Clarithromycin, 500 mg 14 pcs

Pharmacotherapeutic group:

Macrolide antibiotic

ATC code: J01FA09

Pharmacological properties

Pharmacodynamics

The semisynthetic antibiotic of the macrolide group. It has antibacterial action, interacting with 50S ribosomal subunit of bacteria and inhibiting protein synthesis in the microbial cell. It acts on extra- and intracellularly located pathogens.

Clarithromycin has demonstrated high in vitro activity against standard and isolated cultures of bacteria. It is highly effective against many aerobic and anaerobic gram-positive and gram-negative microorganisms. In vitro studies confirm high effectiveness of clarithromycin against Legionella pneumophila, Mycoplasma pneumoniae and Helicobacter pylori.

The activity of clarithromycin against most strains of the following microorganisms has been proven in in vitro studies and in clinical practice:

Aerobic Gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes;

aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrheae, Legionella pneumophila;

other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR); Mycobacteria: Mycobacterium leprae, Mycobacterium chelonae, Mycobacterium kansasii, Mycobacterium fortuitum, Mycobacterium avium complex (MAC): Mycobacterium avium, Mycobacterium intracellulare;

Helicobacter pylori.

The Enterobacteriaceae, Pseudomonas spp. and other non-lactose degrading Gram-negative bacteria are insensitive to clarithromycin.

The production of β-lactamase has no effect on clarithromycin activity. Most staphylococcal strains resistant to methicillin and oxacillin are also resistant to clarithromycin.

Clarithromycin is also effective in vitro against most strains of the microorganisms listed below:

Aerobic Gram-positive microorganisms: Streptococcus agalactiae, Streptococcus spp. (groups C, F, G), Streptococcus spp. Viridans group;

aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida;

anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes;

anaerobic gram-negative microorganisms: Bacteroides melaninogenicus;

Spirochaetes: Borrelia burgdorferi, Treponema pallidum;

Campylobacter: Campylobacter jejuni.

The main metabolite of clarithromycin in humans is the microbiologically active metabolite 14-hydroxyclarithromycin. The microbiological activity of the metabolite is the same as that of the parent substance, or 1-2 times weaker against most microorganisms. The exception is Naemophilus influenzae, against which the effectiveness of the metabolite is 2 times higher. The starting substance and its main metabolite have either additive or synergistic effect against Naemophilus influenzae under in vitro and in vivo conditions depending on the bacterial culture.

Pharmacokinetics

Absorption and distribution

On oral administration, clarithromycin is rapidly and actively absorbed in the gastrointestinal tract. Absolute bioavailability is 50%. No cumulation is found when multiple doses of the drug are administered, and the metabolic pattern in the human body does not change. Food slows down absorption; taking food immediately before taking the drug increases bioavailability by 25% on average. Maximum equilibrium concentrations (Cmax) of clarithromycin and 14-hydroxyclarithromycin were achieved after the fifth dose at a dose of 500 mg twice daily, averaging 2.7-2.9 µg/ml and 0.83-0.88 µg/ml, respectively.

Clarithromycin binds to plasma proteins by 70% at concentrations ranging from 0.45 µg/ml to 4.5 µg/ml. At a concentration of 45 µg/ml, the degree of binding decreases to 41%, probably as a result of saturation of the binding sites. This is observed only at concentrations many times higher than the therapeutic concentration.

Clarithromycin and 14-hydroxyclarithromycin are well distributed to all tissues and body fluids. After oral administration of clarithromycin, its content in cerebrospinal fluid remains low (with normal GEB permeability

1-2% of serum levels). Its content in tissues is usually several times its content in serum.

Metabolism and excretion

Clarithromycin is metabolized in cytochrome P450 system with participation of CYP3A4, CYP3A5, CYP3A7 isoenzymes to form the main microbiologically active metabolite 14-hydroxyclarithromycin. When multiple doses of the drug are administered, the nature of metabolism in the human body does not change.

At equilibrium concentrations of 14-hydroxyclarithromycin do not increase in proportion to clarithromycin doses, and the elimination half-lives (T1/2) of clarithromycin and its main metabolite increase with increasing doses. The nonlinear nature of clarithromycin pharmacokinetics is associated with decreased formation of 14-hydroxylated and N-demethylated metabolites at higher doses, indicating nonlinearity of clarithromycin metabolism when taken at high doses.

The T1/2 of clarithromycin and 14-hydroxyclarithromycin are 4.5-4.8 hours and 6.9-8.7 hours, respectively, when taken at a dose of 500 mg twice daily.

Extracted by the kidneys and intestines (20-30% unchanged, the rest as metabolites). In a single dose of 250 mg and 1200 mg is excreted by the kidneys 37.9 % and 46 %, the intestines 40.2 % and 29.1 %, respectively.

Pharmacokinetics in special clinical cases

Hepatic disorders

. No clarithromycin dose adjustment is required in patients with moderate to severe hepatic impairment but with preserved renal function; equilibrium concentrations (Csas) and systemic clearance of clarithromycin do not differ from these in healthy patients. The Cs of 14-hydroxyclarithromycin is lower in people with hepatic impairment than in healthy subjects.

Kidney disease

In patients with impaired renal function, plasma Cmax and Cmin, T1/2, area under the concentration-time curve (AUC) of clarithromycin and 14-hydroxyclarithromycin are increased. The elimination constant and renal excretion decreases. The degree of change in these parameters depends on the degree of renal impairment.

Elderly patients

In elderly patients, blood concentrations of clarithromycin and 14-hydroxyclarithromycin were higher and excretion slower than in younger adults. Changes in pharmacokinetics in elderly patients are thought to be primarily related to changes in creatinine clearance and renal functional status rather than to patient age.

HIV infection

The Cs of clarithromycin and 14-hydroxyclarithromycin in patients with HIV infection who received clarithromycin in usual doses (500 mg twice daily) were similar to those in healthy subjects. However, when clarithromycin is used and at higher doses that may be required for the treatment of mycobacterial infections, concentrations of the antibiotic may be significantly higher than usual. In HIV-infected patients who received clarithromycin at a dose of 1 g per day and 2 g per day in 2 doses, Cmax was typically 2-4 mcg/ml and 5-10 mcg/ml, respectively. When using the drug in higher doses, a prolongation of the T1/2 was observed compared to that in healthy subjects receiving clarithromycin in usual doses. The increased plasma concentrations and longer half-life when using clarithromycin at higher doses are consistent with the known non-linearity of the drug’s pharmacokinetics.

Indications

Active ingredient

Composition

Composition per tablet:

The active ingredient:

Clarithromycin ̶ 500.00 mg.

Associates:

croscarmellose sodium – 42.50 mg,

microcrystalline cellulose – 222.50 mg,

silicon dioxide colloid – 25.50 mg,

Pregelatinized starch – 34.00 mg,

Stearic acid ̶ 8.50 mg,

Sodium stearyl fumarate – 17.00 mg.

Shell

. VIVACOAT® RA-2P-097 [hypromellose (hydroxypropyl methylcellulose 6 cPs) – 18.330 mg, titanium dioxide – 15.068 mg, polydextrose (E1200) – 7.050 mg, talc – 3.290 mg, Macrogol – 3350 (polyethylene glycol – 3350) – 2.820 mg, quinoline yellow dye (E104) – 0.423 mg, iron oxide yellow dye (E172) – 0.019 mg] – 47.000 mg.

How to take, the dosage

Interaction

Co-administration with such drugs as astemizole, cisapride, pimozide, terfenadine, ergotamine, dihydroergotamine, midazolam (oral dosage forms), simvastatin, lovastatin is contraindicated due to the possibility of serious side effects (see “Contraindications”).

Cyzapride and pimozide

Cyzapride and pimozide can increase concentration of cisapride, increase QT interval, and cause cardiac arrhythmias, including ventricular tachycardia including pirouette, ventricular fibrillation.

Terphenadine and astemizole

When used concomitantly the following may occur: increased terphenadine/astemizole blood concentrations, occurrence of cardiac arrhythmias, increased QT interval, ventricular tachycardia, ventricular fibrillation and pirouette tachycardia.

Ergotamine/dihydroergotamine

When used together, the following effects associated with acute poisoning by drugs of the ergotamine group are possible: vascular spasm, ischemia of the extremities and other tissues, including the central nervous system.

The effect of other drugs on clarithromycin

Drugs that are inducers of the CYP3A isoenzyme (e.g.: rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) may induce the metabolism of clarithromycin. This can lead to subtherapeutic concentrations of clarithromycin, resulting in decreased efficacy. In addition, plasma concentration of CYP3A isoenzyme inducer should be monitored, which may increase due to inhibition of CYP3A isoenzyme inducer by clarithromycin. When rifabutin and clarithromycin were used together, there was an increase in plasma concentrations and a decrease in serum concentrations of clarithromycin with an increased risk of uveitis.

The following drugs have proven or suspected effects on plasma concentrations of clarithromycin; doses may need to be adjusted or alternative treatment may be necessary if they are used with clarithromycin.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

. Strong inducers of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, can accelerate the metabolism of clarithromycin and thus decrease the plasma concentration of clarithromycin and weaken its therapeutic effect, and at the same time increase concentrations

14-UNClarithromycin

The strongest inducers of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin, can increase the plasma concentration of clarithromycin and weaken its therapeutic effect, while increasing the concentration of/p>

14-OH clarithromycin, a metabolite that is also microbiologically active. Since microbiological activity of clarithromycin and 14-OH clarithromycin differs with respect to different bacteria, the therapeutic effect may be reduced when clarithromycin and cytochrome P450 isoenzyme inducers are used together.

Etravirin

The concentration of clarithromycin is decreased with etravirin, but the concentration of the active metabolite 14-OH-clarithromycin is increased. Because 14-OH clarithromycin has low activity against Mycobacterium avium complex (MAC) infections, the overall activity against their pathogens may change, so alternative treatments should be considered for the treatment of MAC.

Fluconazole

The co-administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg twice daily in 21 adult volunteers resulted in a 33% and 18% increase in the minimum average equilibrium concentration (Csas) and AUC of clarithromycin, respectively. However, co-administration had no significant effect on the mean equilibrium concentration of the active metabolite 14-OH clarithromycin. Dose adjustment of clarithromycin in case of concomitant administration of fluconazole is not required.

Ritonavir

The co-administration of ritonavir 600 mg daily and clarithromycin 1 g daily may decrease the metabolism of clarithromycin (increase in Cmax by 31%, Cmin by

1 g)./p>

182 % and AUC by 77 %), complete inhibition of 14-hydroxyclarithromycin formation. Due to the wide therapeutic range, no dosage reduction is required in patients with normal renal function. In patients with renal impairment it is reasonable to consider the following dose adjustments: in creatinine clearance 30-60 ml/min the dose of clarithromycin should be reduced by 50%, in creatinine clearance less than 30 ml/min the dose of clarithromycin should be reduced by 75%. Ritonavir should not be coadministered with clarithromycin in doses greater than 1 g per day.

Orderal hypoglycemic agents/insulin

The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin may lead to severe hypoglycemia. Concomitant use of clarithromycin with some oral antidiabetic drugs such as nateglinide, pioglitazone, repaglinide, rosiglitazone due to inhibition of CYP3A isoenzyme by clarithromycin may cause hypoglycemia. Close monitoring of blood glucose concentrations is recommended.

The effect of clarithromycin on other drugs

Antirhythmic drugs (quinidine and disopyramide)

Ventricular pirouette tachycardia may occur when combined with quinidine or disopyramide. When concomitant use of clarithromycin with these drugs, electrocardiograms should be regularly monitored for QT interval prolongation, and serum concentrations of these drugs should be monitored. Cases of hypoglycemia have been reported with clarithromycin and disopyramide in postmarketing use. Blood glucose concentrations should be monitored when using clarithromycin and disopyramide concomitantly.

CYP3A4 interactions

Co-administration of clarithromycin, which is known to inhibit the CYP3A enzyme, and drugs primarily metabolized by the CYP3A isoenzyme may be associated with a mutual increase in their concentrations, which may enhance or prolong both therapeutic and adverse effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of CYP3A isoenzyme, especially if these drugs have a narrow therapeutic range (e.g.: carbamazepine), and/or are intensively metabolized by this enzyme. Dose adjustments should be made if necessary for drugs taken together with clarithromycin. Serum concentrations of drugs primarily metabolized by CYP3A isoenzyme should also be monitored if possible.

The following drugs/classes are metabolized by the same CYP3A isoenzyme as clarithromycin, e.g., alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (eg: warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam, and vinblastine. CYP3A agonists also include the following drugs that are contraindicated for co-administration with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see section “Contraindications”). Drugs that interact similarly through other isoenzymes within the cytochrome P450 system include phenytoin, theophylline and valproic acid.

HMG-CoA reductase inhibitors (statins)

The co-administration of clarithromycin with lovastatin or simvastatin is contraindicated (see “Contraindications.

Co-administration of lovastatin or simvastatin is contraindicated (see section “Contraindications”) due to the fact that these statins are significantly metabolized by CYP3A4 isoenzyme and co-administration with clarithromycin increases their serum concentrations, which leads to an increased risk of myopathy, including rhabdomyolysis. Rare cases of rhabdomyolysis have been reported in patients taking these drugs together. If clarithromycin is required, lovastatin or simvastatin should be discontinued during therapy.

Clarithromycin should be used with caution when combined therapy with statins. If co-administration is necessary, it is recommended to take the lowest dose of statin. Statins that do not depend on CYP3A isoenzyme metabolism (e.g.: fluvastatin) should be used. The development of signs and symptoms of myopathy should be monitored.

Peroral anticoagulants

There is a risk of serious bleeding and significantly increased prothrombin time when clarithromycin and warfarin are used concomitantly. If patients receive clarithromycin and oral anticoagulants concomitantly, prothrombin time and INR should be monitored closely.

Omeprazole

The co-administration of clarithromycin and omeprazole may increase equilibrium plasma concentrations of omeprazole (Cmax, AUC0-24, T1/2 by 30%, 89%, and

34%, respectively).

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized at least in part with CYP3A. At the same time, the CYP3A isoenzyme may be inhibited in the presence of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil may lead to increased inhibitory effects on phosphodiesterase. When these drugs are prescribed together, consideration should be given to reducing the dose of sildenafil, tadalafil, and vardenafil.

Theophylline, carbamazepine

Theophylline or carbamazepine may increase concentration in systemic blood flow.

Tolterodine

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

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

The co-administration of clarithromycin (500 mg twice daily) may increase the AUC of midazolam: 7-fold after oral administration and 2.7-fold after intravenous administration. Co-administration of midazolam and clarithromycin should be avoided. If intravenous form of midazolam is used together with clarithromycin, the patient’s condition should be closely monitored for possible dose adjustment. The same precautions should be applied to other benzodiazepines that are metabolized by the CYP3A isoenzyme, including triazolam and alprazolam. For benzodiazepines whose excretion is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

When clarithromycin and triazolam are used together, central nervous system (CNS) effects such as drowsiness and confusion are possible.

In this regard, it is recommended to monitor the symptoms of CNS disturbance if used together.

Interaction with other drugs

Aminoglycosides

When clarithromycin is coadministered with other ototoxic drugs, especially aminoglycosides, care should be taken to monitor vestibular and auditory function both during and after therapy.

Colchicine

Colchicine is a substrate of both CYP3A and the carrier protein responsible for excretion of the drug, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are taken together, inhibition of Pgp and/or CYP3A may increase the effect of colchicine.

The concomitant use of clarithromycin and colchicine is contraindicated (see section “Contraindications”).

Digoxin

Digoxin is thought to be a substrate of Pgp. Clarithromycin is known to inhibit Pgp. When digoxin and clarithromycin are coadministered, the inhibition of Pgp by clarithromycin may enhance the effects of digoxin. Concomitant administration of digoxin and clarithromycin may also result in increased serum concentrations of digoxin. Significant clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias, have been reported in some patients. Serum digoxin concentrations should be closely monitored when clarithromycin and digoxin are coadministered.

Zidovudine

The concomitant oral administration of clarithromycin and zidovudine in adult

HIV-infected patients may decrease the equilibrium concentration of zidovudine.

Because clarithromycin affects the absorption of zidovudine when taken orally, interactions can be largely avoided by taking clarithromycin and zidovudine 4 hours apart.

This type of interaction does not occur in HIV-infected children receiving clarithromycin in suspension form with zidovudine or dideoxynosine. Because clarithromycin can interfere with the absorption of zidovudine when taken orally at the same time in adult patients, this interaction is unlikely to occur with intravenous clarithromycin.

Phenytoin and valproic acid

There are data on interactions of CYP3A inhibitors (including clarithromycin) with drugs that are not metabolized by CYP3A (phenytoin and valproic acid). For these drugs, when combined with clarithromycin, determination of their serum concentrations is recommended, since there have been reports of elevated concentrations.

Bidirectional drug interactions

Atazanavir

Clarithromycin and atazanavir are both CYP3A substrates and inhibitors. There is evidence of a bidirectional interaction between these drugs. Co-administration of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may lead to a two-fold increase in the effect of clarithromycin and a 70% decrease in 14-OH clarithromycin, with a 28% increase in the AUC of atazanavir. Due to the wide therapeutic range of clarithromycin, no dose reduction is required in patients with normal renal function.

In patients with moderate renal impairment (creatinine clearance

30-60 ml/min) the dose of clarithromycin should be reduced by 50%. In patients with creatinine clearance less than 30 ml/min, the clarithromycin dose should be reduced by 75%. Clarithromycin in doses greater than 1000 mg per day should not be used together with protease inhibitors.

Slow calcium channel blockers

Care should be taken with clarithromycin concomitantly with slow calcium channel blockers that are metabolized by CYP3A4 (e.g.: verapamil, amlodipine, diltiazem) because of the risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as of “slow” calcium channel blockers may increase with concomitant use. Arterial hypotension, bradyarrhythmia and lactoacidosis are possible with concomitant use of clarithromycin and verapamil.

The co-administration of clarithromycin may cause decreased blood pressure, bradyarrhythmia, and lactic acidosis.

Itraconazole

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

Saquinavir

Clarithromycin and saquinavir are substrates and inhibitors of CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Concomitant use of clarithromycin (500 mg 2 times daily) and saquinavir

(in soft gelatin capsules, 1200 mg 3 times daily) may increase AUC and

Cs of saquinavir by 177 % and 187 % and of clarithromycin by 40 %. No dose adjustments are required when these two drugs are used together for a limited time and in the doses/compounds indicated above. The results of drug interaction studies with saquinavir monotherapy may not correspond to the effects observed with saquinavir/ritonavir therapy. The potential effects of ritonavir on clarithromycin should be considered when taking saquinavir together with ritonavir.

Special Instructions

Prolonged use of antibiotics can lead to the formation of colonies with increased numbers of insensitive bacteria and fungi. Appropriate therapy should be administered if superinfection occurs.

When using clarithromycin, cases of liver dysfunction (increased concentration of hepatic enzymes in the blood, hepatocellular and/or cholestatic hepatitis with or without jaundice) have been reported. Liver dysfunction can be severe, but is usually reversible. There are cases of hepatic failure with fatal outcome, mainly associated with the presence of serious comorbidities and/or concomitant use of other drugs. In case of signs and symptoms of hepatitis, such as anorexia, jaundice, darkened urine, itching, abdominal pain on palpation, clarithromycin therapy should be stopped immediately.

In the presence of chronic liver disease, serum enzymes should be monitored regularly.

In treatment with almost all antibacterials, including clarithromycin, there have been cases of pseudomembranous colitis, the severity of which may vary from mild to life-threatening. Antibacterials can alter the normal gut microflora, which can lead to growth of Clostridium difficile. Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients who experience diarrhea after antibiotic use. After a course of antibiotic therapy, careful medical follow-up of the patient is necessary. Cases of pseudomembranous colitis have been described 2 months after antibiotic treatment.

Clarithromycin should be used with caution in patients with coronary heart disease, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 bpm), and concomitant use with class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol) antiarrhythmic drugs. In these conditions and when concomitant use of the drug with these drugs, ECG monitoring for QT interval prolongation should be performed regularly.

Cross-resistance to clarithromycin and other macrolide antibiotics and to lincomycin and clindamycin may develop.

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

Mild to moderate skin and soft tissue infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes. Both pathogens may be resistant to macrolides. Therefore, it is important to test for sensitivity.

Macrolides can be used for infections caused by Corynebacterium minutissimum (erythrazma), common acne and rye, and in situations where penicillin cannot be used.

In case of acute hypersensitivity reactions such as anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), clarithromycin should be stopped immediately and appropriate therapy should be started.

If used together with warfarin or other indirect anticoagulants, MHO and prothrombin time should be monitored.

Impact on driving and operating ability

Perhaps caution should be exercised when driving vehicles and engaging in other potentially dangerous activities, as some of the clarithromycin side effects, such as dizziness and somnolence, may adversely affect driving and performing potentially dangerous activities that require increased concentration and quick psychomotor reactions.

Contraindications

Side effects

The adverse effects are presented according to the effects on organs and systems.

The adverse events noted with clarithromycin listed below are distributed according to the frequency of occurrence according to the following gradation: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), infrequent (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), unspecified frequency (cannot be calculated from available data).

Infectious and parasitic diseases: infrequent oral mucosal candidiasis. As with the use of other antibacterial drugs secondary infections are also possible (development of microbial resistance).

Blood and lymphatic system disorders: rare – leukopenia, eosinophilia, neutropenia, thrombocytopenia; unspecified frequency – agranulocytosis, hemorrhages.

Intrinsic system disorders: frequent – rash; infrequent – allergic reactions (urticaria, skin itching), anaphylactic/anaphylactoid reactions; unspecified frequency – Stevens-Johnson syndrome, toxic epidermal necrolysis – Lyell syndrome (potentially life-threatening), drug rash with eosinophilia and systemic symptomatology (DRESS syndrome); angioedema.

Mental disorders: frequent – insomnia; infrequent – somnolence; unspecified frequency – confusion, depersonalization, depression, disorientation, hallucinations, psychotic disorders, “nightmare” dreams, mania.

Nervous system disorders: frequently – headache, change of taste (dysgeusia); infrequently – dizziness, paresthesia, tremor, asthenia, anxiety; rarely – anosmia; unspecified frequency – seizures.

Senses: often – agueusia (loss of taste); infrequent – vertigo, tinnitus; rare – hearing loss, which resolves after discontinuation of the drug; unspecified frequency – parosmia.

Cardiovascular system disorders: infrequent prolongation of the QT interval in ECG (as in other macrolides); rare ventricular tachycardia, including “torsade de pointes” type, atrial flutter and ventricular fibrillation.

Gastro-intestinal tract disorders: frequent – diarrhea, nausea, abdominal pain, dyspepsia; infrequent – vomiting, glossitis, stomatitis, bloating, pseudomembranous colitis, anorexia, impaired appetite, constipation, belching, flatulence, dry oral mucosa, gastritis; unspecified frequency – acute pancreatitis, discolored teeth and tongue.

Hepatic and biliary tract disorders: infrequent – hepatocellular and cholestatic hepatitis, cholestasis, cholestatic jaundice; very rare – in single cases death from liver failure was registered, which were usually observed in the presence of serious comorbidities and / or concomitant use of other medicines.

Skin and subcutaneous tissue: often – hyperhidrosis; rarely – rye, unspecified frequency – acne.

Muscular system and connective tissue: infrequent – myalgia, arthralgia; unspecified frequency – myopathy.

Renal and urinary tract: infrequent interstitial nephritis; unspecified frequency – renal failure.

Laboratory measures: frequent – increase of “liver” enzymes activity; infrequent – increase of creatinine concentration, hypoglycemia (including in concurrent use of hypoglycemic agents), increase of alkaline phosphatase activity, bilirubin increase; unspecified frequency – increase of international normalized ratio (INR) value, prolongation of prothrombin time, urine color changes.

General disorders: infrequent – malaise, chest pain, chills, fatigue.

Immunocompromised patients

In patients with AIDS and other immunodeficiencies who receive clarithromycin at higher doses for long term treatment of mycobacterial infections, it is often difficult to distinguish adverse effects of the drug from symptoms of HIV infection or a concomitant disease.

The most common adverse events in patients taking a daily dose of clarithromycin equal to 1000 mg were: nausea, vomiting, perversion of taste, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing loss, elevated blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations. Low frequency adverse events, such as dyspnea, insomnia, and dry mouth, have also been reported.

In patients with suppressed immunity, laboratory values were evaluated by analyzing their significant deviations from the norm (sharp increase or decrease). Based on this criterion, 2-3% of patients who received clarithromycin at a dose of 1000 mg daily registered a significant increase in blood ALT and AST concentrations, as well as a decrease in leukocyte and platelet counts. A small number of patients also registered an increase in residual urea nitrogen concentration.

Overdose

Symptoms: large doses of clarithromycin may cause nausea, vomiting, abdominal pain, diarrhea, headache, confusion.

Treatment: gastric lavage, symptomatic therapy. Hemodialysis and peritoneal dialysis have no significant effect on serum concentrations of clarithromycin, as is common with other macrolide drugs.

Similarities