Instructions for use Clarithromycin-Darnitsa film-coated tablets 500 mg No. 14
Composition
active ingredient: clarithromycin;
1 tablet contains clarithromycin 500 mg;
Excipients: microcrystalline cellulose, povidone, crospovidone, sodium lauryl sulfate, talc, stearic acid, magnesium stearate, sepifilm 752 white, polyethylene glycol 4000 (macrogol 4000).
Dosage form
Film-coated tablets.
Main physicochemical properties:
500 mg tablets: film-coated tablets, white, oblong in shape, with a biconvex surface.
Pharmacotherapeutic group
Antimicrobials for systemic use. Macrolides. 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 efficacy 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 MIC of erythromycin.
Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It is bactericidal against H. pylori, and clarithromycin is more active at neutral pH than at acidic pH. In vitro and in vivo data demonstrate the high efficacy of clarithromycin 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.
Microbiology. Clarithromycin is active in vitro and in clinical practice against most strains of such microorganisms.
Aerobic gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyogenes, Listeria monocytogenes.
Aerobic gram-negative microorganisms: Haemophilus influenza, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila.
Other microorganisms: Mycoplasma pneumonia, 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- and oxacillin-resistant staphylococcal strains are insensitive to clarithromycin.
Helicobacter pylori.
Clarithromycin is active in vitro against most strains of such microorganisms, however, clinical efficacy and safety of its use 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.
Other microorganisms: Chlamydia trachomatis.
Spirochetes: Borrelia burgdorferi, Treponema pallidum.
Campylobacter: Campylobacter jejuni.
Clarithromycin has a bactericidal effect against several strains of bacteria: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella catarrhalis, Neisseria gonorrhoeae, H. Pylori, Campylobacter spp.
The main metabolite of clarithromycin in humans is the microbiologically active 14-hydroxyclarithromycin (14-OH clarithromycin). In most microorganisms, the microbiological activity of the metabolite is the same as the parent substance or 1-2 times weaker, with the exception of H. influenzae, against which the effectiveness of the metabolite is 2 times higher. In vitro and in vivo, the parent substance and its main metabolite exhibit either an additive or synergistic effect against H. influenzae, depending on the strain of the microorganism.
Pharmacokinetics
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract after oral administration of the drug in tablet form. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first-pass metabolism. Clarithromycin can be used regardless of food intake, since food does not affect the bioavailability of clarithromycin tablets. Food slightly delays the onset of clarithromycin absorption and the formation of the 14-hydroxymetabolite. The pharmacokinetics of clarithromycin are nonlinear; however, steady-state concentrations are achieved within 2 days of drug administration. When using 250 mg 2 times a day, 15-20% of the unchanged drug is excreted in the urine. At a dose of 500 mg 2 times a day, urinary excretion of the drug is more intense (approximately 36%). 14-hydroxyclarithromycin is the major metabolite, accounting for 10–15% of the administered dose in the urine. Most of the remainder of the dose is excreted in the feces, primarily in the bile. 5–10% of the parent compound is recovered in the feces.
When 500 mg of clarithromycin is administered 3 times daily, plasma concentrations of clarithromycin are increased compared to a dose of 500 mg twice daily.
Clarithromycin tissue concentrations are several times higher than the drug concentration in the blood. Elevated concentrations have been found in both tonsillar and lung tissues. Clarithromycin is 80% bound to plasma proteins at therapeutic doses.
Clarithromycin penetrates the gastric mucosa. The content of clarithromycin in the gastric mucosa and tissue is higher when clarithromycin is used together with omeprazole than when clarithromycin is used alone.
Indication
Treatment of infections caused by microorganisms sensitive to clarithromycin. Upper respiratory tract infections, i.e. nasopharynx (tonsillitis, pharyngitis) and paranasal sinus infections. Lower respiratory tract infections (bronchitis, acute croupous pneumonia and primary atypical pneumonia). Skin and soft tissue infections (impetigo, folliculitis, erysipeloid, furunculosis, infected wounds). Acute and chronic odontogenic infections. Disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum or Mycobacterium kansasii. Eradication of pylori in patients with duodenal ulcer when suppressing hydrochloric acid secretion (clarithromycin activity against H. pylori is higher at neutral pH than at acidic pH).
Contraindication
Hypersensitivity to macrolide antibiotics or to other components of the drug.
Concomitant use of clarithromycin and any of the following medicinal products: 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); oral midazolam (see section 4.5).
Congenital or acquired prolongation of the QT interval or ventricular arrhythmias, including torsades de pointes in history (see sections "Special instructions", "Interaction with other medicinal products and other types of interactions").
Hypokalemia (risk of QT prolongation) (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other types of interactions").
Severe hepatic insufficiency in combination with renal insufficiency (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other types of interactions").
Concomitant use of clarithromycin and other strong CYP3A4 inhibitors with colchicine (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other types of interactions").
Concomitant use of clarithromycin with ticagrelor or ranolazine.
Interaction with other medicinal products and other types of interactions
Clarithromycin does not interact with oral contraceptives.
The use of the following medications is strictly contraindicated due to the possible development of severe interaction effects.
Cisapride, pimozide, astemizole, terfenadine
Increased serum levels of cisapride have been observed in patients receiving clarithromycin and cisapride concomitantly. This may lead to QT prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been observed in patients receiving clarithromycin and pimozide concomitantly (see Contraindications).
Macrolides have been reported to alter the metabolism of terfenadine, leading to increased serum levels of terfenadine, sometimes associated with arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see Contraindications). In a study of 14 volunteers, concomitant administration of clarithromycin and terfenadine 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 are observed with the simultaneous use of astemizole and other macrolides.
Ergot alkaloids.
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.
The concomitant use of clarithromycin and alkaloids containing granules is contraindicated (see section "Contraindications").
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)
Caution should be exercised when prescribing clarithromycin concomitantly with other statins. In situations where concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. A statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) may be used. Patients should be monitored for symptoms of myopathy.
Effect of 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 effect of other drugs on the concentration of clarithromycin in the blood, known or hypothetical, which may require dose changes or the use of 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 Mycobacterium avium complex (MAC), the overall activity against this pathogen may be altered. Therefore, alternatives to clarithromycin should be considered for the treatment of MAC.
Fluconazole.
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in steady-state Cmin of clarithromycin by 33% and AUC by 18%.
The steady-state concentrations of the active metabolite 14-OH-clarithromycin are not significantly altered by co-administration with fluconazole. No dose adjustment of clarithromycin is required.
Ritonavir.
A pharmacokinetic study has shown that co-administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours results in significant inhibition of clarithromycin metabolism. Clarithromycin Cmax increased by 31%, Cmin by 182%, and AUC by 77% with co-administration of ritonavir. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the large therapeutic window, no dose reduction of clarithromycin is required in patients with normal renal function. However, dose adjustment is required in patients with renal insufficiency: for patients with creatinine clearance 30–60 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with severe renal insufficiency (creatinine clearance < 30 ml/min), the dose of clarithromycin should be reduced by 75%. Doses of clarithromycin exceeding 1 g/day should not be used with ritonavir.
Similar dose adjustments should be made in patients with renal impairment when ritonavir is used as a pharmacokinetic enhancer with other HER2 protease inhibitors, including atazanavir and saquinavir.
Effect of clarithromycin on the pharmacokinetics of other drugs.
Antiarrhythmic drugs.
There have been reports of torsades de pointes occurring 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.
There have been post-marketing reports of hypoglycemia with concomitant use of clarithromycin and disopyramine. Therefore, blood glucose levels should be monitored when clarithromycin and disopyramine are administered concomitantly.
Interactions not related to CYP3A.
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 range (e.g., carbamazepine) and is extensively metabolized by this enzyme.
The following drugs or drug classes are known (or suspected) to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cyclostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (warfarin), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine.
However, this list is not complete. A similar mechanism of interaction has been observed with phenytoin, theophylline, and valproate, which are metabolized by a different isoenzyme of the cytochrome P450 system.
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.
Oral anticoagulants.
The combined use of clarithromycin and oral anticoagulants may potentiate the effect of the latter, which requires careful monitoring of prothrombin time in patients.
Omeprazole.
The use of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers leads to an increase in the equilibrium plasma concentrations of omeprazole (Cmax, AUC0-24 and t1/2 increased by 30%, 89% and 34%, respectively). When omeprazole was used alone, the average pH of gastric juice measured over 24 hours was 5.2, when omeprazole was used simultaneously with clarithromycin - 5.7.
Sildenafil, tadalafil and vardenafil.
Each of these phosphodiesterase inhibitors is metabolized (at least in part) by CYP3A, and CYP3A may be inhibited by concomitant clarithromycin. There is a potential for increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil) when co-administered with clarithromycin, which may require a reduction in the dose of the phosphodiesterase inhibitor.
Theophylline, carbamazepine.
A slight but statistically significant increase in theophylline or carbamazepine plasma concentrations may occur 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 coadministered with CYP3A inhibitors such as clarithromycin.
Triazolebenzodiazepines (alprazolam, midazolam, triazolam).
The combined use of oral midazolam and clarithromycin (500 mg twice daily) should be avoided. The AUC of midazolam increased 2.7-fold after intravenous administration of midazolam. When intravenous midazolam is administered with clarithromycin, the patient should be closely monitored for timely dose adjustment. With the oromucosal route of administration of midazolam, in which presystemic elimination of the drug can be excluded, an interaction similar to that observed with intravenous administration of midazolam is more likely to be observed than with oral administration.
The same precautions should be taken 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 reports of drug interactions and the development of central nervous system adverse events (such as drowsiness and confusion) with the simultaneous use of clarithromycin and triazolam. The patient should be monitored, taking into account the possibility of increased pharmacological effects on the central nervous system.
Other types of interactions.
Aminoglycosides.
Clarithromycin should be used with caution in patients with renal or hepatic impairment. Patients should be monitored for clinical signs of colchicine toxicity. The dose of colchicine should be reduced when administered concomitantly with clarithromycin in patients with normal renal and hepatic function. Concomitant administration 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 the efflux transporter P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are coadministered, inhibition of Pgp by clarithromycin may result in increased digoxin exposure. During post-marketing surveillance, 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 administration of clarithromycin immediate-release tablets and zidovudine in HIV-infected patients may result in decreased steady-state serum concentrations of zidovudine. Since clarithromycin may interfere with the absorption of oral zidovudine when administered concomitantly, this interaction can be largely avoided by separating the doses of clarithromycin and zidovudine by 4 hours. This interaction has not been reported with clarithromycin suspension and zidovudine or dideoxynazine in children. This interaction is unlikely when clarithromycin is administered by intravenous infusion.
Phenytoin and valproate
There have been 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.
Mutual influence of medicines.
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 for 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, using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg/day should not be coadministered with protease inhibitors.
Calcium channel blockers.
Due to the risk of hypotension, caution should be exercised when clarithromycin is coadministered with calcium channel blockers metabolized by CYP3A4 (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 reported in patients receiving clarithromycin and 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 symptoms of enhanced or prolonged pharmacological effects.
Saquinavir.
Coadministration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), which are substrates and inhibitors of CYP3A, in 12 healthy volunteers 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 when both drugs are coadministered for a limited period of time and at the above-mentioned doses/formulations. The results of a drug interaction study using soft gelatin capsules may not reflect the effects observed with saquinavir as a hard gelatin capsule. The results of a drug interaction study using saquinavir alone may not reflect the effects observed with saquinavir/ritonavir therapy. If saquinavir is used with ritonavir, the possible effects of ritonavir on clarithromycin should be considered (see above).
Application features
Clarithromycin should not be used in pregnant women without careful benefit/risk assessment, especially in the first trimester of pregnancy.
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.
Hepatic dysfunction, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis with or without jaundice, have been reported with clarithromycin. These hepatic dysfunctions may be severe but are usually reversible. Fatal hepatic failure has been reported in some cases, and was mostly associated with serious underlying diseases and/or concomitant medication. Clarithromycin should be discontinued immediately if symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.
The drug should be used with caution in patients with impaired liver function, with moderate or severe renal impairment, since clarithromycin is mainly excreted by the liver and kidneys.
The possibility of Clostridium difficile-associated diarrhea should always be considered in all patients 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 administration of antibacterial agents. If pseudomembranous colitis occurs, clarithromycin should be discontinued regardless of the indication for which it was prescribed. Microbial testing should be performed and appropriate treatment initiated. Drugs that inhibit peristalsis should be avoided.
Exacerbation of myasthenia gravis symptoms has been reported in patients taking clarithromycin.
Colchicine
Colchicine toxicity (including fatal outcomes) has been reported with concomitant use of clarithromycin and colchicine, particularly in the elderly, including patients with renal insufficiency. Concomitant use of colchicine and clarithromycin is contraindicated (see section 4.3).
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.
QT prolongation.
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). Due to the 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 concomitantly taking other drugs associated with QT prolongation (see section “Interaction with other medicinal products and other forms of interaction”).
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 history of QT prolongation or with a history of ventricular arrhythmia (see section "Contraindications").
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.
Skin and soft tissue infections of mild to moderate severity.
These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, susceptibility testing is important. In cases where β-lactam antibiotics cannot be used (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 (e.g. 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, severe cutaneous adverse reactions (e.g. acute generalized exanthematous pustulosis, Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS), Henoch–Schönlein disease, clarithromycin therapy should be discontinued immediately and appropriate treatment should be initiated immediately.
Attention should be paid to the possibility of cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.
Oral hypoglycemic agents/insulin.
Concomitant use of clarithromycin and oral hypoglycemic agents (e.g. sulfonylureas) and/or insulin may result in severe hypoglycemia. When used concomitantly with hypoglycemic agents such as nateglinide, pioglitazone, repaglinide and rosiglitazone, clarithromycin may inhibit CYP3A, which may result in hypoglycemia. Close monitoring of glucose levels is recommended.
Oral anticoagulants.
Concomitant use of clarithromycin with warfarin is associated with a risk of serious bleeding, significant elevations in INR (international normalized ratio) and prothrombin time. INR and prothrombin time should be monitored regularly while patients are receiving concomitant clarithromycin and oral anticoagulants.
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 clarithromycin and these statins. Patients should be monitored for symptoms of myopathy. If clarithromycin treatment cannot be avoided, lovastatin or simvastatin should be discontinued for the duration of treatment. Caution should be exercised when clarithromycin is co-administered with statins. In situations where 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 considered.
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").
The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection may result in the emergence of microbial resistance. In a small number of patients, H. pylori may develop resistance to clarithromycin.
Attention should be paid to the possibility of cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.
Ability to influence reaction speed when driving vehicles or other mechanisms
There are currently no reports. However, when driving or operating other mechanisms, it is recommended to exercise extreme caution, taking into account the possibility of developing undesirable reactions from the nervous system, such as seizures, dizziness, vertigo, hallucinations, confusion, disorientation, etc.
Use during pregnancy or breastfeeding
The safety of clarithromycin during pregnancy or breastfeeding has not been established. Based on the results of animal studies, there is a risk of harmful effects on fetal development.
Clarithromycin should not be used during pregnancy unless the benefit to the mother outweighs the risk to the fetus.
Clarithromycin passes into breast milk, so breastfeeding should be discontinued during treatment.
Method of administration and doses
Clarithromycin tablets should be taken orally, without chewing, with a small amount of water. The drug can be taken regardless of meals, since food does not affect the bioavailability of clarithromycin.
The recommended dose of clarithromycin for adults and children aged 12 years and over is 250 mg every 12 hours, with more severe infections the dose may be increased to 500 mg every 12 hours. The usual duration of treatment depends on the extent and severity of the infection and is 6 to 14 days.
Treatment of odontogenic infections. The recommended dose is 250 mg every 12 hours for 5 days.
Use in patients with mycobacterial infections. The initial dose for adults is 500 mg 2 times a day. If there is no improvement in clinical signs or bacteriological parameters within 3-4 weeks of treatment, the dose of clarithromycin can be increased to 1000 mg 2 times a day. Treatment of disseminated infections caused by Mycobacterium avium complex (MAC) in AIDS patients is continued as long as the clinical and microbiological efficacy of the drug is medically proven. Clarithromycin can be used in combination with other antimycobacterial agents.
