of clarithromycin.
Adverse reactions
The most common and common
