Instructions Fromilid granules for preparation of suspension for oral use 250 mg/5 ml bottle 60 ml
Composition
active ingredient: clarithromycin;
5 ml of suspension (1 syringe) contains 250 mg of clarithromycin;
Excipients: carbomer, povidone, hypromellose phthalate (HP 55), talc, purified castor oil, xanthan gum, orange flavor, citric acid, sodium saccharin, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, colloidal anhydrous silicon dioxide, titanium dioxide (E 171), sucrose, potassium sorbate.
Dosage form
Granules for preparation of suspension for oral use.
Main physicochemical properties: small, heterogeneous granules from white to almost white in color with an orange aroma.
Pharmacotherapeutic group
Antimicrobials for systemic use. Macrolides, lincosamides and streptogramins. Clarithromycin.
ATX code J01F A09.
Pharmacological properties
Pharmacodynamics
Clarithromycin is a semisynthetic 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. 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 two times lower than the MICs of erythromycin.
Clarithromycin is highly effective against Legionella pneumophila and Mycoplasma pneumoniae. It is bactericidal against Helicobacter pylori, with clarithromycin being more active at neutral pH than at acidic pH. Clarithromycin is effective against clinically relevant strains of mycobacteria. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as gram-negative bacteria that do not produce lactose, are insensitive to clarithromycin.
Clarithromycin is active in vitro and in clinical practice against most strains of such microorganisms.
Aerobic gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes.
Aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila.
Other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR).
Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC), which include Mycobacterium avium, Mycobacterium intracellulare.
Beta-lactamases of microorganisms do not affect the effectiveness of clarithromycin.
Most methicillin (oxacillin)-resistant staphylococcal strains are insensitive to clarithromycin.
Helicobacter: Helicobacter pylori.
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.
Other microorganisms: Chlamydia trachomatis.
Anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.
Anaerobic Gram-negative microorganisms: Bacteriodes melaninogenicus.
Spirochetes: Borrelia burgdorferi, Treponema pallidum.
Campylobacter: Campylobacter jejuni.
Clarithromycin has bactericidal activity against several strains of bacteria: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter spp.
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 H. influenzae, against which the efficacy of the metabolite is 2 times higher. 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
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract. Microbiologically active 14-OH-clarithromycin is formed during the first pass through the liver. Food does not significantly affect the bioavailability of the drug. Although the pharmacokinetics of clarithromycin are not linear, stable concentrations are established within two consecutive days of taking the drug.
Clarithromycin concentrations in body tissues are several times higher than in serum. Increased concentrations of clarithromycin are observed in tonsillar and lung tissues. Clarithromycin concentrations in middle ear fluid exceed serum concentrations. Clarithromycin, when used in therapeutic doses, is approximately 80% bound to plasma proteins. 14-OH-clarithromycin is the main metabolite excreted by the kidneys and accounts for approximately 10-15% of the administered dose. Most of the remainder of the dose is excreted primarily in the bile. 5-10% of the parent compound is excreted in the feces.
Steady-state concentrations of clarithromycin in patients with hepatic impairment and healthy volunteers do not differ, except for lower concentrations of 14-OH-clarithromycin in hepatic dysfunction.
In patients with renal impairment who received 500 mg of clarithromycin, pharmacokinetic parameters increased with the severity of renal impairment.
The age of patients does not affect the pharmacokinetic parameters of clarithromycin.
HIV-infected children receiving clarithromycin at doses of 15-30 mg/kg/day (dose divided into two doses) had higher plasma concentrations of clarithromycin and a longer half-life.
Indication
Infections caused by microorganisms sensitive to clarithromycin:
lower respiratory tract infections (bronchitis, acute croupous pneumonia, primary atypical pneumonia); upper respiratory tract infections (tonsillitis, pharyngitis) and paranasal sinus infections; acute otitis media; skin and appendage infections (folliculitis, impetigo, erysipelas, furunculosis, infected wounds); disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium kansasii.
Contraindication
Hypersensitivity to clarithromycin or other macrolide antibiotics or to any of the ingredients of the drug.
Concomitant use of astemizole, cisapride, pimozide, terfenadine (as this may lead to prolongation of the QT interval and the development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsades de pointes), ergot alkaloids, e.g. ergotamine, dihydroergotamine (as this may lead to ergotoxicity), HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4 (lovastatin or simvastatin), due to an increased risk of myopathy, including rhabdomyolysis (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use").
Concomitant use of clarithromycin and oral midazolam (see sections “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 torsades de pointes (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use").
Hypokalemia (risk of QT prolongation). Severe hepatic insufficiency and concomitant renal insufficiency.
Concomitant use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine in patients with renal or hepatic impairment (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use").
Concomitant use of clarithromycin with ticagrelor or ranolazine.
Interaction with other medicinal products and other types of interactions
The use of the following drugs is strictly contraindicated due to the possible development of severe interaction effects:
Cisapride, pimozide, astemizole, terfenadine
Increased serum levels of cisapride have been observed when co-administered with clarithromycin, which may lead to QT prolongation and arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed when pimozide and clarithromycin are co-administered (see section 4.3).
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 torsades de pointes (see section 4.3). 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 any clinically apparent effect. Similar effects have been observed with 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 use of clarithromycin and ergot alkaloids is contraindicated (see section 4.3).
Oral midazolam
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 section 4.3).
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, simultaneous 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, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.
Caution should be exercised when prescribing clarithromycin concomitantly with statins. If concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest effective dose of the statin. A statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) may be used. Patients should be monitored for signs and symptoms of myopathy.
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 suspected 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 concomitant use of clarithromycin and inducers of cytochrome P450 enzymes.
Etravirine
Clarithromycin activity was attenuated by etravirine, but concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against MAC, the overall activity against this pathogen may be altered. Therefore, alternatives 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
It has been reported that the use of 200 mg of ritonavir every 8 hours and 500 mg of clarithromycin every 12 hours resulted in a significant inhibition of the metabolism of clarithromycin. Cmax of clarithromycin increased by 31%, Cmin by 182% and AUC by 77%. There was complete inhibition of the formation of 14-OH-clarithromycin. Due to the large therapeutic window, a dose reduction of clarithromycin is not required in patients with normal renal function. However, dose adjustment is necessary in patients with renal insufficiency: for patients with CLCR 30-60 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with severe renal insufficiency (CLCR < 30 ml/min), the dose of clarithromycin should be reduced by 75%. Clarithromycin at doses exceeding 1 g per day should not be used with ritonavir.
The same dose adjustment should be made in patients with renal impairment 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.
During post-marketing use, there have been reports of hypoglycemia with concomitant use of these agents.
Cyclosporine, tacrolimus, and sirolimus
Concomitant administration of oral clarithromycin and cyclosporine or tacrolimus resulted in a greater than 2-fold increase in Cmin for both cyclosporine and tacrolimus. Similar effects are expected for sirolimus. When initiating clarithromycin therapy in patients already receiving the above agents, plasma levels of cyclosporine, tacrolimus, or sirolimus should be closely monitored and the dose reduced if necessary. When clarithromycin is discontinued, patients should be closely monitored for cyclosporine, tacrolimus, or sirolimus plasma levels to adjust the dose.
Warfarin
The use of clarithromycin in patients taking warfarin may lead to potentiation of the effects of warfarin. In such patients, prothrombin time should be monitored regularly (see sections 4.4 and 4.8).
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.
CYP3A-related interactions
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 enhance or prolong its therapeutic effect and the risk of adverse reactions.
Dose adjustments may be necessary and, if possible, serum concentrations of drugs metabolized by CYP3A should be closely monitored in patients receiving concomitant clarithromycin.
The following drugs or drug classes are 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 in combination with omeprazole in healthy adult volunteers resulted in an increase in the equilibrium concentrations of omeprazole. When using omeprazole alone, the average pH of gastric juice measured over 24 hours was 5.2, when using omeprazole with clarithromycin - 5.7.
Sildenafil, tadalafil and vardenafil
There is a possibility of increased plasma concentrations of phosphodiesterase inhibitors that are at least partially metabolized by CYP3A (sildenafil, tadalafil and vardenafil), therefore, when they are used concomitantly with clarithromycin, a reduction in the dose of phosphodiesterase inhibitors should be considered.
Theophylline, carbamazepine
Clinical trial results have shown that there is a slight but statistically significant (p<0.05) increase in theophylline or carbamazepine plasma concentrations when co-administered with clarithromycin.
Tolterodine
Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoform (CYP2D6). However, in 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 used 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 postmarketing 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 increased CNS 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 co-administered, inhibition of Pgp and CYP3A by clarithromycin may result in increased exposure to colchicine. Concomitant use of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see sections 4.3 and 4.4).
Digoxin
Digoxin is considered a Pgp substrate. Clarithromycin is known to inhibit Pgp. When used concomitantly, inhibition of Pgp may result in increased digoxin exposure. In postmarketing experience, 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.
Zidovudine
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, but this can be largely avoided by separating the doses of clarithromycin and zidovudine by 4 hours. This interaction has not been reported in children with clarithromycin suspension and zidovudine or dideoxynazine. This interaction is unlikely with intravenous infusion of clarithromycin. Phenytoin and valproate
There have been spontaneous or published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not metabolized by CYP3A (e.g., phenytoin and valproate). It is recommended that serum levels of such drugs be monitored when coadministered with clarithromycin. Increased serum levels have been reported.
When clarithromycin is used concomitantly with other ototoxic agents, especially aminoglycosides, vestibular and auditory function should be monitored during and after treatment (see section "Special warnings and precautions for use").
Two-way effects of medications
Atazanavir
Coadministration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, 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. Doses of clarithromycin greater than 1000 mg daily 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, bradyarrhythmia, and lactic acidosis have been observed in patients receiving clarithromycin concomitantly 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 with clarithromycin, patients should be closely monitored for signs or symptoms of an enhanced or prolonged pharmacological effect.
Sakvinavirsh
The use of clarithromycin (500 mg twice daily) with saquinavir (soft gelatin capsules, 1200 mg three times daily), which are substrates and inhibitors of CYP3A, resulted in a 177% increase in steady-state AUC and a 187% increase in Cmax compared to saquinavir alone. The AUC and Cmax of clarithromycin were increased by approximately 40% compared to clarithromycin alone. No dose adjustment is necessary if both drugs are administered concomitantly for a limited period of time and at the above-mentioned doses/formulations. The results of a drug interaction study with the use of soft gelatin capsules may not be consistent with the effects observed with saquinavir in the form of hard gelatin capsules. The results of a drug interaction study with saquinavir alone may not be consistent with the effects observed with saquinavir/ritonavir therapy. When saquinavir is used with ritonavir, the potential effects of ritonavir on clarithromycin should be considered (see section above).
Verapamil
Hypotension, bradyarrhythmia, and lactic acidosis have been reported with concomitant use of clarithromycin and verapamil.
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”).
Caution is recommended in patients with severe renal impairment (see section "Method of administration and dosage").
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 is mainly excreted by the liver. Caution should be exercised when using the drug in patients with moderate or severe hepatic and renal impairment (see "Dosage and Administration").
Fatal hepatic failure has been reported with clarithromycin (see Adverse Reactions), and was generally associated with serious underlying medical conditions and/or concomitant medication. Clarithromycin should be discontinued immediately if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.
Clostridium difficile-associated diarrhea, ranging from mild to fatal, has been reported with nearly all antibacterial agents, including clarithromycin. Antibacterial therapy alters the normal flora of the colon, which may lead to overgrowth of Clostridium difficile. The possibility of Clostridium difficile-associated diarrhea should be considered in all patients presenting with diarrhea following antibiotic therapy. A careful medical history is necessary, as Clostridium difficile-associated diarrhea has been reported up to 2 months after the administration 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.
Colchicine toxicity (including fatal outcomes) has been reported with concomitant use of clarithromycin and colchicine, particularly in elderly patients, including those with renal impairment. Concomitant use of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (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 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 disturbances, or clinically significant bradycardia.
Patients with electrolyte imbalances such as hypomagnesemia. Clarithromycin should not be used in patients with hypokalemia (see Contraindications).
Patients who are concomitantly taking other drugs that cause QT prolongation (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 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 with 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 cannot be used (e.g., in cases of 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 those caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, erysipelas, and in situations where penicillins cannot be used.
In the event of severe acute hypersensitivity reactions such as anaphylaxis, severe cutaneous adverse reactions (e.g. acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)), Henoch-Schonlein-Schönlein disease, clarithromycin therapy should be discontinued immediately and appropriate treatment should be initiated immediately.
HMG-CoA reductase inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when clarithromycin is co-administered 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, the lowest approved dose of the statin is recommended. A statin that is not metabolized by CYP3A (e.g. fluvastatin) may be used (see section 4.5).
Oral hypoglycemic agents/insulin
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).
Concomitant use of clarithromycin with warfarin may increase the risk of serious bleeding, significant elevations in INR (international normalized ratio) and prothrombin time. INR and prothrombin time should be monitored closely while patients are receiving clarithromycin and oral anticoagulants.
The use of any antimicrobial therapy, including clarithromycin, for the treatment of Helicobacter pylori infection may lead to the emergence of microbial resistance.
Attention should be paid to the possible cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.
Patients who are hypersensitive to lincomycin or clindamycin should be prescribed clarithromycin with caution due to possible hypersensitivity to clarithromycin.
Clarithromycin should be used with caution concomitantly with inducers of the cytochrome CYP3A4 enzyme (see section “Interaction with other medicinal products and other types of interactions”).
Exacerbation of myasthenia gravis symptoms has been reported in patients taking clarithromycin.
Saccharose
The drug contains sucrose, so patients with rare hereditary forms of fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase insufficiency should not take this drug. The sucrose content should also be taken into account when prescribing this drug to patients with diabetes mellitus.
Ability to influence reaction speed when driving vehicles or other mechanisms
There are no data on the effects. However, it is necessary to take into account the possible occurrence of adverse reactions from the nervous system, such as convulsions, dizziness, vertigo, hallucinations, confusion, disorientation, which may affect the speed of psychomotor reactions.
Use during pregnancy or breastfeeding
The safety of clarithromycin during pregnancy and lactation has not been established. Clarithromycin should only be administered in exceptional cases when the expected benefit to the mother outweighs the potential risk to the fetus.
Clarithromycin is excreted in breast milk. Clarithromycin should not be given to women who are breastfeeding.
Method of administration and doses
For the treatment of non-mycobacterial infections, the recommended dose of Fromilid® for children aged 6 months to 12 years is 7.5 mg/kg body weight 2 times a day, the maximum dose is 500 mg (10 ml) 2 times a day (every 12 hours). The duration of treatment is usually 5-10 days, depending on the type of pathogen and the severity of the disease. The suspension should be used regardless of food intake (can be taken with milk).
Table 1.
Dosage of the drug depending on the child's body weight
| Child's body weight* (kg) | 250 mg/5 ml (syringe) | Dose, mg |
| 8-11 | 1.25 ml 2 times a day (¼) | 62.5 mg |
| 12-19 | 2.5 ml 2 times a day (½) | 125 mg |
| 20-29 | 3.75 ml 2 times a day (¾) | 187.5 mg |
| 30-40 | 5 ml 2 times a day (1) | 250 mg |
* For children weighing up to 8 kg, the dose should be calculated per kilogram of body weight (7.5 mg/kg 2 times a day).
Dosage in renal failure
For children with creatinine clearance less than 0.5 ml/s (30 ml/min) or with serum creatinine > 290 µmol/l (3.3 mg/dL), the dose should be reduced by 50% or the dosing interval should be doubled. Treatment should not exceed 14 days.
Mycobacterial infections
For
