Clar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLAR (KLAR)

Composition:

Active substance: clarithromycin;

1 tablet contains clarithromycin 250 mg or 500 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, povidone (K-30), colloidal anhydrous silicon dioxide, magnesium stearate; film coating: Opadry Yellow 20H82975 (hypromellose, propylene glycol, titanium dioxide (E 171), hydroxypropyl cellulose, vanillin, sorbic acid, iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 250 mg: film-coated tablets, light yellow in color, oval-shaped, biconvex, with engraving "D" on one side and "62" on the other side;

Tablets 500 mg: film-coated tablets, light yellow in color, oval-shaped, biconvex, with engraving "D" on one side and "63" on the other side.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Macrolides, lincosamides and streptogramins. Macrolides. Clarithromycin. ATC code J01FA09.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Clarithromycin is an antibiotic belonging to the group of macrolide antibiotics. It exerts antibacterial activity by selectively binding to the 50S ribosomal subunit of susceptible bacteria, thereby preventing translocation of activated amino acids. It inhibits intracellular protein synthesis in susceptible bacteria.

The 14-hydroxy metabolite of clarithromycin, a product of clarithromycin metabolism, is also microbiologically active. The metabolite is less active than the parent compound against most organisms, including Mycobacterium spp. An exception is Haemophilus influenzae, against which the 14-hydroxy metabolite is twice as active as the parent compound.

Minimum inhibitory concentrations (MICs) of this metabolite are equal or two-fold higher compared to MICs of the parent compound, except for Haemophilus influenzae, against which the activity of the 14-hydroxy metabolite is two times higher than that of the parent compound.

Clarithromycin is generally active against the following microorganisms in vitro:

Gram-positive bacteria: Staphylococcus aureus (methicillin susceptible), Streptococcus pyogenes (Group A beta-hemolytic streptococci), alpha-hemolytic streptococci (viridans group), Streptococcus (Diplococcus) pneumoniae, Streptococcus agalactiae, Listeria monocytogenes.

Gram-negative bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila, Bordetella pertussis, Helicobacter pylori, Campylobacter jejuni.

Mycoplasmas: Mycoplasma pneumoniae, Ureaplasma urealyticum.

Other microorganisms: Chlamydia trachomatis, Mycobacterium avium, Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium intracellulare.

Anaerobes: Macrolide-susceptible Bacteroides fragilis, Clostridium perfringens, Peptococcus species, Peptostreptococcus species, Propionibacterium acnes.

Clarithromycin has bactericidal activity against several bacterial strains, including Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori, and Campylobacter spp.

Breakpoint values

Pharmacokinetics.

Absorption

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract, primarily in the small intestine, but undergoes extensive first-pass metabolism in the liver following oral administration. The absolute bioavailability of clarithromycin (1 tablet 250 mg) is approximately 50%. Food slightly delays absorption but does not affect bioavailability. Therefore, this drug can be administered independently of food intake. Due to its chemical structure (6-O-methylerythromycin), clarithromycin is sufficiently stable in the acidic environment of the stomach. In adults, after administration of clarithromycin 250 mg twice daily, the maximum plasma concentration was 1–2 µg/mL; after administration of 500 mg twice daily, it was 2.8 µg/mL. After administration of clarithromycin 250 mg twice daily, the peak level of the microbiologically active 14-hydroxy metabolite in plasma was 0.6 µg/mL. Steady-state levels are achieved after 2 days of treatment.

Distribution

Clarithromycin penetrates well into body fluids and tissues. The volume of distribution is 200–400 L. Clarithromycin concentrations in certain tissues are several times higher than in plasma. High concentrations have been found in tonsils and lungs. Clarithromycin also penetrates into gastric mucosa. At therapeutic levels, protein binding of clarithromycin to plasma proteins is approximately 70%.

Biotransformation and elimination

Clarithromycin is rapidly and extensively metabolized in the liver. Hepatic metabolism occurs via the cytochrome P450 system. Three metabolites have been described: N-demethylclarithromycin, decadinocyl clarithromycin, and 14-hydroxyclarithromycin. The pharmacokinetics of clarithromycin is nonlinear due to saturation of hepatic metabolism at higher doses. The elimination half-life (t1/2) increases from 2–4 hours after administration of clarithromycin 250 mg twice daily to 5 hours with 500 mg twice daily. The elimination half-life of the active 14-hydroxy metabolite is 5–6 hours after administration of clarithromycin 250 mg twice daily.

Approximately 20–40% of clarithromycin is excreted unchanged in urine. This proportion increases with increasing dose. 10–15% of the dose is excreted in urine as the 14-hydroxy metabolite. The remainder is excreted in feces. In renal impairment, plasma levels of clarithromycin increase if the dose is not reduced. Total plasma clearance is approximately 700 mL/min (11.7 mL/s), and renal clearance is approximately 170 mL/min (2.8 mL/s).

Special patient populations

In renal impairment, plasma levels of clarithromycin and its active metabolite increase.

Clinical characteristics.

Indications.

Treatment of bacterial infections caused by microorganisms sensitive to clarithromycin:

• bacterial pharyngitis;
• mild to moderate community-acquired pneumonia;
• acute bacterial sinusitis (properly diagnosed);
• exacerbation of chronic bronchitis;
• mild to moderate skin and soft tissue infections;
• in appropriate combination with antibacterial therapeutic regimens and a suitable ulcer-healing agent, for eradication of Helicobacter pylori in patients with H. pylori-associated peptic ulcer disease.

Clar 250 mg and 500 mg tablets are indicated for adults and children aged 12 years and older.

Attention should be paid to official recommendations regarding appropriate use of antibacterial agents.

Contraindications.

Hypersensitivity to the active substance (clarithromycin) or to other macrolides, or to any of the excipients of the medicinal product.

Concomitant use with any of the following active substances: astemizole, cisapride, pimozide, or terfenadine, as this may lead to QT interval prolongation (congenital or documented acquired QT prolongation) and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes.

Concomitant use with ticagrelor, ivabradine, or ranolazine is contraindicated.

Concomitant use with ergotamine or dihydroergotamine is contraindicated, as this may lead to ergot toxicity.

Concomitant use with lomitapide is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Clarithromycin should not be used:

• in patients with a history of QT interval prolongation or ventricular cardiac arrhythmia, including torsades de pointes;
• in patients with electrolyte imbalance (hypokalemia or hypomagnesemia) due to the risk of QT interval prolongation;
• concomitantly with HMG-CoA reductase inhibitors (statins) that are predominantly metabolized by CYP3A4 (lovastatin or simvastatin), due to increased risk of myopathy, including rhabdomyolysis;
• in patients with severe hepatic dysfunction accompanied by renal impairment;
• as with other potent CYP3A4 inhibitors, clarithromycin should not be used in patients receiving colchicine.

Interaction with other medicinal products and other forms of interaction.

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

Cisapride, pimozide, astemizole, and terfenadine

Elevated levels of cisapride have been reported in patients receiving clarithromycin concomitantly with cisapride. This may lead to QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been observed in patients receiving clarithromycin concomitantly with pimozide.

Macrolides have been reported to alter the metabolism of terfenadine, leading to increased terfenadine levels, which has sometimes been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes. In one study involving 14 healthy volunteers, co-administration of terfenadine and clarithromycin resulted in a 2- to 3-fold increase in serum levels of the acid metabolite of terfenadine and QT prolongation, although no clinically apparent effects were observed.

Similar effects have also been observed with concomitant use of astemizole and other macrolides.

Ergotamine/dihydroergotamine

Post-marketing reports indicate that concomitant use of clarithromycin with ergotamine or dihydroergotamine is associated with acute ergot toxicity, characterized by vasospasm and ischemia of extremities and other tissues, including the central nervous system. Concomitant use of clarithromycin with these agents is contraindicated.

Hydroxychloroquine and 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.

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated, 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 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 statins. If 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 dependent on CYP3A metabolism (e.g., fluvastatin) may be considered. Monitoring for signs and symptoms of myopathy is required.

Lomitapide

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

Use of clarithromycin is also contraindicated with ergot alkaloids, oral midazolam, HMG-CoA reductase inhibitors predominantly metabolized by CYP3A4 (e.g., lovastatin and simvastatin), colchicine, ticagrelor, ivabradine, and ranolazine (see section "Contraindications").

Effect of other medicinal products on clarithromycin

Medicinal products that are inducers of CYP3A (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may stimulate 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 prescribing information for the respective CYP3A4 inhibitor). Concomitant use of rifabutin and clarithromycin has led to increased rifabutin levels and decreased clarithromycin serum levels, with an increased risk of uveitis.

The effect of the following medicinal products on clarithromycin blood concentration is known or suspected, and 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 the metabolism of clarithromycin, reducing its plasma concentration while 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 when clarithromycin is used concomitantly with enzyme inducers.

Etravirine

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

Fluconazole

Concomitant administration of fluconazole 200 mg once daily and clarithromycin 500 mg twice daily to 21 healthy volunteers resulted in a 33% and 18% increase in steady-state minimum plasma concentration (Cmin) and area under the concentration-time curve (AUC) of clarithromycin, respectively. At steady state, the concentration of the active metabolite 14-OH-clarithromycin was not significantly altered with concomitant 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. When ritonavir was co-administered, the maximum plasma concentration (Cmax) of clarithromycin increased by 31%, Cmin by 182%, and AUC by 77%. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic index, dose reduction of clarithromycin is not required in patients with normal renal function. However, dose adjustment is necessary in patients with renal impairment: for creatinine clearance of 30–60 mL/min, the clarithromycin dose should be reduced by 50%; for creatinine clearance < 30 mL/min, the dose should be reduced by 75%. Clarithromycin doses exceeding 1 g per day should not be administered concomitantly with ritonavir.

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

Effect of clarithromycin on other medicinal products

CYP3A-related interactions

Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, with a medicinal product primarily metabolized by CYP3A, may lead to increased plasma concentrations of the latter, thereby potentially enhancing or prolonging its therapeutic effect and adverse reactions. Clarithromycin should be used with caution in patients receiving medicinal products that are CYP3A substrates, particularly if the CYP3A substrate has a narrow therapeutic index (e.g., carbamazepine) and/or is extensively 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 is recommended for patients receiving clarithromycin concomitantly.

The following medicinal products or groups of products are known (or suspected) to be metabolized by the CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g., warfarin), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam, and vinblastine. 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

Direct oral anticoagulants 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 medicinal products, especially in patients at high risk of bleeding (see section "Special precautions for use").

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 associated with systemic corticosteroids when used concomitantly.

Antiarrhythmic agents

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

Post-marketing reports have also described hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, blood glucose monitoring is necessary when these medicinal products 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 leading to hypoglycemia. Close monitoring of blood glucose levels is recommended.

Omeprazole

Clarithromycin (500 mg every 8 hours) was administered in combination with omeprazole (40 mg once daily) to healthy volunteers.

Plasma concentrations of omeprazole at steady state increased (Cmax, AUC0–24, and t1/2 increased by 30%, 89%, and 34%, respectively) when administered concomitantly with clarithromycin. When omeprazole was administered alone, the mean gastric pH measured over 24 hours was 5.2; with concomitant administration of omeprazole and clarithromycin, the mean pH was 5.7.

Sildenafil, tadalafil, and vardenafil

Each of these phosphodiesterase inhibitors is at least partially metabolized by the CYP3A enzyme, which may be inhibited when clarithromycin is administered concomitantly. There is a potential for increased plasma concentrations of the phosphodiesterase inhibitor when used concomitantly with clarithromycin. Consideration should be given to reducing the dose of sildenafil, tadalafil, or vardenafil when used concomitantly with clarithromycin.

Theophylline, carbamazepine

Clinical studies have shown a small but statistically significant increase in plasma levels of theophylline or carbamazepine when used concomitantly with clarithromycin.

Dose reduction may be necessary.

Tolterodine

Tolterodine is primarily metabolized by the CYP2D6 isoenzyme of cytochrome P450. However, in a subset of the population lacking CYP2D6, the primary metabolic pathway is CYP3A. In this subpopulation, inhibition of CYP3A leads to a significant increase in tolterodine concentration. Patients with reduced metabolism via CYP2D6 may require a reduced dose of tolterodine 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 by 2.7-fold after intravenous administration and by 7-fold after oral administration. Concomitant use of oral midazolam and clarithromycin should be avoided. When midazolam is administered intravenously with clarithromycin, patients should be closely observed for timely dose adjustment. The same precautions should be applied when using other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam.

For benzodiazepines whose metabolism does not depend on CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

Post-marketing reports have described drug interactions and central nervous system adverse reactions (e.g., somnolence and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored for possible pharmacological effects on the central nervous system.

Other types of interactions

Aminoglycosides

Clarithromycin should be used with caution concomitantly with other ototoxic agents, especially aminoglycosides.

Colchicine

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

Digoxin

Digoxin is considered a substrate of the efflux transporter P-gp. Clarithromycin is known to be an inhibitor of P-gp. Concomitant use of clarithromycin and digoxin may lead to increased digoxin exposure due to P-gp inhibition by clarithromycin. Post-marketing surveillance has also reported increased serum digoxin concentrations in patients receiving clarithromycin and digoxin concomitantly. In some patients, signs of digitalis toxicity, including potentially fatal arrhythmias, have developed. Serum digoxin concentrations should be closely monitored in patients receiving digoxin and clarithromycin concomitantly.

Zidovudine

Concomitant oral administration of clarithromycin tablets and zidovudine to HIV-infected patients may lead to reduced steady-state concentrations of zidovudine. Since clarithromycin affects the absorption of concurrently administered oral zidovudine, this interaction can largely be avoided by maintaining a 4-hour interval between doses of clarithromycin and zidovudine. This interaction was not observed with clarithromycin suspension and zidovudine or didanosine in HIV-infected children. When clarithromycin is administered by intravenous infusion, such interaction is not expected.

Phenytoin and valproate

There have been spontaneous or published reports of interactions between CYP3A inhibitors, including clarithromycin, and medicinal products not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Serum level monitoring of these medicinal products is recommended when used concomitantly with clarithromycin. Increased serum levels have been reported.

Bidirectional drug interactions

Atazanavir

Clarithromycin and atazanavir are both substrates and inhibitors of CYP3A. Evidence supports a bidirectional drug interaction. Concomitant administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) 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 index, dose reduction is not required in patients with normal renal function. In patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the clarithromycin dose should be reduced by 50%, and by 75% in patients with creatinine clearance < 30 mL/min, using the appropriate clarithromycin formulation.

Clarithromycin doses exceeding 1000 mg per day 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 (e.g., verapamil, amlodipine, diltiazem). The interaction may increase plasma concentrations of both clarithromycin and calcium channel blockers.

Arterial hypotension, bradyarrhythmia, and lactic acidosis have been observed in patients receiving clarithromycin and verapamil concomitantly.

Itraconazole

Clarithromycin and itraconazole are both substrates and inhibitors of CYP3A, resulting in a bidirectional drug interaction.

Clarithromycin may increase itraconazole plasma levels and vice versa; when itraconazole is used with clarithromycin, patients should be closely monitored for signs or symptoms of enhanced or prolonged pharmacological effect.

Saquinavir

Clarithromycin and saquinavir are both substrates and inhibitors of CYP3A. Evidence supports a bidirectional drug interaction. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax of saquinavir being 177% and 187% higher, respectively, compared to saquinavir alone. Meanwhile, AUC and Cmax of clarithromycin increased by approximately 40% compared to clarithromycin alone. Dose adjustment is not required if both medicinal products are used concomitantly for a limited period and at the aforementioned doses and formulations. Results from drug interaction studies using soft gelatin capsules may not reflect effects observed with hard gelatin capsules of saquinavir. Results from drug interaction studies conducted only with saquinavir may not reflect effects observed with saquinavir/ritonavir therapy. When saquinavir is used with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.

Special precautions for use.

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

Clarithromycin is primarily eliminated via the liver. Therefore, caution should be exercised when administering this antibiotic to patients with impaired hepatic function. Caution is also advised when administering clarithromycin to patients with moderate or severe renal impairment.

Cases of hepatic failure with fatal outcome have been reported. Some patients had concomitant liver disease or were receiving other hepatotoxic medicinal products. Patients should be advised to discontinue treatment and seek medical advice if signs and symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Pseudomembranous colitis, as well as Clostridium difficile-associated diarrhea ranging from mild to severe and potentially life-threatening, has been reported with the use of nearly all antibacterial agents, including clarithromycin. Antibacterial therapy may alter the normal gut flora, leading to overgrowth of Clostridium difficile. Clostridium difficile-associated diarrhea should be considered in all patients presenting with diarrhea following antibacterial use. A careful medical history is essential, as cases of Clostridium difficile-associated diarrhea have been reported even up to two months after antibacterial therapy. Clarithromycin should be discontinued regardless of the indication for which it was prescribed, and appropriate microbiological testing and treatment should be initiated. Medicinal products that inhibit gastrointestinal motility should be avoided.

Post-marketing reports have described the development of colchicine toxicity with concomitant use of clarithromycin and colchicine, particularly in elderly patients, including those with renal impairment. Some cases resulted in death. Concomitant use of clarithromycin and colchicine is contraindicated.

Caution is required when clarithromycin is used concomitantly with triazolobenzodiazepines (e.g., triazolam, midazolam).

Caution should be exercised when clarithromycin is used concomitantly with other ototoxic agents, particularly aminoglycosides. Monitoring of vestibular and auditory function during and after treatment is recommended.

Cardiovascular events

Prolongation of cardiac repolarization and QT interval, indicating a risk of cardiac arrhythmia including torsades de pointes, has been observed with macrolide therapy, including clarithromycin. Since the following conditions may increase the risk of cardiac arrhythmias (including torsades de pointes), clarithromycin should be used with caution in these patients:

• With ischemic heart disease, severe heart failure, conduction disorders, or clinically significant bradycardia.
• Patients receiving other medicinal products associated with QT interval prolongation.
• Concomitant use of clarithromycin with astemizole, cisapride, pimozide, and terfenadine is contraindicated.
• Clarithromycin should not be used in patients with congenital or documented acquired QT prolongation or a history of ventricular arrhythmias.

Epidemiological study results on the risk of adverse cardiovascular outcomes with macrolide use vary. Some observational studies have shown a rare short-term risk of arrhythmia, myocardial infarction, and fatal cardiovascular events associated with macrolide use, including clarithromycin. These findings should be balanced against the benefits of treatment when prescribing clarithromycin.

Pneumonia:

Due to possible 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.

Soft tissue and skin infections of mild to moderate severity:

These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, each of which may be resistant to macrolides. Therefore, susceptibility testing is important. In cases where beta-lactam antibiotics cannot be used (e.g., due to allergy), other antibiotics such as clindamycin may be considered as first-line therapy. Currently, macrolides are indicated only for 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 or severe skin adverse reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, or toxic epidermal necrolysis), clarithromycin therapy should be discontinued immediately and appropriate treatment initiated promptly.

Caution is required when clarithromycin is used concomitantly with medicinal products that are inducers of the CYP3A4 enzyme.

HMG-CoA reductase inhibitors (statins):

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated. Clarithromycin should be used with caution when administered simultaneously with other statins.

Cases of rhabdomyolysis have been reported in patients receiving clarithromycin concomitantly with statins. Patients should be monitored for signs and symptoms of myopathy. If concomitant use of clarithromycin and statins cannot be avoided, the lowest approved statin dose is recommended. A statin not metabolized by CYP3A (e.g., fluvastatin) may be considered.

Oral hypoglycemic agents/insulin:

Concomitant use of clarithromycin with oral hypoglycemic agents (e.g., sulfonylureas) and/or insulin may result in pronounced hypoglycemia. Close monitoring of blood glucose levels is recommended.

Oral anticoagulants:

Concomitant use of clarithromycin with warfarin may increase the risk of serious bleeding, with marked elevation of the international normalized ratio (INR) and prothrombin time. 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 section "Interaction with other medicinal products and other forms of interaction"). INR and prothrombin time should be monitored frequently while patients are receiving clarithromycin and oral anticoagulants.

Antibacterial therapy, including clarithromycin, used to treat Helicobacter pylori infection may lead to selection of resistant microorganisms.

As with other antibiotics, prolonged use may result in overgrowth of resistant bacteria or fungi. If superinfection occurs, appropriate therapy should be initiated.

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

Use during pregnancy or breastfeeding.

Pregnancy

The safety of clarithromycin use during pregnancy has not been established. Due to variable results from animal studies and human experience, the possibility of adverse effects on embryofetal development cannot be excluded. Some observational studies investigating clarithromycin use during the first and second trimesters of pregnancy have reported an increased risk of spontaneous abortion compared to pregnant women who did not use clarithromycin or other antibiotics during this period. Available epidemiological studies on the risk of major congenital malformations associated with macrolide use, including erythromycin, during pregnancy have yielded conflicting results. Therefore, clarithromycin should not be used during pregnancy without careful benefit-risk assessment.

Lactation

The safety of clarithromycin use during breastfeeding has not been established. Clarithromycin is excreted in human breast milk in small amounts. It has been estimated that exclusively breastfed infants receive approximately 1.7% of the maternal dose of clarithromycin, adjusted for body weight.

Fertility

There are no data on the effect of clarithromycin on human fertility. Limited animal data in rats do not indicate an effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

There are no data on the effect of clarithromycin on the ability to drive vehicles or operate machinery. However, adverse reactions such as dizziness, vertigo, confusion, and disorientation, which may affect such abilities, should be taken into account.

Method of Administration and Dosage

Dosing

The dosage depends on the type and severity of infection and must always be determined by a physician.

Adults and adolescents (aged 12 years and older)

• Standard dosage: the usual dose is 250 mg twice daily (in the morning and evening).
• High dosage (treatment of severe infections): in severe infections, the usual dose may be increased to 500 mg twice daily.

Children under 12 years of age

The use of clarithromycin in tablet form is not recommended in children under 12 years of age and weighing less than 30 kg. In clinical studies, clarithromycin suspension was used in children aged from 6 months to 12 years. Therefore, clarithromycin should be administered in suspension form to children under 12 years of age.

For children weighing more than 30 kg, the adult dosage should be used.

Renal impairment

In patients with impaired renal function (creatinine clearance less than 30 mL/min), the clarithromycin dosage should be reduced by half, i.e., 250 mg once daily or 250 mg twice daily in cases of more severe infections. In such patients, the duration of treatment should not exceed 14 days.

Hepatic impairment

Caution should be exercised when administering clarithromycin to patients with impaired liver function.

Eradication of Helicobacter pylori in peptic ulcer disease

When selecting antibiotics for Helicobacter pylori eradication, individual patient tolerance, national, regional, and local data on microbial susceptibility, and medical care guidelines should be taken into account.

Clarithromycin is usually administered in combination with another antibiotic and a proton pump inhibitor for 1 week.

Treatment may be repeated if the patient remains positive for Helicobacter pylori on testing.

Duration of treatment:

The duration of treatment depends on the type and severity of infection and must always be determined by a physician.

• Typically, treatment lasts 7–14 days.

Treatment should be continued for at least 2 days after symptoms have resolved.

• For infections caused by Streptococcus pyogenes (group A beta-hemolytic streptococcus), the duration of treatment should be at least 10 days.
• Combination therapy for Helicobacter pylori eradication should be administered for 7 days.

Method of administration:

The tablet should be swallowed whole with sufficient liquid (e.g., one glass of water), independent of food intake.

Children.

The use of clarithromycin in tablet form is not recommended in children under 12 years of age and weighing less than 30 kg. In clinical studies, clarithromycin suspension was used in children aged from 6 months to 12 years. Therefore, clarithromycin should be administered in suspension form to children under 12 years of age.

For children weighing more than 30 kg, the adult dosage should be used.

Overdose.

Symptoms

Reports indicate that ingestion of large amounts of clarithromycin is expected to cause gastrointestinal disturbances. In one patient with a history of bipolar disorder, ingestion of 8 g of clarithromycin resulted in mental status changes, paranoid behavior, hypokalemia, and hypoxemia.

Treatment

Treatment should include prompt removal of unabsorbed drug and supportive measures. As with other macrolides, hemodialysis and peritoneal dialysis are not expected to significantly affect serum clarithromycin levels.

In case of overdose with intravenous clarithromycin (powder for solution for injection), administration should be discontinued and all appropriate supportive measures should be taken.

Adverse reactions.

Summary of safety profile

The most common and general adverse reactions during clarithromycin treatment in adults and children are abdominal pain, diarrhea, nausea, vomiting, and taste disturbance. These adverse reactions are usually of mild severity and are consistent with the known safety profile of macrolide antibiotics.

There is no significant difference in the frequency of these gastrointestinal adverse reactions between patient groups with or without mycobacterial infection.

The adverse reactions listed below have been reported in clinical trials and in the post-marketing period with the use of clarithromycin in the following dosage forms: immediate-release tablets, granules for oral suspension, powder for injection solution, prolonged-release tablets, and modified-release tablets. These reactions are considered at least possibly related to the use of clarithromycin and are listed by system organ classes and frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), and frequency not known (adverse reactions from post-marketing reports, for which the frequency cannot be estimated based on available data). Within each frequency category, adverse reactions are listed in order of decreasing severity, where severity could be assessed.

Infections and infestations

Uncommon: cellulitis, candidiasis, gastroenteritis, infection, vaginal infection.

Frequency not known: pseudomembranous colitis, bejel (endemic syphilis).

Blood and lymphatic system disorders

Uncommon: leukopenia, neutropenia, thrombocytosis, eosinophilia.

Frequency not known: agranulocytosis, thrombocytopenia.

Immune system disorders

Uncommon: anaphylactoid reaction, hypersensitivity.

Frequency not known: anaphylactic reaction, angioneurotic edema.

Metabolism and nutrition disorders

Uncommon: anorexia, decreased appetite.

Psychiatric disorders

Common: insomnia.

Uncommon: anxiety, restlessness.

Frequency not known: psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.

Nervous system disorders

Common: dysgeusia, headache, taste disturbance.

Uncommon: loss of consciousness, dyskinesia, dizziness, somnolence, tremor.

Frequency not known: seizures, ageusia, parosmia, anosmia, paresthesia.

Ear and labyrinth disorders

Uncommon: dizziness, hearing impairment, tinnitus.

Frequency not known: hearing loss.

Cardiac disorders

Uncommon: cardiac arrest, atrial fibrillation, QT interval prolongation, extrasystoles, palpitations.

Frequency not known: torsades de pointes, ventricular tachycardia, ventricular fibrillation.

Vascular disorders

Common: vasodilation.

Frequency not known: hemorrhage.

Respiratory, thoracic and mediastinal disorders

Uncommon: asthma, epistaxis, pulmonary embolism.

Gastrointestinal disorders

Common: diarrhea, vomiting, dyspepsia, nausea, abdominal pain.

Uncommon: esophagitis, gastroesophageal reflux disease, gastritis, proctalgia, stomatitis, glossitis, abdominal distension, constipation, dry mouth, eructation, flatulence.

Frequency not known: acute pancreatitis, change in tongue color, change in tooth color.

Hepatobiliary disorders

Common: abnormal liver function tests.

Uncommon: cholestasis, hepatitis, increased levels of ALT, AST, GGT.

Frequency not known: hepatic failure, hepatocellular jaundice.

Skin and subcutaneous tissue disorders

Common: rash, hyperhidrosis.

Uncommon: bullous dermatitis, pruritus, urticaria, maculopapular rash.

Frequency not known: severe cutaneous adverse reactions (SCARs) (e.g., acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acne).

Musculoskeletal and connective tissue disorders

Uncommon: muscle spasms, skeletal muscle rigidity, myalgia.

Frequency not known: rhabdomyolysis, myopathy.

Renal and urinary disorders

Uncommon: increased blood creatinine, increased blood urea.

Frequency not known: renal failure, interstitial nephritis.

General disorders and administration site conditions

Very common: phlebitis at the injection site.

Common: pain at the injection site, inflammation at the injection site.

Uncommon: malaise, chill, asthenia, chest pain, chills, increased fatigue.

Investigations

Uncommon: change in albumin-globulin ratio, increased blood alkaline phosphatase, increased blood lactate dehydrogenase.

Frequency not known: increased INR, prolonged prothrombin time, change in urine color.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 tablets per blister pack, 1 or 3 blister packs in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Aurobindo Pharma Limited - Unit III / Aurobindo Pharma Limited - Unit III.

Manufacturer's address and place of business.

Survey No. 313, 314 - Blocks I, II, III, IV, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, Telangana State, 500090, India / Survey no.: 313, 314 - Block I, II, III, IV, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, Telangana State, 500090, India.