Fromilid uno, 500 mg 5 pcs

Pharmacodynamics

Clarithromycin is a semi-synthetic antibiotic of macrolide group and has antibacterial effect by interacting with 50S ribosomal subunit and inhibiting protein synthesis of bacteria sensitive to it.

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

Clarithromycin is highly active against Legionella pneumophila, Mycoplasma pneumoniae under in vitro conditions. It has a bactericidal effect against Helicobacter pylori; this activity of clarithromycin is higher at neutral pH than at acidic pH.

In addition, in vitro and in vivo data indicate that clarithromycin is active against clinically relevant mycobacterial species. Enterobacteriaceae and Pseudomonas spp. as well as other non-lactose-fermenting Gram-negative bacteria are not sensitive to clarithromycin.

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

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) – complex including: Mycobacterium avium, Mycobacterium intracellulare.

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

Helicobacter pylori. Sensitivity of Helicobacter pylori to clarithromycin was studied in Helicobacter pylori isolates isolated from 104 patients before the start of therapy with the drug. Clarithromycin-resistant Helicobacter pylori strains were isolated in 4 patients, moderately resistant strains were isolated in 2 patients, and the remaining 98 patients had Helicobacter pylori isolates sensitive to clarithromycin.

Clarithromycin has action in vitro and against most strains of the following microorganisms (however, the safety and efficacy of clarithromycin in clinical practice has not been confirmed by clinical studies, and the practical value remains unclear):

Aerobic gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groupsC, 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.

Campylobacter: Campilobacter jejuni.

The main metabolite of clarithromycin in humans is the microbiologically active metabolite 14-hydroxyclarithromycin (14-OH-clarithromycin).

The microbiological activity of the metabolite is the same as that of the parent substance, or 2 times weaker against most microorganisms. The exception is Haemophilus influenzae, against which the effectiveness of the metabolite is twice as high. The parent compound and its main metabolite have either additive or synergistic effect against Haemophilus influenzae under in vitro and in vivo conditions depending on the bacterial strain.

Pharmacokinetics

Absorption. The drug is rapidly absorbed in the gastrointestinal tract. Absolute bioavailability is about 50%. When taking repeated doses of the drug, cumulation was practically not found, and the character of metabolism in human body did not change.

Distribution, metabolism and excretion

In vitro. Clarithromycin binds to blood plasma proteins by 70% at concentrations from 0.45 to 4.5 µg/ml. At a concentration of 45 µg/ml, the binding decreases to 41%, probably as a result of saturation of the binding sites.

This is observed only at concentrations many times greater than the therapeutic concentration.

Healthy. In patients taking 500 mg of clarithromycin once daily after a meal, the Cmax of clarithromycin and 14-OH-clarithromycin in plasma was 1.3 and 0.48 µg/mL, respectively. T1/2 of clarithromycin and the metabolite were 5.3 and 7.7 h, respectively. When a single dose of clarithromycin in the dosage form – sustained release film-coated tablets, 1000 mg (2 × 500 mg), the Cmax of clarithromycin and its hydroxylated metabolite in blood plasma was 2.4 and 0.67 µg/ml, respectively. The T1/2 of clarithromycin when administered at a dose of 1,000 mg was 5.8 h, whereas the same figure for 14-OH clarithromycin was 8.9 h.

The Tmax with oral administration of both 500 and 1000 mg of clarithromycin was approximately 6 h. The Cmax of 14-OH-clarithromycin did not increase in proportion to the oral dose of clarithromycin, whereas the T1/2 of both clarithromycin and its hydroxylated metabolite tended to lengthen with increasing dose. This nonlinear pharmacokinetics of clarithromycin combined with decreased formation of 14-hydroxylated and N-demethylated products at high doses indicates a nonlinear metabolism of clarithromycin that becomes more pronounced at higher doses.

The kidneys excrete approximately 40% of the oral dose of clarithromycin; the intestines excrete approximately 30%.

Patients. Clarithromycin and its metabolite (14-OH clarithromycin) are rapidly absorbed into tissues and body fluids. There is limited evidence that the concentration of clarithromycin in cerebrospinal fluid when ingested is negligible (i.e., only 1-2% of the serum concentration with normal blood-brain barrier permeability). Concentrations in tissues are usually several times higher than in serum.

Liver function impairment. No dose adjustment of clarithromycin is required in patients with moderate to severe hepatic impairment but with preserved renal function. Plasma Css and systemic clearance of clarithromycin do not differ between patients in this group and healthy patients. Css of 14-OH clarithromycin is lower in patients with liver dysfunction than in healthy patients.

Renal dysfunction. Impaired renal function increases plasma Cmax and Cmin of clarithromycin, T1/2, AUC of clarithromycin and its metabolite (14-OH clarithromycin). The elimination constant and renal excretion decreases. The degree of change in these parameters depends on the degree of renal impairment.

In elderly patients. In elderly patients, plasma concentrations of clarithromycin and its metabolite (14-OH clarithromycin) were higher and excretion slower than in the younger group. However, after adjustment for renal creatinine clearance, there were no differences in the two groups. Thus, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, not age.

Indications

Infectious and inflammatory diseases caused by clarithromycin-sensitive microorganisms:

Active ingredient

Composition

1 film-coated sustained release tablet contains:

Core:

Active substance:

Clarithromycin 500.00 mg

Excipients:

Alginate sodium, calcium alginate sodium, lactose monohydrate, povidone K25, polysorbate-80, colloidal silicon dioxide, magnesium stearate, talc

Shell film:

Hypromellose, talc, iron oxide yellow dye (E172), titanium dioxide (E171), propylene glycol

How to take, the dosage

Fromilide® uno is administered orally.

The tablet should be swallowed whole, without breaking or chewing.

Adults and children over 12 years old: 1 tablet (500 mg) once a day with meals.

For tonsillitis and acute otitis media:Adults and children over 18 years of age – 1 tablet (500 mg) once a day with a meal.

In severe infections, the dose is increased to 2 tablets (1000 mg) once a day with meals.

Usual duration of treatment is from 5 to 14 days. The exceptions are community-acquired pneumonia and sinusitis, which require 6 to 14 days of treatment.

Kidney function disorders

Fromilide®, film-coated tablets, 250 mg, is the usual recommended dose for patients with severe renal impairment (CKR less than 30 ml/min) once daily, in which case Fromilide®, film-coated tablets, 250 mg may be used. In more severe infections, the recommended dose is 1 tablet 500 mg with prolonged release clarithromycin.

In patients with moderate renal impairment (CK of 30 to 60 ml/min), no dose adjustment is required.

Interaction

The use of the following drugs concomitantly with clarithromycin is contraindicated due to with the possibility of serious side effects

Cisapride, pimozide, terfenadine, and astemizole

When clarithromycin is taken concomitantly with cisapride, pimozide, terfenadine, or astemizole, increased plasma concentrations of the latter have been reported, which may result in prolonged QT interval on the ECG and cardiac arrhythmias, including ventricular tachycardia (including “pirouette” ventricular tachycardia) and ventricular fibrillation (see See section “Contraindications”).

Sorgonum alkaloids

Postmarketing studies indicate that the following effects associated with acute poisoning by ergotamine-group drugs are possible when clarithromycin is used concomitantly with ergotamine or dihydroergotamine: vascular spasm, limb and other tissue ischemia, including the central nervous system (CNS). Simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see section “Contraindications”).

HMG-CoA reductase inhibitors (statins)

The concomitant administration of clarithromycin with lovastatin or simvastatin is contraindicated (see concomitant use of clarithromycin is contraindicated (see section “Contraindications”) due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme, and concomitant use with clarithromycin increases their serum concentrations, which leads to an increased risk of myopathy, including rhabdomyolysis. Rhabdomyolysis has been reported in patients taking clarithromycin concomitantly with these drugs. If clarithromycin should be used, lovastatin or simvastatin should be discontinued during therapy.

Clarithromycin should be used with caution in case of combined therapy with other statins. It is recommended to use statins whose metabolism is not dependent on CYP3A isoenzyme (e.g., fluvastatin). In case concomitant administration is necessary, it is recommended to take the lowest dose of statin. The development of signs and symptoms of myopathy should be controlled.

Midazolam for oral administration

The concomitant use of midazolam and clarithromycin in tablet form (500 mg twice daily) showed a 7-fold increase in the AUC of midazolam after oral administration. Concomitant use of clarithromycin with oral midazolam is contraindicated.

Effects of other drugs on clarithromycin

Drugs that are CYP3A isoenzyme inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort preparations) may induce clarithromycin metabolism. This may lead to subtherapeutic concentrations of clarithromycin and, consequently, to a decrease in its efficacy. In addition, it is necessary to monitor the plasma concentration of CYP3A isoenzyme inducer, which may increase due to inhibition of CYP3A isoenzyme by clarithromycin. When using rifabutin and clarithromycin concomitantly, an increase in rifabutin concentration and a decrease in clarithromycin plasma concentration were observed with an increased risk of uveitis.

The following drugs have proven or suspected effects on clarithromycin plasma concentrations and may require dose adjustments or switching to alternative treatment

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 therapeutic effect, while increasing the plasma concentration of 14-OH clarithromycin, a metabolite that is also microbially active. Since microbiological activity of clarithromycin and 14-OH clarithromycin is different for different bacteria, the therapeutic effect can be decreased when using clarithromycin and cytochrome P450 system inducers at the same time.

Etravirin

Plasma concentrations of clarithromycin are decreased when used concomitantly with etravirine, but plasma concentrations of the active metabolite 14-OH-clarithromycin are increased. Since 14-OH clarytromycin has low activity against MAC infections, the overall activity against these pathogens may change, therefore alternative treatment should be considered for MAC treatment.

Fluconazole

The concomitant administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg twice daily in 21 healthy volunteers resulted in a 33% and 18% increase in the mean minimum equilibrium concentration (Cmin) of clarithromycin and AUC, respectively. However, concomitant 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

Pharmacokinetic study showed that concomitant administration of ritonavir at a dose of 200 mg every 8 hours and clarithromycin at a dose of 500 mg every 12 hours resulted in marked inhibition of clarithromycin metabolism. Concomitant administration of ritonavir increased Cmah clarithromycin by 31%, Cmin increased by 182% and AUC increased by 77%. Complete inhibition of 14-OH clarithromycin formation was observed. Due to the wide therapeutic range of clarithromycin, no dose reduction is required in patients with normal renal function. In patients with renal impairment, it is reasonable to consider the following dose adjustments: for a CKR of 30-60 ml/min, the clarithromycin dose should be reduced by 50%. Similar dose adjustments should be considered in patients with reduced renal function if ritonavir is used as a pharmacokinetic “enhancer” when using other HIV protease inhibitors, including atazanavir and saquinavir (see subsection “Bidirectional Drug Interactions”).

Ritonavir should not be taken concomitantly with clarithromycin in doses greater than 1 g/day.

Effects of clarithromycin on other drugs

Antiarrhythmic agents (quinidine and disopyramide)

Ventricular pirouette tachycardia may occur when clarithromycin and quinidine or disopyramide are used simultaneously. When concomitant use of clarithromycin with these drugs, regular ECG monitoring for QT interval prolongation should be performed and serum concentrations of these drugs should be monitored.

In post-marketing use, cases of hypoglycemia have been reported with clarithromycin and disopyramide concomitantly. Blood glucose concentrations should be monitored when using clarithromycin and disopyramide concomitantly.

Hypoglycemic agents for oral administration/insulin

The concomitant use of clarithromycin and oral hypoglycemic agents (e.g., sulfonylurea derivatives) and/or insulin may result in marked hypoglycemia. Concomitant use of clarithromycin with some hypoglycemic drugs (e.g. nateglinide, pioglitazone, repaglinide and rosiglitazone) may lead to inhibition of CYP3A isoenzyme by clarithromycin, which may result in hypoglycemia. Close monitoring of blood glucose concentration is recommended.

Interactions due to isoenzyme CYP3A

Concurrent administration of clarithromycin, which is known to inhibit the CYP3A isoenzyme, and drugs primarily metabolized by the CYP3A isoenzyme may be associated with a mutual increase in their concentrations, which may increase or prolong both therapeutic and side 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 drugs that are extensively metabolized by this isoenzyme. Dose adjustments should be made for drugs taken concomitantly with clarithromycin if necessary. Serum concentrations of drugs that are primarily metabolized by CYP3A isoenzyme should also be monitored if possible.

The following drugs/classes are metabolized by the same CYP3A isoenzyme as clarithromycin: alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (e.g., warfarin), atypical antipsychotics (e.g., quetiapine), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. CYP3A inhibitors also include the following drugs that are contraindicated for concomitant use 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.

Direct anticoagulants

The concomitant use of warfarin and clarithromycin may cause bleeding, marked increase in INR and prolongation of prothrombin time. In case of concomitant use with warfarin or other indirect anticoagulants it is necessary to monitor INR and prothrombin time.

Omeprazole

Clarithromycin (500 mg every 8 hours) was studied in healthy adult volunteers in combination with omeprazole (40 mg daily). When clarithromycin and omeprazole were used concomitantly, equilibrium plasma concentrations of omeprazole were increased (Cmax, AUC0-24 and T1/2 increased by 30 %, 89 % and 34 %, respectively). The mean gastric pH over 24 hours was 5.2 (when taking omeprazole alone) and 5.7 (when taking omeprazole simultaneously with clarithromycin).

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized at least in part by the CYP3A isoenzyme. However, the CYP3A isoenzyme may be inhibited in the presence of clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to increased inhibitory effects on phosphodiesterase. When using these drugs concomitantly with clarithromycin, consider reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline, carbamazepine

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

Tolterodine

The primary metabolism of Tolterodine is through the CYP2D6 isoenzyme. However, in a portion of the population lacking the CYP2D6 isoenzyme, metabolism occurs via the CYP3A isoenzyme. In this population, suppression of the CYP3A isoenzyme leads to significantly higher serum concentrations of tolterodine. In a population with low metabolism through the CYP2D6 isoenzyme, a dose reduction of tolterodine may be required with concomitant use of CYP3A isoenzyme inhibitors such as clarithromycin.

Benzodiazepines (e.g., alprazolam, midazolam [solution for intravenous injection], triazolam)

When midazolam and clarithromycin tablets (500 mg twice daily) were used concomitantly, there was a 2.7-fold increase in the AUC of midazolam after intravenous administration of midazolam. If intravenous solution dosage form of midazolam is used concomitantly with clarithromycin, the patient’s condition should be closely monitored for possible adjustment of the dose of midazolam. Administration of the drug through the oral mucosa, which allows bypassing the presystemic elimination of the drug, is likely to result in an interaction similar to that seen with intravenous administration of midazolam rather than with oral administration.

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

Concurrent use of clarithromycin and triazolam may affect CNS, e.g., drowsiness and confusion. Therefore, in case of concomitant use, it is recommended to monitor the symptoms of CNS disturbance.

Interactions with other drugs

Colchicine

Colchicine is a substrate of both the CYP3A isoenzyme and the transfer protein P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to be CYP3A and Pgp isoenzyme inhibitors. If clarithromycin and colchicine are used concomitantly, inhibition of Pgp and/or CYP3A isoenzyme may lead to increased effect of colchicine. The development of clinical symptoms of colchicine poisoning should be controlled. There have been post-marketing reports of cases of colchicine poisoning when concomitantly administered with clarithromycin, more often in elderly patients. Some of the described cases occurred in patients with renal insufficiency. Some cases have been reported to be fatal. Concomitant use of clarithromycin and colchicine is contraindicated (see section “Contraindications”).

Digoxin

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

Zidovudine

The simultaneous ingestion of clarithromycin and zidovudine tablets by HIV-infected adults may result in a decrease in the equilibrium plasma concentration of zidovudine. Because clarithromycin affects oral absorption of zidovudine, interactions can be largely avoided by taking clarithromycin and zidovudine at 4-hour intervals. No such interaction has been observed in HIV-infected children taking clarithromycin infant suspension with zidovudine or dideoxynosine. Because clarithromycin can interfere with the absorption of zidovudine when taken simultaneously orally in adult patients, such an interaction is unlikely when clarithromycin is used intravenously.

Phenytoin and valproic acid

There is evidence of interaction of CYP3A isoenzyme inhibitors (including clarithromycin) with drugs that are not metabolized by CYP3A isoenzyme (phenytoin and valproic acid). For these drugs, when concomitantly used with clarithromycin, it is recommended to determine their serum concentrations, since there have been reports of elevated concentrations.

Double-drug interactions

Atazanavir

Clarithromycin and atazanavir are both substrates and CYP3A isoenzyme inhibitors. There is evidence of a bidirectional interaction between these drugs. Concomitant use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may result in a twofold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure with a 28% increase in atazanavir AUC. 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 (CKD 30-60 ml/min) the dose of clarithromycin should be reduced by 50%. In patients with CKR less than 30 ml/min, the clarithromycin dose should be reduced by 75% using an appropriate clarithromycin dosage form. Clarithromycin in doses greater than 1000 mg/day should not be used concomitantly with protease inhibitors.

Slow calcium channel blockers

When using clarithromycin and slow calcium channel blockers that are metabolized by CYP3A4 isoenzyme (e.g., verapamil, amlodipine, diltiazem) simultaneously, caution should be exercised because of the risk of arterial hypotension. Concomitant use may increase plasma concentrations of clarithromycin and “slow” calcium channel blockers. Arterial hypotension, bradyarrhythmia and lactoacidosis are possible when concomitant use of clarithromycin and verapamil.

Itraconazole

Clarithromycin and itraconazole are both substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Clarithromycin may increase the plasma concentration of itraconazole, while itraconazole may increase the plasma concentration of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be closely monitored for symptoms of increased or prolonged 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 (soft gelatin capsules, 1200 mg 3 times daily) in 12 healthy volunteers caused a 177% and 187% increase in plasma AUC and Cmah saquinavir compared to taking saquinavir alone, respectively. The AUC and Cmah values of clarithromycin were approximately 40% higher than those of clarithromycin alone therapy. No dose adjustments are required when the two drugs are used concomitantly for a limited time in the doses/compositions indicated above. The results of drug interaction studies using saquinavir in soft gelatin capsules may not correspond to the effects observed when using saquinavir in hard gelatin capsules. The results of studies of drug interactions during therapy with saquinavir alone may not correspond to the effects observed during therapy with the saquinavir/ritonavir combination. The potential effects of ritonavir on clarithromycin should be considered when taking saquinavir concomitantly 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.

Hepatic dysfunction (increased plasma liver enzyme activity, hepatocellular and/or cholestatic hepatitis with or without jaundice) has been reported with clarithromycin.

Hepatic dysfunction can be severe, but is usually reversible. There have been cases of fatal liver failure, mostly related to the presence of serious comorbidities and/or concomitant use of other medications. In case of signs and symptoms of hepatitis, such as anorexia, jaundice, darkened urine, itching of the skin, abdominal pain on palpation, clarithromycin therapy should be stopped immediately.

In the presence of chronic liver disease, regular monitoring of serum liver enzyme activity is necessary.

When treated with almost all antibacterial agents, including clarithromycin, there have been described cases of pseudomembranous colitis, the severity of which may vary from mild to life-threatening. Antibacterials can change normal gut flora, which can lead to growth of Clostridium difficile.

Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients with 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 use.

Long QT interval. A prolonged period of myocardial repolarization and the QT interval, increasing the risk of cardiac arrhythmias and pirouette arrhythmias, have been reported with macrolides, including clarithromycin. Clarithromycin use may increase the risk of ventricular arrhythmias (including pirouette arrhythmias), so clarithromycin should be used with caution:

– in patients with CHD, severe heart failure, impaired cardiac conduction, clinically significant bradycardia;

– in patients with water-electrolyte disorders, such as hypomagnesemia. Clarithromycin should not be administered to patients with hypokalemia;

– when concomitantly used with other drugs associated with prolongation of the QT interval (see “Interaction”).

The development of cross-resistance to clarithromycin and other antibiotics of the macrolide group, as well as to lincomycin and clindamycin is possible.

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 antibiotic sensitivity.

Macrolides can be used for infections caused by Corynebacterium minutissimum (erythrasma), acne vulgaris 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 and drug rash with eosinophilia and systemic symptoms (DRESS syndrome), clarithromycin should be stopped immediately and appropriate therapy started.

In case of concomitant use with warfarin or other indirect anticoagulants, the INR and PV should be monitored (see “Interaction”).

Impact on driving and operating ability. There are no data on the effect of clarithromycin on the ability to drive and operate machinery. The potential for dizziness, vertigo, confusion and disorientation that may occur with this drug should be considered.

Caution should be exercised when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration and quick psychomotor reactions.

Synopsis

Oval, biconvex, film-coated tablets with a brown-yellow color, marked U on one side.

Breakage appearance: a rough mass of white or almost white color with a brown-yellow film coating.

Contraindications

– severe renal impairment (creatinine Cl less than 30 ml/min);

– concomitant administration of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine (see “Interaction”).

– concomitant administration of clarithromycin with ergot alkaloids, e.g. ergotamine, dihydroergotamine (see “Interactions”).

– concomitant administration of clarithromycin with oral midazolam (see “Interactions”).

– concomitant administration of clarithromycin with HMG-CoA reductase inhibitors (statins) that are largely metabolized by the CYP3A4 isoenzyme (lovastatin, simvastatin) due to an increased risk of myopathy, including rhabdomyolysis (see “Interaction”). “Interactions);

– concomitant use of clarithromycin with colchicine;

– concomitant use with ticagrelor or ranolazine;

– history of ECG QT interval prolongation (congenital or documented QT interval prolongation), history of ventricular arrhythmias or pirouette-type ventricular tachycardia;

– hypokalemia (risk of ECG QT interval prolongation);

– severe hepatic impairment concurrent with renal impairment;

– a history of cholestatic jaundice/hepatitis that developed with clarithromycin (see “Special Precautions. “

– porphyria;

– lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;

– period of breastfeeding;

– age under 18 years of age (with indications: tonsillitis, acute otitis media), under 12 years of age (for other indications).

With caution: moderate to severe renal failure; moderate to severe hepatic failure; concomitant administration of clarithromycin with benzodiazepines such as alprazolam, triazolam, midazolam for IV administration (see “Interactions”). Interaction); concomitant administration with drugs that are metabolized by CYP3A isoenzymes, e.g. carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (e.g. warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine (see “Interaction”). “Interaction”); concomitant administration with drugs that induce the CYP3A4 isoenzyme, e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort (see “Interaction”). “Interaction”); concomitant administration with BCCs that are metabolized by CYP3A4 isoenzymes (e.g. verapamil, amlodipine, diltiazem); concomitant administration with other ototoxic drugs, especially aminoglycosides; concomitant use with statins that do not depend on CYP3A4 isoenzyme metabolism (e.g. fluvastatin); patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 bpm), and patients with cardiac insufficiency./min), as well as patients who simultaneously take antiarrhythmic drugs of class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol); pregnancy.

Side effects

The World Health Organization (WHO) classification of the incidence of adverse effects is: 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; frequency unknown – cannot be estimated based on available data. Within each group, adverse effects are presented in decreasing order of severity.

Allergic reactions: Frequent – skin rash; infrequent – anaphylactoid reaction1, hypersensitivity, bullous1 dermatitis, pruritus, urticaria, maculopapular rash3; frequency unknown – anaphylactic reaction, angioneurotic edema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptomatology (DRESS syndrome).

Nervous system disorders: Frequent – headache, insomnia; infrequent – loss of consciousness1, dyskinesia1, dizziness, somnolence, tremor, restlessness, increased excitability3; frequency unknown – seizures, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disorders (“nightmare” dreams), paresthesia, mania.

Skin disorders: often – intense sweating; frequency unknown – acne, hemorrhages.

Urinary system disorders: frequency unknown – renal failure, interstitial nephritis.

Metabolism and nutrition: infrequent – anorexia, decreased appetite.

Musculoskeletal system: infrequent – muscle spasm, musculoskeletal stiffness, myalgia; frequency unknown – rhabdomyolysis2.5, myopathy.

Digestive system disorders: frequent – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; infrequent – esophagitis1, gastroesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, bloating4, constipation, dry oral mucosa, belching, flatulence, cholestasis4, hepatitis including. including cholestatic or hepatocellular4; frequency unknown – acute pancreatitis, discoloration of tongue and teeth, liver failure, cholestatic jaundice.

Respiratory system: infrequent – bronchial asthma1, nasal bleeding2, pulmonary embolism1.

Senses: frequent – dysgeusia (perversion of taste); infrequent – vertigo, impaired hearing, tinnitus; frequency unknown – deafness, agueusia (loss of taste), parosmia, anosmia.

Particularly cardiac disorders: frequently – vasodilation1; infrequently – sudden cardiac arrest1, atrial fibrillation1, prolongation of QT interval in ECG, extrasystole1, atrial flutter; frequently unknown – ventricular tachycardia including “pirouette” type, ventricular fibrillation.

Laboratory measures: frequent – deviation of laboratory indicators of liver function; infrequent – increased concentration of creatinine1, increased concentration of urea1 in blood plasma, change in albumin/globulin ratio1, leukopenia, neutropenia4, eosinophilia4, thrombocythemia3, increased activity of AJIT, ACT, GGT4, ALP4, LDH4 in blood plasma; frequency unknown – agranulocytosis, thrombocytopenia, increased INR, prolongation of PV, color changes in urine, increased plasma bilirubin concentration.

Others: infrequent – malaise4, hyperthermia3, asthenia, chest pain4, chills4, increased fatigue4.

Infectious and parasitic diseases: infrequent – cellulitis1, candidiasis, gastroenteritis2, secondary infections3 (including vaginal); frequency unknown – pseudomembranous colitis, rye.

Patients with suppressed immunity

In patients with AIDS and other immunodeficiencies receiving 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 co-morbidity.

The most common adverse events in patients taking a daily dose of clarithromycin equal to 1000 mg were: nausea, vomiting, dysgeusia (perversion of taste), abdominal pain, diarrhea, skin rash, flatulence, headache, constipation, hearing disorders, and increased ACT and ALT activity in blood plasma. There have also been cases of adverse events with low frequency of occurrence, such as: dyspnea, insomnia, and dry oral mucosa.

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, in 2-3% of patients who received clarithromycin at a dose of 1000 mg daily, a significant increase in plasma ACT and ALT activity was recorded, as well as a decrease in leukocyte and platelet counts. A small number of patients also registered an increase in plasma residual urea nitrogen concentration.

1 These adverse reactions have been reported in clinical studies as well as in post-marketing use of clarithromycin in the form of lyophilisate for preparation of solution for infusion.

2 Reports of these adverse reactions have been received during clinical studies as well as post-marketing use of clarithromycin in the dosage form of film-coated sustained release tablets.

3 These adverse reactions have been reported in clinical studies as well as in post-marketing use of clarithromycin in the oral suspension powder form.

4 Reports of these adverse reactions have been received during clinical studies as well as post-marketing use of clarithromycin in the dosage form of film-coated tablets.

5 In some reports of rhabdomyolysis, clarithromycin has been taken concomitantly with other drugs known to be associated with rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

Overdose

Symptoms: ingestion of a high dose of clarithromycin can cause gastrointestinal symptoms.

One patient with a history of bipolar disorder has described mental status changes, paranoid behavior, hypokalemia, and hypoxemia after taking 8 g of clarithromycin.

Treatment: in case of overdose the unabsorbed drug should be removed from the gastrointestinal tract (gastric lavage, activated charcoal, etc.) and symptomatic therapy should be conducted. Hemodialysis and peritoneal dialysis have no significant effect on serum concentrations of clarithromycin, as is the case with other macrolide drugs.

Pregnancy use

Safety of clarithromycin use during pregnancy and breastfeeding has not been established.

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

Clarithromycin is excreted with the breast milk. If it is necessary to take it during breastfeeding, breastfeeding should be stopped.

Similarities