Instructions for use Aziklar 500 film-coated tablets 500 mg No. 10
Composition
active ingredient: 1 tablet contains clarithromycin 250 mg or 500 mg;
excipients: lactose monohydrate, corn starch, povidone, croscarmellose sodium, microcrystalline cellulose, talc, sodium lauryl sulfate, film coating (hydroxypropylmethylcellulose, diamond blue (E 133), polyethylene glycol) (250 mg tablets);
lactose monohydrate, corn starch, povidone, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, talc, sodium lauryl sulfate, film coating (hydroxypropylmethylcellulose, tartrazine (E 102), polyethylene glycol) (500 mg tablets).
Dosage form
Film-coated tablets.
Main physicochemical properties:
250 mg tablets: round, biconvex tablets, film-coated, blue;
500 mg tablets: oblong, biconvex tablets, film-coated, yellow.
Pharmacotherapeutic group
Antimicrobials for systemic use. Macrolides. ATX code J01F A09.
Pharmacological properties
Pharmacodynamics. Clarithromycin is a semi-synthetic macrolide antibiotic. The antibacterial effect is due to inhibition of protein synthesis by binding to the 50S subunit of the ribosome of sensitive bacteria. It mainly acts bacteriostatically, but against certain microorganisms it exhibits a bactericidal effect. The drug exhibits high specific activity against a wide range of aerobic and anaerobic gram-positive and gram-negative microorganisms. The minimum inhibitory concentration for clarithromycin is usually half that 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 not susceptible 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 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- and oxacillin-resistant strains of staphylococci are not susceptible to clarithromycin.
Helicobacter: H. Pylori.
Clarithromycin is active in vitro against most strains of the following 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, H. pylori and Campylobacter spp.
The main metabolite of clarithromycin in humans is the microbiologically active 14-hydroxyclarithromycin (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 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 effectively absorbed from the gastrointestinal tract, mainly in the small intestine; it remains active in the presence of gastric juice; administration with food slightly slows down absorption, but does not affect the extent of absorption. The bioavailability of the drug is approximately 55%.
It is metabolized in the liver by the cytochrome P450 system with the participation of the CYP3A4 isoenzyme in three main ways (demethylation, hydroxylation and hydrolysis) to 8 metabolites. Approximately 20% of the drug after absorption is metabolized to form 14-hydroxyclarithromycin, which has similar biological activity to clarithromycin.
Maximum serum concentrations of clarithromycin are reached after 2-3 hours and are 1-2 μg/ml after administration of 250 mg twice daily and 3-4 μg/ml after administration of 500 mg twice daily. Approximately 80% of the drug is bound to plasma proteins. The elimination half-life increases from 2-4 hours after administration of 250 mg of clarithromycin twice daily to 5 hours after administration of 500 mg of the drug twice daily. The elimination half-life of the active 14-hydroxymetabolite ranges from 5 to 6 hours after administration of 250 mg of clarithromycin twice daily.
70-80% is excreted in the feces, approximately 20-30% in the urine in unchanged form. This proportion increases with increasing dose of the drug. In renal failure, the concentration of clarithromycin in plasma increases if the dose is not reduced.
Indication
Treatment of infections caused by microorganisms susceptible to clarithromycin
- Infections of the upper respiratory tract, i.e. nasopharynx (tonsillitis, pharyngitis), and infections of the paranasal sinuses.
- 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 H. pylori in patients with duodenal ulcer when suppressing hydrochloric acid secretion (the activity of clarithromycin against H. pylori at neutral pH is higher than at acidic pH).
Contraindication
Hypersensitivity to clarithromycin or to any component of the drug, or to other macrolide antibiotics. Concomitant use of clarithromycin and any of the following drugs: 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 metabolized by CYP3A4 (lovastatin or simvastatin) due to an increased risk of myopathy, including rhabdomyolysis (see "Special instructions", "Interaction with other medicinal products and other types of interactions").
Concomitant use of clarithromycin and oral midazolam (see Interactions with other medicinal products and other forms of interaction).
History of QT prolongation or ventricular cardiac arrhythmias, including torsades de pointes (see "Special warnings and precautions for use", "Interaction with other medicinal products and other types of interactions").
Hypokalemia (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 "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 is metabolized in the liver, where it inhibits the activity of certain enzymes of the cytochrome P450 system. Accordingly, the metabolism of various drugs that are metabolized with the participation of these enzymes (such as alprazolam, astemizole, terfenadine, cisapride, pimozide, carbamazepine, hexobarbital, bromocriptine, valproate, rifabutin, warfarin, digoxin, ergot alkaloids, triazolam, midazolam, methylprednisolone, quinidine, sildenafil, disopyramide, phenytoin, cyclosporine, tacrolimus, zidovudine, theophylline, vinblastine) may be reduced. This leads to an increase in their serum concentrations; toxic effects may occur. Therefore, clinical monitoring is necessary, and if necessary, determination of serum concentrations of these drugs.
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, pimozide, and terfenadine have been observed when co-administered 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 the concomitant use of astemizole and other macrolides.
Ergot alkaloids
Concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with 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 Contraindications).
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
The activity of clarithromycin is reduced by etravirine, but the concentration of the active metabolite 14-OH-clarithromycin is increased. Since 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), the 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 concentration of the active metabolite 14-OH-clarithromycin is not significantly altered by co-administration with fluconazole. No dose adjustment of clarithromycin is required.
Ritonavir
Ritonavir and clarithromycin significantly inhibit the metabolism of clarithromycin. Due to the wide therapeutic window, dose reduction of clarithromycin is not necessary in patients with normal renal function.
Concomitant treatment with ritonavir increases the serum concentration of clarithromycin, so it should not be administered at a dose of more than 1 g per day. However, dose adjustment is necessary for 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%.
The same dose adjustment 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 are 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.
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.
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/or is extensively metabolized by this enzyme.
Dose adjustment and, if possible, close monitoring of serum concentrations of a drug metabolized by CYP3A may be necessary for patients concomitantly taking 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 in combination with omeprazole may lead to an increase in the equilibrium concentrations of omeprazole, but no dosage adjustment is required.
Sildenafil, tadalafil and vardenafil
There is a possibility of increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil and vardenafil) when co-administered with clarithromycin, which may require a reduction in the dose of phosphodiesterase inhibitors.
Theophylline, carbamazepine
Tolterodine
Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoform (CYP2D6). However, in patients lacking CYP2D6, metabolism occurs via CYP3A and 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)
The combined use of oral midazolam and clarithromycin should be avoided. When intravenous midazolam is used with clarithromycin, the patient's condition should be carefully 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 reports of drug interactions and the development of central nervous system adverse events (such as drowsiness and confusion) with the concomitant use of clarithromycin and triazolam. The patient should be monitored for possible 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. Patients should be monitored for clinical signs of colchicine toxicity. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function. Concomitant use of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see Contraindications, Precautions for Use).
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.
Zidovudine
Concomitant use 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, a 4-hour interval should be maintained between the administration of clarithromycin and zidovudine. No such interaction has been reported with the use of clarithromycin suspension and zidovudine or dideoxynazine in children.
Phenytoin and valproate
There have been reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (including 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 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. Clarithromycin doses 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 clarithromycin is coadministered 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 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 signs or symptoms of enhanced or prolonged pharmacological effects.
Coadministration of clarithromycin (500 mg twice daily) with saquinavir, soft gelatin capsules, 1200 mg three times daily, both 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 doses and dosage forms mentioned above. The results of a drug interaction study with the soft gelatin capsules may not be consistent with the effects observed with saquinavir as a hard gelatin capsule. 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 possible effects of ritonavir on clarithromycin should be considered (see above).
Concomitant use of clarithromycin with colchicine, especially in elderly patients with impaired renal function, increases the toxicity of the latter. Colchicine toxicity (including fatal outcomes) has been reported with concomitant use of clarithromycin and colchicine.
Clarithromycin does not affect the effectiveness of oral contraceptives.
HMG-CoA reductase inhibitors (statins).
The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see Contraindications) because these statins
are extensively metabolized by CYP3A4 and co-administration 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. If clarithromycin treatment cannot be avoided, lovastatin or simvastatin therapy should be discontinued during the course of treatment.
Clarithromycin should be used with caution when co-administered with statins. In situations where co-administration of clarithromycin with statins cannot be avoided, it is recommended to use 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 symptoms of myopathy.
During post-marketing use, there have been reports of hypoglycemia with the simultaneous use of clarithromycin and disopyramide, therefore, monitoring of blood glucose levels is necessary when these agents are used simultaneously.
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.
Aminoglycosides.
Clarithromycin should be used with caution in combination with other ototoxic agents, especially aminoglycosides (see Precautions).
Application features
Clarithromycin should not be administered to pregnant women without careful benefit/risk assessment, especially during the first trimester of pregnancy.
Prolonged or repeated use of clarithromycin may lead to the development of superinfection caused by microorganisms that are not susceptible to the drug. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy should be initiated.
The drug should be used with caution in patients with severe renal insufficiency.
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 has been associated with serious underlying diseases 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.
If severe diarrhea occurs during treatment, the possibility of pseudomembranous colitis should be excluded. Clostridium difficile-associated diarrhea, ranging from mild to fatal, has been reported with nearly all antibacterial agents, including clarithromycin. The possibility of Clostridium difficile-associated diarrhea should always 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 antibiotic therapy.
Exacerbation of myasthenia gravis symptoms has been reported in patients taking clarithromycin.
Colchicine toxicity (including fatal outcomes) has been reported with concomitant use of clarithromycin and colchicine, particularly in the elderly, including patients with renal impairment. If concomitant use of colchicine and clarithromycin is necessary, patients should be observed for possible clinical signs of colchicine toxicity. The dose of colchicine should be reduced in all patients receiving concomitant colchicine and clarithromycin. 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 Interactions with other medicinal products and other forms of interaction).
Due to the risk of QT prolongation, clarithromycin should be used with caution in patients with ischemic heart disease, severe heart failure, hypomagnesemia, bradycardia (<50 beats/min), or when used concomitantly with other drugs associated with QT prolongation. Clarithromycin should not be used in patients with congenital or history of QT prolongation or with a history of ventricular cardiac arrhythmia (see 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.
Mild to moderate skin and soft tissue infections
These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, which may be resistant to macrolides. Susceptibility testing is therefore important. If 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 some 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 Interactions with other medicinal products and other forms of interaction).
Hypersensitivity to clarithromycin may occur in patients sensitive to lincomycin or clindamycin. Therefore, the drug should be prescribed with caution to such patients.
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.
Oral hypoglycemic agents/insulin
Concomitant use of clarithromycin and oral hypoglycemic agents (such as 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 carries a risk of serious bleeding, significant elevations in INR (international normalized ratio) and prothrombin time. While patients are receiving clarithromycin and oral anticoagulants concomitantly, INR and prothrombin time should be monitored frequently.
HMG-CoA reductase inhibitors (statins)
The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications").
Clarithromycin should be used with caution when 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 Interactions with other medicinal products and other forms of interaction).
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.
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.
Use during pregnancy or breastfeeding
The drug should only be used if the expected benefit to the mother outweighs the potential risk to the fetus or child. Clarithromycin is excreted in breast milk, so breastfeeding should be discontinued during treatment.
The ability to influence the reaction speed when driving or working with other mechanisms
Until the individual reaction to the drug is determined, caution is recommended when driving or operating complex machinery, especially at the beginning of therapy or when changing the dosage. 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, etc.
Method of administration and doses
The tablets should be taken whole (do not crush or chew) with liquid. Food intake has little effect on the absorption of the drug, but may slightly slow down this process.
For adults and children aged 12 years and over, the recommended dose is 250 mg of clarithromycin every 12 hours; for severe infections, the dose may be increased to 500 mg every 12 hours.
Usually the course of treatment is 6 - 14 days. Treatment should continue for at least 2 more days after the disappearance of the main symptoms of the disease. The duration of treatment depends on the course of the disease and is determined by the doctor individually for each patient.
Treatment of odontogenic infections.
The recommended dose is 250 mg every 12 hours for 5 days.
Use in patients with mycobacterial infection.
The initial dose for adults is 500 mg twice daily. If there is no improvement in clinical signs or bacteriological parameters within 3-4 weeks of treatment, the dose of clarithromycin may be increased to 1000 mg twice daily.
Treatment of disseminated infections caused by MAOIs in AIDS patients should be continued for as long as the clinical and microbiological efficacy of the drug is medically proven. Clarithromycin can be used in combination with other antimycobacterial agents.
Eradication of H. pylori in patients with duodenal ulcer (adults).
Triple therapy (7–10 days)
Clarithromycin (500 mg) twice daily should be used together with amoxicillin 1000 mg twice daily and omeprazole 20 mg daily for 7–10 days.
Triple therapy (10 days)
Clarithromycin (500 mg) twice daily, lansoprazole 30 mg twice daily, and amoxicillin 1000 mg twice daily for 10 days.
Dual therapy (14 days)
Clarithromycin (500 mg) three times daily with omeprazole 40 mg once daily orally for 14 days, followed by omeprazole 20 mg or 40 mg once daily orally for the next 14 days.
Dual therapy (14 days)
Clarithromycin (500 mg) three times daily with lansoprazole 60 mg once daily orally for 14 days. Further acid suppression may be required to reduce ulcer symptoms.
Clarithromycin has also been used in the following therapeutic regimens:
clarithromycin + tinidazole and omeprazole or lansoprazole;
clarithromycin + metronidazole and omeprazole or lansoprazole;
clarithromycin + tetracycline, bismuth subsalicylate and ranitidine;
clarithromycin + amoxicillin and lansoprazole;
clarithromycin + ranitidine and bismuth citrate.
Use in elderly patients: as for adults.
Use in patients with renal impairment: For patients with severe renal impairment (creatinine clearance less than 30 ml/min), the total daily dose should be halved, i.e. 250 mg once daily or 250 mg twice daily for severe infections. In such patients, the duration of treatment should not exceed 14 days.
Children.
Children under 12 years of age should be
