Instructions Clarithromycin film-coated tablets 500 mg blister No. 10
Composition
active ingredient: clarithromycin;
1 tablet contains clarithromycin, calculated as 100% substance – 250 mg or 500 mg;
excipients: microcrystalline cellulose; sodium starch glycolate (type A); sodium lauryl sulfate; hypromellose; calcium stearate; coating mixture "Opadry II Yellow" (contains: triacetin; hypromellose; lactose, monohydrate; titanium dioxide (E 171); polyethylene glycol; iron oxide yellow (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, yellow in color, with a biconvex surface, with a score on one side of the tablet and embossing "KMP" on the other side. A white core is visible on the cross section.
Pharmacotherapeutic group
Antimicrobials for systemic use. Macrolides. ATX code J01F A09.
Pharmacological properties
Pharmacodynamics
Clarithromycin is a semisynthetic macrolide antibiotic. The antibacterial effect of clarithromycin is determined by its binding to the 50S ribosomal subunit of sensitive bacteria and inhibition of protein biosynthesis. The drug exhibits high in vitro activity against a wide range of aerobic and anaerobic gram-positive and gram-negative microorganisms, including hospital strains. The minimum inhibitory concentrations (MICs) of clarithromycin are usually two times lower than the MICs of erythromycin.
Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It is bactericidal against H. Pylori, and clarithromycin activity at neutral pH is higher than at acidic pH. In vitro and in vivo data indicate high efficacy of clarithromycin against clinically relevant strains of mycobacteria. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as gram-negative bacteria that do not produce lactose, 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), which include Mycobacterium avium, Mycobacterium intracellulare.
Beta-lactamases of microorganisms do not affect the effectiveness 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 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: Bacteriodes melaninogenicus.
Spirochetes: Borrelia burgdorferi, Treponema pallidum.
Campylobacter: Campylobacter jejuni.
Clarithromycin has bactericidal activity against several strains of bacteria: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori and Campylobacter spp.
The main metabolite of clarithromycin in humans is the microbiologically active 14-hydroxyclarithromycin (14-OH-clarithromycin). For most microorganisms, the microbiological activity of the metabolite is equal to or 1-2 times weaker than the parent substance, with the exception of H. influenzae, against which the effectiveness of the metabolite is 2 times higher. In vitro and in vivo, the parent substance and its main metabolite exhibit either an additive or synergistic effect against H. influenzae, depending on the strain of the microorganism.
Sensitivity tests
Quantitative methods that require measurement of zone diameter provide a more accurate estimate of bacterial susceptibility to antimicrobial agents. One recommended susceptibility testing procedure uses disks impregnated with 15 μg of clarithromycin (Kirby-Bauer diffusion test); interpretation involves relating the diameter of the zone of inhibition for this disk to the MIC values for clarithromycin. The MIC is determined by broth or agar dilution.
In these procedures, a laboratory result of “susceptible” indicates that the infecting organism is likely to respond to therapy. A result of “resistant” indicates that the infecting organism is likely not to respond to therapy. A result of “intermediate susceptibility” indicates that the therapeutic effect of the drug may be questionable or that the organism will be susceptible at higher doses (intermediate susceptibility is also referred to as moderate susceptibility).
Country or region-specific information on absolute limits of susceptibility, resistance and intermediate susceptibility ranges should be taken into account.
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract after oral administration of the drug in tablet form. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first-pass metabolism. Clarithromycin can be used regardless of food intake, since food does not affect the bioavailability of clarithromycin tablets. Food slightly delays the onset of clarithromycin absorption and the formation of the 14-hydroxymetabolite. The pharmacokinetics of clarithromycin are nonlinear, but steady-state concentrations are achieved within 2 days of drug administration. When using 250 mg 2 times a day, 15-20% of the unchanged drug is excreted in the urine. At a dose of 500 mg 2 times a day, urinary excretion of the drug is more intense (approximately 36%). 14-hydroxyclarithromycin is the major metabolite, accounting for 10-15% of the administered dose in the urine. Most of the remainder of the dose is excreted in the feces, primarily in the bile. 5-10% of the parent compound is recovered in the feces.
When 500 mg of clarithromycin is administered 3 times a day, plasma concentrations of clarithromycin are increased compared to those when a dose of 500 mg is administered 2 times a day.
Clarithromycin concentrations in tissues are several times higher than those in blood. Elevated concentrations have been found in both tonsillar and lung tissues. Clarithromycin is 80% bound to plasma proteins at therapeutic doses.
Clarithromycin penetrates the gastric mucosa. The content of clarithromycin in the gastric mucosa and tissue is higher when clarithromycin is used together with omeprazole than when clarithromycin is used alone.
Indication
Treatment of infections caused by microorganisms susceptible to clarithromycin:
Upper respiratory tract infections, i.e. nasopharynx (tonsillitis, pharyngitis), and sinus infections.
Lower respiratory tract infections (bronchitis, acute croupous pneumonia and primary atypical pneumonia) (see sections “Pharmacological properties. Pharmacodynamics” and “Special instructions for use” for susceptibility testing).
Skin and soft tissue infections (impetigo, folliculitis, erysipeloid, furunculosis, infected wounds) (see sections "Pharmacological properties. Pharmacodynamics" and "Special instructions for use" for susceptibility 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 when suppressing hydrochloric acid secretion (clarithromycin activity against H. pylori at neutral pH is higher than at acidic pH).
Contraindication
Hypersensitivity to macrolide antibiotics and to other components of the drug.
Concomitant use of clarithromycin and any of the following drugs: astemizole, cisapride, pimozide, terfenadine (as this may lead to prolongation of the QT interval and the development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsades de pointes), ergot alkaloids, e.g. ergotamine, dihydroergotamine (as this may lead to ergotoxicity), HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4 (lovastatin or simvastatin), due to an increased risk of myopathy, including rhabdomyolysis (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use").
Concomitant use of clarithromycin and oral midazolam (see section “Interaction with other medicinal products and other types of interactions”).
Congenital or established acquired prolongation of the QT interval or history of ventricular cardiac arrhythmias, including torsades de pointes (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use").
Clarithromycin should not be administered to patients with electrolyte disturbances (hypokalemia or hypomagnesemia due to the risk of QT prolongation).
Severe hepatic insufficiency in combination with renal insufficiency.
Concomitant use of clarithromycin and other strong CYP3A4 inhibitors with colchicine (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use").
Concomitant use of clarithromycin with ticagrelor, ivabradine, or ranolazine.
Concomitant use of clarithromycin with lomitapide is contraindicated (see section 4.5).
Interaction with other medicinal products and other types of interactions
Clarithromycin does not interact with oral contraceptives.
The use of the following drugs is strictly contraindicated due to the possible development of severe interaction effects.
Cisapride, pimozide, astemizole, terfenadine
Macrolides have been reported to alter the metabolism of terfenadine, leading to increased serum levels of terfenadine, sometimes associated with arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see Contraindications). In a study of 14 volunteers, concomitant administration of clarithromycin and terfenadine resulted in a 2- to 3-fold increase in the acid metabolite of terfenadine and a prolongation of the QT interval, without any clinically apparent effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
Ergot alkaloids
Postmarketing reports indicate that concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with the development of acute ergotism, characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system (CNS). 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 area under the pharmacokinetic concentration-time curve (AUC) of midazolam increased 7-fold after oral administration of midazolam. Concomitant use of oral midazolam and clarithromycin is contraindicated (see section 4.3).
HMG-CoA reductase inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3) as these statins are extensively metabolised by CYP3A4 and co-administration with clarithromycin increases their plasma concentrations, which in turn increases the risk of myopathy, including rhabdomyolysis. Rhabdomyolysis has been reported in patients receiving concomitant clarithromycin and these statins. If clarithromycin treatment cannot be avoided, 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 a statin cannot be avoided, it is recommended to prescribe the lowest approved dose of the statin. A statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) may be used. Patients should be monitored for signs and symptoms of myopathy.
The use of clarithromycin is also contraindicated with ivabradine (see section "Contraindications").
Hydroxychloroquine and chloroquine
Clarithromycin should be used with caution in patients receiving drugs that prolong the QT interval due to the potential for causing cardiac arrhythmias and serious cardiovascular adverse reactions.
Effects of other drugs on 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. In addition, monitoring of plasma levels of the CYP3A inducer, which may be increased due to inhibition of CYP3A by clarithromycin, may be necessary (see also the Summary of Product Characteristics of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has been shown to increase rifabutin levels and decrease clarithromycin serum levels, with a concomitant increase in the risk of uveitis.
The following are drugs that are known or suspected to affect clarithromycin blood concentrations and may require a change in clarithromycin dose or the use of alternative therapy.
Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine
Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, may accelerate the metabolism of clarithromycin, reducing its plasma concentration but increasing the concentration of 14-OH-clarithromycin, the microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against different bacteria, the expected therapeutic effect may not be achieved due to the simultaneous use of clarithromycin and inducers of cytochrome P450 enzymes.
Etravirine
Clarithromycin activity was attenuated 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 and 18% increase in AUC of clarithromycin. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered by coadministration of fluconazole. No dose adjustment of clarithromycin is required.
A pharmacokinetic study showed that co-administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. Clarithromycin Cmax was increased by 31%, Cmin by 182%, and AUC by 77% with co-administration of ritonavir. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic range, no dose reduction of clarithromycin is necessary in patients with normal renal function. However, dose adjustment is necessary in 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%. Doses of clarithromycin exceeding 1 g/day should not be used with ritonavir.
The same dose adjustment should be made for patients with renal impairment when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir (see “Bidirectional drug interactions” below).
Effect of clarithromycin on other medicinal products
Antiarrhythmic drugs
There have been postmarketing reports of torsades de pointes occurring with concomitant use of clarithromycin with quinidine or disopyramide. ECG monitoring is recommended for early detection of QT prolongation when clarithromycin is administered with these drugs. Serum concentrations of these drugs should be monitored during clarithromycin therapy.
During post-marketing use, there have been reports of hypoglycemia with the simultaneous use of clarithromycin and disopyramide, therefore, monitoring of blood glucose levels is necessary when these agents are used simultaneously.
Oral hypoglycemic agents/insulin
When used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide, clarithromycin may inhibit the CYP3A enzyme, which may cause hypoglycemia. Close monitoring of glucose levels is recommended.
CYP3A-related interactions
Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, and a drug that is primarily metabolized by CYP3A may result in increased plasma concentrations of the latter, which in turn may enhance or prolong its therapeutic effect and adverse effects. Caution should be exercised when administering clarithromycin to patients receiving therapy with drugs that are CYP3A substrates, especially if the CYP3A substrate has a narrow therapeutic index (e.g., carbamazepine) and/or is extensively metabolized by this enzyme. Dosage adjustment and, if possible, close monitoring of serum concentrations of the drug that is primarily metabolized by CYP3A may be necessary in patients receiving clarithromycin concomitantly.
The following drugs or drug classes 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), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vinblastine, but this list is not exhaustive. A similar mechanism of interaction has been observed with phenytoin, theophylline, and valproate, which are metabolized by other cytochrome P450 isoenzymes.
Omeprazole
Clarithromycin (500 mg every 8 hours) was administered in combination with omeprazole (40 mg daily) to healthy adult volunteers. Steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24 and t1/2 increased by 30%, 89% and 34%, respectively). The mean gastric pH measured over 24 hours was 5.2 with omeprazole alone and 5.7 with omeprazole and clarithromycin.
Sildenafil, tadalafil and vardenafil
Each of these phosphodiesterase inhibitors is metabolized (at least in part) by CYP3A, and CYP3A may be inhibited by concomitant clarithromycin. Concomitant administration of clarithromycin with sildenafil, tadalafil, or vardenafil may result in increased exposure to the phosphodiesterase inhibitor, and a reduction in the dose of sildenafil, tadalafil, or vardenafil should be considered.
Theophylline, carbamazepine
Clinical trial results have shown that there is a slight but statistically significant (p≤0.05) increase in theophylline or carbamazepine plasma concentrations when co-administered with clarithromycin.
Tolterodine
Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoform (CYP2D6). However, in a population of patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A results in significantly increased plasma concentrations of tolterodine. In such patients, a reduction in the dose of tolterodine may be necessary when administered with CYP3A inhibitors such as clarithromycin.
When midazolam was coadministered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous administration of midazolam. When intravenous midazolam is coadministered with clarithromycin, the patient should be closely monitored for dose adjustments. With oromucosal administration of midazolam, where presystemic elimination of the drug can be avoided, interactions similar to those seen with intravenous midazolam are more likely to occur than with oral administration. The same precautions should be observed with other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines that are not eliminated by CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interactions with clarithromycin are unlikely.
There have been post-marketing reports of drug interactions and CNS adverse events (such as drowsiness and confusion) with concomitant use of clarithromycin and triazolam. The patient should be monitored for possible potentiation of CNS pharmacological effects.
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. When clarithromycin and colchicine are used concomitantly, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Concomitant use of clarithromycin and colchicine is contraindicated (see sections 4.3 and 4.4).
Digoxin
Digoxin is considered a substrate for the efflux transporter Pgp. Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are coadministered, inhibition of Pgp by clarithromycin may result in increased digoxin exposure. Increased serum digoxin concentrations have been reported in postmarketing experience in patients receiving clarithromycin concomitantly with digoxin. Some patients have developed signs of digitalis toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be closely monitored in patients receiving clarithromycin concomitantly.
Zidovudine
Concomitant oral administration of clarithromycin tablets and zidovudine in HIV-infected adult patients may result in decreased steady-state serum concentrations of zidovudine. Since clarithromycin may interfere with the absorption of oral zidovudine when administered concomitantly, this can be largely avoided by separating the doses of clarithromycin and zidovudine by 4 hours. No such interaction has been reported with clarithromycin suspension and zidovudine or didanosine in HIV-infected children. Such an interaction is unlikely with clarithromycin given as an intravenous infusion.
Phenytoin and valproate
There have been spontaneous or published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). It is recommended that serum levels of these drugs be monitored when co-administered with clarithromycin. Increased serum levels have been reported.
Corticosteroids
Caution should be exercised when clarithromycin is coadministered with systemic or inhaled corticosteroids that are primarily metabolized by CYP3A due to the potential for increased systemic exposure to corticosteroids. Patients should be closely monitored for adverse reactions to systemic corticosteroids during concomitant use.
Bidirectional drug interactions
Atazanavir
Concomitant administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), which are CYP3A substrates and inhibitors, resulted in a 2-fold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, no dose reduction is necessary for patients with normal renal function. The clarithromycin dose should be reduced by 50% for patients with CLCR 30–60 mL/min and by 75% for patients with CLCR <30 mL/min, using an appropriate clarithromycin formulation. Clarithromycin doses greater than 1000 mg daily should not be administered with protease inhibitors.
Calcium channel blockers
Due to the risk of hypotension, caution should be exercised when administering clarithromycin concomitantly with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem). The interaction may result in increased plasma concentrations of both clarithromycin and the calcium channel blocker. Hypotension, bradyarrhythmias, and lactic acidosis have been reported in patients receiving clarithromycin and verapamil concomitantly.
Itraconazole
Saquinavir
Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), which are substrates and inhibitors of CYP3A, in 12 healthy volunteers resulted in an increase in the steady-state AUC and Cmax of saquinavir by 177% and 187%, respectively, compared with the same values observed with saquinavir alone. At the same time, the AUC and Cmax of clarithromycin increased by approximately 40% compared with the use of clarithromycin alone. No dose adjustment is necessary if both drugs are used simultaneously for a limited period of time at the doses/pharmaceutical forms studied. The results of a drug interaction study with the use of soft gelatin capsules may not correspond to the effects observed with the use of saquinavir in the form of hard gelatin capsules. The results of drug interaction studies with saquinavir alone may not be consistent with the effects observed with saquinavir/ritonavir therapy. When saquinavir is used with ritonavir, the potential effects of ritonavir on clarithromycin should be considered (see above).
Direct-acting oral anticoagulants (DOACs) (rivaroxaban, apixaban)
The oral APDs dabigatran and edoxaban are substrates for the efflux transporter P-gp.
Rivaroxaban and apixaban are metabolized by CYP3A4 and are also substrates for P-gp.
Clarithromycin should be used with caution when used concomitantly with these drugs, especially in patients at high risk of bleeding (see section 4.4).
Lomitapide
Concomitant use of clarithromycin with lomitapide may increase transaminase levels (see section "Contraindications").
Application features
The drug contains lactose as an excipient, so the drug should not be used in patients with galactose intolerance, lactase deficiency or glucose/galactose malabsorption.
The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection may lead to the emergence of microbial resistance.
Clarithromycin should not be prescribed to pregnant women without careful benefit/risk assessment, especially in the first trimester of pregnancy.
Prolonged use of clarithromycin, like other antibiotics, may cause overgrowth of non-susceptible bacteria and fungi.
If superinfection occurs, appropriate therapy should be initiated.
Since clarithromycin is metabolized in the liver and excreted primarily through the liver and kidneys, the drug should be used with particular caution in patients with impaired liver function, moderate or severe renal impairment, and in elderly patients (aged 65 years and older).
The drug should be used with caution in patients with severe renal insufficiency (see section "Method of administration and dosage").
Hepatic dysfunction, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis with or without jaundice, have been reported with clarithromycin. These hepatic dysfunctions may be severe and are usually reversible. Fatal hepatic failure has been reported in some cases, and was mostly associated with serious underlying medical conditions and/or concomitant medication. Clarithromycin should be discontinued immediately if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal tenderness develop.
Pseudomembranous colitis, ranging from mild to life-threatening, has been reported with nearly all antibacterial agents, including macrolides. Clostridium difficile-associated diarrhea (CDAD), ranging from mild to fatal, has been reported with nearly all antibacterial agents, including clarithromycin. Antibacterial therapy disrupts the normal intestinal flora, which may lead to overgrowth of C. difficile. The possibility of C. difficile-associated diarrhea should be considered in all patients presenting with diarrhea following antibiotic therapy. A careful history should be taken, as C. difficile-associated diarrhea has been reported as early as 2 months after antibiotic therapy. If pseudomembranous colitis occurs, clarithromycin should be discontinued, regardless of the indication for which it was prescribed. Microbiological investigation should be performed and appropriate treatment initiated. Drugs that inhibit peristalsis should be avoided.
Colchicine
Colchicine toxicity has been reported with concomitant use of clarithromycin and colchicine, particularly in elderly patients, including those with renal impairment. Fatal outcomes have been reported in some of these patients (see Interactions). Concomitant use of clarithromycin and colchicine is contraindicated (see Contraindications).
Caution should be exercised when clarithromycin is used concomitantly with triazolebenzodiazepines such as triazolam, intravenous or oromucosal midazolam (see section 4.5).
Prolongation of cardiac repolarization and QT interval, indicating a risk of cardiac arrhythmia and torsades de pointes, has been observed with macrolides, including clarithromycin (see section 4.8). Since the following situations may lead to an 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 disturbances, or clinically significant bradycardia.
Patients who are concomitantly taking other drugs associated with QT prolongation (see section “Interaction with other medicinal products and other types of interactions”).
Concomitant use of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated (see section "Contraindications").
Clarithromycin should not be used in patients with congenital or established acquired QT prolongation or a history of ventricular arrhythmia (see section "Contraindications").
Epidemiological studies investigating the risk of adverse cardiovascular events with macrolides have shown mixed results. Some observational studies have identified a rare short-term risk of arrhythmia, myocardial infarction, and cardiovascular mortality associated with the use of macrolides, including clarithromycin. These findings should be weighed against the benefits of clarithromycin.
Pneumonia
Given the emerging resistance of Streptococcus pneumoniae to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin for the treatment of community-acquired pneumonia. In the case of nosocomial pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.
Mild to moderate skin and soft tissue infections
These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Susceptibility testing is therefore important. In cases where beta-lactam antibiotics cannot be used (e.g., in cases of allergy), other antibiotics, such as clindamycin, may be used as first-line agents. Macrolides currently have a role only in the treatment of some skin and soft tissue infections (e.g., infections caused by Corynebacterium minutissimum, acne vulgaris, erysipelas) and in situations where penicillins cannot be used.
In the event of the development of severe acute hypersensitivity reactions such as anaphylaxis, severe cutaneous adverse reactions (e.g. acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), Henoch-Schonlein syndrome, clarithromycin therapy should be discontinued immediately and appropriate treatment should be initiated immediately.
Clarithromycin should be used with caution when administered concomitantly with inducers of the cytochrome CYP3A4 enzyme (see section “Interaction with other medicinal products and other types of interactions”).
Attention should be paid to the possibility of cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.
HMG-CoA reductase inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see Contraindications). Caution should be exercised when clarithromycin is co-administered with other statins. Rhabdomyolysis has been reported in patients receiving clarithromycin and statins concomitantly. Patients should be monitored for signs and symptoms of myopathy.
In situations where concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. A statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) may be used (see section 4.5).
Oral hypoglycemic agents/insulin
Concomitant use of clarithromycin and oral hypoglycemic agents
