Klacid^® (Tablets, Granules, Lyophilisate) Instructions for Use

ATC Code

J01FA09 (Clarithromycin)

Active Substance

Clarithromycin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antibiotic of the macrolide group

Pharmacotherapeutic Group

Systemic antibacterial agents; macrolides, lincosamides, and streptogramins; macrolides

Pharmacological Action

A semisynthetic antibiotic of the macrolide group. It exerts an antibacterial action by interacting with the 50S ribosomal subunit of bacteria and suppressing protein synthesis in susceptible bacteria.

Clarithromycin has demonstrated high in vitro activity against both standard laboratory bacterial strains and those isolated from patients in clinical practice. It shows high activity against many aerobic and anaerobic gram-positive and gram-negative microorganisms. The minimum inhibitory concentrations (MIC) of clarithromycin for most pathogens are lower than the MIC of erythromycin by an average of one log₂ dilution.

Clarithromycin in vitro is highly active against Legionella pneumophila and Mycoplasma pneumoniae. It has a bactericidal effect against Helicobacter pylori; this activity of clarithromycin is higher at a neutral pH than at an acidic pH. Furthermore, in vitro and in vivo data indicate that Clarithromycin acts on clinically significant species of mycobacteria. Enterobacteriaceae and Pseudomonas spp., as well as other non-lactose-fermenting gram-negative bacteria, are not susceptible to clarithromycin.

The activity of clarithromycin against most strains of the microorganisms listed below has been proven both in vitro and in clinical practice for the diseases listed in the “Indications” section.

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) – a complex including Mycobacterium avium, Mycobacterium intracellulare.

Production of β-lactamase does not affect the activity of clarithromycin.

Most strains of staphylococci resistant to methicillin and oxacillin are also resistant to clarithromycin.

Helicobacter pylori

The susceptibility of Helicobacter pylori to clarithromycin was studied on Helicobacter pylori isolates obtained from 104 patients before the start of therapy with the drug. Resistant strains of Helicobacter pylori were isolated from 4 patients, strains with intermediate resistance from 2 patients, and the Helicobacter pylori isolates from the remaining 98 patients were susceptible to clarithromycin.

Clarithromycin is active in vitro against most strains of the microorganisms listed below; however, the safety and efficacy of using clarithromycin in clinical practice have not been confirmed by clinical studies, and the clinical significance remains unclear.

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.

The main metabolite of clarithromycin in the human body is the microbiologically active metabolite 14-hydroxyclarithromycin (14-OH-Clarithromycin). The microbiological activity of the metabolite is the same as that of the parent compound or 1-2 times weaker against most microorganisms. An exception is Haemophilus influenzae, against which the metabolite’s effectiveness is 2 times higher. The parent compound and its main metabolite exert either an additive or synergistic effect against Haemophilus influenzae in vitro and in vivo, depending on the bacterial strain.

Susceptibility Testing

Quantitative methods requiring measurement of zone diameter of growth inhibition provide the most precise estimates of bacterial susceptibility to antimicrobial agents. One recommended methodology for determining susceptibility uses discs impregnated with 15 mcg of clarithromycin (Kirby-Bauer disc diffusion method); when interpreting the test, the zone diameters of growth inhibition correlate with the MIC values of clarithromycin. MIC values are determined by the broth or agar dilution method.

When using these methodologies, a laboratory report stating that a strain is “susceptible” indicates that the infectious pathogen is likely to respond to treatment. A report of “resistant” indicates that the pathogen is unlikely to respond to treatment. A report of “intermediate resistance” suggests that the therapeutic effect of the drug may be equivocal or the microorganism may be susceptible when using higher doses of the drug (“intermediate resistance” is also called “moderate resistance”).

Pharmacokinetics

Absorption

Initial pharmacokinetic data were obtained from studies of clarithromycin tablets. The drug is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability of 250 mg clarithromycin tablets is approximately 50%. Food slightly delayed the onset of absorption and the formation of the active metabolite 14-OH-clarithromycin but did not affect the bioavailability of the drug.

Distribution, Metabolism and Excretion

In in vitro studies, the binding of clarithromycin to plasma proteins averaged about 70% at clinically significant concentrations ranging from 0.45 to 4.5 mcg/ml.

Healthy volunteers. The bioavailability and pharmacokinetics of clarithromycin suspension were studied in healthy adults and children. After a single dose in adults, the overall bioavailability of the suspension was equivalent to or slightly exceeded that of the tablet (in both cases, the dose was 250 mg). As with the tablets, food slightly delayed the absorption of the clarithromycin suspension but did not affect the overall bioavailability of the drug. The C_max, AUC, and T_1/2 of clarithromycin after taking the pediatric suspension (after meals) were 0.95 mcg/ml, 6.5 mcg×h/ml, and 3.7 h, respectively, and after taking a 250 mg tablet (on an empty stomach) – 1.10 mcg/ml, 6.3 mcg×h/ml, and 3.3 h, respectively.

When clarithromycin suspension was taken at a dose of 250 mg every 12 hours in adults, steady-state concentrations (C_ss) in the blood were reached by the fifth dose. The pharmacokinetic parameters were as follows: C_max – 1.98 mcg/ml, AUC – 11.5 mcg×h/ml, time to reach maximum concentration (T_max) – 2.8 h and T_1/2 – 3.2 h for clarithromycin and, respectively, 0.67, 5.33, 2.9 and 4.9 for 14-OH-clarithromycin.

In healthy individuals, serum concentrations peaked within 2 hours after oral administration on an empty stomach. When taking the drug in tablet form at a dose of 250 mg every 12 hours, peak steady-state serum concentrations of clarithromycin were reached within 2-3 days and were approximately 1 mcg/ml. The corresponding C_max values for a dose of 500 mg every 12 hours ranged from 2 mcg/ml to 3 mcg/ml.

The T_1/2 of clarithromycin was 3-4 hours when taking 250 mg tablets every 12 hours but increased to 5-7 hours after taking 500 mg every 12 hours. The steady-state C_max values of the main metabolite, 14-OH-clarithromycin, are about 0.6 mcg/ml, and the T_1/2 when taking the drug at a dose of 250 mg every 12 hours is 5-6 hours. When taking clarithromycin at a dose of 500 mg every 12 hours, the steady-state C_max of 14-OH-clarithromycin is somewhat higher (up to 1 mcg/ml), and the T_1/2 is about 7 hours. With both doses, steady-state concentrations of the metabolite are usually reached within 2-3 days.

When using clarithromycin at a dose of 250 mg every 12 hours, approximately 20% of the dose is excreted by the kidneys unchanged. When taking clarithromycin at a dose of 500 mg every 12 hours, approximately 30% of the dose is excreted by the kidneys unchanged. The renal clearance of clarithromycin does not significantly depend on the dose and is approximately equal to the normal glomerular filtration rate. The main metabolite determined in urine is 14-OH-Clarithromycin, which accounts for 10-15% of the dose (250 or 500 mg every 12 hours).

Patients. Clarithromycin and its metabolite 14-OH-Clarithromycin rapidly penetrate into body tissues and fluids. Tissue concentrations are usually several times higher than serum concentrations.

The table shows examples of tissue and serum concentrations

In children requiring oral antibiotic treatment, Clarithromycin demonstrated high bioavailability, and its pharmacokinetic profile was similar to that in adults taking the same dosage form. The drug is rapidly and well absorbed in children. Food slightly delays the absorption of clarithromycin but does not significantly affect its bioavailability or pharmacokinetic properties. The steady-state pharmacokinetic parameters of clarithromycin, achieved after 5 days (ninth dose), were as follows: C_max – 4.60 mcg/ml, AUC – 15.7 mcg×h/ml and T_max – 2.8 h; the corresponding values for the metabolite 14-OH-clarithromycin were 1.64 mcg/ml, 6.69 mcg×h/ml and 2.7 h, respectively. The calculated T_1/2 of clarithromycin and its metabolite were 2.2 and 4.3 h, respectively.

In patients with otitis media, 2.5 hours after the fifth dose (7.5 mg/kg twice daily), the mean concentrations of clarithromycin and its metabolite in middle ear fluid were 2.53 and 1.27 mcg/g. The concentrations of the drug and its metabolite were 2 times higher than the serum concentrations.

Pharmacokinetics in Special Clinical Cases

Impaired liver function. The C_ss of clarithromycin in patients with impaired liver function did not differ from those in healthy individuals, while the concentrations of 14-OH-clarithromycin were lower. The reduced formation of 14-OH-clarithromycin in patients with impaired liver function was at least partially offset by an increase in the renal clearance of clarithromycin compared to that in healthy individuals.

Impaired renal function. The pharmacokinetics of clarithromycin were also altered in patients with impaired renal function receiving the drug in repeated doses of 500 mg. In such patients, plasma concentrations, T_1/2, C_max, C_min, and AUC of clarithromycin and its metabolite were higher than in healthy individuals. The deviations of these parameters correlated with the degree of renal failure: with more severe impairment of renal function, the differences were more significant (see the “Dosage Regimen” section).

Elderly patients. In elderly patients, the blood concentration of clarithromycin and its metabolite 14-OH-clarithromycin was higher, and elimination was slower than in a group of young people (when taking clarithromycin in repeated doses of 500 mg). However, after correcting the results for renal CrCl, there were no differences between the two groups. Thus, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, not age.

Patients with mycobacterial infections. The C_ss of clarithromycin and 14-OH-clarithromycin in HIV-infected patients receiving Clarithromycin at usual doses (tablets for adults, suspension for children) were similar to those in healthy individuals. However, when taking clarithromycin at higher doses, which may be required for the treatment of mycobacterial infections, the antibiotic concentrations may significantly exceed the usual ones.

In HIV-infected children taking Clarithromycin at a dose of 15-30 mg/kg/day in two divided doses, steady-state C_max values typically ranged from 8 to 20 mcg/ml. However, in HIV-infected children receiving clarithromycin suspension at a dose of 30 mg/kg/day in 2 divided doses, C_max reached 23 mcg/ml. When the drug was taken at higher doses, a prolongation of T_1/2 was noted compared to that in healthy individuals receiving Clarithromycin at usual doses. The increase in plasma concentration and prolongation of T_1/2 with the use of clarithromycin at higher doses are associated with the nonlinear pharmacokinetics of the drug.

Indications

Infectious and inflammatory diseases in children caused by microorganisms susceptible to clarithromycin

• Infections of the lower respiratory tract (such as bronchitis, pneumonia);
• Infections of the upper respiratory tract (such as pharyngitis, sinusitis);
• Infections of the skin and soft tissues (such as folliculitis, cellulitis, erysipelas);
• Disseminated or localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare;
• Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii;
• Acute otitis media.

ICD codes

Dosage Regimen

Lyophilisate

Individual. For oral administration in adults and children over 12 years of age, a single dose is 0.25-1 g, frequency of administration is 2 times/day.

For children under 12 years of age, the daily dose is 7.5-15 mg/kg/day in 2 divided doses.

In children, Clarithromycin should be used in the appropriate dosage form intended for this category of patients.

The duration of treatment depends on the indications.

For patients with impaired renal function (CrCl less than 30 ml/min or serum creatinine level greater than 3.3 mg/dl), the dose should be reduced by half or the interval between doses should be doubled.

Maximum daily doses for adults – 2 g, for children – 1 g.

Granules

For oral administration. The prepared suspension can be taken with or without food, including with milk.

To prepare the suspension, gradually add water to the bottle up to the mark (60, 70, or 100 ml) and shake. The prepared suspension can be stored for 14 days at a temperature from 15°C (59°F) to 30°C (86°F). Before each use, the suspension should be shaken well.

Dose for non-mycobacterial infections

The recommended daily dose of clarithromycin suspension for non-mycobacterial infections in children is 7.5 mg/kg twice daily (maximum – 500 mg twice daily). The usual duration of treatment is 5-10 days, depending on the pathogen and the severity of the condition.

The table provides dosing recommendations for children based on body weight.

* In children with body weight <8 kg, the dose is selected based on weight (7.5-15 mg/kg twice daily).

Patients with impaired renal function

In children with CrCl less than 30 ml/min/1.73 m², the dose of clarithromycin should be reduced by half (e.g., 125 (250) mg/day or 125 mg (250 mg) twice daily for more severe infections). In such cases, the course of treatment should not exceed 14 days, although the usual duration of treatment is 5-10 days.

Tablets

The drug is taken orally with or without food.

For adults and children over 12 years of age – 1 tablet (250 mg) twice daily. Clarithromycin 500 mg twice daily is used in case of more severe infections. The usual duration of treatment is from 5 to 14 days.

Exceptions are community-acquired pneumonia and sinusitis, which require treatment from 6 to 14 days.

For mycobacterial infections, excluding tuberculosis, the recommended dose of clarithromycin is 500 mg twice daily.

For the treatment of disseminated MAC infections in AIDS patients, treatment should be continued as long as there is clinical and microbiological efficacy. Clarithromycin should be prescribed in combination with other antimicrobial agents active against these pathogens. The duration of treatment for other non-tuberculous mycobacterial infections is determined by the physician.

For the prevention of infections caused by MAC, the recommended dose of clarithromycin for adults is 500 mg twice daily.

For odontogenic infections, the dose of clarithromycin is 250 mg (1 tablet) twice daily for 5 days.

For the eradication of Helicobacter pylori in patients with peptic ulcer disease caused by Helicobacter pylori infection, Clarithromycin can be prescribed at 500 mg twice daily in combination with other antimicrobial agents and proton pump inhibitors for 7-14 days, in accordance with national and international guidelines for the treatment of Helicobacter pylori infection.

Patients with impaired renal function (CrCl less than 30 ml/min) are prescribed half the usual dose of clarithromycin (in this case, a dose of 250 mg is used). Treatment of such patients should not exceed 14 days.

The use of clarithromycin in tablet form in children under 12 years of age has not been studied.

Adverse Reactions

WHO classification of frequency of adverse effects: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), including isolated reports, frequency unknown (cannot be estimated from the available data). The list of adverse reactions grouped by system organ class and frequency is presented in Table 1.

Table 1. Information on the frequency of adverse reactions registered in clinical studies of clarithromycin

* In some reports of rhabdomyolysis, Clarithromycin was taken concomitantly with other medicinal products known to be associated with rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

¹Reports of these adverse reactions were received during clinical trials and post-marketing use of Klacid^®, lyophilisate for solution for infusion.

²Reports of these adverse reactions were received during clinical trials and post-marketing use of Klacid^® SR, prolonged-release film-coated tablets.

³Reports of these adverse reactions were received during clinical trials and post-marketing use of Klacid^®, granules for oral suspension.

⁴Reports of these adverse reactions were received during the use of Klacid^®, film-coated tablets.

Immunocompromised patients

In AIDS and other immunocompromised patients receiving Clarithromycin at higher doses for long periods for the treatment of mycobacterial infections, it is often difficult to distinguish adverse drug effects from symptoms of HIV infection or underlying disease.

The most common adverse events in patients taking a daily dose of clarithromycin of 1000 mg were: nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing impairment, increased blood AST and ALT. Adverse events with low frequency, such as dyspnea, insomnia, and dry mouth, were also noted.

In immunocompromised patients, laboratory parameters were assessed by analyzing their significant deviations from normative values (sharp increase or decrease). Based on this criterion, 2-3% of patients receiving Clarithromycin at a dose of 1000 mg daily had a significant increase in blood AST and ALT, as well as a decrease in white blood cell and platelet counts. A small number of patients also had an increase in blood urea nitrogen.

Children

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

Contraindications

• Hypersensitivity to clarithromycin, macrolides, or any of the excipients of the drug;
• Concomitant use of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine (see section “Drug Interactions”);
• Concomitant use of clarithromycin with lomitapide (see section “Drug Interactions”);
• Concomitant use of clarithromycin with ergot alkaloids, e.g., ergotamine, dihydroergotamine (see section “Drug Interactions”);
• Concomitant use of clarithromycin with orally administered midazolam (see section “Drug Interactions”);
• Concomitant use of clarithromycin with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by the CYP3A4 isoenzyme (lovastatin or simvastatin), due to an increased risk of myopathy, including rhabdomyolysis (see section “Drug Interactions”);
• Concomitant use of clarithromycin with colchicine (see section “Drug Interactions”);
• Concomitant use of clarithromycin with ticagrelor or ranolazine;
• History of QT interval prolongation (congenital or documented acquired QT interval prolongation) or ventricular arrhythmia, including torsades de pointes (see sections “Special Precautions” and “Drug Interactions”);
• Should not be used in patients with electrolyte disturbances (hypokalemia or hypomagnesemia) due to the risk of QT interval prolongation (see section “Special Precautions”);
• Severe hepatic impairment occurring concurrently with renal impairment;
• History of cholestatic jaundice/hepatitis associated with the use of clarithromycin (see section “Special Precautions”);
• Porphyria.

With caution

• Moderate and severe renal impairment;
• Moderate and severe hepatic impairment;
• Concomitant use of clarithromycin with benzodiazepines such as alprazolam, triazolam, midazolam for intravenous administration or for application to the oral mucosa (see section “Drug Interactions”);
• Concomitant use with drugs that are metabolized by the CYP3A isoenzyme, e.g., carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (e.g., warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine (see section “Drug Interactions”);
• Concomitant use with drugs that induce the CYP3A4 isoenzyme, e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort (see section “Drug Interactions”);
• Concomitant use of clarithromycin with statins not dependent on CYP3A metabolism (e.g., fluvastatin) (see section “Drug Interactions”);
• Concomitant use with slow calcium channel blockers that are metabolized by the CYP3A4 isoenzyme (e.g., verapamil, amlodipine, diltiazem);
• Concomitant use of clarithromycin with direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, especially in patients at high risk of bleeding;
• In patients with coronary artery disease, severe heart failure, conduction disorders, or clinically significant bradycardia, and in patients concomitantly taking class IA antiarrhythmics (quinidine, procainamide) and class III antiarrhythmics (dofetilide, amiodarone, sotalol);
• Pregnancy;
• Diabetes mellitus (the drug contains sucrose).

Use in Pregnancy and Lactation

Pregnancy

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

Based on various results obtained in animal studies and human experience, the possibility of adverse effects on embryofetal development cannot be excluded. Some observational studies evaluating exposure to clarithromycin in the first and second trimesters of pregnancy found an increased risk of spontaneous abortion compared to no antibiotic therapy or use of other antibiotics at similar stages of pregnancy. Available epidemiological studies on the risk of major congenital malformations with the use of macrolides, including Clarithromycin, during pregnancy show conflicting results.

Use of clarithromycin during pregnancy (especially in the first trimester) is possible only if there is no alternative therapy and the potential benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

It has been established that a breastfed infant may receive approximately 1.7% of the maternal dose of clarithromycin adjusted for maternal body weight. The safety of clarithromycin for breastfed infants has not been established. If use during breastfeeding is necessary, breastfeeding should be discontinued.

Fertility

Studies in rats showed no effect on fertility.

Use in Hepatic Impairment

The drug is contraindicated in severe hepatic impairment occurring concurrently with renal impairment, and in a history of cholestatic jaundice/hepatitis associated with the use of clarithromycin.

The drug should be used with caution in moderate and severe hepatic impairment.

Use in Renal Impairment

The drug should be used with caution in moderate and severe renal impairment.

Special Precautions

Prolonged use of antibiotics may lead to the colonization of bacteria and fungi with increased numbers of non-susceptible organisms. If superinfection occurs, appropriate therapy should be instituted.

Prescribing clarithromycin to pregnant women should be done with careful assessment of the risk-benefit ratio, especially during the first three months of pregnancy.

Cases of hepatic dysfunction (increased liver enzyme levels in the blood, hepatocellular and/or cholestatic hepatitis with or without jaundice) have been reported with the use of clarithromycin. Hepatic dysfunction can be severe but is usually reversible. There have been cases of fatal liver failure, mainly associated with serious underlying diseases and/or concomitant use of other drugs. If signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal tenderness, clarithromycin therapy should be discontinued immediately.

In patients with chronic liver disease, regular monitoring of serum enzymes should be performed.

Cases of pseudomembranous colitis have been reported with virtually all antibacterial agents, including clarithromycin, with severity ranging from mild to life-threatening. Cases of Clostridium difficile-associated diarrhea have been reported with virtually all antibacterial drugs, including clarithromycin, with severity ranging from mild diarrhea to life-threatening colitis. Antibacterial agents can alter the normal flora of the colon, which may lead to the growth of Clostridium difficile. Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients who develop diarrhea after using antibacterial agents. Careful medical supervision of the patient is necessary after a course of antibiotic therapy. Cases of pseudomembranous colitis occurring up to 2 months after antibiotic use have been described.

Treatment with macrolides, including Clarithromycin, has been associated with prolongation of cardiac repolarization and the QT interval, causing a risk of cardiac arrhythmia and torsades de pointes (see section “Adverse Reactions”). Since the following situations may increase the risk of ventricular arrhythmias (including torsades de pointes):

• Clarithromycin should not be used in the following categories of patients:
  • In patients with hypokalemia (see section “Contraindications”);
  • In patients with hypomagnesemia (see section “Contraindications”);
  • Concomitant administration of clarithromycin with astemizole, cisapride, pimozide, and terfenadine is contraindicated (see section “Contraindications”);
  • In patients with congenital or documented acquired QT interval prolongation or a history of ventricular arrhythmia (see section “Contraindications”);
• Clarithromycin should be used with caution in the following categories of patients:
  • In patients with coronary artery disease, severe heart failure, conduction disorders, or clinically significant bradycardia;
  • In patients concomitantly taking other drugs associated with QT interval prolongation (see section “Drug Interactions”).

In all patients taking hydroxychloroquine or chloroquine, the benefit-risk ratio should be carefully weighed before prescribing clarithromycin due to a potentially increased risk of cardiovascular events and cardiovascular mortality (see section “Drug Interactions”).

Epidemiological studies on the risk of adverse cardiovascular outcomes with macrolide use have yielded conflicting results. Some observational studies have identified a short-term risk of arrhythmia, myocardial infarction, and cardiovascular death associated with the use of macrolides, including Clarithromycin. When prescribing clarithromycin, the expected benefit of the drug should be weighed against these risks.

Cross-resistance may develop between clarithromycin and other macrolide antibiotics, as well as lincomycin and clindamycin.

Given the increasing resistance of Streptococcus pneumoniae to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin to patients with community-acquired pneumonia. For hospital-acquired pneumonia, Clarithromycin should be used in combination with appropriate antibiotics.

Mild to moderate skin and soft tissue infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes. Both pathogens can be resistant to macrolides. Therefore, it is important to perform a susceptibility test. Macrolides can be used for infections caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas, as well as in situations where penicillin cannot be used.

In case of acute hypersensitivity reactions, such as anaphylactic reaction, severe cutaneous adverse drug reactions (e.g., acute generalized exanthematous pustulosis), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), clarithromycin should be discontinued immediately and appropriate therapy initiated.

In case of concomitant use with warfarin or other indirect anticoagulants, INR and prothrombin time should be monitored (see section “Drug Interactions”).

Caution should be exercised when clarithromycin is used concomitantly with direct oral anticoagulants such as dabigatran, rivaroxaban, and apixaban, especially in patients at high risk of bleeding (see subsection “Drug Interactions”).

Excipients

The drug Klacid^®, granules for oral suspension, contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicine.

When prescribing the drug to patients with diabetes mellitus, it should be taken into account that the drug contains sucrose: Klacid^®, granules for oral suspension 125 mg/5 ml, in 1 ml of suspension – 0.055 XE or 0.55 g of sucrose; Klacid^®, granules for oral suspension 250 mg/5 ml, in 1 ml of suspension – 0.046 XE or 0.46 g of sucrose.

The drug Klacid^®, granules for oral suspension, contains castor oil, which may cause stomach upset and diarrhea.

Effects on ability to drive and use machines

There are no data on the effect of clarithromycin on the ability to drive and use machines. Caution should be exercised when driving vehicles and operating machinery, considering the potential for dizziness, vertigo, confusion, and disorientation that may occur when taking this drug.

Overdose

Symptoms taking clarithromycin in a high dose may cause symptoms of gastrointestinal disturbances. In one patient with a history of bipolar disorder, after taking 8 g of clarithromycin, altered mental status, paranoid behavior, hypokalemia, and hypoxemia were described.

Treatment in case of overdose, the unabsorbed drug should be removed from the gastrointestinal tract (gastric lavage, administration of activated charcoal, etc.) and symptomatic therapy should be administered. Hemodialysis and peritoneal dialysis do not significantly affect the serum concentration of clarithromycin, which is also typical for other macrolide drugs.

Drug Interactions

Concomitant use of the following drugs with clarithromycin is contraindicated due to the possibility of serious adverse effects

Cisapride, pimozide, terfenadine and astemizole

Concomitant use of clarithromycin with cisapride, pimozide, terfenadine, or astemizole has been reported to increase plasma concentrations of the latter, which may lead to QT interval prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section “Contraindications”).

Ergot alkaloids

Post-marketing studies indicate that when clarithromycin is used concomitantly with ergotamine or dihydroergotamine, the following effects associated with acute ergotamine toxicity may occur: vasospasm, ischemia of the extremities and other tissues, including the CNS. Concomitant use of clarithromycin and ergot alkaloids is contraindicated (see section “Contraindications”).

Orally administered midazolam

When midazolam and clarithromycin tablets (500 mg twice daily) were used concomitantly, the AUC of midazolam increased 7-fold after oral administration. Concomitant use of clarithromycin with orally administered midazolam is contraindicated (see section “Contraindications”).

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section “Contraindications”) because these statins are extensively metabolized by the isoenzyme CYP3A4, and co-administration with clarithromycin increases their serum concentrations, which leads to an increased risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking Clarithromycin concomitantly with these drugs. If clarithromycin use is necessary, lovastatin or simvastatin should be discontinued during therapy.

Clarithromycin should be used with caution in combination therapy with statins. If concomitant use is necessary, the lowest possible dose of the statin should be administered. Statins that are not dependent on CYP3A metabolism (e.g., fluvastatin) are recommended. The development of signs and symptoms of myopathy should be monitored.

Lomitapide

Concomitant use of clarithromycin with lomitapide is contraindicated due to the risk of significant increases in plasma transaminase activity (see section “Contraindications”).

Effect of Other Medicinal Products on Clarithromycin

Observational data have shown that concomitant use of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Due to a possible similar risk with the use of other macrolides in combination with hydroxychloroquine or chloroquine, the benefit-risk ratio should be carefully weighed before prescribing Clarithromycin to any patients taking hydroxychloroquine or chloroquine.

Drugs that are inducers of CYP3A (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) may induce the metabolism of clarithromycin. This can lead to subtherapeutic concentrations of clarithromycin, resulting in reduced efficacy. Furthermore, the plasma concentration of the CYP3A isoenzyme inducer should be monitored, as it may increase due to inhibition of CYP3A by clarithromycin. When rifabutin and clarithromycin were co-administered, an increase in plasma concentration of rifabutin and a decrease in serum concentration of clarithromycin were observed, with an increased risk of uveitis.

The following drugs have a proven or suspected influence on the plasma concentration of clarithromycin; if they are used concomitantly with clarithromycin, dose adjustment or alternative treatment may be required.

Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine

Strong inducers of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, may accelerate the metabolism of clarithromycin and thus decrease the plasma concentration of clarithromycin while increasing the concentration of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against different bacteria, the therapeutic effect may be reduced when clarithromycin is co-administered with enzyme inducers.

Etravirine

The concentration of clarithromycin is decreased when used with etravirine, but the concentration of the active metabolite 14-OH-clarithromycin is increased. Since 14-OH-Clarithromycin has low activity against Mycobacterium avium complex (MAC) infections, the overall activity against their pathogens may change; therefore, alternative treatment for MAC should be considered.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers led to an increase in the mean minimum steady-state concentration (C_min) and AUC of clarithromycin by 33% and 18%, respectively. Concomitant administration did not significantly affect the mean steady-state concentration of the active metabolite 14-OH-clarithromycin. Dose adjustment of clarithromycin is not required when co-administered with fluconazole.

Ritonavir

A pharmacokinetic study showed that concomitant administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours led to marked suppression of clarithromycin metabolism. With concomitant ritonavir, the C_max of clarithromycin increased by 31%, C_min increased by 182%, and AUC increased by 77%. Complete suppression of the formation of 14-OH-clarithromycin was noted. Due to the wide therapeutic range of clarithromycin, a dose reduction is not required in patients with normal renal function. In patients with renal impairment, the following dose adjustments should be considered: for CrCl 30-60 ml/min, the dose of clarithromycin should be reduced by 50%; for CrCl less than 30 ml/min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be co-administered with clarithromycin at doses exceeding 1 g/day.

Similar dose adjustments should be considered in patients with impaired renal function if ritonavir is used as a pharmacokinetic “booster” with other HIV protease inhibitors, including atazanavir and saquinavir (see “Bidirectional Drug Interactions”).

Effect of Clarithromycin on Other Medicinal Products

Antiarrhythmic drugs (quinidine and disopyramide)

Torsades de pointes ventricular tachycardia may occur with the concomitant use of clarithromycin and quinidine or disopyramide. When clarithromycin is used concomitantly with these drugs, regular ECG monitoring for QT interval prolongation should be performed, and serum concentrations of these drugs should be monitored.

Post-marketing use has reported cases of hypoglycemia with concomitant use of clarithromycin and disopyramide. Blood glucose concentrations should be monitored when clarithromycin and disopyramide are used concomitantly.

Oral hypoglycemic agents/insulin

Severe hypoglycemia may be observed with the concomitant use of clarithromycin and oral hypoglycemic agents (e.g., sulfonylurea derivatives) and/or insulin. Concomitant use of clarithromycin with some hypoglycemic drugs (e.g., nateglinide, pioglitazone, repaglinide, and rosiglitazone) may lead to inhibition of the CYP3A isoenzyme by clarithromycin, resulting in hypoglycemia. Careful monitoring of blood glucose is recommended.

Interaction mediated by CYP3A

Concomitant use of clarithromycin, which is a known inhibitor of the CYP3A isoenzyme, and drugs primarily metabolized by CYP3A may be associated with a mutual increase in their concentrations, which may enhance or prolong both therapeutic and adverse effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the CYP3A isoenzyme, especially if these drugs have a narrow therapeutic range (e.g., carbamazepine), and/or are extensively metabolized by this enzyme. If necessary, dose adjustment of the drug taken with clarithromycin should be performed. Also, whenever possible, monitoring of serum concentrations of drugs primarily metabolized by CYP3A should be performed.

The metabolism of the following drugs/classes is mediated by the same CYP3A isoenzyme as the metabolism of clarithromycin, for example, alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (e.g., warfarin), atypical antipsychotics (e.g., quetiapine), quinidine, rifabutin, sildenafil, tacrolimus, triazolam, and vinblastine. The following drugs, which are contraindicated for concomitant use with clarithromycin, are also CYP3A agonists: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin, and ergot alkaloids. Drugs that interact similarly through other isoenzymes within the cytochrome P450 system include phenytoin, theophylline, and valproic acid.

Indirect anticoagulants

Bleeding, pronounced increase in INR and prothrombin time may occur with concomitant use of warfarin and clarithromycin. When used concomitantly with warfarin or other indirect anticoagulants, INR and prothrombin time should be monitored.

Direct oral anticoagulants

The direct oral anticoagulant dabigatran is a substrate for the efflux transporter protein P-glycoprotein (Pgp). Rivaroxaban and apixaban are metabolized with the participation of the CYP3A4 isoenzyme and are also substrates for Pgp. Caution should be exercised when co-administering clarithromycin with these drugs, especially in patients at high risk of bleeding (see section “Special Precautions”).

Omeprazole

Clarithromycin (500 mg every 8 hours) was studied in healthy adult volunteers in combination with omeprazole (40 mg daily). When clarithromycin and omeprazole were co-administered, the steady-state plasma concentrations of omeprazole were increased (C_max, AUC_0-24, and T_1/2 increased by 30%, 89%, and 34%, respectively). The mean 24-hour gastric pH was 5.2 when omeprazole was taken alone and 5.7 when omeprazole was taken concomitantly with clarithromycin.

Sildenafil, tadalafil, and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by the CYP3A isoenzyme. At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil, or vardenafil may lead to an increase in the inhibitory effect on phosphodiesterase. When these drugs are used concomitantly with clarithromycin, a dose reduction of sildenafil, tadalafil, and vardenafil should be considered.

Theophylline, carbamazepine

Concomitant use of clarithromycin and theophylline or carbamazepine may lead to an increase in the systemic concentrations of these drugs.

Tolterodine

The primary metabolism of tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a portion of the population lacking CYP2D6, metabolism occurs via CYP3A. In this population group, inhibition of CYP3A leads to significantly higher serum concentrations of tolterodine. In the population with low CYP2D6 metabolism, a dose reduction of tolterodine may be required in the presence of CYP3A inhibitors such as Clarithromycin.

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

When midazolam and clarithromycin tablets (500 mg twice daily) were co-administered, the AUC of midazolam increased 2.7-fold after intravenous administration of midazolam. If intravenous midazolam is used concomitantly with clarithromycin, the patient’s condition should be carefully monitored for possible dose adjustment. Administration of the drug via the oral mucosa, which bypasses presystemic elimination of the drug, is likely to lead to an interaction similar to that observed with intravenous midazolam administration rather than oral administration.

The same precautions should be applied to other benzodiazepines that are metabolized by the CYP3A isoenzyme, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on the CYP3A isoenzyme (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

CNS effects, such as drowsiness and confusion, may occur with concomitant use of clarithromycin and triazolam. Therefore, in case of concomitant use, symptoms of CNS impairment should be monitored.

Interactions with Other Drugs

Colchicine

Colchicine is a substrate of both the CYP3A isoenzyme and the P-glycoprotein (Pgp) transporter. Clarithromycin and other macrolides are known inhibitors of the CYP3A isoenzyme and Pgp. When clarithromycin and colchicine are co-administered, inhibition of Pgp and/or the CYP3A isoenzyme may lead to increased effects of colchicine. Post-marketing reports of colchicine poisoning have been reported with concomitant use with clarithromycin, more frequently in elderly patients. Some of the described cases occurred in patients with renal impairment. Some cases were reported to be fatal. Concomitant use of clarithromycin and colchicine is contraindicated (see section “Contraindications”).

Digoxin

Digoxin is presumed to be a substrate for Pgp. Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased effects of digoxin. Post-marketing studies have shown that concomitant use of digoxin and clarithromycin may also lead to increased serum concentrations of digoxin. Some patients experienced clinical symptoms of digoxin toxicity, including potentially fatal arrhythmias. When clarithromycin and digoxin are used concomitantly, serum digoxin concentrations should be carefully monitored.

Zidovudine

Concomitant administration of clarithromycin tablets and zidovudine in adult HIV-infected patients may lead to decreased steady-state concentrations of zidovudine. Since Clarithromycin affects the absorption of orally administered zidovudine, the interaction can be largely avoided by taking Clarithromycin and zidovudine 4 hours apart. No such interaction was observed in HIV-infected children taking the pediatric suspension of clarithromycin with zidovudine or didanosine. Since Clarithromycin may interfere with the absorption of zidovudine when both are taken orally in adult patients, such an interaction is unlikely with intravenous clarithromycin.

Phenytoin and valproic acid

There is evidence of interaction of CYP3A isoenzyme inhibitors (including Clarithromycin) with drugs that are not metabolized by the CYP3A isoenzyme (phenytoin and valproic acid). For these drugs, when used concomitantly with clarithromycin, monitoring of their serum concentrations is recommended, as there are reports of their increase.

Bidirectional Drug Interactions

Atazanavir

Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of a bidirectional interaction between these drugs. Concomitant use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may lead to a two-fold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure, with a 28% increase in the AUC of atazanavir. Due to the wide therapeutic range of clarithromycin, a dose reduction is not required in patients with normal renal function. In patients with moderate renal impairment (CrCl 30-60 ml/min), the dose of clarithromycin should be reduced by 50%. In patients with CrCl less than 30 ml/min, the dose of clarithromycin should be reduced by 75%, using the appropriate clarithromycin dosage form for this purpose. Clarithromycin at doses exceeding 1000 mg/day should not be used concomitantly with protease inhibitors.

Calcium channel blockers

Caution should be exercised when clarithromycin is used concomitantly with calcium channel blockers that are metabolized by the CYP3A4 isoenzyme (e.g., verapamil, amlodipine, diltiazem), as there is a risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as calcium channel blockers, may increase with concomitant use. Arterial hypotension, bradyarrhythmia, and lactic acidosis are possible with concomitant use of clarithromycin and verapamil.

Itraconazole

Clarithromycin and itraconazole are both substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Clarithromycin may increase the plasma concentration of itraconazole, while itraconazole may increase the plasma concentration of clarithromycin. Patients simultaneously taking itraconazole and Clarithromycin should be carefully examined for symptoms of enhanced or prolonged pharmacological effects of these drugs.

Saquinavir

Clarithromycin and saquinavir are both substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Concomitant use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg three times daily) in 12 healthy volunteers caused an increase in the AUC and C_max of saquinavir by 177% and 187%, respectively, compared with saquinavir alone. The AUC and C_max values of clarithromycin were approximately 40% higher than with clarithromycin monotherapy. When these two drugs are used concomitantly for a limited time at the doses/formulations specified above, no dose adjustment is required. The results of the drug interaction study using saquinavir soft gelatin capsules may not correspond to the effects observed with saquinavir hard gelatin capsules. The results of the drug interaction study with saquinavir monotherapy may not correspond to the effects observed with saquinavir/ritonavir therapy. When saquinavir is used concomitantly with ritonavir, the potential effect of ritonavir on Clarithromycin should be taken into account.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F); shelf life – 3 years. Do not use after the expiration date stated on the packaging.

The prepared suspension should be stored at a temperature between 15°C (59°F) and 30°C (86°F); shelf life of the prepared suspension – 14 days.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.