Clabel® 500
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLABEL® 500 (CLABEL 500)
Composition:
Active substance: clarithromycin;
One tablet contains 500 mg of clarithromycin;
Excipients: sodium croscarmellose, pregelatinized starch, colloidal anhydrous silicon dioxide, povidone, stearic acid, magnesium stearate, talc, microcrystalline cellulose, propylene glycol, Opadry Yellow OY-S-32924: hypromellose, titanium dioxide (E 171), propylene glycol, hydroxypropyl cellulose, polysorbate 80, quinoline yellow (E 104), sorbic acid, vanillin.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties. Oval, biconvex film-coated tablets with a smooth surface, yellow in color.
Pharmacotherapeutic group.
Antibacterials for systemic use. Macrolides. ATC code J01FA09.
Pharmacological Properties
Pharmacodynamics
Clarithromycin is a semi-synthetic antibiotic of the macrolide group. 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 efficacy in vitro 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 two times lower than those of erythromycin.
Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It exerts a bactericidal effect against H. pylori. The activity of clarithromycin at neutral pH is higher than at acidic pH. In vitro and in vivo data indicate high efficacy of clarithromycin against clinically significant strains of mycobacteria. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as non-lactose-fermenting gram-negative bacteria, are not susceptible to clarithromycin.
Microbiology
Clarithromycin is active in vitro and in clinical practice against most strains of the following microorganisms.
Aerobic gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes.
Aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila.
Other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR).
Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC), including Mycobacterium avium, 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 action 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-hydroxyclarithromycin (14-OH-clarithromycin). For most microorganisms, the microbiological activity of the metabolite is equal to or 1–2 times weaker than that of the parent compound, except for H. influenzae, against which the metabolite is twice as effective. In vitro and in vivo, the parent compound and its main metabolite exhibit either additive or synergistic effects against H. influenzae, depending on the microbial strain.
Susceptibility Testing
Quantitative methods requiring measurement of 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 diffusion method) are used; the diameter of the inhibition zone for this disk is correlated with MIC values for clarithromycin. MIC is determined by broth or agar dilution methods.
When performing these tests, a laboratory conclusion of "susceptible" indicates that the infecting microorganism is likely to respond to therapy. A conclusion of "resistant" indicates that the infecting microorganism is unlikely to respond to therapy. A conclusion of "intermediate susceptibility" suggests that the therapeutic effect of the drug may be uncertain or that the microorganism may be susceptible if higher doses are used (intermediate susceptibility is also referred to as moderate susceptibility).
Country- or region-specific data on absolute breakpoints for susceptibility, resistance, and intermediate susceptibility should be taken into account.
Pharmacokinetics
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract after oral administration in tablet form. The microbiologically active metabolite, 14-hydroxyclarithromycin, is formed via first-pass metabolism. Clarithromycin can be administered independently of food intake, as food does not affect the bioavailability of clarithromycin tablets. Food slightly delays the onset of absorption of clarithromycin and formation of the 14-hydroxy metabolite. The pharmacokinetics of clarithromycin is nonlinear; however, steady-state concentrations are achieved within 2 days of drug administration. After administration of 500 mg twice daily, approximately 36% of the unchanged drug is excreted in urine. 14-Hydroxyclarithromycin is the main metabolite excreted in urine, accounting for 10–15% of the administered dose. The majority of the remaining dose is excreted in feces, primarily via bile. 5–10% of the original compound is found in feces.
When 500 mg of clarithromycin is administered three times daily, plasma concentrations of clarithromycin are higher compared to those achieved with a dose of 500 mg twice daily.
Concentrations of clarithromycin in tissues are several times higher than plasma concentrations. Elevated concentrations have been detected in both tonsillar and lung tissues. At therapeutic doses, clarithromycin is approximately 80% bound to plasma proteins.
Clarithromycin penetrates into the gastric mucosa. The concentration of clarithromycin in the gastric mucosa and gastric tissue is higher when clarithromycin is administered concomitantly with omeprazole than with clarithromycin monotherapy.
Clinical characteristics.
Indications.
Treatment of infections caused by microorganisms sensitive to clarithromycin:
- Infections of the upper respiratory tract, i.e. nasopharynx (tonsillitis, pharyngitis), and infections of the paranasal sinuses.
- Infections of the lower respiratory tract (bronchitis, acute lobar pneumonia, and primary atypical pneumonia) (see "Special precautions for use" and "Pharmacological properties. Pharmacodynamics" regarding sensitivity testing).
- Skin and soft tissue infections (impetigo, folliculitis, erysipeloid, furunculosis, infected wounds) (see "Special precautions for use" and "Pharmacological properties. Pharmacodynamics" regarding sensitivity testing).
- Acute and chronic odontogenic infections.
- Disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii.
- Eradication of H. pylori in patients with duodenal ulcer under conditions of inhibition of hydrochloric acid secretion (clarithromycin activity against H. pylori at neutral pH is higher than at acidic pH).
Contraindications.
Hypersensitivity to macrolide antibiotics and to any other components of the drug. Concomitant use of clarithromycin with any of the following drugs: astemizole, cisapride, pimozide, terfenadine (as this may lead to QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes), ergot alkaloids, e.g. ergotamine, dihydroergotamine (as this may lead to ergot toxicity), HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to increased risk of myopathy, including rhabdomyolysis (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").
Concomitant use of clarithromycin and oral midazolam (see "Interaction with other medicinal products and other forms of interaction").
Congenital or known acquired QT interval prolongation or history of ventricular cardiac arrhythmias, including torsades de pointes (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction"). Electrolyte disturbances (hypokalemia or hypomagnesemia), risk of QT interval prolongation.
Severe hepatic impairment and 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 of clarithromycin with ticagrelor, ivabradine, or ranolazine.
Concomitant use of clarithromycin and lomitapide (see section "Interaction with other medicinal products and other forms of interaction").
Interaction with other medicinal products and other forms of interaction.
Clarithromycin does not interact with oral contraceptives.
The following drugs are strictly contraindicated due to the potential for severe interaction consequences.
Cisapride, pimozide, astemizole, terfenadine
Increased serum levels of cisapride have been reported in patients receiving clarithromycin and cisapride concomitantly. This may lead to QT interval prolongation and development of arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been observed in patients receiving clarithromycin and pimozide concomitantly (see section "Contraindications").
Macrolides have been reported to alter terfenadine metabolism, leading to increased serum levels of terfenadine, which has sometimes been associated with arrhythmias such as QT interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section "Contraindications"). In a study involving 14 volunteers, concomitant administration of clarithromycin and terfenadine resulted in a 2- to 3-fold increase in serum levels of terfenadine acid metabolite and QT interval prolongation, which did not result in any clinically evident effect. Similar effects were observed with concomitant use of astemizole and other macrolides.
Ergot alkaloids
Post-marketing reports indicate that concomitant use of clarithromycin with ergotamine or dihydroergotamine has been associated with signs of acute ergotism characterized by vasospasm and ischemia of extremities and other tissues, including the central nervous system. Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see "Contraindications").
Oral midazolam
When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 7-fold after oral administration of midazolam. Concomitant use of oral midazolam and clarithromycin is contraindicated (see section "Contraindications").
HMG-CoA reductase inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications"), as these statins are extensively metabolized by CYP3A4 and concomitant use with clarithromycin increases their plasma concentration, thereby increasing the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin and these statins concomitantly. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.
Caution should be exercised when prescribing clarithromycin concomitantly with other statins. In situations where concomitant use of clarithromycin with statins cannot be avoided, it is recommended to use the lowest registered dose of the statin. Use of a statin not dependent on CYP3A metabolism (e.g. fluvastatin) may be considered. Monitoring of patients for signs and symptoms of myopathy is necessary.
Lomitapide
Concomitant use of clarithromycin with lomitapide is contraindicated due to the potential for significant increase in transaminase levels (see "Contraindications").
Concomitant use of clarithromycin with ticagrelor, ivabradine, and ranolazine, which are predominantly metabolized by CYP3A4, is contraindicated (see "Contraindications").
Effect of other medicinal products on clarithromycin.
Medicinal products that are CYP3A inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce clarithromycin metabolism. 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 instructions for medical use of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has led to increased rifabutin levels and decreased clarithromycin levels in serum, with a concomitant increased risk of uveitis.
The following medicinal products are known or suspected to affect clarithromycin blood concentration and may require dose adjustment of clarithromycin or alternative therapy.
Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine
Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, may accelerate clarithromycin metabolism, decreasing its plasma concentration, but increasing the concentration of 14-OH-clarithromycin – a microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin varies against different bacteria, the expected therapeutic effect may not be achieved with concomitant use of clarithromycin and cytochrome P450 enzyme inducers.
Etravirine
The effect of clarithromycin was reduced by etravirine, but concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), the overall activity against this pathogen may be altered. Therefore, alternative agents to clarithromycin should be considered for the treatment of MAC.
Fluconazole
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in a 33% increase in steady-state Cmin of clarithromycin and an 18% increase in AUC. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered with concomitant fluconazole use. Dose adjustment of clarithromycin is not required.
Ritonavir
A pharmacokinetic study showed that concomitant administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. Cmax of clarithromycin increased by 31%, Cmin by 182%, and AUC by 77% with concomitant ritonavir use. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic range, dose reduction of clarithromycin is not necessary for patients with normal renal function. However, dose adjustment is required for patients with renal impairment: for patients with CLCR 30–60 mL/min, the clarithromycin dose should be reduced by 50%. For patients with CLCR < 30 mL/min, the clarithromycin dose should be reduced by 75%. Clarithromycin doses exceeding 1 g/day should not be used with ritonavir.
The same dose adjustment should be applied for patients with impaired renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir (see below "Bidirectional drug interactions").
Effect of clarithromycin on other medicinal products.
Antiarrhythmic agents
Post-marketing reports exist of torsades de pointes occurring with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended to detect QT interval prolongation promptly during concomitant use of clarithromycin with these drugs. Serum concentrations of these drugs should be monitored during clarithromycin therapy.
Post-marketing use reports include hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, glucose level 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 glucose level monitoring is recommended.
CYP3A-related interactions
Concomitant use of clarithromycin, a known CYP3A enzyme inhibitor, with a drug primarily metabolized by CYP3A may lead to increased plasma concentration of the latter, thereby enhancing or prolonging its therapeutic effect and adverse effects. Caution should be exercised when using clarithromycin in patients receiving therapy with CYP3A substrate drugs, especially if the CYP3A substrate has a narrow therapeutic range (e.g. carbamazepine) and/or is extensively metabolized by this enzyme. Dose adjustment may be needed and, if possible, careful monitoring of serum concentrations of the drug primarily metabolized by CYP3A is recommended for patients concomitantly receiving clarithromycin.
Corticosteroids
Caution should be exercised when using clarithromycin concomitantly with systemic or inhaled corticosteroids that are predominantly metabolized by CYP3A, due to potential increased systemic effects of corticosteroids. Patients should be closely monitored for adverse reactions of systemic corticosteroids when used concomitantly.
It is known (or suspected) that the following medicinal products or groups of products are metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vinblastine, but this list is not exhaustive. A similar interaction mechanism has been observed with phenytoin, theophylline, and valproate, which are metabolized by other cytochrome P450 isoenzymes.
Direct oral anticoagulants. Direct oral anticoagulants dabigatran and edoxaban are substrates for the efflux transporter P-glycoprotein (Pgp). Rivaroxaban and apixaban are metabolized by CYP3A4 and are also Pgp substrates. Use of direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban concomitantly with clarithromycin requires caution, especially in patients at high risk of bleeding (see section "Special precautions for use").
Omeprazole
Clarithromycin (500 mg every 8 hours) was used in combination with omeprazole (40 mg daily) in healthy adult volunteers. Plasma concentrations of omeprazole increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively). When omeprazole was used 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 concomitantly administered clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil, or vardenafil may lead to increased exposure to the phosphodiesterase inhibitor; therefore, consideration should be given to reducing the dose of sildenafil, tadalafil, or vardenafil.
Theophylline, carbamazepine
Results of clinical studies 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 CYP2D6 isoenzyme of cytochrome P450 (CYP2D6). However, in the population of patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in tolterodine plasma concentrations. In such patients, dose reduction of tolterodine may be necessary when used with CYP3A inhibitors such as clarithromycin.
Triazolobenzodiazepines (e.g. alprazolam, midazolam, triazolam)
When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous administration of midazolam. With intravenous administration of midazolam and clarithromycin, careful monitoring of the patient's condition is required for timely dose adjustment. With oromucosal administration of midazolam, where presystemic elimination of the drug may be bypassed, an interaction similar to that observed with intravenous midazolam, rather than oral, is more likely. The same precautions should be observed when using other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination does not depend on CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.
There are post-marketing reports of drug interaction and development of adverse effects on the central nervous system (such as somnolence and confusion) with concomitant use of clarithromycin and triazolam. The patient should be observed, considering the possible increase in pharmacological effects on the CNS.
Other types of interactions
Colchicine
Colchicine is a substrate of CYP3A and the efflux transporter 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 sections "Contraindications", "Special precautions for use").
Digoxin
Digoxin is considered a substrate of the efflux transporter P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. With concomitant use of clarithromycin and digoxin, inhibition of Pgp by clarithromycin may lead to increased digoxin exposure. Post-marketing surveillance has reported increased digoxin serum concentrations in patients using clarithromycin with digoxin. In some patients, signs of digitalis toxicity developed, including potentially fatal arrhythmias. Digoxin serum concentrations should be carefully monitored in patients receiving concomitant clarithromycin and digoxin.
Zidovudine
Concomitant oral administration of clarithromycin tablets and zidovudine in HIV-infected adult patients may lead to decreased steady-state serum concentrations of zidovudine. Since clarithromycin may interfere with 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 use of clarithromycin suspension and zidovudine or didanosine in HIV-infected children. This interaction is unlikely with intravenous infusion of clarithromycin.
Phenytoin and valproate
There have been spontaneous or published reports of interaction between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g. phenytoin and valproate). Serum level monitoring of these drugs is recommended when prescribed concomitantly with clarithromycin. Increased serum levels have been reported.
Bidirectional drug interactions
Hydroxychloroquine and chloroquine
Observational data indicate that concomitant use of azithromycin and hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Due to the potential for similar risk with other macrolides used in combination with hydroxychloroquine or chloroquine, the benefit-risk ratio should be carefully weighed before prescribing clarithromycin to patients taking hydroxychloroquine or chloroquine. Clarithromycin should be used with caution in patients receiving drugs that prolong the QT interval, due to the potential for inducing cardiac arrhythmias and serious cardiovascular adverse reactions.
Atazanavir
Concomitant use of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, resulted in a doubling of clarithromycin exposure and a 70% reduction in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, dose reduction is not necessary for 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 of clarithromycin. Clarithromycin doses higher than 1000 mg per day 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 (such as verapamil, amlodipine, diltiazem). Concentrations in plasma of both clarithromycin and calcium channel blockers may be increased during interaction. In patients receiving clarithromycin and verapamil concomitantly, arterial hypotension, bradyarrhythmias, and lactic acidosis have been observed.
Itraconazole
Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, thus clarithromycin may increase itraconazole plasma levels 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
Concomitant use of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, in 12 healthy volunteers resulted in a 177% and 187% increase in steady-state AUC and Cmax of saquinavir, respectively, compared to those observed with 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 drugs are used concomitantly for a limited period at the studied doses/forms. Results of the drug interaction study using soft gelatin capsules may not correspond to effects observed with hard gelatin capsules of saquinavir. Results of the drug interaction study using saquinavir alone may not correspond to effects observed with saquinavir/ritonavir therapy. When saquinavir is used with ritonavir, possible effects of ritonavir on clarithromycin should be considered (see above).
Special precautions for use.
The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection may lead to the development of microbial resistance.
Clarithromycin should not be prescribed to pregnant women without careful assessment of the benefit-risk ratio, particularly during the first trimester of pregnancy.
Prolonged use of clarithromycin, as with other antibiotics, may result in overgrowth of non-susceptible bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated. Since clarithromycin is metabolized in the liver and primarily excreted via the liver and kidneys, it should be used with particular caution in patients with hepatic impairment, moderate or severe renal impairment, and elderly patients (over 65 years of age).
The drug should be used with caution in patients with severe renal insufficiency. Cases of hepatic dysfunction, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, have been reported during clarithromycin therapy. This hepatic dysfunction may be severe, although it is usually reversible. In some cases, fatal hepatic failure has been reported, primarily associated with serious underlying diseases and/or concomitant medications. Clarithromycin should be discontinued immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, darkening of urine, pruritus, or abdominal tenderness.
Pseudomembranous colitis, ranging from moderate to life-threatening in severity, has been reported with the use of nearly all antibacterial agents, including macrolides. Cases of Clostridium difficile-associated diarrhea (CDAD), ranging from mild severity to fatal colitis, have been reported with the use of nearly all antibacterial agents, including clarithromycin. Antibacterial therapy alters the normal gut flora, which may lead to overgrowth of C. difficile. The possibility of Clostridium difficile-associated diarrhea should always be considered in any patient presenting with diarrhea after antibiotic use. A careful medical history is essential, as cases of Clostridium difficile-associated diarrhea have been reported up to two months after administration of antibacterial agents. If pseudomembranous colitis develops, clarithromycin therapy should be discontinued regardless of the indication for which it was prescribed. Microbiological investigation should be performed and appropriate treatment initiated. Agents that inhibit peristalsis should be avoided.
Colchicine
Cases of colchicine toxicity (including fatal outcomes) have been reported with concomitant use of clarithromycin and colchicine, particularly in elderly patients and those with renal impairment (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of clarithromycin with colch游戏副本
Dosage and Administration
The recommended dose of clarithromycin for adults and children aged 12 years and older is 250 mg (administer clarithromycin preparations at the corresponding dosage) every 12 hours. In more severe infections, the dose may be increased to 500 mg (1 tablet) every 12 hours. The usual duration of treatment depends on the severity of infection and ranges from 6 to 14 days.
Clarithromycin may be administered independently of food intake, as food does not affect the bioavailability of clarithromycin.
Treatment of odontogenic infections.
The recommended dose is 250 mg (administer clarithromycin preparations at the corresponding dosage) every 12 hours for 5 days.
Use in patients with mycobacterial infection.
The initial dose for adults is 500 mg twice daily. If no clinical or bacteriological improvement is observed within 3–4 weeks of treatment, the clarithromycin dose may be increased to 1000 mg twice daily.
Treatment of disseminated infections caused by Mycobacterium avium complex (MAC) in AIDS patients should continue for as long as clinically and microbiologically confirmed efficacy is maintained. Clarithromycin may be used in combination with other antimycobacterial agents.
Eradication of H. pylori in patients with duodenal ulcer (adults).
Triple therapy (7–10 days)
Clarithromycin (500 mg) twice daily should be administered together with amoxicillin 1000 mg twice daily and omeprazole 20 mg daily for 7–10 days.
Triple therapy (10 days)
Clarithromycin (500 mg) twice daily, lanzoprazole 30 mg twice daily, and amoxicillin 1000 mg twice daily for 10 days.
Double therapy (14 days)
Clarithromycin (500 mg) three times daily together with omeprazole 40 mg once daily orally for 14 days, followed by omeprazole 20 mg or 40 mg once daily orally for the subsequent 14 days.
Double therapy (14 days)
Clarithromycin (500 mg) three times daily together with lanzoprazole 60 mg once daily orally for 14 days. Further acid suppression may be required to reduce ulcer symptoms.
Clarithromycin has also been used in the following therapeutic regimens:
clarithromycin + tinidazole and omeprazole or lanzoprazole;
clarithromycin + metronidazole and omeprazole or lanzoprazole;
clarithromycin + tetracycline, bismuth subcitrate, and ranitidine;
clarithromycin + amoxicillin and lanzoprazole;
clarithromycin + ranitidine bismuth citrate.
Use in elderly patients: as for adults.
Use in patients with renal impairment: in patients with severe renal impairment (creatinine clearance < 30 mL/min), the dose should be halved, e.g., 250 mg once daily or 250 mg (administer clarithromycin preparations at the corresponding dosage) twice daily in more severe infections. In such patients, the duration of treatment should not exceed 14 days.
Children.
The use of clarithromycin tablets in children under 12 years of age has not been studied.
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, altered mental status, paranoid behavior, hypokalemia, and hypoxemia developed.
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 affect serum clarithromycin concentrations.
Side effects
The most common and frequent adverse reactions associated with clarithromycin treatment in adults and children are abdominal pain, diarrhea, nausea, vomiting, and taste perversion. These adverse reactions are usually mild and consistent with the well-known safety profile of macrolide antibiotics. During clinical studies, no significant difference was observed in the frequency of these gastrointestinal adverse reactions between patient groups with or without mycobacterial infections.
Below are the adverse reactions observed during clinical trials and post-marketing use of various dosage forms and doses of clarithromycin, including immediate-release tablets. Adverse reactions at least possibly related to clarithromycin are listed by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), and frequency not known* (reactions reported during post-marketing surveillance; frequency cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity when severity could be assessed.
Infections and infestations: uncommon – cellulitis1, candidiasis, gastroenteritis2, infection3, vaginal infection; frequency not known – pseudomembranous colitis, Whipple's disease.
Blood and lymphatic system disorders: uncommon – leukopenia, neutropenia4, thrombocytosis3, eosinophilia4; frequency not known – agranulocytosis, thrombocytopenia.
Immune system disorders: uncommon – anaphylactoid reactions1, hypersensitivity; frequency not known – anaphylactic reactions, angioedema.
Metabolism and nutrition disorders: uncommon – anorexia, decreased appetite; frequency not known – hypoglycemia.
Psychiatric disorders: common – insomnia; uncommon – anxiety, nervousness3; frequency not known – psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.
Nervous system disorders: common – dysgeusia (disturbance of taste sensation), headache, taste perversion; uncommon – loss of consciousness1, dyskinesia1, dizziness, somnolence, tremor; frequency not known – seizures, ageusia (loss of taste sensation), parosmia, anosmia, paresthesia.
Ear and labyrinth disorders: uncommon – vertigo, hearing impairment, tinnitus; frequency not known – hearing loss.
Cardiac disorders: uncommon – cardiac arrest1, atrial fibrillation1, QT interval prolongation, extrasystoles1, palpitations; frequency not known – torsades de pointes, ventricular tachycardia, ventricular fibrillation.
Vascular disorders: common – vasodilation1; frequency not known – hemorrhage.
Respiratory, thoracic and mediastinal disorders: uncommon – asthma1, epistaxis2, pulmonary embolism1.
Gastrointestinal disorders: common – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; uncommon – esophagitis1, gastroesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence; frequency not known – acute pancreatitis, tongue discoloration, tooth discoloration.
Hepatobiliary disorders: common – abnormal liver function tests; uncommon – cholestasis4, hepatitis4, increased levels of ALT, AST, GGT4; frequency not known – hepatic failure, hepatocellular jaundice.
Skin and subcutaneous tissue disorders: common – rash, hyperhidrosis; uncommon – bullous dermatitis1, pruritus, urticaria, maculopapular rash3; frequency not known – severe skin reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acne, Schönlein-Henoch disease.
Musculoskeletal and connective tissue disorders: uncommon – muscle spasms3, skeletal muscle rigidity1, myalgia2; frequency not known – rhabdomyolysis**, myopathy.
Renal and urinary disorders: uncommon – increased blood creatinine1, increased blood urea1; frequency not known – renal failure, interstitial nephritis.
General disorders and administration site conditions: very common – phlebitis at injection site1; common – pain at injection site1, inflammation at injection site1; uncommon – malaise4, fever3, asthenia, chest pain4, chills4, fatigue4.
Investigations: uncommon – altered albumin-globulin ratio1, increased blood alkaline phosphatase4, increased blood lactate dehydrogenase4; frequency not known – increased international normalized ratio, prolonged prothrombin time, change in urine color.
* Since these reactions have been reported voluntarily and the patient population size is unknown, it is not always possible to precisely determine their frequency or causal relationship to drug exposure. The overall clinical experience with clarithromycin exceeds 1 billion patient-days.
** In some reports of rhabdomyolysis, clarithromycin was co-administered with other medicinal products known to be associated with rhabdomyolysis (e.g., statins, fibrates, colchicine, or allopurinol).
1,2,3,4 These adverse reactions were reported only with the following formulations: 1 – lyophilized powder for infusion solution, 2 – extended-release tablets, 3 – suspension, 4 – immediate-release tablets.
The frequency, type, and severity of adverse reactions in children are expected to be similar to those in adults.
Patients with impaired immune system.
In patients with AIDS and other immunocompromised patients receiving high doses of clarithromycin for prolonged periods to treat mycobacterial infections, it may be difficult to distinguish adverse reactions related to drug administration from symptoms of the underlying or concomitant diseases.
In adult patients receiving clarithromycin at a daily dose of 1000 mg, the most commonly reported adverse effects were nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, abdominal distension, headache, constipation, hearing disturbances, and increased serum ALT and AST levels. Dyspnea, insomnia, and dry mouth occurred less frequently.
In these immunocompromised patients, laboratory parameters were evaluated by analyzing those values outside the significant abnormal range (i.e., extreme upper or lower limit) for a given test. By this criterion, significant abnormal elevations in ALT and AST levels and abnormal decreases in white blood cell and platelet counts were observed in 2–3% of patients receiving 1000 mg of clarithromycin daily. A smaller percentage of patients showed increased blood urea nitrogen levels.
Shelf life. 2 years.
Storage conditions.
Store in a dry, light-protected place at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging.
7 tablets per blister, 2 blisters per cardboard pack.
Prescription category. Prescription only.
Manufacturer.
NOBEL ILAC SANAYI VE TICARET A.S.
Address.
Sankaklar Quarter, Eskikaraağaç Street No:299, 81100 Duzce, Turkey.