Clabax od

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLABAX OD

Composition:

Active substance: clarithromycin;

1 tablet contains 500 mg of clarithromycin;

Excipients: hypromellose; lactose monohydrate; microcrystalline cellulose; povidone; colloidal anhydrous silicon dioxide; sodium stearyl fumarate; talc; magnesium stearate; propylene glycol; titanium dioxide (E 171); vanillin; hydroxypropylcellulose; quinoline yellow dye (E 104).

Pharmaceutical form. Prolonged-release coated tablets.

Main physicochemical properties: light-yellow, biconvex, oval-shaped, coated tablets; tablets are marked with "CLNXL" in black edible ink on one side and are smooth on the other side.

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

Pharmacological Properties

Pharmacodynamics

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

Microbiology

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

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

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

Clarithromycin is active in vitro and clinically against most strains of the following microorganisms:

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

Aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila.

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

Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC), which includes Mycobacterium avium and Mycobacterium intracellulare.

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

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

Helicobacter: H. pylori.

Clarithromycin is active in vitro against most strains of the following microorganisms; however, clinical efficacy and safety of its use have not been established:

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

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

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

Anaerobic gram-negative microorganisms: Bacteroides melaninogenicus.

Spirochetes: Borrelia burgdorferi, Treponema pallidum.

Campylobacters: Campylobacter jejuni.

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

The main metabolite of clarithromycin in the human body is the microbiologically active 14-OH-clarithromycin. For most microorganisms, the microbiological activity of the metabolite is equal to or 1–2 times weaker than that of the parent substance, except for H. influenzae, against which the metabolite is twice as effective. In vitro and in vivo, the parent compound and its main metabolite exhibit either additive or synergistic effects against H. influenzae, depending on the microbial strain.

Susceptibility Testing

Quantitative methods requiring measurement of inhibition zone diameters provide the most accurate assessment of bacterial susceptibility to antimicrobial agents. In one of the recommended procedures for susceptibility testing, disks impregnated with 15 mcg of clarithromycin (Kirby-Bauer disk diffusion method) are used; the diameter of the inhibition zone for this disk is correlated with MIC values for clarithromycin when interpreting results. MIC is determined by broth or agar dilution methods.

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

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

Breakpoints

The following breakpoints have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Pharmacokinetics.

The pharmacokinetics of prolonged-release clarithromycin tablets were compared with those of immediate-release tablets of 250 and 500 mg. The extent of absorption was equivalent when equivalent doses were administered. Absolute bioavailability is approximately 50%. No accumulation was observed upon repeated administration, and the metabolic pattern in humans remains unchanged.

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

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

Healthy volunteers. After oral administration of 500 mg once daily of prolonged-release clarithromycin tablets following food intake, steady-state maximum plasma concentrations (Cmax) of clarithromycin and 14-OH-clarithromycin were 1.3 and 0.48 mcg/mL, respectively. Elimination half-lives of the drug and its metabolite were 5.3 and 7.7 hours, respectively. After administration of 1000 mg clarithromycin daily as prolonged-release tablets, steady-state maximum concentrations of clarithromycin and 14-OH-clarithromycin averaged 2.4 mcg/mL and 0.67 mcg/mL, respectively. Elimination half-lives of the parent compound and its major metabolite were 5.8 and 8.9 hours, respectively. Tmax after administration of 500 mg and 1000 mg daily was reached within 6 hours. Steady-state concentrations of 14-OH-clarithromycin do not increase proportionally with clarithromycin dose, and elimination half-lives of clarithromycin and its major metabolite increase with higher doses. The nonlinear pharmacokinetics of clarithromycin, combined with overall reduced formation of 14-hydroxylated and N-demethylated metabolites at higher doses, indicate that nonlinear metabolism of clarithromycin becomes more pronounced at high doses. Approximately 40% of the clarithromycin dose is excreted in urine and 30% via the feces.

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

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

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

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

Clinical characteristics.

Indications.

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

• Lower respiratory tract infections (e.g., bronchitis, pneumonia).
• Upper respiratory tract infections (e.g., sinusitis, pharyngitis).
• Skin and soft tissue infections (e.g., folliculitis, impetigo).

Contraindications.

• Hypersensitivity to macrolide antibiotics or to any of the components of the medicinal product.
• Concomitant use with any of the following drugs: astemizole, cisapride, pimozide, terfenadine [due to the risk of QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes], ergot alkaloids such as ergotamine, dihydroergotamine (due to the risk of ergot toxicity), HMG-CoA reductase inhibitors (statins) predominantly metabolized by CYP3A4: lovastatin or simvastatin (due to increased risk of myopathy, including rhabdomyolysis). See also sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction".
• Concomitant use of clarithromycin and lomitapide (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of clarithromycin and oral midazolam (see "Interaction with other medicinal products and other forms of interaction").
• History of QT interval prolongation or ventricular cardiac arrhythmias, including torsades de pointes (see "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").
• Electrolyte imbalance: hypokalemia or hypomagnesemia (due to the risk of QT interval prolongation).
• Severe hepatic impairment with concomitant renal impairment.
• Concomitant use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine (see "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with ticagrelor, ivabradine, or ranolazine is contraindicated.
• Creatinine clearance less than 30 mL/min (since this formulation does not allow dose reduction below 500 mg per day).

Interaction with other medicinal products and other forms of interaction.

Clarithromycin does not interact with oral contraceptives.

The following medicinal products are strictly contraindicated due to the potential for severe interaction consequences.

Cisapride, pimozide, domperidone, astemizole, terfenadine

Increased serum levels of cisapride have been observed when used concomitantly with clarithromycin, which may lead to QT interval prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been reported with concomitant use of pimozide and clarithromycin (see "Contraindications").

Macrolides have been reported to alter the metabolism of terfenadine, leading to increased serum levels of terfenadine, which has sometimes been associated with cardiac arrhythmias such as QT interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see "Contraindications"). In a study involving 14 volunteers, concomitant administration of terfenadine and clarithromycin resulted in a 2–3-fold increase in the serum level of the acid metabolite of terfenadine and QT interval prolongation, although no clinically apparent effect was observed. Similar effects have been observed with concomitant use of astemizole and other macrolides.

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.

Ergot alkaloids

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

Oral midazolam

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

HMG-CoA reductase inhibitors (statins)

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

Concomitant 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").

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

Corticosteroids

Caution should be exercised when clarithromycin is used concomitantly with systemic or inhaled corticosteroids predominantly metabolized by CYP3A due to the potential for increased systemic corticosteroid effects. Patients receiving concomitant therapy should be closely monitored for adverse reactions associated with systemic corticosteroids.

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

Effect of other medicinal products on the pharmacokinetics of clarithromycin

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

Medicinal products known or suspected to affect clarithromycin blood concentration, thus dose adjustment or alternative therapy may be required.

Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine

Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, may accelerate 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 differs against various bacteria, the expected therapeutic effect may not be achieved with concomitant use of clarithromycin and cytochrome P450 enzyme inducers.

Etravirine

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

Fluconazole

Administration of fluconazole 200 mg daily together with clarithromycin 500 mg twice daily in 21 volunteers resulted in a 33% increase in the steady-state Cmin of clarithromycin and an 18% increase in AUC. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered with concomitant use of fluconazole. No dose adjustment of clarithromycin is required.

Ritonavir

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

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

Effect of clarithromycin on the pharmacokinetics of other medicinal products

Antiarrhythmic agents

Post-marketing reports exist of torsades de pointes occurring with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended for timely detection of QT interval prolongation. During therapy with clarithromycin, serum concentrations of these drugs should be monitored.

Post-marketing use reports include hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, blood glucose monitoring is necessary when these agents are used together.

Oral hypoglycemic agents / insulin

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

CYP3A-related interactions |

Concomitant use of clarithromycin, a known CYP3A enzyme inhibitor, with a drug predominantly metabolized by CYP3A, may lead to increased plasma concentrations of the latter, thereby enhancing or prolonging its therapeutic effect and increasing the risk of adverse reactions. Caution should be exercised when administering clarithromycin to patients receiving therapy with CYP3A substrate drugs, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine) and/or is predominantly metabolized by this enzyme. Dose adjustment and, if possible, careful monitoring of serum concentrations of the CYP3A-metabolized drug may be required for patients receiving clarithromycin concomitantly.

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

Direct oral anticoagulants (DOACs).

Direct oral DOACs dabigatran and edoxaban are substrates of the P-glycoprotein (Pgp) efflux transporter. Rivaroxaban and apixaban are metabolized by CYP3A4 and are also Pgp substrates. Concomitant use of direct oral anticoagulants such as dabigatran, rivaroxaban, and apixaban with clarithromycin requires caution, especially in patients at high risk of bleeding (see section "Special precautions for use").

Omeprazole

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

Sildenafil, tadalafil, and vardenafil

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

Theophylline, carbamazepine

Results of clinical studies showed a slight but statistically significant (p≤0.05) increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.

Tolterodine

Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoenzyme (CYP2D6). However, in the population of patients without CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in tolterodine plasma concentrations. For such patients, dose reduction of tolterodine may be necessary when used with CYP3A inhibitors such as clarithromycin.

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

With the oromucosal route of midazolam administration, where presystemic elimination of the drug may be bypassed, an interaction similar to that observed with intravenous midazolam administration, rather than oral, is more likely.

When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous administration and 7-fold after oral administration of midazolam. With intravenous administration of midazolam and clarithromycin, careful patient monitoring is required for timely dose adjustment. The same precautions should be observed when using other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is independent of CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

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

Other types of interactions

Aminoglycosides

Clarithromycin should be used with caution when administered concomitantly with other ototoxic agents, especially aminoglycosides (see "Special precautions for use").

Colchicine

Colchicine is a substrate of CYP3A and P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. With concomitant use of clarithromycin and colchicine, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased colchicine exposure. Concomitant use of clarithromycin and colchicine is contraindicated (see "Contraindications", "Special precautions for use").

Digoxin

Digoxin is considered a substrate of P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. With concomitant use, inhibition of Pgp may lead to increased digoxin exposure. Post-marketing reports have described increased serum digoxin concentrations in patients receiving clarithromycin together with digoxin. In some patients, signs of digoxin toxicity developed, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored in patients receiving digoxin with clarithromycin.

Zidovudine

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

Phenytoin and valproate

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

Bidirectional drug interactions

Atazanavir

Administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, resulted in a doubling of clarithromycin exposure and a 70% reduction in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, dose reduction is not necessary in patients with normal renal function. The clarithromycin dose should be reduced by 50% in patients with creatinine clearance of 30–60 mL/min and by 75% in patients with creatinine clearance <30 mL/min, using the appropriate formulation. Clarithromycin doses exceeding 1000 mg daily should not be used 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). Plasma concentrations of both clarithromycin and calcium channel blockers may increase with interaction. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving clarithromycin with verapamil.

Itraconazole

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

Saquinavir

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

Special precautions for use

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

Prolonged or repeated use of antibiotics may lead to overgrowth of resistant bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated.

Clarithromycin is primarily eliminated via the liver. Therefore, caution should be exercised when administering the drug to patients with hepatic impairment, as well as those with moderate or severe renal impairment.

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

During clarithromycin therapy, hepatic function disturbances have been reported, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis with or without jaundice. These hepatic abnormalities may be severe in nature but are usually reversible. In some cases, hepatic failure with fatal outcome has been reported, primarily associated with serious underlying diseases and/or concomitant medication. Clarithromycin therapy should be discontinued immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, darkening of urine, pruritus, or abdominal pain/tenderness.

Pseudomembranous colitis, ranging from moderate to life-threatening severity, has been reported with the use of nearly all antibacterial agents, including macrolides. Clostridium difficile-associated diarrhea (CDAD), ranging from mild to colitis with fatal outcome, has been reported with the use of nearly all antibacterial agents, including clarithromycin. Antibacterial therapy may disrupt the normal intestinal flora, leading to overgrowth of C. difficile. The possibility of Clostridium difficile-associated diarrhea should always be considered in any patient presenting with diarrhea following antibiotic use. Furthermore, careful medical history is essential, as cases of Clostridium difficile-associated diarrhea have been reported even up to 2 months after antibiotic administration.

Therefore, in the event of persistent diarrhea during clarithromycin therapy, discontinuation of clarithromycin should be considered regardless of the indication for treatment. Testing for the causative microorganism should be performed and appropriate treatment initiated. Agents that inhibit intestinal motility should be avoided.

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

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

Clarithromycin should be used with caution when administered concomitantly with other ototoxic agents, particularly aminoglycosides. Monitoring of vestibular and auditory function should be performed during and after treatment.

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

• Patients with ischemic heart disease, severe heart failure, conduction disorders, or clinically significant bradycardia.
• Patients with electrolyte imbalances, such as hypomagnesemia. Clarithromycin must not be used in patients with hypokalemia (see "Contraindications").
• Patients receiving concomitant medications associated with QT interval prolongation (see "Interaction with other medicinal products and other forms of interaction").

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

Clarithromycin must not be used in patients with congenital or documented acquired QT interval prolongation or with a history of ventricular arrhythmia (see "Contraindications").

Epidemiological study results on the risk of adverse cardiovascular outcomes with macrolide use are conflicting. Some observational studies have shown a certain short-term risk of arrhythmia, myocardial infarction, and cardiovascular mortality associated with macrolide use, including clarithromycin. When prescribing clarithromycin, the risks should be weighed against the benefits of treatment.

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.

Skin and soft tissue infections of mild to moderate severity

These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, each of which may be macrolide-resistant. Therefore, susceptibility testing is essential. When beta-lactam antibiotics cannot be used (e.g., due to allergy), other antibiotics such as clindamycin may be considered as first-line agents. Currently, macrolides play a limited role in the treatment of certain skin and soft tissue infections, including those caused by Corynebacterium minutissimum, acne vulgaris, erysipelas, and in situations where penicillins cannot be used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, or severe skin adverse reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, Schönlein-Henoch disease), clarithromycin therapy should be discontinued immediately and appropriate treatment initiated without delay.

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

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

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications"). Clarithromycin should be used with caution when co-administered with other statins. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. When concomitant use of clarithromycin with statins cannot be avoided, it is recommended to use the lowest approved statin dose. A statin not dependent on CYP3A metabolism (e.g., fluvastatin) may be considered (see "Interaction with other medicinal products and other forms of interaction").

Oral hypoglycemic agents / insulin

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

Oral anticoagulants

Concomitant use of clarithromycin with warfarin increases the risk of serious bleeding, significant elevation of INR (International Normalized Ratio), and prothrombin time. Frequent monitoring of INR and prothrombin time is required while patients are receiving both clarithromycin and oral anticoagulants.

Caution is advised when clarithromycin is used concomitantly with direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban, particularly in patients at high risk of bleeding (see "Interaction with other medicinal products and other forms of interaction").

Excipients

The medicinal product contains lactose; therefore, it should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

The medicinal product contains 16.0 mg of sodium per tablet. For patients on a sodium-controlled diet who take 2 tablets once daily, the total sodium intake (32 mg per daily dose) should be taken into account.

Use during pregnancy or breastfeeding

The safety of clarithromycin use during pregnancy or breastfeeding has not been established. Based on animal studies and human experience, a harmful effect on embryonic and fetal development cannot be excluded. Some observational studies assessing the impact of clarithromycin during the first or second trimester of pregnancy have shown an increased risk of pregnancy loss compared to no antibacterial therapy or use of other antibacterial agents during the same period. Available epidemiological studies on the risk of congenital malformations associated with macrolide use, including clarithromycin, during pregnancy have yielded conflicting results. Clarithromycin should not be used during pregnancy without careful benefit-risk assessment.

Clarithromycin passes into breast milk in small amounts. The amount of clarithromycin received by an exclusively breastfed infant is estimated to be approximately 1.7% of the maternal dose adjusted for body weight.

Ability to affect reaction speed when driving or operating machinery

No data are available on this aspect. However, the possible occurrence of nervous system adverse reactions such as seizures, dizziness, vertigo, hallucinations, confusion, and disorientation should be considered before driving or operating machinery.

Method of Administration and Dosage

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

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

Tablets should be swallowed whole without chewing.

Patients with Renal Impairment. This formulation should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min), as it does not allow adequate dose reduction. Such patients should receive immediate-release clarithromycin tablets (e.g., "Clabax" 250 mg tablets). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the dose should be reduced by 50%, up to a maximum dose of one extended-release tablet per day.

Children.

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

Overdose.

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

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

Adverse reactions.

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

The adverse reactions listed below occurred during clinical studies and post-marketing use of various dosage forms and strengths of clarithromycin, including extended-release formulations. Adverse reactions considered at least possibly related to clarithromycin are categorized by system organ class and frequency: more than 10% – very common, 1–10% – common, 0.1–1% – uncommon, frequency not known* (reactions reported during post-marketing surveillance; frequency cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity when severity could be assessed.

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

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

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

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

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

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

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

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

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

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

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

Hepatobiliary disorders: common – abnormal liver function tests; uncommon – cholestasis^4, hepatitis^4, increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT)^4; frequency not known – hepatic failure, cholestatic jaundice, hepatocellular jaundice.

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

Musculoskeletal and connective tissue disorders: uncommon – muscle spasms^3, skeletal muscle rigidity^1, myalgia^2; frequency not known – rhabdomyolysis^2 [in some reports of rhabdomyolysis, clarithromycin was used concomitantly with other medicinal products known to be associated with rhabdomyolysis (such as statins, fibrates, colchicine, or allopurinol)], myopathy.

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

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

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

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

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

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

Patients in whom tablet residue is observed in feces and whose condition does not improve during treatment should be advised to switch to another formulation of clarithromycin (e.g., suspension) or to another antibiotic.

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

Patients with impaired immune system.

In patients with AIDS and other immunocompromised patients receiving high doses of clarithromycin for longer than recommended for the treatment of mycobacterial infections, it was often difficult to distinguish adverse reactions related to drug administration from symptoms of underlying or concomitant diseases.

In adult patients receiving clarithromycin at a daily dose of 1000 mg, the most common adverse effects were nausea, vomiting, altered taste, abdominal pain, diarrhea, rash, abdominal distension, headache, constipation, hearing impairment, and increased ALT and AST levels. Dyspnea, insomnia, and dry mouth occurred uncommonly. In 2–3% of patients, serious abnormal elevations in ALT and AST levels and abnormal decreases in white blood cell and platelet counts were observed. A smaller percentage of patients showed increased blood urea levels.

Shelf life. 2 years.

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

Packaging. 5 tablets per blister, 1 blister per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.

Industrial Area 3, Dewas - 455001, India.