Clacid

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

Composition:

Active substance: clarithromycin;

5 ml of ready-to-use suspension contains clarithromycin 125 or 250 mg;

Excipients: carbomers (carbopol 974P), povidone K-90, hypromellose phthalate, castor oil, silicon dioxide, maltodextrin, sucrose, titanium dioxide (E 171), xanthan gum, combined fruit flavor, potassium sorbate, anhydrous citric acid.

Pharmaceutical form. Granules for oral suspension.

Main physicochemical characteristics: granules – free-flowing granules of white to almost white color with a fruity odor; ready-to-use suspension – opaque suspension of white to almost white color with a fruity odor.

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 activity 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 two times lower than those of erythromycin.

Clarithromycin exhibits high in vitro activity against Legionella pneumophila and Mycoplasma pneumoniae. It has bactericidal activity against H. pylori, with higher activity at neutral pH compared to acidic pH. In vitro and in vivo data indicate high activity of clarithromycin against clinically significant strains of mycobacteria. In vitro studies have shown that Enterobacteriaceae and Pseudomonas strains, as well as other non-lactose-producing gram-negative bacteria, are insensitive 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 insensitive 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.

Camphylobacters: 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 primary metabolite of clarithromycin in humans is the microbiologically active 14-hydroxyclarithromycin (14-OH-clarithromycin). For most microorganisms, the microbiological activity of the metabolite is equal to or 1–2 times weaker than that of the parent compound, except for H. influenzae, against which the metabolite is twice as effective. 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 zone diameter provide the most accurate assessment of bacterial susceptibility to antimicrobial agents. In one of the recommended procedures for susceptibility testing, disks impregnated with 15 mcg of clarithromycin (Kirby-Bauer diffusion method) are used; the zone diameter inhibition for this disk is interpreted in relation to the MIC values for clarithromycin. MIC is determined by broth or agar dilution methods.

When performing these procedures, a laboratory report stating "susceptible" indicates that the infecting microorganism is likely to respond to therapy. A report stating "resistant" indicates that the infecting microorganism is unlikely to respond to therapy. A report 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 data on absolute breakpoints for susceptibility, resistance, and intermediate susceptibility should be taken into account.

Pharmacokinetics.

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract. The microbiologically active 14-OH-clarithromycin is formed during first-pass metabolism in the liver. When the drug is taken with food, the onset of absorption and formation of 14-OH-clarithromycin is slightly delayed, but overall bioavailability remains unchanged. Although the pharmacokinetics of clarithromycin are nonlinear, steady-state concentrations are achieved within two consecutive days of drug administration.

Pharmacokinetic parameters after administration of the fifth dose (250 mg clarithromycin suspension) were as follows: Cmax – 1.98 µg/mL, AUC – 11.5 µg·h/mL, Tmax – 2.8 hours, and T½ – 3.2 hours for clarithromycin, and 0.67 µg/mL, 5.33 µg·h/mL, 2.9 hours, and 4.9 hours for 14-OH-clarithromycin, respectively.

Tissue concentrations of clarithromycin in the body are several times higher than serum concentrations. Elevated concentrations of clarithromycin are observed in tonsillar and lung tissues. Concentrations in middle ear fluid exceed those in serum. In vitro data indicate that clarithromycin binds to human plasma proteins by approximately 70% at clinically relevant concentrations ranging from 0.45 to 4.5 µg/mL. 14-OH-clarithromycin is the main metabolite excreted by the kidneys, accounting for approximately 10–15% of the administered dose. The majority of the remainder is excreted in feces, primarily via bile. 5–10% of the parent compound is excreted in feces.

Steady-state concentrations of clarithromycin in patients with impaired liver function do not differ from those in healthy volunteers, except for lower concentrations of 14-OH-clarithromycin in hepatic dysfunction.

In patients with impaired renal function receiving 500 mg of clarithromycin, pharmacokinetic parameter values increased proportionally with the severity of renal impairment.

Patient age does not affect the pharmacokinetic parameters of clarithromycin.

In HIV-infected children receiving clarithromycin at doses of 15–30 mg/kg/day (divided into two doses), higher plasma concentrations of clarithromycin and a longer elimination half-life were observed.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to clarithromycin:

• Lower respiratory tract infections (e.g., bronchitis, acute lobar pneumonia, primary atypical pneumonia) (see "Special precautions" and "Pharmacological properties. Pharmacodynamics" regarding susceptibility testing).
• Upper respiratory tract infections, i.e., nasopharyngeal infections (tonsillitis, pharyngitis), and infections of the paranasal sinuses.
• Acute otitis media.
• Skin and soft tissue infections (such as impetigo, erysipelas, folliculitis, furunculosis, infected wounds) (see "Special precautions" and "Pharmacological properties. Pharmacodynamics" regarding susceptibility testing).
• Disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii.

Contraindications.

Hypersensitivity to macrolide antibiotics or to any of the components of the drug.

Concomitant use of astemizole, cisapride, pimozide, terfenadine (as this may lead to QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes), ergot alkaloids, such as ergotamine, dihydroergotamine (as this may lead to 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 interval 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 insufficiency and concomitant renal insufficiency.

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").

Interaction with other medicinal products and other forms of interaction.

The use of the following medicinal products is strictly contraindicated due to the potential for severe interaction consequences.

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 taking clarithromycin and pimozide concomitantly (see "Contraindications"). Macrolides have been reported to alter the metabolism of terfenadine, leading to increased serum levels of terfenadine, which has sometimes been associated with arrhythmias such as QT interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see "Contraindications"). In a study involving 14 volunteers, concomitant administration of clarithromycin and terfenadine resulted in a 2- to 3-fold increase in the serum level of the acidic metabolite of terfenadine and QT interval prolongation, without any clinically apparent effect. Similar effects 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 midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 7-fold after oral administration of midazolam. Concomitant use of oral midazolam and clarithromycin is contraindicated (see "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 their 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 these statins. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.

Caution should be exercised when prescribing clarithromycin concomitantly with other statins. If concomitant use of clarithromycin with statins cannot be avoided, it is recommended to use the lowest approved dose of the statin. Use of a statin not dependent on CYP3A metabolism (e.g., fluvastatin) may be considered. Monitoring of patients for symptoms of myopathy is necessary.

Lomitapide

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

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

Effect of other medicinal products on clarithromycin.

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

The effect of the following medicinal products on clarithromycin blood concentration is known or suspected, and therefore dose adjustment of clarithromycin 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 the metabolism of clarithromycin, 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 diminished by etravirine; however, concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), the overall activity against this pathogen may be altered. Therefore, for the treatment of MAC, consideration should be given to the use of alternative agents to clarithromycin.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in a 33% increase in the 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 significantly inhibited the metabolism of clarithromycin. Cmax of clarithromycin increased by 31%, Cmin by 182%, and AUC by 77% with concomitant use of ritonavir. Complete inhibition of the formation of 14-OH-clarithromycin was observed. Due to the wide therapeutic range, dose reduction of clarithromycin is not necessary for patients with normal renal function. However, dose adjustment is required for patients with renal insufficiency: for patients with CLCR 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For patients with CLCR < 30 mL/min, the dose of clarithromycin should be reduced by 75%. Clarithromycin doses 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 together with other HIV protease inhibitors, including atazanavir and saquinavir (see below "Bidirectional drug interactions").

Effect of clarithromycin on other medicinal products.

Antiarrhythmic agents

Post-marketing reports have documented cases of torsades de pointes with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended to detect QT interval prolongation promptly when clarithromycin is used concomitantly 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, blood glucose monitoring is necessary when these agents are used concomitantly.

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 monitoring of glucose levels is recommended.

CYP3A-related interactions |

Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, and a medicinal product primarily metabolized by CYP3A, may result in increased plasma concentration of the latter, thereby potentially enhancing or prolonging its therapeutic and adverse effects. Caution should be exercised when administering clarithromycin to patients receiving medicinal products that are CYP3A substrates, 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 medicinal product primarily metabolized by CYP3A should be performed in patients receiving clarithromycin concomitantly.

Glucocorticoids

Caution should be exercised when using clarithromycin concomitantly with systemic or inhaled glucocorticoids that are predominantly metabolized by CYP3A, due to the potential for increased systemic effects of glucocorticoids. Patients should be closely monitored for adverse reactions to systemic glucocorticoids 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, tacrolimus, terfenadine, triazolam, and vinblastine, but this list is not exhaustive. A similar interaction mechanism has been observed with phenytoin, theophylline, and valproate, which are metabolized by other cytochrome P450 isoenzymes.

Direct oral anticoagulants (DOACs)

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 should be exercised 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). When omeprazole was administered alone, the mean gastric pH measured over 24 hours was 5.2; with concomitant administration of 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 lead to increased exposure to the phosphodiesterase inhibitor; therefore, consideration should be given to reducing the dose of sildenafil, tadalafil, or vardenafil.

Theophylline, carbamazepine

Results of clinical studies have shown 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 the population of patients without CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in plasma concentrations of tolterodine. For such patients, dose reduction of tolterodine may be necessary when used concomitantly 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 administration of midazolam. With intravenous administration of midazolam and clarithromycin, careful monitoring of the patient is required for timely dose adjustment. With oromucosal administration of midazolam, where presystemic elimination of the drug may be bypassed, an interaction similar to that observed with intravenous midazolam rather than oral administration 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 have documented drug interactions and adverse effects on the central nervous system (such as somnolence and confusion) with concomitant use of clarithromycin and triazolam. Patient monitoring is recommended, considering the potential for increased 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. Concomitant use of clarithromycin and colchicine may result in increased colchicine exposure due to inhibition of P-gp and/or CYP3A by clarithromycin. Concomitant use of clarithromycin with 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. Concomitant use of clarithromycin and digoxin may result in increased digoxin exposure due to P-gp inhibition by clarithromycin. Post-marketing observations have reported increased serum digoxin concentrations in patients receiving clarithromycin concomitantly with digoxin. In some patients, signs of digitalis toxicity, including potentially fatal arrhythmias, developed. Serum digoxin concentrations should be carefully monitored in patients receiving digoxin concomitantly with clarithromycin.

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 taken concomitantly, but this can largely be avoided by maintaining a 4-hour interval between doses of clarithromycin and zidovudine. Such interaction has not been reported with the use of clarithromycin suspension and zidovudine or didanosine in HIV-infected children. This interaction is unlikely when clarithromycin is administered intravenously.

Phenytoin and valproate

Spontaneous or published reports have documented interactions between CYP3A inhibitors, including clarithromycin, and medicinal products not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Monitoring of serum levels of these medicinal products is recommended when administered concomitantly with clarithromycin. Increased serum levels have been reported.

Bidirectional drug interactions

Hydroxychloroquine and chloroquine

Observational data indicate 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 weighed before prescribing clarithromycin to patients taking hydroxychloroquine or chloroquine. Clarithromycin should be used with caution in patients receiving medicinal products that prolong the QT interval, due to the potential risk of cardiac arrhythmia 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 for patients with normal renal function. The dose of clarithromycin should be reduced by 50% for patients with creatinine clearance 30–60 mL/min and by 75% for patients with creatinine clearance <30 mL/min. Clarithromycin doses higher than 1000 mg daily should not be used concomitantly with protease inhibitors.

Calcium channel blockers

Due to the risk of arterial hypotension, clarithromycin should be used with caution concomitantly with calcium channel blockers metabolized by CYP3A4 (such as verapamil, amlodipine, diltiazem). Plasma concentrations of both clarithromycin and calcium channel blockers may increase with interaction. In patients receiving clarithromycin and verapamil concomitantly, arterial hypotension, bradyarrhythmias, and lactic acidosis have been observed.

Itraconazole

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

Saquinavir

Concomitant use 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 the steady-state AUC and Cmax of saquinavir, respectively, compared to those observed with saquinavir alone. Meanwhile, AUC and Cmax of clarithromycin increased by approximately 40% compared to clarithromycin alone. Dose adjustment is not necessary if both medicinal products are used concomitantly for a limited period at the studied doses/forms. The results of the drug interaction study using soft gelatin capsules may not correspond to the effects observed with hard gelatin capsules of saquinavir. The results of the drug interaction study using saquinavir alone may not correspond to the effects observed with saquinavir/ritonavir 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 non-susceptible bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated.

Clarithromycin is primarily eliminated by the liver. Therefore, caution should be exercised when administering the drug to patients with impaired hepatic function. 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 function abnormalities, including elevated liver enzymes, as well as hepatocellular and/or cholestatic hepatitis with or without jaundice, have been reported during clarithromycin therapy. These hepatic abnormalities may be severe in nature but are usually reversible. Rare cases of fatal hepatic failure have been reported, primarily associated with serious underlying diseases and/or concomitant medications. 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 moderate 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, which may lead to overgrowth of C. difficile. Clostridium difficile-associated diarrhea should always be considered in any patient presenting with diarrhea following antibiotic use. A careful medical history is essential, as cases of C. difficile-associated diarrhea have been reported up to two months after antibacterial therapy. Therefore, clarithromycin treatment should be discontinued regardless of the initial indication. Microbiological testing should be performed and appropriate therapy 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 administration of clarithromycin and colchine is contraindicated (see "Contraindications").

Concomitant use of clarithromycin with triazolobenzodiazepines such as triazolam, or intravenous or oromucosal midazolam, should be used 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 arrhythmias including 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 following patient groups:

• Patients with ischemic heart disease, severe heart failure, conduction disorders, or clinically significant bradycardia.
• Patients receiving concomitant medications 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 is contraindicated in patients with congenital or documented acquired QT prolongation or a history of ventricular arrhythmias (see "Contraindications").
• The benefit/risk ratio should be carefully evaluated before prescribing clarithromycin to patients receiving 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 investigating the risk of adverse cardiovascular outcomes with macrolide use have shown variable results. Some observational studies have reported 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

Due to emerging resistance of Streptococcus pneumoniae to macrolides, susceptibility testing is important 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, both of which may be macrolide-resistant. Therefore, susceptibility testing is important. When beta-lactam antibiotics cannot be used (e.g., due to allergy), alternative antibiotics such as clindamycin may be considered as first-line therapy. 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, or erysipelas, and in situations where penicillin-based therapy is contraindicated.

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 co-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. If concomitant use of clarithromycin and statins cannot be avoided, the lowest registered dose of the statin should be prescribed. 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 result in pronounced hypoglycemia. Close monitoring of blood glucose levels is recommended.

Oral anticoagulants

Concomitant use of clarithromycin and warfarin may increase the risk of serious bleeding, with marked elevation of the INR (International Normalized Ratio) and prothrombin time. The INR and prothrombin time should be frequently monitored 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, particularly in patients at high risk of bleeding (see "Interaction with other medicinal products and other forms of interaction").

Excipients

The product contains sucrose; therefore, patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not use this product. The sucrose content should also be considered when prescribing this product to patients with diabetes mellitus.

Klacid® oral granules for suspension also contain castor oil, which may cause gastrointestinal disturbances and diarrhea.

Use during pregnancy or breastfeeding

Pregnancy

The safety of clarithromycin use during pregnancy has not been established. Based on conflicting results from animal studies and human experience, a potential adverse effect on embryofetal development cannot be excluded. Some observational studies evaluating the use of clarithromycin 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 associated with macrolide use, including clarithromycin, during pregnancy provide conflicting results. Therefore, clarithromycin 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 dose of clarithromycin, adjusted for maternal body weight.

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

Ability to influence the speed of reactions when driving or operating machinery

Data on this are lacking. However, possible adverse reactions affecting the nervous system, such as seizures, dizziness, vertigo, hallucinations, confusion, and disorientation, which may impair psychomotor performance, should be taken into account.

Dosage and administration.

For the treatment of non-mycobacterial infections, the recommended dose of Klacid® suspension for infants and children aged 6 months to 12 years is 7.5 mg/kg body weight twice daily; the maximum dose is 500 mg twice daily. The duration of treatment is usually 5–10 days, depending on the type of pathogen and severity of the disease. The suspension should be administered independently of food intake (it can be taken with milk).

Table 1

Dosage according to the child's body weight (administration twice daily)

Child's body weight* (kg)	125 mg/5 ml		250 mg/5 ml
	dose of suspension (ml) per single administration	equivalent to clarithromycin (mg)	dose of suspension (ml) per single administration	equivalent to clarithromycin (mg)
8 – 11	2.5 ml	62.5 mg	1.25 ml	62.5 mg
12 – 19	5.0 ml	125 mg	2.5 ml	125 mg
20 – 29	7.5 ml	187.5 mg	3.75 ml	187.5 mg
30 – 40	10.0 ml	250 mg	5.0 ml	250 mg

* For children with body weight up to 8 kg, the dose should be calculated per kilogram of body weight (7.5 mg/kg twice daily).

Mycobacterial infections

The recommended pediatric dose of Klacid® suspension for the treatment of mycobacterial infections is 7.5 to 15 mg/kg body weight twice daily, depending on the physician's individual clinical assessment of the patient's condition and severity of the disease; however, the maximum dose should not be exceeded—500 mg twice daily.

Treatment should continue as long as clinical efficacy from the use of the drug is observed (additional antimiycobacterial agents may be required).

Table 2

Recommended dosing for children with mycobacterial infection according to body weight

Child's body weight* (kg)	volume of Klacid® 125 mg/5 ml suspension (twice daily)		volume of Klacid® 250 mg/5 ml suspension (twice daily)
	7.5 mg/kg twice daily	15 mg/kg twice daily	7.5 mg/kg twice daily	15 mg/kg twice daily
8 – 11	2.5 ml	5 ml	1.25 ml	2.5 ml
12 – 19	5 ml	10 ml	2.5 ml	5 ml
20 – 29	7.5 ml	15 ml	3.75 ml	7.5 ml
30 – 40	10 ml	20 ml	5 ml	10 ml

* For children with body weight up to 8 kg, the dose should be calculated per kilogram of body weight (7.5–15 mg/kg twice daily).

Dosing in renal insufficiency

For children with creatinine clearance less than 30 mL/min/1.73 m², the dose of Klacid® should be reduced by 50%, i.e., to 250 mg once daily or 250 mg twice daily in more severe infections. In such patients, treatment should not exceed 14 days.

Method for preparing the suspension.

To prepare the suspension, add water to the bottle containing the granules up to the mark indicated on it and shake until all solid particles are converted into a suspension. If necessary, add more water up to the aforementioned mark. Avoid vigorous and/or prolonged shaking. The bottle should be shaken before each administration to resuspend the suspension.

Children.

Clinical studies of clarithromycin in suspension form were conducted in children aged 6 months to 12 years; therefore, clarithromycin in suspension form is indicated for children aged 6 months to 12 years.

Overdose.

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

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 affect serum clarithromycin concentrations.

Side effects

The most common and frequent adverse reactions during clarithromycin treatment in adults and children are abdominal pain, diarrhea, nausea, vomiting, and taste disturbances. 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 gastrointestinal adverse reactions between patient groups with or without mycobacterial infections.

The adverse reactions listed below occurred during clinical trials and post-marketing use of various dosage forms and strengths of clarithromycin, including the oral suspension. The 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 category, adverse reactions are presented in order of decreasing severity, when severity could be assessed.

Infections and infestations: uncommon – cellulitis¹, candidiasis, gastroenteritis², infection³, vaginal infection; frequency not known – pseudomembranous colitis, trench mouth.

Blood and lymphatic system disorders: uncommon – leukopenia, neutropenia⁴, thrombocytosis³, eosinophilia⁴; frequency not known – agranulocytosis, thrombocytopenia.

Immune system disorders: uncommon – anaphylactoid reactions¹, 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, nervousness³; frequency not known – psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.

Nervous system disorders: common – dysgeusia (disturbance of taste sensation), headache; uncommon – loss of consciousness¹, dyskinesia¹, 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 arrest¹, atrial fibrillation¹, QT interval prolongation, extrasystoles¹, palpitations; frequency not known – torsades de pointes, ventricular tachycardia, ventricular fibrillation.

Vascular disorders: common – vasodilation¹; frequency not known – hemorrhage.

Respiratory, thoracic and mediastinal disorders: uncommon – asthma¹, epistaxis², pulmonary embolism¹.

Gastrointestinal disorders: common – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; uncommon – esophagitis¹, gastroesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, abdominal distension⁴, constipation, dry mouth, eructation, flatulence; frequency not known – acute pancreatitis, tongue discoloration, tooth discoloration.

Hepatobiliary disorders: common – abnormal liver function tests; uncommon – cholestasis⁴, hepatitis⁴, increased levels of ALT, AST, GGT⁴; frequency not known – liver failure, hepatocellular jaundice.

Skin and subcutaneous tissue disorders: common – rash, hyperhidrosis; uncommon – bullous dermatitis¹, pruritus, urticaria, maculopapular rash³; frequency not known – severe skin adverse 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 spasms³, skeletal muscle rigidity¹, myalgia²; frequency not known – rhabdomyolysis^2**, myopathy.

Renal and urinary disorders: uncommon – increased blood creatinine¹, increased blood urea¹; frequency not known – renal failure, interstitial nephritis.

General disorders and administration site conditions: very common – phlebitis at injection site¹; common – pain at injection site¹, inflammation at injection site¹; uncommon – malaise⁴, fever³, asthenia, chest pain⁴, chills⁴, fatigue⁴.

Investigations: uncommon – change in albumin/globulin ratio¹, increased blood alkaline phosphatase⁴, increased blood lactate dehydrogenase⁴; frequency not known – increased international normalized ratio, prolonged prothrombin time, change in urine color.

* Frequency not known: these reactions have been reported voluntarily from a population of unknown size. It is 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 (such as statins, fibrates, colchicine, or allopurinol).

1,2,3,4 These adverse reactions were reported only with the following formulations: 1 – lyophilized powder for solution for infusion, 2 – extended-release tablets, 3 – suspension, 4 – immediate-release tablets.

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

Patients with impaired immune system.

In patients with AIDS and other immunocompromised patients who received high doses of clarithromycin for prolonged periods for the treatment of mycobacterial infections, it may be difficult to distinguish adverse reactions related to drug use from symptoms of the underlying or concomitant diseases.

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

In these immunocompromised patients, laboratory parameters were monitored, focusing on values outside the significant abnormal range (i.e., extreme upper or lower limits) for each test. By this criterion, significant abnormal elevations in ALT and AST levels and abnormal decreases in white blood cell and platelet counts were observed in 2–3% of patients receiving 1000 mg of clarithromycin daily. A smaller percentage of patients showed increased blood urea nitrogen levels.

Shelf life. 2 years; reconstituted suspension in the bottle – 14 days from the date of reconstitution.

Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 30 °C.

Packaging. Vial containing granules for reconstitution to 60 ml or 100 ml of suspension, with a measuring spoon or oral syringe, in a cardboard box.

Prescription category. Prescription only.

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

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