Fromilide - instructions for use, doses, side effects, contraindications

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Dosage form: & nbspGranules for preparation of suspension for oral administration

Composition:

1 bottle contains 25 g of granules:

active substance: clarithromycin 1,500 g;

Excipients: carbomer 934P 0.9000 g, povidone 0.1763 g, hypromellose phthalate (HP 55) 1.3741 g, talc 0.4122 g, castor oil 0.1374 g, xanthan gum 0.2000 g, banana flavor 0.1900 g, citric acid, anhydrous 0.0550 g, potassium sorbate 0.1330 g, silicon dioxide colloidal, anhydrous 0.0900 g, titanium dioxide 0.0220 g, sucrose 19,8100 g.

Description:

Granules for the preparation of a suspension for ingestion: small granules from white to light yellow color, with the smell of a banana.

Description of the slurry: a homogeneous aqueous suspension of a yellowish white color with the smell of a banana.

Pharmacotherapeutic group:antibiotic-macrolide

Pharmacodynamics:

Clarithromycin is a semisynthetic antibiotic in the macrolide group and has an antibacterial effect by interacting with the 50S ribosomal subunit and suppressing protein synthesis of bacteria sensitive to it.

Clarithromycin demonstrated high activity in conditions in vitro for 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.The minimum inhibitory concentrations (MPC) of clarithromycin for most pathogens are less than the erythromycin MPC, on average one log₂ breeding.

Clarithromycin in conditions in vitro highly active in relation to Legionella pneumophila, Mycoplasma pneumoniae. Has a bactericidal effect against Helicobacter pylori, this activity of clarithromycin is higher at neutral pH than with acid. In addition, the data in the conditions in vitro and in vivo indicate that clarithromycin acts on clinically significant species of mycobacteria. Enterobacteriaceae and Pseudomonas spp. As well as other non-fermenting lactose, gram-negative bacteria are not sensitive to clarithromycin.

The activity of clarithromycin against most strains listed below microorganisms is proved both in conditions in vitro, and in clinical practice for the diseases listed in the section "Indications for use."

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.

Othermicroorganisms:

- Mycoplasma pneumoniae,

- Chlamydia pneumoniae (TWAR).

Mycobacteria:

- Mycobacterium leprae,

- Mycobacterium kansasii,

- Mycobacterium chelonae,

- Mycobacterium fortuitum,

- Mycobacterium avium complex (MAC) - a complex that includes: Mycobacterium avium, Mycobacterium intracellulare.

The production of beta-lactamase does not affect the activity of clarithromycin. Most strains of staphylococcus aureus resistant to methicillin and oxacillin are resistant to clarithromycin.

Helicobacter pylori

Sensitivity Helicobacter pylori to clarithromycin was studied on isolates Helicobacter pylori, isolated from 104 patients prior to initiation of drug therapy. In 4 patients, strains resistant to clarithromycin were isolated Helicobacter pylori, in 2 patients - strains with moderate resistance, in the remaining 98 patients, isolates Helicobacter pylori were sensitive to clarithromycin.

Clarithromycin exerts its effect in conditions in vitro and for most strains of the following microorganisms (however, the safety and efficacy of clarithromycin in clinical practice has not been confirmed by clinical studies, and practical significance remains unclear):

Aerobic Gram-positive microorganisms:

- Streptococcus agalactiae,

- Streptococci (groups C, F, G),

- Viridans group streptococci.

Aerobic Gram-negative microorganisms:

- Bordetella pertussis,

- Pasteurella multocida,

Anaerobic Gram-positive microorganisms:

- Clostridium perfringens,

- Peptococcus niger,

- Propionibacterium acnes.

Anaerobic Gram-negative microorganisms:

Bacteroides melaninogenicus.

Spirochetes:

- Borrelia burgdorferi,

- Treponema pallidum.

Campylobacteria:

- Campylobacter jejuni.

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

The microbiological activity of the metabolite is the same as that of the starting material, or 2 times weaker in respect of most microorganisms. The exception is Haemophilus influenzae, in relation to which the efficiency of the metabolite is twice as high. The starting compound and its main metabolite exert either an additive or a synergistic effect onHaemophilus influenzae in conditions in vitro and in vivo depending on the strain of bacteria.

Pharmacokinetics:

Suction

The first data on pharmacokinetics were obtained in the study of clarithromycin tablets. The drug is rapidly absorbed in the gastrointestinal tract. Absolute bioavailability of 500 mg of clarithromycin tablets is approximately 50%. Eating somewhat delayed the onset of absorption and the formation of an active metabolite (14-OH-clarithromycin), but did not affect the bioavailability of the drug.

Distribution, metabolism and excretion

In vitro

In studies in vitro the binding of clarithromycin to blood plasma proteins averaged about 70% at clinically significant concentrations from 0.45 to 4.5 μg / ml.

Healthy

Bioavailability and pharmacokinetics of clarithromycin suspension were studied in healthy adults and children. With a single admission in adults, the bioavailability of the suspension was equivalent to that of tablets (in both cases, the dose was 250 mg) or slightly higher. As in the case of tablets, the intake of food somewhat delayed the absorption of the clarithromycin suspension, but did not affect the overall bioavailability of the drug. The maximum concentration (C_mOh), the area under the "concentration-time" curve (AUC) and half-life (T_1/2) of clarithromycin in blood plasma when using a suspension (after eating) in children was 0.95 μg / ml, 6.5 μg.h / ml and 3.7 hours, respectively, and when taking the tablet 250 mg (fasting) - 1, 1 μg / ml, 6.3 μg.h / ml and 3.3 hours, respectively. When receiving a suspension of clarithromycin at a dose of 250 mg every 12 hours in adults, the equilibrium concentrations in the blood plasma were reached by taking a fifth dose. The pharmacokinetics parameters were as follows: C_mOh - 1.98 μg / ml, AUC - 11.5 μg.h / ml, the time to reach the maximum concentration (TC_mOh) - 2.8 hours and T_1/2- 3.2 hours for clarithromycin and, accordingly, 0.67, 5.33, 2.9 and 4.9 for 14-OH-clarithromycin.

In healthy people, serum concentrations reached a maximum within 2 hours after oral administration on an empty stomach. When taking the drug in the form of tablets at a dose of 250 mg every 12 hours, the peak equilibrium concentrations of clarithromycin in the blood serum were achieved within 2-3 days and were approximately 1 μg / ml. Appropriate peak concentrations for a dose of 500 mg every 12 hours were from 2 μg / ml to 3 μg / ml.

T_1/2clarithromycin was 3-4 hours with 250 mg tablets taken every 12 hours, but increased to 5-7 hours after administration of 500 mg every 12 hours. The maximum equilibrium concentration of the main metabolite, 14-OH-clarithromycin, is about 0.6 μg / ml, and T_1/2when taking the drug at a dose of 250 mg every 12 hours is 5-6 hours. When taking clarithromycin at a dose of 500 mg every 12 hours, the maximum equilibrium concentration of 14-OH-clarithromycin is slightly higher (up to 1 μg / ml), and T_1/2 is about 7 hours. When both doses are used, the equilibrium concentrations of the metabolite are usually achieved within 2-3 days. When using clarithromycin at a dose of 250 mg every 12 hours, approximately 20% of the dose is excreted by the kidneys unchanged. When taking clarithromycin at a dose of 500 mg every 12 hours, approximately 30% of the dose is removed by the kidneys unchanged. The renal clearance of clarithromycin is substantially independent of the dose and is approximately equal to the normal glomerular ratefiltering. The main metabolite, determined in urine, is 14-OH-clarithromycin, the proportion of which is 10-15% from the ingested dose (250 or 500 mg every 12 hours).

Patients

Clarithromycin and its metabolite (14-OH-clarithromycin) rapidly penetrate into tissues and body fluids. Tissue concentrations are usually several times higher than serum concentrations.

The table gives examples of tissue and serum concentrations:

Concentrations (250 mg every 12 hours)
Type of fabric	Tissue (μg / g)	Serum (μg / ml)
Tonsils	1,6	0,8
Lungs	8,8	1,7

In children who needed antibiotic treatment for oral administration, clarithromycin showed high bioavailability, while the profile of his pharmacokinetics was similar to that of adults taking the same dosage form. The drug is quickly and well absorbed in children. The intake of food somewhat delays the absorption of clarithromycin, but does not significantly affect its bioavailability or pharmacokinetic properties. The equilibrium parameters of the pharmacokinetics of clarithromycin achieved after 5 days (ninth dose) were as follows: C_max- 4.60 μg / ml, AUC - 15.7 μg.h / ml and T_1/2- 2.8 hours, the corresponding values for the metabolite (14-OH-clarithromycin) were 1.64 μg / ml, 6.69 μg.h / ml and 2.7 hours, respectively. Calculated T_1/2clarithromycin and its metabolite are 2.2 and 4.3 hours, respectively.

In patients with otitis media 2.5 hours after taking the fifth dose (7.5 mg / kg 2 times a day), the mean concentrations of clarithromycin and its metabolite in the middle ear fluid were 2.53 and 1.27 μg / g. The concentrations of clarithromycin and its metabolite in the middle ear fluid were twice as high as serum concentrations.

Impaired liver function

The equilibrium concentrations of clarithromycin in patients with impaired hepatic function do not differ from those in healthy people, while the concentrations of 14-OH-clarithromycin were lower. Reduction in the formation of 14-OH-clarithromycin in patients with impaired liver function was at least partially offset by an increase in renal clearance of clarithromycin in comparison with that in healthy individuals.

Impaired renal function

The pharmacokinetics of clarithromycin also changed in patients with impaired renal function who received the drug in repeated doses of 500 mg. In such patients, T_1/2, FROM_mOh, the minimum concentration (C_max) and AUC clarithromycin in the blood plasma and its metabolite were higher than in healthy people.The deviations of these parameters correlated with the degree of renal failure. With more pronounced impairment of renal function, the differences were more significant (see section "Method of administration and dose").

Elderly patients

In elderly patients, the concentration of clarithromycin and its metabolite (14-OH-clarithromycin) in the blood plasma was higher, and excretion was slower than in a group of young people. However, after correction for renal clearance of creatinine (CC), there was no difference in both groups. Thus, the main effect on the pharmacokinetic parameters of clarithromycin is the function of the kidneys, not age.

Patients with mycobacterial infections

The equilibrium concentrations of clarithromycin and 14-OH-clarithromycin in patients with HIV infection who received clarithromycin in usual doses (tablets - in adults patients, suspension - in children of childhood), were similar to those in healthy people. However, when taking clarithromycin at higher doses that may be required for the treatment of mycobacterial infections, the antibiotic concentrations can be significantly higher than usual.

In children with HIV infection, who took clarithromycin in a dose of 15-30 mg / kg / day in 2 divided doses, the equilibrium values of C_max typically comprised between 8 and 20 μg / ml. However, in children with HIV infection who received a suspension of clarithromycin at a dose of 30 mg / kg / sug in 2 divided doses, C_max reached 23 μg / ml. When taking the drug at higher doses, there was an increase in 33/2 compared with that in healthy people who received clarithromycin in usual doses. Increase in plasma concentration and lengthening T_1/2when using clarithromycin in higher doses is associated with the non-linear pharmacokinetics of the drug.

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to clarithromycin:

- infections of the lower respiratory tract (such as bronchitis, pneumonia);

- upper respiratory tract infections (such as pharyngitis, sinusitis);

- infections of the skin and soft tissues (such as folliculitis, inflammation of the subcutaneous tissue, erysipelas):

- disseminated or localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare;

- localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii;

- acute otitis media.

Contraindications:

- Hypersensitivity to clarithromycin, other components of the drug and other macrolides;

- simultaneous reception of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with ergot alkaloids, for example, ergotamine dihydroergotamine (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with midazolam for oral administration (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with inhibitors of HMG-CoA reductase (statins), which are largely metabolized by the isoenzyme CYP3A4 (lovastatin, simvastatin), due to an increased risk of myopathy, including rhabdomyolysis (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with colchicine;

- simultaneous reception of clarithromycin with ticagrelor or ranolazine;

- prolongation of QT interval on an electrocardiogram (ECG) in anamnesis, ventricular arrhythmia or ventricular tachycardia of the "pirouette" type;

- hypokalemia (risk of prolonging the QT interval on the ECG);

- severe hepatic insufficiency,flowing simultaneously with renal insufficiency;

- Cholestatic jaundice / hepatitis in history, developed with the use of clarithromycin (see section "Special instructions");

- porphyria;

- the period of breastfeeding;

- congenital intolerance to fructose, insufficiency of the enzyme sugarase-isomaltase, glucose-galactose malabsorption syndrome (the preparation contains sucrose).

Carefully:

- Renal failure of moderate to severe severity;

- hepatic insufficiency of moderate and severe degree;

- simultaneous reception of clarithromycin with benzodiazepines, such as alprazolam, triazolam, midazolam for intravenous use (see "Interaction with Other Drugs");

- simultaneous reception of clarithromycin with other ototoxic drugs, especially aminoglycosides (see section "Interaction with other medicinal products");

- simultaneous reception with drugs that are metabolized by the isoenzyme CYP3A, for example, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus. vinblastine (cm.section "Interaction with other drugs");

- simultaneous administration with drugs inducing isoenzyme CYP3A4, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, Hypericum perforated (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with statins that do not depend on the metabolism of the isoenzyme CYP3A (for example, fluvastatin) (see the section "Interaction with other drugs");

- simultaneous reception with blockers of "slow" calcium channels, which are metabolized by the isoenzyme CYP3A4 (for example, verapamil, amlodipine, diltiazem);

- Patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats per minute), and patients taking antiarrhythmic drugs of the IA class simultaneously (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol);

- diabetes mellitus (the preparation contains sucrose);

- pregnancy.

Pregnancy and lactation:

The safety of clarithromycin during pregnancy and during 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 in breast milk. If you need to take during breastfeeding, breastfeeding should be stopped.

Dosing and Administration:

To prepare the suspension, 42 ml of water is necessary.

Pre-shake the vial to make the granules scatter in it. Add 1/4 of the required volume of water to the vial and shake until the granules dissolve. Then add the rest of the water and shake well. The volume of the finished suspension should be at the level of circular risk on the vial.

The finished suspension should be stored for 14 days at a temperature of no higher than 25 ° C, in a place protected from light.

Before each reception, the suspension should be shaken well.

Dose for non-mycobacterial infections

The recommended daily dose of clarithromycin suspension in non-mycobacterial infections in children is 7.5 mg / kg 2 times a day (maximum - 500 mg 2 times a day). The usual duration of treatment is 5-10 days, depending on the pathogen and the severity of the condition.

The table shows recommendations for dosing in children taking into account the body weight:

Body weight *, kg	Single dose at reception of 2 times a day, ml (7.5 mg / kg 2 times a day)
8-11	2,5
12-19	5
20-29	7,5
30-40	10

* In children with a body weight <8 kg, the dose is selected by body weight (about 7.5 mg / kg 2 times a day)

Dosing for mycobacterial infections

In children with disseminated or localized mycobacterial infections (Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium kansasii) the recommended daily dose of clarithromycin is 7.5-15 mg / kg 2 times a day.

Treatment with clarithromycin should be continued as long as the clinical effect remains. Clarithromycin should be administered in combination with other antimicrobial agents active against these pathogens.

The table gives recommendations for dosing in children with mycobacterial infections taking into account the body weight:

Body weight *, kg	Single dose at reception of 2 times a day, ml
	7.5 mg / kg 2 times a day	15 mg / kg 2 times a day
8-11	2,5	5
12-19	5	10
20-29	7.5	15
30-40	10	20

* In children with a body weight <8 kg, the dose is selected by body weight (7.5-15 mg / kg 2 times a day)

Dosing for patients with impaired renal function

In children with CC less than 30 ml / min, the dose of clarithromycin should be reduced in half (for example, 125 mg per day or 125 mg twice a day for more severe infections). In such cases, the course of treatment should not exceed 14 days, although the usual duration of treatment is 5-10 days.

Side effects:

Classification of the incidence of adverse events (number of reported cases / number of patients) recommended by the World Health Organization (WHO): very often (≥ 1/10); often (≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10 000, <1/1000); very rarely (<1/10 000), the frequency is unknown (side effects from the post-marketing application experience, the frequency can not be estimated based on available data).

Allergic reactions: often - skin rash; infrequently anaphylactoid reaction¹, hypersensitivity, bullous¹ dermatitis, itchy skin, hives, maculopapular rash³; frequency unknown - anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptomatology (DRESS syndrome).

From the nervous system: often - headache, insomnia; infrequently - loss of consciousness¹, dyskinesia¹, dizziness, drowsiness, tremor, anxiety, increased excitability³; frequency is unknown - convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disturbances ("nightmarish" dreams), paresthesia, mania.

From the skin: often - intense sweating; frequency is unknown - acne, hemorrhages.

From the urinary system: frequency unknown - renal failure, interstitial nephritis.

From the side of metabolism and nutrition: infrequently - anorexia, decreased appetite.

From the side of the musculoskeletal system: infrequently - muscle spasm, musculoskeletal stiffness, myalgia; frequency unknown - rhabdomyolysis²*, myopathy.

From the digestive system: often - diarrhea, vomiting, dyspepsia, nausea, pain in the abdomen; infrequently - esophagitis¹, gastroesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, bloating⁴, constipation, dryness of the oral mucosa, eructations, flatulence, holography⁴, hepatitis, including cholestatic or hepatocellular⁴; frequency unknown - acute pancreatitis, discoloration of the tongue and teeth, hepatic insufficiency, cholestatic jaundice.

From the respiratory system: infrequently - bronchial asthma¹, nose bleed², pulmonary embolism¹.

From the sense organs: often - dysgeusia (perversion of taste); infrequently - vertigo, hearing impairment, ringing in the ears; frequency is unknown - deafness, agevzia (loss of taste sensations), parosmia, anosmia.

From the side of the cardiovascular system: often - vasodilation¹; infrequent - sudden cardiac arrest¹, atrial fibrillation¹, prolongation of QT interval on ECG, extrasystole¹, atrial flutter; The frequency is unknown - ventricular tachycardia, including the "pirouette" type.

Laboratory indicators: often - deviation of laboratory parameters of liver function; infrequent increase in creatinine concentration¹, increased urea concentration¹ in blood plasma, a change in the albumin / globulin ratio¹, leukopenia, neutropenia⁴, eosinophilia⁴, thrombocythemia, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyl transferase (GGT)⁴, alkaline phosphatase⁴(APF), lactate dehydrogenase (LDH)⁴in the blood plasma; frequency unknown - agranulocytosis, thrombocytopenia, increase in the value of the international normalized ratio (MNO), prolongation of prothrombin time, change in urine color, increase in bilirubin concentration in blood plasma.

Other: infrequent - malaise¹, hyperthermia³, asthenia, chest pain⁴, chills⁴, increased fatigue⁴.

Infectious and parasitic diseases: infrequently - cellulite¹, candidiasis, gastroenteritis², secondary infections³ (including vaginal); frequency unknown - pseudomembranous colitis, erysipelas.

Patients with depressed immunity

In patients with AIDS and other immunodeficiency clarithromycin at higher doses for a long time to treat mycobacterial infections, it is often difficult to distinguish the undesirable effects of the drug from the symptoms of HIV infection or a concomitant disease.

The most frequent adverse events in patients taking a daily dose of clarithromycin equal to 1000 mg were: nausea, vomiting, dysgeusia, abdominal pain, diarrhea, skin rash, flatulence, headache, constipation, hearing impairment, increased activity ACT and ALT in blood plasma. There have also been cases of adverse events with a low incidence, such as: shortness of breath, insomnia and dryness of the oral mucosa.

In patients with suppressed immunity, laboratory indicators were evaluated, analyzing their significant deviations from the norm (a sharp increase or decrease). Based on this criterion, 2-3% of patients who received clarithromycin in a dose of 1000 mg daily, there was a significant increase in ACT and ALT activity in the blood plasma, as well as a decrease in the number of leukocytes and platelets. A small number of patients also reported an increase in the concentration of residual urea nitrogen in the blood plasma.

* In some reports of rhabdomyolysis clarithromycin was taken concomitantly with other drugs (LS), with the reception of which, as is known, is associated with the development of rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

¹ Reports of these adverse reactions were obtained during clinical trials, as well as post-marketing use of clarithromycin in the dosage form of lyophilizate for the preparation of a solution for infusion.

²Reports of these adverse reactions were obtained during clinical trials, as well as the post-marketing application of clarithromycin in the form of a sustained-release tablet coated with a film coat.

³Reports of these adverse reactions were obtained during clinical trials, as well as post-marketing use of clarithromycin in a powdered dosage form to prepare a suspension for oral administration.

⁴Reports of these adverse reactions were obtained during clinical trials, as well as post-marketing use of clarithromycin in tablet formulations coated with a film coat.

Overdose:

Symptoms: ingestion of a large dose of clarithromycin can cause symptoms of violations from the gastrointestinal tract.

In one patient with bipolar disorder in the history after the administration of 8 g of clarithromycin, changes in the mental state, paranoid behavior, hypokalemia and hypoxemia are described.

Treatment: when an overdose should be removed unabsorbed drug from the gastrointestinal tract (gastric lavage, taking activated charcoal, etc.) and conduct symptomatic therapy. Hemodialysis and peritoneal dialysis do not have a significant effect on the concentration of clarithromycin in the blood serum, which is also characteristic of other drugs of the macrolide group.

Interaction:

The use of the following drugs simultaneously with clarithromycin is contraindicated in connection with the possibility of developing serious side effects:

Cisapride, pimozide, terfenadine and astemizole

With concurrent administration of clarithromycin with cisapride, pimozide, terfenadine, or astemizole, an increase in plasma concentrations was reported, which may lead to an extended QT interval on the ECG and the appearance of cardiac arrhythmias, including ventricular tachycardia (including ventricular pirouette tachycardia) and ventricular fibrillation (see section "Contraindications").

Alkaloids of ergot

Postmarketing studies show that with the simultaneous use of clarithromycin with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with drugs of the ergotamine group are possible: vascular spasm, ischemia of limbs and other tissues, including the central nervous system. Simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see the section "Contraindications"),

Inhibitors of GMC-CoA reductase (statins)

Simultaneous reception of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications" section) due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme and concomitant use with clarithromycin increases their serum concentrations, leading to an increased risk of myopathy, including rhabdomyolysis.There have been reports of rhabdomyolysis in patients taking clarithromycin simultaneously with these drugs. If it is necessary to use clarithromycin, stop taking lovastatin or simvastatin for the duration of therapy.

Clarithromycin should be used with caution in the case of combination therapy with other statins. It is recommended to use statins, the metabolism of which does not depend on the isoenzyme CYP3A (for example, fluvastatin). In case of the need for simultaneous administration, it is recommended to take the lowest dose of statin. It should monitor the development of signs and symptoms of myopathy.

The effect of other drugs on clarithromycin

Drugs that are inducers of the isoenzyme CYP3A (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort pitted), can induce the metabolism of clarithromycin. This can lead to a subtherapeutic concentration of clarithromycin and, accordingly, to a decrease in its effectiveness. In addition, it is necessary to observe the concentration of the inductor of the CYP3A isoenzyme in the blood plasma, which can be increased due to inhibition of the isoenzyme CUR3A by clarithromycin.With the simultaneous use of rifabutin and clarithromycin, there was an increase in rifabutin concentration and a decrease in the concentration of clarithromycin in blood plasma with an increased risk of uveitis.

The following drugs have a proven or suspected effect on the concentration of clarithromycin in the blood plasma, in the case of their simultaneous use with clarithromycin, a dose adjustment or alternative treatment may be required

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

Strong inductors of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin can accelerate the metabolism of clarithromycin and. thus, to reduce the concentration of clarithromycin in the blood plasma and to weaken the therapeutic effect, and at the same time to increase the concentration in the blood plasma of the 14-OH-clarithromycin metabolite, which is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs with respect to different bacteria, the therapeutic effect may decrease with the simultaneous use of clarithromycin and inducers of the cytochrome P450 system.

Etravirine

The concentration of clarithromycin in the blood plasma decreases with simultaneous use with etravirine, but the concentration in the blood plasma of the active metabolite of 14-OH-clarithromycin increases. Since 14-OH-clarithromycin 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 simultaneous administration of fluconazole at a dose of 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in the mean minimum concentration of clarithromycin (C_min) and AUC by 33% and 18% respectively. At the same time, simultaneous administration did not significantly affect the average equilibrium concentration of the active metabolite of 14-OH-clarithromycin. Correction of the dose of clarithromycin in the case of simultaneous administration of fluconazole is not required.

Ritonavir

Pharmacokinetic Study shook that simultaneous reception of ritonavir at a dose of 200 mg every 8 hours and clarithromycin and a dose of 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. With simultaneous reception of ritonavir C_max clarithromycin increased by 31%, C_min increased by 182% and AUC increased by 77%. The complete suppression of the formation of 14-OH-clarithromycin was noted. Due to the wide therapeutic range of clarithromycin, a reduction in its dose in patients with normal renal function is not required. In patients with renal insufficiency, it is advisable to consider the following options for dose adjustment: with a QC of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%.

Ritonavir should not be taken concomitantly with clarithromycin at doses exceeding 1 g / day.

Action of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Possible occurrence of ventricular tachycardia such as "pirouette" with simultaneous use of clarithromycin and quinidine or disopyramide. With the simultaneous use of clarithromycin with these drugs, ECG monitoring should be performed regularly to prolong the QT interval, and serum concentrations of these drugs should be monitored.

In post-marketing use, cases of development of hypoglycemia were reported with concurrent administration of clarithromycin and disopyramide.It is necessary to monitor the concentration of glucose to the blood with the simultaneous use of clarithromycin and disopyramide.

Hypoglycemic agents for ingestion / insulin

With the simultaneous use of clarithromycin and hypoglycemic agents for oral administration (eg, sulfonylurea derivatives) and / or insulin, pronounced hypoglycemia can be observed. Simultaneous use of clarithromycin with some hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) can lead to inhibition of the CYP3A isoenzyme by clarithromycin, which can lead to hypoglycemia. A careful control of the concentration of glucose in the blood is recommended.

Interactions caused by the isoenzyme CYP3A

Simultaneous reception of clarithromycin, which is known to inhibit the CYP3A isoenzyme, and drugs primarily metabolized by the CYP3A isoenzyme, can be associated with a mutual increase in their copy of grace, which can enhance or prolong both therapeutic, hacking and side effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the isoenzyme CYP3A,especially if these drugs have a narrow therapeutic range (for example, carbamazepine), and / or drugs that are intensely metabolized by this isoenzyme. If necessary, a dose adjustment of the drug taken concomitantly with clarithromycin should be performed. Also, if possible, monitoring of serum concentrations of drugs that are primarily metabolized by the CYP3A isoenzyme should be conducted.

Metabolism of the following drugs / classes is carried out by the same isoenzyme CYP3A as the metabolism of clarithromycin: alprazolam, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also, inhibitors of the isoenzyme CYP3A include the following drugs, contraindicated for simultaneous use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see the section "Contraindications"). To drugs interacting in a similar manner through other isoenzymes within the cytochrome P450 system include: phenytoin, theophylline and valproic acid.

Indirect anticoagulants

With the simultaneous administration of warfarin and clarithromycin, bleeding, a marked increase in INR and prolongation of prothrombin time is possible. In the case of simultaneous use with warfarin or other indirect anticoagulants, it is necessary to monitor MNO and prothrombin time.

Omeprazole

Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily). With simultaneous use of clarithromycin and omeprazole, equilibrium plasma concentrations of omeprazole were increased (C_max, AUC0-24 and T1 / 2 increased by 30%, 89% and 34% respectively). The average pH value of the stomach for 24 hours was 5.2 (with omeprazole alone) and 5.7 (with omeprazole simultaneously with clarithromycin).

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by the participation of the CYP3A isoenzyme. At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin. Simultaneous use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to an increase in the inhibitory effect on phosphodiesterase.When using these drugs simultaneously with clarithromycin, the possibility of reducing the dose of sildenafil, tadalafil and vardenafil should be considered.

Theophylline, carbamazepine

With the simultaneous use of clarithromycin and theophylline or carbamazepine, an increase in the concentration of these drugs in the systemic circulation is possible.

Tolterodin

The primary metabolism of tolterodine is via the isoenzyme CYP2D6. However, in the part of the population devoid of the isoenzyme CYP2D6, the metabolism occurs through the isoenzyme CYP3A. In this population, suppression of the CYP3A isoenzyme results in significantly higher serum concentrations of tolterodine. In a population with a low level of metabolism via the CYP2D6 isoenzyme, a dose reduction of tolterodine may be required while using CYP3A isoenzyme inhibitors, such as clarithromycin.

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

With the simultaneous use of midazolam and clarithromycin tablets (500 mg twice daily), an increase in midazolam AUC was observed: 2.7 times after intravenous administration of midazolam and 7 times after oral administration.The simultaneous use of clarithromycin with midazolam for oral administration is contraindicated. If concurrent with clarithromycin is used midazolam in the form of a drug - a solution for intravenous administration, the patient's condition should be carefully monitored for the possible correction of the dose of midazolam. The same precautions should also be applied to other benzodiazepines that are metabolized by the CYP3A isoenzyme, including triazolam and alprazolam. For benzodiazepines, the excretion of which does not depend on the isoenzyme CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

With the simultaneous use of clarithromycin and triazolam, there may be an effect on the central nervous system, for example, drowsiness and confusion. In this regard, in the case of simultaneous use, it is recommended to monitor the symptoms of violation of the DSP.

Interactions with other drugs

Aminoglycosides

With simultaneous reception of clarithromycin with other ototoxic drugs.

especially aminoglycosides, care must be taken to monitor the functions of the vestibular and hearing aids, both during therapy,and after its termination.

Colchicine

Colchicine is a substrate for both the proenzyme CYP3A and the carrier protein P-glycoprotein (Pgp). It is known that clarithromycin and other macrolides are inhibitors of the isoenzyme CYP3A and Pgp. With the simultaneous use of clarithromycin and colchicine, inhibition of Pgp and / or isoenzyme CYP3A can lead to increased colchicine action. It should monitor the development of clinical symptoms of colchicine poisoning. Post-marketing reports on cases of colchicine poisoning with its simultaneous administration with clarithromycin are registered, more often in elderly patients. Some of these cases occurred with patients suffering from kidney failure. As reported, some cases ended in a fatal outcome. Simultaneous use of clarithromycin and colchicine is contraindicated (see section "Contraindications").

Digoxin

It is assumed that digoxin is the substrate of Pgp. It is known that clarithromycin inhibits Pgp. With the simultaneous use of clarithromycin and digoxin, inhibition of Pgplarithromycin may lead to an increase in the action of digoxin.The simultaneous administration of digoxin and clarithromycin can also lead to an increase in serum digoxin concentration. Some patients experienced clinical symptoms of digoxin poisoning. including potentially fatal arrhythmias. With the simultaneous administration of clarithromycin and digoxin, the concentration of digoxin in serum should be carefully monitored.

Zidovudine

Simultaneous reception of tablets of clarithromycin and zidovudine inside adult HIV-infected patients can lead to a decrease in the equilibrium concentration of zidovudine in blood plasma. Because the clarithromycin influences the absorption of zidovudine when ingested, interactions can be largely avoided by taking clarithromycin and zidovudine with an interval of 4 hours. Similar interaction was not observed in HIV-infected children who took a children's suspension of clarithromycin with zidovudine or dideoxyinosine. Because the clarithromycin may interfere with the absorption of zidovudine when administered simultaneously in adults in adults, this interaction is unlikely with the use of clarithromycin intravenously.

Phenytoin and valproic acid

There are data on the interaction of inhibitors of the isoenzyme CYP3A (including clarithromycin) with drugs that are not metabolized by the CYP3A isoenzyme (phenytoin and valproic acid). For these drugs with simultaneous application with clarithromycin, it is recommended to determine their serum concentrations, since there are reports of their increase.

Bi-directional interaction of drugs

Atazanavir

Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of bi-directional interaction of these drugs. The simultaneous use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once a day) can lead to a twofold increase in the effect of clarithromycin and a reduction in the effect of 14-OH-clarithromycin by 70% with an increase in Atazanavir AUC by 28%. Due to the wide therapeutic range of clarithromycin, reducing its dose in patients with normal renal function is not required. In patients with moderate renal insufficiency (KK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%.In patients with QC less than 30 ml / min, the dose of clarithromycin should be reduced by 75%, using the appropriate dosage form of clarithromycin for this. Clarithromycin in doses exceeding 1000 mg / day, can not be used simultaneously with protease inhibitors.

Blocks of "slow" calcium channels

With the simultaneous use of clarithromycin and blockers of "slow" calcium channels, which are metabolized by the isoenzyme CYP3A4 (for example, verapamil, amlodipine, diltiazem), you should be careful, since there is a risk of arterial hypotension. With simultaneous use, plasma concentrations of clarithromycin and "slow" calcium channel blockers can increase. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible with concurrent administration of clarithromycin and verapamil.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bi-directional interaction of the drugs. Clarithromycin can increase the concentration of itraconazole in the blood plasma, while itraconazole can increase the plasma concentration of clarithromycin. Patients simultaneously taking itraconazole and clarithromycin, should be carefully examined for signs of increased or prolonged pharmacological effects of these drugs.

Saquinavir

Clarithromycin and saquinavir are substrates and inhibitors of the CYP3A isoenzyme, which determines the bi-directional interaction of the drugs. The simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg 3 times a day) in 12 healthy volunteers caused an increase in AUC and C_max saquinavir in blood plasma by 177% and 187%, respectively, compared with the administration of saquinavir alone. The values of AUC and C_max clarithromycin were approximately 40% higher than with single clarithromycin alone. With the simultaneous use of these two drugs for a limited time in the doses / formulations mentioned above, dose adjustment is not required. The results of a study of drug interactions using saquinavir in soft gelatin capsules may not correspond to the effects observed with saquinavir in hard gelatin capsules. Results of drug interaction studies with saquinavir alonemay not correspond to the effects observed with saquinavir / ritonavir combination therapy. When taking saquinavir concomitantly with ritonavir, the potential effect of ritonavir on clarithromycin.

Special instructions:

Long-term use of antibiotics can lead to the formation of colonies with an increased number of insensitive bacteria and fungi. When superinfection is necessary to appoint appropriate therapy.

When applying clarithromycin, hepatic dysfunction was reported (increased activity of liver enzymes in the blood plasma, hepatocellular and / or cholestatic hepatitis with or without jaundice). Hepatic dysfunction can be severe, but is usually reversible. There are cases of hepatic insufficiency with a fatal outcome, mainly related to the presence of serious concomitant diseases and / or simultaneous use of other medicines. When signs and symptoms of hepatitis such as anorexia, jaundice, darkening of the urine, pruritus, abdominal tenderness in palpation, it is necessary to immediately stop the treatment with clarithromycin.

In the presence of chronic liver diseases it is necessary to carry out regular monitoring of the activity of "hepatic" enzymes of serum of the crope.

In the treatment of almost all antibacterial agents, including clarithromycin, cases of pseudomembranous colitis are described, the severity of which varies from mild to life-threatening. Antibiotic drugs can change the normal intestinal microflora, which can lead to growth Clostridium difficile. Pseudomembranous colitis caused by Clostridium difficile, it is necessary to suspect all patients with the appearance of diarrhea after using antibacterial agents. After the course of antibiotic therapy, careful medical supervision of the patient is necessary. The cases of development of pseudomembranous colitis after 2 months after the application of antibiotics were described.

Clarithromycin should be used with caution in patients with IHD, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and also with simultaneous use with antiarrhythmic drugs IA class (quinidine, procainamide) and III class (dofetilide. amiodarone, sotalol).In these conditions and with the simultaneous use of clarithromycin with these drugs, ECG monitoring should be performed on a regular basis for the lengthening of the interval QT.

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

Given the growing resistance Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing in the appointment of clarithromycin to patients with community-acquired pneumonia. With hospital pneumonia clarithromycin should be used in combination with appropriate antibiotics.

Infections of the skin and soft tissues of mild and moderate severity are most often caused Staphylococcus aureus and Streptococcus pyogenes. In this case, both pathogens can be resistant to macrolides. Therefore, it is important to conduct a test to determine the sensitivity to antibiotics.

Macrolides can be used for infections caused by Corynebacterium minutissimum, diseases acne vulgaris and erysipelas, as well as in situations where penicillin can not be used.

In the 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) should immediately stop taking clarithromycin and begin appropriate therapy. In the case of simultaneous use with warfarin or other indirect anticoagulants, it is necessary to monitor INR and prothrombin time (see section "Interaction with other drugs").

When prescribing the drug to patients with diabetes it is necessary to take into account that the preparation Ofromilid®, granules for the preparation of the suspension for ingestion, 125 mg / 5 ml, contains sucrose (in 1 ml of the finished suspension contains 0.033 units of bread (HG) or 0.33 g of sucrose ).

Effect on the ability to drive transp. cf. and fur:

Data on the effect of clarithromycin on the ability to drive and machinery are absent.

Care should be taken when driving vehicles and mechanisms, taking into account the potential for dizziness, vertigo, confusion and disorientation that may occur when using this drug.

Form release / dosage:

Granules for oral suspension, 125 mg / 5 ml.

Packaging:

25 g of the preparation in a vial of dark glass with a capacity of 100 ml, with a circular risk for 60 ml of the finished suspension,Sealed with a plastic stopper with a dissector of liquid and a plastic lid with the control of the first opening.

1 bottle complete with a dispensing syringe and instruction but application in a pack of cardboard.

Storage conditions:

The granules are stored at a temperature of no higher than 30 ° C.

Ready suspension should be stored for 14 days at a temperature of no higher than 25 ° C, in a place protected from light.

Keep out of the reach of children.

Shelf life:

2 of the year.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N014777 / 02

Date of registration:15.08.2008

Date of cancellation:2018-04-09

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, d.d. Slovenia

Representation: & nbspKRKA KRKA Slovenia

Information update date: & nbsp09.04.2018

Illustrated instructions

Instructions

Frommylid® (Fromilid®)