Clacid® sr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLAZID® SR (KLACID® SR)

Composition:

Active substance: clarithromycin;

One tablet contains 500 mg of clarithromycin;

Excipients: anhydrous citric acid, sodium alginate, sodium-calcium alginate, lactose monohydrate, povidone K30, talc, stearic acid, magnesium stearate;

Coating: hypromellose, polyethylene glycol 400, polyethylene glycol 8000, titanium dioxide (E 171), quinoline yellow (E 104), sorbic acid.

Pharmaceutical form. Prolonged-release film-coated tablets.

Main physicochemical properties: film-coated ovaloid tablets, yellow in color, without any marking.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Macrolides. ATC code J01FA09.

Pharmacological properties.

Pharmacodynamics.

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

Microbiology

The antibacterial action of clarithromycin is due to its binding to the 50S ribosomal subunit of susceptible bacteria and inhibition of protein biosynthesis.

The drug demonstrates high in vitro activity against a broad spectrum of aerobic and anaerobic gram-positive and gram-negative microorganisms, including hospital strains. Minimum inhibitory concentrations (MICs) of clarithromycin are usually twice lower than those of erythromycin.

In vitro, clarithromycin shows high activity against Legionella pneumophila and Mycoplasma pneumoniae. In vitro studies have shown that Enterobacteriaceae and Pseudomonas strains, as well as other gram-negative bacteria that do not ferment lactose, are not susceptible to clarithromycin.

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 includes Mycobacterium avium and Mycobacterium intracellulare.

Beta-lactamases produced by microorganisms do not affect the efficacy of clarithromycin.

Most methicillin- and oxacillin-resistant Staphylococcus strains 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 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: Bacteroides melaninogenicus.

Spirochetes: Borrelia burgdorferi, Treponema pallidum.

Campylobacters: Campylobacter jejuni.

Clarithromycin exerts bactericidal activity against several bacterial strains: 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-OH–clarithromycin. For most microorganisms, the microbiological activity of the metabolite is equal to or 1–2 times weaker than that of the parent compound, except for H. influenzae, against which the metabolite is twice as active. In vitro and in vivo, the parent compound and its main metabolite exhibit either additive or synergistic effects against H. influenzae, depending on the microbial strain.

Susceptibility testing

Quantitative methods requiring measurement of inhibition zone diameters provide the most accurate assessment of bacterial susceptibility to antimicrobial agents. One of the recommended procedures for susceptibility testing uses disks impregnated with 15 μg of clarithromycin (Kirby–Bauer diffusion method); during interpretation, the inhibition zone diameter for this disk is correlated with MIC values for clarithromycin. MIC is determined by broth or agar dilution methods.

When performing these procedures, a laboratory conclusion of "susceptible" indicates that the infecting microorganism is likely to respond to therapy. A conclusion of "resistant" indicates that the infecting microorganism is unlikely to respond to therapy. A conclusion of "intermediate susceptibility" suggests that the therapeutic effect of the drug may be uncertain, or that the microorganism may be susceptible if higher doses are used (intermediate susceptibility is also referred to as moderate susceptibility).

Country- or region-specific information regarding absolute breakpoints for susceptibility, resistance, and intermediate susceptibility should be taken into account.

Breakpoints

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has established the following breakpoints.

Pharmacokinetics.

The pharmacokinetics of prolonged-release clarithromycin tablets were compared with those of immediate-release tablets at doses of 250 and 500 mg. The extent of absorption was equivalent when equivalent doses were administered. Absolute bioavailability is approximately 50%. With repeated administration, no accumulation occurs and the metabolic pattern in the human body does not change.

In vitro. In vitro studies indicate that clarithromycin binding to human plasma proteins averages 70% at concentrations of 0.45–4.5 mcg/mL. A decrease in binding to 41% at a concentration of 45.0 mcg/mL suggests possible binding saturation, but this occurred only at concentrations significantly exceeding therapeutic levels.

In vivo. Animal studies have demonstrated that clarithromycin concentrations in all body tissues, except the central nervous system, are several times higher than in blood serum. The highest concentrations were observed in the liver and lungs, where tissue-to-plasma concentration ratios reached values from 10 to 20.

Healthy volunteers. After oral administration of 500 mg once daily of prolonged-release clarithromycin tablets taken with food, steady-state maximum plasma concentrations (Cmax) of clarithromycin and 14-OH-clarithromycin are 1.3 and 0.48 mcg/mL, respectively. Elimination half-lives of the drug and its metabolite are 5.3 and 7.7 hours, respectively. After administration of 1000 mg once daily of prolonged-release clarithromycin tablets, steady-state Cmax values for clarithromycin and 14-OH-clarithromycin are on average 2.4 mcg/mL and 0.67 mcg/mL, respectively. Elimination half-lives of the parent compound and its main metabolite are 5.8 and 8.9 hours, respectively. Tmax after administration of 500 mg and 1000 mg once daily is reached at 6 hours. Steady-state concentrations of 14-OH-clarithromycin do not increase proportionally with the clarithromycin dose, and elimination half-lives of clarithromycin and its main metabolite increase with dose escalation. The non-linear pharmacokinetics of clarithromycin, combined with overall reduced formation of 14-hydroxylated and N-demethylated metabolites at higher doses, indicates that non-linear metabolism of clarithromycin becomes more pronounced at higher doses. Approximately 40% of the clarithromycin dose is excreted in urine and 30% via the gastrointestinal tract.

Patients. Clarithromycin and its 14-OH-metabolite are widely distributed into tissues and body fluids. After oral administration, clarithromycin levels in cerebrospinal fluid remain low (1–2% of serum levels under normal blood-brain barrier conditions). Clarithromycin concentrations in tissues are generally several times higher than in serum.

Hepatic impairment. Dose adjustment of clarithromycin is not required in patients with moderate or severe hepatic impairment who have normal renal function.

Renal impairment. In patients with renal impairment, minimum and maximum plasma concentrations, elimination half-life, and area under the concentration-time curve of clarithromycin and 14-OH-clarithromycin increase. Elimination and urinary excretion rates decrease. The degree of change in these parameters depends on the severity of renal impairment: the more severe the impairment, the more pronounced the changes in parameters.

Elderly patients. In elderly patients, blood levels of clarithromycin and 14-OH-clarithromycin were higher and elimination was slower compared to younger patients. Changes in pharmacokinetics in elderly patients are primarily related to impaired renal function rather than to patient age.

Clinical characteristics.

Indications.

Treatment of infections caused by microorganisms sensitive to clarithromycin in adults and children aged 12 years and older.

• Lower respiratory tract infections (e.g., bronchitis, pneumonia) (see "Special precautions" and "Pharmacological properties. Pharmacodynamics" regarding susceptibility testing).
• Upper respiratory tract infections (e.g., sinusitis, pharyngitis).
• Skin and soft tissue infections (e.g., folliculitis, impetigo) (see "Special precautions" and "Pharmacological properties. Pharmacodynamics" regarding susceptibility testing).

Contraindications.

• Hypersensitivity to macrolide antibiotics or any component of the drug.
• Concomitant use with any of the following drugs: astemizole, cisapride, pimozide, terfenadine (due to risk of QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes), ergot alkaloids such as ergotamine and dihydroergotamine (due to risk of ergot toxicity), HMG-CoA reductase inhibitors (statins) that are predominantly metabolized by CYP3A4 (lovastatin or simvastatin) due to increased risk of myopathy, including rhabdomyolysis (see "Special precautions", "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of clarithromycin and oral midazolam (see "Interaction with other medicinal products and other forms of interaction").
• Congenital or documented acquired QT prolongation or history of ventricular cardiac arrhythmias, including torsades de pointes (see "Special precautions", "Interaction with other medicinal products and other forms of interaction").
• Electrolyte disturbances (hypokalemia or hypomagnesemia), due to risk of QT interval prolongation.
• Severe hepatic impairment with concomitant renal impairment.
• Concomitant use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine (see "Special precautions", "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of clarithromycin with ticagrelor, ivabradine, or ranolazine.
• Concomitant use of clarithromycin with lomitapide (see "Interaction with other medicinal products and other forms of interaction").
• Creatinine clearance less than 30 mL/min (since this formulation does not allow dose reduction below 500 mg daily). All other formulations may be used in such patients.

Interaction with other medicinal products and other forms of interaction.

Clarithromycin does not interact with oral contraceptives.

Use of the following medicinal products is strictly contraindicated due to the potential for severe interaction outcomes.

Cisapride, pimozide, astemizole, terfenadine

Increased serum levels of cisapride have been reported in patients receiving clarithromycin and cisapride concomitantly. This may lead to QT interval prolongation and development of 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, resulting in increased serum levels of terfenadine, which has sometimes been 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 serum concentration of terfenadine acid metabolite and QT interval prolongation, without clinically apparent effects. Similar phenomena have been observed with concomitant use of astemizole and other macrolides.

Ergot alkaloids

Post-marketing reports indicate that concomitant use of clarithromycin with ergotamine or dihydroergotamine has been associated with signs of acute ergotism, characterized by vasospasm and ischemia of extremities and other tissues, including the central nervous system. Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see "Contraindications").

Oral midazolam

When oral midazolam is administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increases 7-fold. Concomitant use of oral midazolam and clarithromycin is contraindicated (see "Contraindications").

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications"), as these statins are predominantly metabolized by CYP3A4, and concomitant use with clarithromycin increases their plasma concentration, thereby increasing the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin concomitantly with the aforementioned statins. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.

Clarithromycin should be used with caution when administered concomitantly with other statins. In situations where concomitant use of clarithromycin with statins cannot be avoided, it is recommended to use the lowest registered dose of the statin. Use of a statin not dependent on CYP3A metabolism (e.g., fluvastatin) may be considered. Monitoring for symptoms of myopathy is required.

Lomitapide

Concomitant use of clarithromycin with lomitapide is contraindicated due to the potential for significant increases in transaminase levels (see "Contraindications").

Concomitant use of clarithromycin with ticagrelor, ivabradine, and ranolazine, which are predominantly metabolized by CYP3A4, is contraindicated (see "Contraindications").

Effects of other medicinal products on clarithromycin

Medicinal products that are CYP3A inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) may induce clarithromycin metabolism. This may lead to subtherapeutic clarithromycin levels and reduced efficacy. Additionally, monitoring of plasma levels of the CYP3A inducer may be necessary, as they may be increased due to CYP3A inhibition by clarithromycin (see also the prescribing information for the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has resulted in increased rifabutin levels and decreased clarithromycin levels in serum, with an increased risk of uveitis.

The following medicinal products are known or suspected to affect clarithromycin blood concentrations, and thus dose adjustment or alternative therapy may be required.

Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine

Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, may accelerate clarithromycin metabolism, reducing its plasma concentration but increasing the concentration of 14-OH-clarithromycin – a microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin varies against different bacteria, the expected therapeutic effect may not be achieved with concomitant use of clarithromycin and cytochrome P450 enzyme inducers.

Etravirine

The effect of clarithromycin was reduced by etravirine; however, concentrations of the active metabolite 14-OH-clarithromycin increased. Since 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Therefore, alternative agents to clarithromycin should be considered for the treatment of MAC.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in a 33% increase in steady-state Cmin of clarithromycin and an 18% increase in AUC. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered with concomitant use of fluconazole. Dose adjustment of clarithromycin is not required.

Ritonavir

A pharmacokinetic study showed that concomitant administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. Cmax of clarithromycin increased by 31%, Cmin by 182%, and AUC by 77% with concomitant ritonavir. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic range, dose reduction of clarithromycin is not required in patients with normal renal function. Dose adjustment is required in patients with renal impairment: for patients with CLCR 30–60 mL/min, the clarithromycin dose should be reduced by 50%. For patients with CLCR < 30 mL/min, the clarithromycin dose should be reduced by 75%. In this case, this formulation should not be used, as it does not allow adequate dose reduction (for this patient group, immediate-release clarithromycin tablets (Klacid®, 250 mg tablets) may be used). Doses of clarithromycin exceeding 1 g/day should not be used concomitantly with ritonavir.

The same dose adjustments should be applied to patients with impaired renal function when ritonavir is used as a pharmacokinetic booster with other HIV protease inhibitors, including atazanavir and saquinavir (see below "Bidirectional drug interactions").

Effects of clarithromycin on other medicinal products

Antiarrhythmic agents

Post-marketing reports describe cases of torsades de pointes with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended to detect QT prolongation promptly during concomitant use of clarithromycin with these agents. Serum concentrations of these agents should be monitored during clarithromycin therapy.

Post-marketing use has reported hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, glucose monitoring is required when these agents are used together.

Oral hypoglycemic agents/insulin

When used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide, clarithromycin may inhibit the CYP3A enzyme, potentially causing hypoglycemia. Careful glucose monitoring is recommended.

CYP3A-related interactions |

Concomitant use of clarithromycin, a known CYP3A enzyme inhibitor, with a drug primarily metabolized by CYP3A, may increase the latter's plasma concentration, thereby enhancing or prolonging its therapeutic and adverse effects. Caution is advised when using clarithromycin in patients receiving therapy with CYP3A substrate drugs, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine) and/or is predominantly metabolized by this enzyme. Dose adjustment may be required, and, if possible, careful monitoring of serum concentrations of the drug primarily metabolized by CYP3A is recommended for patients receiving clarithromycin concomitantly.

Corticosteroids

Caution should be exercised when using clarithromycin concomitantly with systemic or inhaled corticosteroids that are primarily metabolized by CYP3A, due to the potential for increased systemic corticosteroid effects. Patients should be closely monitored for adverse reactions to systemic corticosteroids when used concomitantly.

It is known (or suspected) that the following medicinal products or groups of products are metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g., warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam, and vinblastine, but this list is not exhaustive. A similar interaction mechanism has been noted with phenytoin, theophylline, and valproate, which are metabolized by other cytochrome P450 isoenzymes.

Direct oral anticoagulants (DOACs)

The DOACs dabigatran and edoxaban are substrates of the efflux transporter P-glycoprotein (P-gp). Rivaroxaban and apixaban are metabolized via CYP3A4 and are also P-gp substrates. Caution is advised when using clarithromycin concomitantly with these agents, especially in patients at high risk of bleeding (see "Special precautions").

Omeprazole

Clarithromycin (500 mg every 8 hours) was administered in combination with omeprazole (40 mg daily) to healthy adult volunteers. Steady-state plasma concentrations of omeprazole increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively) with concomitant clarithromycin. When omeprazole was administered alone, the mean gastric pH measured over 24 hours was 5.2; with concomitant omeprazole and clarithromycin, it was 5.7.

Sildenafil, tadalafil, and vardenafil

Each of these phosphodiesterase inhibitors is metabolized (at least partially) via CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil, or vardenafil may increase exposure to the phosphodiesterase inhibitor; therefore, consideration should be given to reducing the dose of sildenafil, tadalafil, or vardenafil.

Theophylline, carbamazepine

Clinical study results show a slight but statistically significant (p≤0.05) increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.

Tolterodine

Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoenzyme (CYP2D6). However, in patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in plasma concentrations of tolterodine. Dose reduction of tolterodine may be necessary when used with CYP3A inhibitors such as clarithromycin.

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)

When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous midazolam administration. Close patient monitoring is required when midazolam is administered intravenously with clarithromycin to allow prompt dose adjustment. With oromucosal midazolam administration, where presystemic elimination may be bypassed, an interaction similar to that observed with intravenous midazolam (rather than oral) is more likely. The same precautions should be observed when using other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination does not depend on CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

Post-marketing reports describe drug interactions and adverse central nervous system effects (such as drowsiness and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the potential for enhanced pharmacological effects on the CNS.

Other types of interactions

Colchicine

Colchicine is a substrate of CYP3A and the efflux transporter P-glycoprotein (P-gp). Clarithromycin and other macrolides are known to inhibit CYP3A and P-gp. When clarithromycin and colchicine are used concomitantly, inhibition of P-gp and/or CYP3A by clarithromycin may lead to increased colchicine exposure. Concomitant use of clarithromycin and colchicine is contraindicated (see "Contraindications", "Special precautions").

Digoxin

Digoxin is considered a substrate of the efflux transporter P-glycoprotein (P-gp). Clarithromycin is known to inhibit P-gp. When clarithromycin and digoxin are used concomitantly, inhibition of P-gp by clarithromycin may lead to increased digoxin exposure. Post-marketing surveillance has reported increased serum digoxin concentrations in patients receiving clarithromycin concomitantly with digoxin. In some patients, signs of digoxin toxicity developed, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored in patients receiving concomitant clarithromycin and digoxin.

Zidovudine

Concomitant oral administration of clarithromycin tablets and zidovudine in HIV-infected adult patients may result in decreased steady-state serum concentrations of zidovudine. Clarithromycin may interfere with the absorption of oral zidovudine when administered simultaneously; this can largely be avoided by maintaining a 4-hour interval between doses of clarithromycin and zidovudine. Such interaction has not been reported with clarithromycin suspension and zidovudine or didanosine in HIV-infected children. This interaction is unlikely when clarithromycin is administered intravenously.

Phenytoin and valproate

There have been spontaneous and published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Serum levels of these drugs should be monitored when co-administered with clarithromycin. Increased serum levels have been reported.

Bidirectional drug interactions

Hydroxychloroquine and chloroquine

Observational data suggest that concomitant use of azithromycin and hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Due to the potential for similar risk with other macrolides used in combination with hydroxychloroquine or chloroquine, the benefit-risk ratio should be carefully evaluated before prescribing clarithromycin to patients taking hydroxychloroquine or chloroquine. Clarithromycin should be used with caution in patients receiving drugs that prolong the QT interval, due to the potential for cardiac arrhythmias and serious cardiovascular adverse reactions.

Atazanavir

Concomitant use of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, resulted in a doubling of clarithromycin exposure and a 70% reduction in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, dose reduction is not necessary in patients with normal renal function. The clarithromycin dose should be reduced by 50% in patients with creatinine clearance of 30–60 mL/min and by 75% in patients with creatinine clearance <30 mL/min, using an appropriate dosage form. Clarithromycin doses exceeding 1000 mg daily should not be used concomitantly with protease inhibitors.

Calcium channel blockers

Due to the risk of hypotension, clarithromycin should be used with caution when administered concomitantly with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem). Interactions may increase plasma concentrations of both clarithromycin and calcium channel blockers. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving clarithromycin and verapamil concomitantly.

Itaconazole

Clarithromycin and itraconazole are both substrates and inhibitors of CYP3A, and thus clarithromycin may increase plasma levels of itraconazole and vice versa. Patients receiving itraconazole concomitantly with clarithromycin should be closely monitored for signs of enhanced or prolonged pharmacological effect.

Saquinavir

Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, in 12 healthy volunteers resulted in a 177% and 187% increase in steady-state AUC and Cmax of saquinavir, respectively, compared to administration of saquinavir alone. At the same time, AUC and Cmax of clarithromycin increased by approximately 40% compared to administration of clarithromycin alone. Dose adjustment is not necessary if both drugs are used concomitantly for a limited period at the studied doses/formulations. Results from drug interaction studies using soft gelatin capsules may not reflect effects observed with hard gelatin capsule formulations of saquinavir. Results from drug interaction studies using saquinavir alone may not reflect effects observed with saquinavir/ritonavir combination therapy. When saquinavir is used with ritonavir, the potential effect of ritonavir on clarithromycin should be considered (see above).

Special precautions for use.

Clarithromycin should not be prescribed to pregnant women without careful assessment of the benefit-risk ratio, especially during the first trimester of pregnancy.

Prolonged use of clarithromycin, as with other antibiotics, may lead to overgrowth of resistant bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated.

Clarithromycin is primarily eliminated via the liver. Therefore, caution should be exercised when administering the drug to patients with hepatic impairment. The drug should also be used with caution in patients with moderate or severe renal impairment.

The drug should be used with caution in patients with severe renal insufficiency.

Hepatic dysfunction, including elevated liver enzymes, hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported during clarithromycin therapy. This hepatic dysfunction may be severe in nature and is usually reversible. In some cases, fatal hepatic failure has been reported (see "Adverse reactions"), primarily associated with pre-existing liver disease or concomitant use of other hepatotoxic drugs. Clarithromycin therapy should be discontinued immediately if signs or symptoms of hepatitis develop, such as anorexia, jaundice, dark urine, pruritus, or abdominal tenderness.

Pseudomembranous colitis, ranging from mild to life-threatening severity, has been reported with the use of nearly all antibacterial agents, including macrolides. Clostridium difficile-associated diarrhea (CDAD), ranging from mild to fatal colitis, has been reported with the use of nearly all antibacterial agents, including clarithromycin. Antibacterial therapy alters the normal gut flora, potentially leading to overgrowth of C. difficile. Clostridium difficile-associated diarrhea should always be considered in all patients who develop diarrhea following antibiotic use. A careful medical history is essential, as cases have been reported up to two months after antibiotic administration.

Therefore, in the event of persistent diarrhea during clarithromycin therapy, discontinuation of clarithromycin should be considered regardless of the indication for use. Testing for C. difficile should be performed and appropriate treatment initiated. Antiperistaltic agents should be avoided.

Colchicine

Cases of colchicine toxicity (including fatal outcomes) have been reported with concomitant use of clarithromycin and colchicine, particularly in elderly patients and those with renal impairment (see "Interaction with other medicinal products and other forms of interaction"). Concomitant use of clarithromycin with colchicine is contraindicated (see "Contraindications").

Concomitant use of clarithromycin with triazolobenzodiazepines such as triazolam, intravenous or oromucosal midazolam, should be done with caution (see "Interaction with other medicinal products and other forms of interaction").

Cardiovascular complications

Prolongation of cardiac repolarization and QT interval, indicating a risk of cardiac arrhythmia and torsades de pointes, has been observed with macrolide therapy, including clarithromycin (see "Adverse reactions"). Given that the following conditions may increase the risk of ventricular arrhythmias (including torsades de pointes), clarithromycin should be used with caution in the patient groups listed below:

• Patients with ischemic heart disease, severe heart failure, conduction disorders, or clinically significant bradycardia.
• Patients concurrently taking other drugs associated with QT interval prolongation (see "Interaction with other medicinal products and other forms of interaction").
• Clarithromycin is contraindicated in patients with hypokalemia or hypomagnesemia (see "Contraindications").
• Concomitant use of clarithromycin with astemizole, cisapride, pimozide, and terfenadine is contraindicated (see "Contraindications").
• Clarithromycin should not be used in patients with congenital or documented acquired QT prolongation or a history of ventricular arrhythmia (see "Contraindications").
• The benefit-risk ratio should be carefully weighed before prescribing clarithromycin to patients taking hydroxychloroquine or chloroquine, due to the potential for increased risk of cardiovascular events or cardiovascular mortality (see "Interaction with other medicinal products and other forms of interaction").

Epidemiological studies on the risk of adverse cardiovascular outcomes with macrolide use have shown variable results. Some observational studies have identified a small, short-term risk of arrhythmia, myocardial infarction, and cardiovascular mortality associated with macrolide use, including clarithromycin. These findings should be weighed against the benefits of treatment when prescribing clarithromycin.

Pneumonia

Given the increasing resistance of Streptococcus pneumoniae to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin for community-acquired pneumonia. For hospital-acquired 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, which may be macrolide-resistant. Therefore, susceptibility testing is important. In cases where beta-lactam antibiotics cannot be used (e.g., due to allergy), alternative antibiotics such as clindamycin may be considered first-line. Currently, macrolides play a limited role in the treatment of certain skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, erysipelas, and in situations where penicillins cannot be used.

If severe acute hypersensitivity reactions occur, such as anaphylaxis, severe skin reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), or Henoch-Schönlein purpura, clarithromycin therapy should be discontinued immediately and appropriate treatment initiated.

Clarithromycin should be used with caution when co-administered with inducers of the cytochrome CYP3A4 enzyme (see "Interaction with other medicinal products and other forms of interaction").

Cross-resistance between clarithromycin and other macrolides, as well as with lincomycin and clindamycin, should be considered.

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications"). Clarithromycin should be used with caution when administered with other statins. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin and statins concurrently. Patients should be monitored for symptoms of myopathy. When 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 not metabolized by CYP3A (e.g., fluvastatin) may be considered (see "Interaction with other medicinal products and other forms of interaction").

Oral hypoglycemic agents/insulin

Concomitant use of clarithromycin with oral hypoglycemic agents (such as sulfonylureas) and/or insulin may cause marked hypoglycemia. Close monitoring of blood glucose levels is recommended.

Oral anticoagulants

Concomitant use of clarithromycin with warfarin increases the risk of serious bleeding, significantly elevated INR (international normalized ratio), and prolonged prothrombin time. Frequent monitoring of INR and prothrombin time is required while patients are receiving both clarithromycin and oral anticoagulants.

Caution is advised when clarithromycin is used concomitantly 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 forms of interaction").

Excipients

The product contains lactose. If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicine. Patients with rare hereditary forms of galactose intolerance, complete lactase deficiency, or glucose-galactose malabsorption syndrome should not take this product.

The product contains 15.3 mg of sodium per tablet. For patients on a sodium-controlled diet who take 2 tablets once daily, the total sodium intake (30.6 mg per dose) should be taken into account.

Use during pregnancy or breastfeeding

Pregnancy

The safety of clarithromycin use during pregnancy has not been established. Based on varying results from animal studies and human experience, a potential adverse effect on embryofetal development cannot be excluded. Some observational studies evaluating clarithromycin use during the first and second trimesters have reported an increased risk of miscarriage compared to no antibiotic use or use of other antibiotics during the same period. Available epidemiological studies on the risk of major congenital malformations due to macrolide use, including clarithromycin, during pregnancy provide conflicting results. Therefore, the drug should not be used during pregnancy without careful benefit-risk assessment.

Breastfeeding

Clarithromycin is excreted in human breast milk in small amounts. It has been estimated that an exclusively breastfed infant receives approximately 1.7% of the maternal clarithromycin dose, adjusted for maternal body weight.

The safety of clarithromycin use during breastfeeding has not been established.

Ability to influence reaction speed when driving or operating machinery

Data on the effect are lacking. However, the possible occurrence of nervous system adverse reactions such as seizures, dizziness, vertigo, hallucinations, confusion, and disorientation should be considered before driving or operating machinery.

Dosage and Administration

Adults. The recommended dose of clarithromycin for adults and children aged 12 years and older is 500 mg once daily with food. In more severe infections, the dose may be increased to 1000 mg once daily (2 tablets of 500 mg).

The usual duration of treatment is 5 to 14 days, except for the treatment of community-acquired pneumonia and sinusitis, which require 6–14 days of therapy.

Tablets should be swallowed whole, without chewing.

Patients with renal impairment. This formulation should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min), as it does not allow adequate dose reduction. Such patients should receive immediate-release clarithromycin tablets (Klacid®, 250 mg tablets). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the dose should be reduced by 50%; the maximum dose of clarithromycin is 1 prolonged-release tablet per day.

Children.

This medicinal product is indicated for children aged 12 years and older. The use of clarithromycin tablets in children under 12 years of age has not been studied. For children in this age group, the suspension formulation should be used.

Overdose.

Symptoms. Available reports suggest that clarithromycin overdose may cause gastrointestinal symptoms. In one patient with a history of bipolar disorder who ingested 8 grams of clarithromycin, disturbances in mental status, paranoid behavior, hypokalemia, and hypoxemia occurred.

Treatment. Adverse reactions associated with overdose should be managed by immediate gastric lavage and administration of symptomatic therapy. As with other macrolides, hemodialysis or peritoneal dialysis are unlikely to significantly alter serum clarithromycin levels.

Side effects

The most common and frequent adverse reactions associated with clarithromycin treatment in adults and children are abdominal pain, diarrhea, nausea, vomiting, and altered taste. These adverse reactions are usually mild and consistent with the known safety profile of macrolide antibiotics. During clinical studies, no significant difference was observed in the frequency of these gastrointestinal adverse reactions between patient groups with or without mycobacterial infections.

The adverse reactions listed below were observed during clinical trials and post-marketing use of various dosage forms and strengths of clarithromycin, including extended-release tablets. Adverse reactions considered at least possibly related to clarithromycin are categorized by system organ class and frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and frequency not known* (reactions reported during post-marketing surveillance; frequency cannot be estimated from available data). Within each group, adverse reactions are listed in descending order of severity, where severity could be assessed.

Infections and infestations: uncommon – cellulitis^1, candidiasis, gastroenteritis^2, infection^3, vaginal infection; frequency not known – pseudomembranous colitis, botulism.

Blood and lymphatic system disorders: uncommon – leukopenia, neutropenia^4, thrombocytosis^3, eosinophilia^4; frequency not known – agranulocytosis, thrombocytopenia.

Immune system disorders: uncommon – anaphylactoid reactions^1, hypersensitivity; frequency not known – anaphylactic reactions, angioedema.

Metabolism and nutrition disorders: uncommon – anorexia, decreased appetite; frequency not known – hypoglycemia.

Psychiatric disorders: common – insomnia; uncommon – anxiety, nervousness^3; frequency not known – psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.

Central nervous system disorders: common – dysgeusia (disturbance of taste sensation), headache; uncommon – loss of consciousness^1, dyskinesia^1, dizziness, somnolence, tremor; frequency not known – seizures, ageusia (loss of taste sensation), parosmia, anosmia, paresthesia.

Ear and labyrinth disorders: uncommon – vertigo, hearing impairment, tinnitus; frequency not known – hearing loss.

Cardiac disorders: uncommon – cardiac arrest^1, atrial fibrillation^1, QT interval prolongation, extrasystoles^1, palpitations; frequency not known – torsades de pointes, ventricular tachycardia, ventricular fibrillation.

Vascular disorders: common – vasodilation^1; frequency not known – hemorrhage.

Respiratory, thoracic and mediastinal disorders: uncommon – asthma^1, epistaxis^2, pulmonary embolism^1.

Gastrointestinal disorders: common – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; uncommon – esophagitis^1, gastroesophageal reflux disease^2, gastritis, proctalgia^2, stomatitis, glossitis, abdominal distension^4, constipation, dry mouth, eructation, flatulence; frequency not known – acute pancreatitis, tongue discoloration, tooth discoloration.

Hepatobiliary disorders: common – abnormal liver function tests; uncommon – cholestasis^4, hepatitis^4, increased levels of ALT, AST, GGT^4; frequency not known – hepatic failure, hepatocellular jaundice.

Skin and subcutaneous tissue disorders: common – rash, hyperhidrosis; uncommon – bullous dermatitis^1, pruritus, urticaria, maculopapular rash^3; frequency not known – severe skin reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)), acne, Schönlein-Henoch disease.

Musculoskeletal and connective tissue disorders: uncommon – muscle spasms^3, skeletal muscle rigidity^1, myalgia^2; frequency not known – rhabdomyolysis^2**, myopathy.

Renal and urinary disorders: uncommon – increased blood creatinine^1, increased blood urea^1; frequency not known – renal failure, interstitial nephritis.

General disorders and administration site conditions: very common – phlebitis at injection site^1; common – pain at injection site^1, inflammation at injection site^1; uncommon – malaise^4, fever^3, asthenia, chest pain^4, chills^4, fatigue^4.

Investigations: uncommon – altered albumin-globulin ratio^1, increased blood alkaline phosphatase^4, increased blood lactate dehydrogenase^4; frequency not known – increased international normalized ratio (INR), prolonged prothrombin time, change in urine color.

* Frequency not known: these reactions have been reported voluntarily from a population of uncertain size. It is therefore not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The overall clinical experience with clarithromycin exceeds 1 billion patient-days.

** In some reports of rhabdomyolysis, clarithromycin was co-administered with other medicinal products known to be associated with rhabdomyolysis (e.g., statins, fibrates, colchicine, or allopurinol).

^1,^2,^3,^4 Adverse reactions marked with:
^1 – reported only with intravenous lyophilized powder for solution for infusion,
^2 – reported only with extended-release tablets,
^3 – reported only with oral suspension,
^4 – reported only with immediate-release tablets.

Very rarely, there have been reports of finding immediate-release clarithromycin tablets in feces, many of which occurred in patients with anatomical (including ileostomy or colostomy) or functional gastrointestinal disorders associated with shortened gastrointestinal transit time. In several reports, tablet remnants were observed in the context of diarrhea.

Patients in whom tablet residues are found in feces and who do not show clinical improvement during treatment should be advised to switch to another formulation of clarithromycin (e.g., oral suspension) or to another antibiotic.

The frequency, type, and severity of adverse reactions in children are expected to be similar to those in adults.

Patients with impaired immune system.

In patients with AIDS and other immunocompromised patients receiving high doses of clarithromycin for prolonged periods to treat mycobacterial infections, it has often been difficult to distinguish adverse reactions related to drug administration from symptoms of the underlying or concomitant diseases.

In adult patients receiving clarithromycin at a daily dose of 1000 mg, the most commonly reported adverse effects were nausea, vomiting, altered taste, abdominal pain, diarrhea, rash, abdominal distension, headache, constipation, hearing disturbances, and increased serum ALT and AST levels. Dyspnea, insomnia, and dry mouth occurred less frequently.

In these immunocompromised patients, laboratory parameters were evaluated by assessing those values exceeding the limits of significant abnormality (i.e., extreme upper or lower reference limits) for a given test. By this criterion, 2–3% of patients receiving 1000 mg of clarithromycin daily experienced significantly abnormal elevations in ALT and AST levels and abnormal decreases in white blood cell and platelet counts. A smaller percentage of patients showed increased blood urea nitrogen levels.

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25°C.

Packaging. 5 or 7 tablets per blister, 1 blister per cardboard box; 7 tablets per blister, 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. AbbVie S.r.l., Italy.

Manufacturer's address and location of operations.
C.R. 148 Pontina KM 52, SNC - Campoverde di Aprilia (loc. Aprilia) - 04011 Aprilia (LT), Italy.