INSTRUCTION

for medical use of the medical product

 

AZICLAR 250

AZICLAR 500

 

Composition:

active substance: 1 film-coated tablet contains clarithromycin 250 mg or 500 mg;

excipients: lactose monohydrate, corn starch, povidone, croscarmellose sodium, microcrystalline cellulose, talc, sodium lauryl sulfate, film coating (hydroxypropyl methyl cellulose, 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 (hydroxypropyl methyl cellulose, tartrazine (E 102), polyethylene glycol) (500 mg tablets).

 

Dosage form. Film-coated tablets.

Basic physical and chemical properties:

250 mg tablets: round, biconvex tablets, coated with a blue film coat;

500 mg tablets: oblong, biconvex tablets, coated with a yellow film coat.

 

Pharmacotherapeutic group. Antibacterial agents for systemic use. Macrolides.

ATC code J01F А09.

 

Pharmacological properties.

Pharmacodynamics.

Clarithromycin is a semi-synthetic antibiotic of the macrolide group.

Microbiology

The antibacterial activity of clarithromycin is based on its binding to the 50S ribosomal subunit of susceptible bacteria, thereby inhibiting protein biosynthesis. The drug exhibits high in vitro efficacy against a broad spectrum of aerobic and anaerobic Gram-positive and Gram-negative microorganisms, including hospital-acquired strains. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than those of erythromycin.

Clarithromycin shows high in vitro activity against Legionella pneumophila and Mycoplasma pneumoniae. It has a bactericidal effect against Helicobacter pylori; its activity at neutral pH is greater than at acidic pH. Both in vitro and in vivo data indicate high efficacy of clarithromycin against clinically significant strains of mycobacteria. In vitro studies have demonstrated that Enterobacteriaceae and Pseudomonas species, as well as other non-lactose fermenting Gram-negative bacteria, are not susceptible to clarithromycin.

Clarithromycin is active in vitro and in clinical practice for most strains of the following bacteria.

Aerobic gram-positive bacteria: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes.

Aerobic gram-negative bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhаlis, Neisseria gonorrhоeae, Legionella pneumophila.

Other bacteria: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR).

Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium сomplex (MAC), including Mycobacterium avium, Mycobacterium intracellular.

Beta-lactamase bacteria do not affect the efficiency of clarithromycin.

Most methicillin- and oxacillin-resistant strains of staphylococci are not susceptible to clarithromycin.

Helicobacter: H. Pylori.

Clarithromycin is active in vitro for most strains of the following bacteria, but clinical efficacy and safety of clarithromycin have not been established.

Aerobic gram-positive bacteria: Streptococcus agalactiae, Streptococci (C,F,G groups), Viridans group streptococci.

Aerobic gram-negative bacteria: Bordetella pertussis, Pasteurella multocida.

Anaerobic gram-positive bacteria: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.

Anaerobic gram-negative bacteria: Bacteriodes melaninogenicus.

Spirochetes: Borrelia burgdorferi, Treponema pallidum.

Campylobacteria: Campylobacter jejuni.

Clarithromycin has a 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 the human body is microbiologically active 14-hydroxycarrythromycin (14-OH-clarithromycin). For most bacteria, the microbiological activity of the metabolite is equal to or 1-2 times weaker than the parent substance, excluding H. influenzae, against which the effectiveness of the metabolite is 2 times higher. In vitro and in vivo, the maternal substance and its main metabolite exhibit either additive or synergistic effect against H. influenzae, depending on the strain of bacteria.

Susceptibility testing

Quantitative methods requiring measurement of the zone diameter give the most accurate estimates of the susceptibility of bacteria to antimicrobial drugs. In one of the recommended procedures for susceptibility testing, disks impregnated with 15 μg of clarithromycin (Kirby-Bauer test) are used; the correlation between inhibition zone diameter for this disk and MIC values for clarithromycin is performed in the course of interpretation. MIC is determined by the method of broth or agar dilution.

During these procedures, the laboratory’s conclusion, such as “susceptible”, indicates that infecting bacterium, most likely, will respond to therapy. The conclusion, such as "resistant", indicates that the infecting bacterium, unlikely, will not respond to therapy. The conclusion, such as "intermediate susceptibility" indicates that the therapeutic effect of this drug may be questionable or the bacterium will be susceptible if using higher doses (intermediate susceptibility also referred to as moderate susceptibility).

It is necessary to take into account the specific country or region information about the absolute range limits of susceptibility, resistance and intermediate susceptibility.

Pharmacokinetics.

Clarithromycin absorbs quickly and effectively from gastro-intestinal tract after oral administration in the form of tablets. Its microbiologically active metabolite, 14-hydroxyclarithromycin, is formed during first-pass metabolism. Clarithromycin may be used irrespectively of meal’s intake, as food does not influence the bioavailability of clarithromycin tablets. Food slightly slows the initiation of clarithromycin absorption and formation of 14-hydroxymetabolite. Pharmacokinetics of clarithromycin is nonlinear; however its balanced concentration is reached within 2 days of application of the drug. When using 250 mg twice a day, 15-20% of the unchanged drug is excreted in the urine. At the dose of 500 mg twice a day, the excretion of the preparation with urine is more intensive (approximately 36 %). 14-hydroxyclarithromycin is the main metabolite, which is excreted with urine in the volume of 10-15 % of the administrated dose. The most part of the remaining dose is excreted with faeces, mainly with bile. 5-10 % of the initial compound is found in faeces.

When using 500 mg of clarithromycin 3 times a day, plasma concentration of clarithromycin increases in comparison with the dose of 500 mg twice a day.

Concentration clarithromycin in tissues is several times greater than blood concentration of the preparation. Increased concentration has been observed both in tonsillar, and in lung tissue.  Clarithromycin at therapeutic doses is 80 % bound to plasma proteins.

Clarithromycin penetrates into stomach mucous. The content of clarithromycin in stomach mucous and tissue is higher at use of clarithromycin concomitantly with omeprazole than at monotherapy with clarithromycin.

 

Clinical particulars.

Indications.

Treatment of infections caused by clarithromycin-susceptible bacteria:

• - Infections of the upper respiratory tract, i.e. nasopharynx (tonsillitis, pharyngitis) and infections of the paranasal sinuses.
• - Infections of the lower respiratory tract (bronchitis, acute lobar pneumonia and primary atypical pneumonia) (see "Precautions for use" and "Pharmacological properties. Pharmacodynamics" for susceptibility testing).
• - Infections of skin and soft tissue (impetigo, folliculitis, eryzypeloyid, abrasions, infected wounds) (see "Precautions for use" and "Pharmacological properties. Pharmacodynamics" for susceptibility testing).
• - 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, Mycobacterium kаnsasii.
• - Eradication of pylori in patients with duodenal ulcer at suppression of hydrochloric acid secretion (the activity of clarithromycin against H. pylori at neutral pH is higher than at acidic pH).

 

Contraindications.

Hypersensitivity to clarithromycin or any component of the drug, or to other macrolide antibiotics. Concomitant use of clarithromycin and any of the following medicinal products: astemizole, cisapride, pimozide, terfenadine (since it can cause QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and ventricular tachycardia and torsades de pointes), ergot alkaloids, such as ergotamine or dihydroergotamine (since it can lead to ergotoxicity) HMH-CoA reductase inhibitors (statins), largely metabolized by CYP3A4 (lovastatin or simvastatin) due to the increased risk of myopathy, including rhabdomyolysis (see "Precautions for use", "Interaction with other medicinal products and other forms of interaction").

Concomitant administration of oral midazolam and clarithromycin (see "Interaction with other medicinal products and other forms of interaction").

Concomitant administration of clarithromycin and lomitapide (see “Interaction with other medicinal products and other types of interactions”).

Congenital or acquired QT prolongation or ventricular cardiac arrhythmias history, including torsades de pointes (see "Precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Electrolyte imbalances (hypokalemia or hypomagnesemia, due to the risk of prolongation of the QT interval).

Severe hepatic failure and concomitant kidney failure.

Concomitant use of clarithromycin and other strong inhibitors of CYP3A4 with colchicine (see "Precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of clarithromycin and ticagrelor, ivabradine or ranolazine.

 

Interaction with other medicinal products and other forms of interaction.

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

Cisapride, pimozide, astemizole, terfenadine

Increased serum cisapride concentrations have been reported in patients receiving clarithromycin and cisapride concomitantly. This may cause QT interval prolongation and arrhythmias development, including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see "Contraindications").

Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see "Contraindications"). The concomitant administration of clarithromycin and terfenadine resulted in a two to three fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.

Ergot alkaloids

The concomitant administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischemia of the extremities and other tissues including the central nervous system. The concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see "Contraindications").

Oral midazolam

When midazolam tablets and clarithromycin (500 mg 2 times a day) were co-administrated, AUC of midazolam was 7 times increase after oral administration of midazolam. Co-administration of oral midazolam and clarithromycin is contraindicated (see "Contraindications").

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin and lovastatin or simvastatin is contraindicated (see "Contraindications"), as these statins are extensively metabolized by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.

Lomitapide

The concomitant use of clarithromycin with lomitapide is contraindicated due to the possibility of a significant increase in the level of transaminases (see "Contraindications").

Ticagrelor, ivabradine and ranolazine

The use of clarithromycin with ticagrelor, ivabradine and ranolazine is also contraindicated (see "Contraindications").

Effect of other drugs on clarithromycin

Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carabamazepin, phenobarbital, St. Johns wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to a reduced efficacy. Furthermore it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inhibitor administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.

The following drugs are known or suspected to affect circulating concentrations of clarithromycin, therefore clarithromycin dosage adjustment or consideration of alternative treatments may be required.

Efavirenc, nevirapine, rifampicin, rifabutin and rifapentin.

Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and inducers of cytochrome Р450 enzymes.

Etravirine

Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Therefore alternatives to clarithromycin should be considered for the treatment of MAC.

Fluconazole

Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.

Ritonavir

A pharmacokinetic study has demonstrated that co-administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. The clarithromycin C_max increased by 31%, C_min increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Due to the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 g/day should not be co-administered with ritonavir.

Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see "Bidirectional drug interactions").

Effect of clarithromycin on other medical products

Anti-arrhythmic agents

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

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

Oral hypoglycaemic agents/insulin

With certain hypoglycaemic drugs such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycaemia when used concomitantly. Careful monitoring of glucose is recommended.

CYP3A-based interactions |

Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

The following drugs or drug classes are known (or suspected) to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine but this list is not comprehensive. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

Direct oral anticoagulants

The direct oral anticoagulant dabigatran is a substrate for the efflux transporter P-glycoprotein (Pgp). Rivaroxaban and apixaban are metabolized by CYP3A and they are also Pgp substrates.

The use of direct oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, in combination with clarithromycin requires caution, especially in patients who are at high risk of bleeding (see "Precautions of use").

Omeprazole

Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.

Theophylline, carbamazepine

Results of clinical studies indicate there was a modest but statistically significant (p≤0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with clarithromycin.

Tolterodine

The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metabolizer population.

Triazolbenzodiazepins (e.g. adinazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam. Careful monitoring of the patient's condition for timely dose adjustment should be performed in co-administration of intravenous midazolam and clarithromycin. In the case of oromucous route of administration of midazolam, in which presystemic elimination of the drug may be excluded, an interaction similar to that with intravenous administration of midazolam but not with oral administration is likely observed. The same precautions should be taken when using other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines, the elimination of which is independent of CYP3A (temazepam, nitrazepam, lorazepam), the development of clinically relevant interaction with clarithromycin is unlikely.

There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

Other drug interactions

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Co-administration of clarithromycin and colchicine is contraindicated (see "Contraindications", "Precautions for use").

Digoxin

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may cause increased exposure to digoxin. Elevated digoxin serum concentrations in patients treated with clarithromycin and digoxin concomitantly have also been reported in post marketing studies. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored in patients treated with digoxin and clarithromycin concomitantly.

Zidovudine

Concomitant oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Clarithromycin may interfere with the absorption of simultaneously administered oral zidovudine; this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine to allow for a 4-hour interval between clarithromycin and zidovudine administrations. No such interaction has been reported with clarithromycin suspension and zidovudine or dideoxyinosine in HIV-infected children.

Phenytoin and valproate

There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs not thought to be metabolized by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.

Hydroxychloroquine and chloroquine

Clarithromycin should be used with caution in patients receiving medications that prolong the QT interval due to the risk of cardiac arrhythmias and serious cardiovascular adverse reactions.

Corticosteroids

Caution is advised when clarithromycin is co-administered with systemic or inhaled corticosteroids that are predominantly metabolised by CYP3A, as systemic exposure to corticosteroids may increase. In the case of concomitant use, patients should be closely monitored for systemic corticosteroid-related adverse reactions.

Bidirectional drug interactions

Atazanavir

The co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in 2-fold increase in exposure to clarithromycin and 70% decrease in exposure to 14-OH-clarithromycin, with 28% increase in AUC of atazanavir. Due to the large therapeutic range for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 mL/min, the dose of clarithromycin should be reduced by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

Calcium channel blockers

Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.

Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be thoroughly monitored for signs or symptoms of increased or prolonged pharmacologic effect.

Saquinavir

Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatine capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatine capsule formulation may not be representative of the effects seen using the saquinavir hard gelatine capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see above).

 

Precautions for use.

The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection can lead to the development of microbial resistance.

Clarithromycin should not be prescribed to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy.

Long-term or repeated use of antibiotics may cause excessive growth of insusceptible bacteria and fungi. In case of superinfection development, use of clarithromycin should be discontinued and appropriate therapy should be initiated.

Since clarithromycin is metabolised in the liver and primarily eliminated via the hepatic and renal routes, it should be used with particular caution in patients with hepatic impairment, moderate to severe renal impairment, and in elderly patients (aged 65 years and older).

The product should be used with caution in patients with severe renal insufficiency (see "Method of administration and dosage").

Cases of liver dysfunction, including increased levels of liver enzymes, and hepatocellular and/or cholestatic hepatitis with jaundice or without it have been reported. This hepatic dysfunction may be severe, but it is reversible. In some cases, fatal hepatic failure, which was mainly associated with serious major diseases and/or concomitant drug therapy, has been reported. The use of clarithromycin should be immediately discontinued if the signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, itching or pain in the abdomen occur.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clarithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of Clostridium difficile. Clostridium difficile must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since Clostridium difficile has been reported to occur over two months after the administration of antibacterial agents. If pseudomembranous colitis occurs, treatment with clarithromycin should be discontinued regardless of the indications. Microbiological testing should be performed and adequate treatment initiated. Drugs that inhibit peristalsis should be avoided.

Colchicine

There have been post-marketing reports of colchicine toxicity (including lethal outcome) with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency (see "Interaction with other medicinal products and other forms of interaction"). The concomitant administration of clarithromycin and colchicine is contraindicated (see "Contraindications").

Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam intravenous and oromucous midazolam (see "Interaction with other medicinal products and other forms of interaction").

Cardiovascular complications

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatment with macrolides including clarithromycin (see "Adverse Reactions"). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes), clarithromycin should be used with caution in the following patients:

• - patients with ischemic heart disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia;
• - patients with electrolyte balance disorders (see “Contraindications”).
• - patients taking other drugs that are associated with prolongation of QT interval (see "Interacting with other drugs and other types of interactions");

Concomitant use of clarithromycin with astemizole, cisapride, domperidone, pimozide and terfenadine is contraindicated (see "Contraindications");

Clarithromycin cannot be used in patients with congenital or acquired prolongation of the QT interval or with a history of ventricular arrhythmia (see "Contraindications");

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolide use have shown variable results. In some observational studies, a short-term risk of arrhythmia, myocardial infarction, and cardiovascular mortality associated with the use of macrolides, including clarithromycin, has been rarely observed. Consideration of these results should be weighed against the benefits of treatment when prescribing clarithromycin.

Pneumonia

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

Skin and soft tissue infections of mild to moderate severity

These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta–lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

In the event of severe acute hypersensitivity reactions such as anaphylaxis, severe skin adverse reactions (e.g. acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), Schönlein-Henoch disease, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see "Interaction with other medicinal products and other forms of interaction").

It is necessary to pay attention to the possibility cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.

HMG-CoA reductase inhibitors (statins)

The concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). Caution should be exercised when prescribing clarithromycin with other statins. In concomitant use of statins and clarithromycin the development of rhabdomyolysis in patients was reported. It is necessary to monitor the state of patients for signs and symptoms of myopathy. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered (see "Interaction with other medicinal products and other forms of interaction").

Oral hypoglycemic agents/insulin

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

Oral anticoagulants

Caution should be exercised when clarithromycin is used concurrently with direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban and edoxaban, especially in patients at high risk of bleeding (see "Interaction with other medicinal products and other types of interactions").

The concomitant administration of clarithromycin with warfarin may result in serious bleeding, a significant increase in the International Normalised Ratio (INR), and prothrombin time.

While patients are receiving both clarithromycin and oral anticoagulants, INR and prothrombin time should be frequently monitored.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

AZICLAR 500, tablets, contains the colouring agent tartrazine (E102), which may cause allergic reactions.

 

Pregnancy and lactation.

Pregnancy

The safety of using clarithromycin during pregnancy has not been established. Based on the results of animal studies and human usage experience, the potential for harmful effects on the development of the embryo and foetus cannot be ruled out. Some observational studies evaluating the impact of clarithromycin during the first or second trimester of pregnancy have reported an increased risk of miscarriage compared to the absence of antibiotic therapy or the use of other antibiotics during the same period. Available epidemiological studies on the risk of congenital developmental defects with the use of macrolides, including clarithromycin, during pregnancy have yielded conflicting results.

Clarithromycin should not be used during pregnancy without a thorough assessment of the benefit-risk ratio.

Clarithromycin is excreted in human breast milk in small amounts. It has been found that the amount of clarithromycin consumed by an exclusively breastfed infant is approximately 1.7% of the mother's dose, adjusted for her body weight.

Effects on ability to drive vehicles or other mechanisms.

No data are available. However, the potential side effects affecting the nervous system, such as convulsions, dizziness, vertigo, hallucinations, confusion and disorientation should be taken into account before patients drive or use machines.

 

Method of administration and dosage.

The tablets should be swallowed whole (not crushed or chewed) with liquid. Food intake has little effect on the absorption of the drug, although it may slightly delay the process.

The recommended dose for adults and children aged 12 years and older is 250 mg of clarithromycin every 12 hours; in cases of severe infections, the dose may be increased to 500 mg every 12 hours.

The usual duration of treatment is 6 to 14 days. The length of treatment depends on the course of the disease and should be determined individually by the physician for each patient.

Treatment of odontogenic infections.

The recommended dose is 250 mg every 12 hours within 5 days.

Use in patients with mycobacterial infection.

The initial dose for adults is 500 mg twice a day. If within 3-4 weeks of treatment there is no improvement of clinical signs or bacteriological parameters, then clarithromycin dose can be increased up to 1000 mg twice a day.

Treatment of MAC-infections in AIDS patients is prolonged as long as clinical and microbiological efficiency of the preparation last. Clarithromycin should be used in a complex with other anti-mycobacterial agents.

Eradication of  H. pylori у patients in patients with duodenal ulcer (adults).

Triple therapy (7-10 days)

Clarithromycin 500 mg twice a day should be used along with amoxicillin 1000 mg twice a day and omeprazole 20 mg for 7-10 days.

Triple therapy (10 days)

Clarithromycin 500 mg twice a day, lansoprazole 30 mg twice a day and amoxicillin 1000 mg  twice a day for 10 days.

Double therapy (14 days)

Clarithromycin 500 mg 3 times a day along with omeprazole 40 mg once a day orally for 14 days. Then omeprazole 20 mg or 40 mg once a day orally for 14 days.

Double therapy (14 days)

Clarithromycin 500 mg 3 times a day along with lansoprazole 60 mg once a day orally for 14 days. Further suppression of secretion of hydrochloric acid may be required to decrease the occurrence of ulcer.

Clarithromycin is also used in the following therapeutic schemes:

clarithromycin + tinidazole and omeprazole or lansoprazole;

clarithromycin + metronidazole and omeprazole or lansoprazole;

clarithromycin + tetracycline, bismuth subsalicylate and ranitidine;

clarithromycin + amoxicillin and lansoprazole;

clarithromycin + ranitidine bismuth citrate.

Use in elderly patients: similar to adults.

Use in patients with renal failure: for patients with severe renal failure the dose should be decreased two-fold (creatinine clearance <30 ml/min) for example, 250 mg once a day or 250 mg twice a day in more severe infections. In these patients the duration of treatment should not exceed 14 days.

 

Children.

The medicinal product should be used by children over 12 years of age. The use of clarithromycin tablets in children under 12 years of age has not been studied. Children of this age should use the medicinal product in the form of a suspension.

 

Overdose.

Symptoms: Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested eight grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia, and hypoxemia.

Treatment: Adverse reactions accompanying overdose should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, serum levels of clarithromycin are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.

 

Adverse reactions.

The most frequent and common adverse reactions related to clarithromycin therapy for both adult and paediatric population are abdominal pain, diarrhea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics.

The adverse reactions reported during clinical trials and postmarketing use of various clinical formulations and doses of clarithromycin, including immediate release tablets are listed below. The adverse reactions that are possibly related to clarithromycin are divided into system organ and frequency: very common (≥1 / 10), common (≥1 / 100 to ˂1 / 10), uncommon (≥1 / 1000 to ˂1 / 100) and unknown* (postmarketing surveillance adverse reactions; frequency cannot be determined from available data). For each group, the adverse reactions are presented in order of decreasing of symptoms severity, if the severity has been estimated.

Infections and infestations: uncommon – cellulitis¹, candidiasis, gastroenteritis², infection³, vaginal infection; unknown – pseudomembranous colitis, pelvic inflammation.

Blood and lymphatic system disorders: uncommon – leukopenia, neutropenia⁴, thrombocythemia³, eosinophilia⁴; unknown – agranulocytosis, thrombocytopenia.

Immune system disorders: uncommon – anaphylactoid reactions¹, hypersensitivity; unknown – anaphylactic reactions, angioneurotic oedema.

Metabolism and nutrition disorders: uncommon – anorexia, loss of appetite; unknown – hypoglycaemia.

Psychiatric disorders: common – insomnia; uncommon – anxiety, nervousness³; unknown – psychosis, confusion of consciousness, depersonalization, depression, disorientation, hallucinations, nightmares, mania.

Central nervous system disorders: common – dysgeusia (taste disorder), headache, perverted appetite; uncommon – loss of consciousness¹, dyskinesia¹, dizziness, drowsiness, tremor; unknown – convulsions, ageusia (impaired taste), parosmia, anosmia, paraesthesia.

Ear and labyrinth disorders: rare – vertigo, hearing disorder, tinnitus; unknown – hearing loss.

Cardiac disorders: uncommon – cardiac arrest¹, atrial fibrillation¹, QT interval prolongation, extrasystoles¹, palpitation; unknown – torsades de pointes, ventricular tachycardia, ventricular fibrillation.

Vascular disorders: common – vasodilation¹; unknown – haemorrhage.

Respiratory, thoracic and mediastinal disorders: uncommon – asthma¹, nosebleed², pulmonary embolism¹.

Digestive tract disorders: common – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; uncommon - esophagitis¹, gastroesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, abdominal distension⁴, constipation, dry mouth, bloating, flatulence; unknown – acute pancreatitis, tongue colour changes, teeth colour changes.

Hepatobiliary system disorders: common – abnormal liver functional tests; uncommon – cholestasis⁴, hepatitis⁴, increase of ALT, AST, GGT⁴; unknown – liver failure, hepatocellular jaundice.

Skin and subcutaneous tissue disorders: common – rash, hyperhidrosis; uncommon – bullous dermatitis¹, itching, urticaria, maculopapulmonary rash³; unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis, medication skin reaction accompanied by eosinophilia and systemic manifestations (DRESS), acne, Henoch-Schonlein disease.

Musculoskeletal system disorders: uncommon – muscle cramps³, skeletal muscle rigidity¹, myalgia²; unknown - rhabdomyolysis^{2 **}, myopathy.

Renal and urinary system disorders: uncommon – increased blood creatinine concentration¹, increased blood urea concentration¹; unknown - renal failure, interstitial nephritis.

General disorders and reactions at the injection site: very common – phlebitis at the injection site¹; common - pain at the injection site¹, inflammation at the injection site¹; uncommon - malaise⁴, fever³, asthenia, chest pain⁴, chills⁴, tiredness⁴.

Investigations: uncommon - change in the ratio of albumin-globulin¹, increased blood alkaline phosphatase concentration⁴, increased blood lactate dehydrogenase concentration⁴; unknown – increased INR, increased prothrombin time, urine colour changes.

* Since these reactions have been reported voluntarily and the number of patient population is not established, it is not always possible to accurately determine their frequency or causal relationship with drug administration. The overall experience with clarithromycin is more than 1 billion patient-days.  

** In some reports on rhabdomyolysis, clarithromycin has been co-administered with other drugs known to be associated with rhabdomyolysis (such as statins, fibrates, colchicines or allopurinol). 

^1,2,3,4 These adverse reactions were reported only for the following dosage forms: 1 – lyophilized powder for solution for infusion, 2 – prolonged action tablets, 3 – suspensions, 4 – immediate release tablets.

Incidence, type and severity of these adverse reactions in children are expected to be the same as in adults.

Patients with compromised immune system.

In AIDS patients and other immunocompromised patients treated with high doses of clarithromycin for mycobacterial infections for a long time, it is difficult to distinguish the adverse drug reactions and the symptoms of major or concomitant illnesses.

In adult patients treated with clarithromycin at the daily dose of 1000 mg, the most common adverse reactions were nausea, vomiting, pica, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing impairment, increased ALT and AST. Dyspnea, insomnia and dry mouth were uncommon.

In these patients immunocompromised, an assessment of laboratory tests was made by analysing those parameters beyond the limits of a significant abnormal level (that is, the upper or lower limit) for a specific test. According to these limits in 2-3% of patients treated with clarithromycin, a significant increase in levels of ALT and AST and a significant reduction of the number of white blood cells and thrombocytes in the blood were observed. Increased blood urea nitrogen concentrations have been reported in a lower percentage of patients.

 

Adverse Reaction Reporting

Reporting adverse reactions after the registration of a medicinal product is of great importance. It enables the monitoring of the benefit/risk ratio associated with the use of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and cases of lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

 

Shelf life.

3 years.

 

Storage conditions.

Store at temperature not exceeding 2530 °С in the original packaging.

Keep out of reach of children.

 

Packaging.

10 tablets in a blister. 1 blister in a carton.

 

Terms of dispensing. On prescription.

 

Date of last update. 31.07.2024