Universal reference book for medicines
Name of the preparation: Fromilide ® UNO (FROMILID UNO)

Active substance: clarithromycin

Type: Macrolide antibiotic

Manufacturer: KRKA (Slovenia) packing and packing KRKA (Slovenia)
Composition, form of production and packaging
Tablets of prolonged action, covered with a film membrane of
yellow color, oval, biconcave, marked "U" on one side.

1 tab.

clarithromycin 500 mg

Auxiliary substances: sodium alginate - 80 mg, sodium calcium alginate - 90 mg, lactose monohydrate - 225 mg, povidone - 30 mg, polysorbate 80 - 30 mg, silicon dioxide colloid, anhydrous 5 mg, magnesium stearate 10 mg, talc - 30 mg.

The composition of the membrane: hypromellose - 14.45 mg, talc - 1.33 mg, dye quinoline yellow (E104) - 0.5 mg, titanium dioxide - 2.64 mg, propylene glycol - 1.08 mg.

5 pieces.
- blisters (1) - packs of cardboard.
7 pcs.
- blisters (1) - packs of cardboard.
7 pcs.
- blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2015.

PHARMACHOLOGIC EFFECT

Semisynthetic antibiotic from the group of macrolides.
The mechanism of action is associated with inhibition of protein synthesis of microorganisms due to interaction with the 50S subunit of ribosomes of microorganisms. Clarithromycin has an antibacterial effect on both extracellular and intracellular pathogens. The main effect of clarithromycin is bacteriostatic. As a macrolide antibiotic, clarithromycin has a bactericidal effect on Streptococcus pyogenes, Streptococcus pneumoniae and Moraxella catarrhalis.
The activity of clarithromycin against the following pathogens has been proven both in vitro and in clinical practice with the corresponding diseases.

The drug is active against aerobic Gram-positive microorganisms - Streptococcus pyogenes, Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus;aerobic gram-negative microorganisms - Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Legionella pneumophila: other microorganisms - Mycoplasma pneumoniae, Chlamydia pneumoniae;
mycobacterium - Mycobacterium avium complex (MAC) - a complex that includes Mycobacterium avium and Mycobacterium intracellulare.
Beta-lactamases do not affect the activity of clarithromycin.

Clarithromycin in vitro is active against most strains of the following pathogens: aerobic Gram-positive microorganisms - Streptococcus agalactiae, Streptococcus spp.
group viridans, Streptococcus spp. Groups C, F, G, Listeria monocytogenes; aerobic gram-negative microorganisms - Bordetella pertussis, Neisseria gonorrhoeae, Pasteurella multocida; anaerobic Gram-positive microorganisms - Clostridium perfringes, Peptococcus niger, Propionibacterium acnes; anaerobic gram-negative microorganisms - Bacteroides melaninogenicus; spirochete - Borrelia burgdorferi, Treponema pallidum; mycobacteria - Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum; Campylobacter jejuni.
The metabolite of clarithromycin 14-hydroxyclarithromycin also has microbiological activity;
while in relation to Haemophilus influenzae it is 2 times more effective than clarithromycin.
PHARMACOKINETICS

Suction

Clarithromycin is well absorbed from the digestive tract.
Absolute bioavailability is about 50%. Fromilide ® uno is a prolonged dosage form of the drug that provides a sustained release of clarithromycin into the gastrointestinal tract. The time to reach C max when taking the drug at a dose of 500 mg or 1000 mg once a day is about 6 hours. C ss are reached within 3 days. When taking clarithromycin tablets with prolonged action on an empty stomach, bioavailability is reduced by 30%, so it is recommended to take this medication while eating.
Distribution

Binding to plasma proteins reaches 70%.

Clarithromycin prolonged action penetrates well into the lungs, skin and soft tissues, reaching high concentrations in them, while maintaining therapeutic concentrations in the blood plasma.
Concentration in cerebrospinal fluid with oral intake is negligible.
Metabolism

Clarithromycin is metabolized by CYP3A isoenzymes in the liver.
Approximately 20-30% of clarithromycin is rapidly hydroxylated in the liver by isoenzymes CYP3A4, CYP3A5 and CYP3A7 to form 14-hydroxyclarithromycin.
Excretion

T 1/2 when taking the drug at a dose of 500 mg / day is - 5.3 hours, and for 14-hydroxycylarithromycin - 7.7 hours. With the use of 2 tablets of prolonged action per day (1000 mg / day), T 1/2 is 5.8 hours, and for its active metabolite it is 8.9 hours. About 40% of clarithromycin is excreted unchanged by the kidneys and about 30% by the intestine.

Pharmacokinetics in special clinical cases

In elderly patients, plasma concentrations of clarithromycin and 14-hydroxyclarithromycin are higher, and excretion is slower, but there is no need to change the dose of clarithromycin, except in cases of severe renal dysfunction.

In patients with severe renal insufficiency, in comparison with healthy volunteers, after the intake of clarithromycin prolonged action, C max of clarithromycin in blood plasma, AUC, and T 1/2 of clarithromycin increase.
The degree of change correlates with the level of renal failure. It is not recommended to take prolonged clarithromycin at CC <30 ml / min.
In patients with hepatic insufficiency, dose adjustment is not required.

INDICATIONS

Infectious-inflammatory diseases caused by microorganisms sensitive to the preparation:

- infections of the upper respiratory tract and ENT organs (tonsillitis, pharyngitis, sinusitis, acute otitis media);

- infections of the lower respiratory tract (bronchitis, community-acquired pneumonia);

- infections of the skin and soft tissues (including folliculitis, erysipelas).

DOSING MODE

The drug is taken orally, with food.
Tablets should be swallowed whole, not breaking and not chewing.
Adults prescribe in a dose of 500 mg (1 tab.) 1 time / day.

In severe infections: 1000 mg (2 tab.) 1 time / day.

The course of treatment is 5-14 days, with community-acquired pneumonia and sinusitis - 6-14 days.

In elderly patients, there is no need to change the dose of clarithromycin, except in cases of severe renal dysfunction.

Do not use Lemylid ® uno at CC <30 ml / min .

In patients with hepatic insufficiency, dose adjustment is not required.

SIDE EFFECT

Classification of the incidence of adverse events (WHO): very often (? 1/10);
often (from? 1/100 to <1/10); infrequently (from? 1/1000 to <1/100); rarely (from? 1/10 000 to <1/1000); very rarely (from <1/10 000), including individual reports; frequency is unknown (can not be estimated based on available data).
In each group, undesirable effects are presented in order of decreasing severity.

From the digestive system: often - dyspepsia, nausea, abdominal pain, increased activity of liver enzymes;
rarely vomiting, diarrhea, stomatitis, glossitis, candidiasis of the oral mucosa, discoloration of the teeth and tongue, acute pancreatitis, hepatocellular and cholestatic hepatitis, cholestatic jaundice, pseudomembranous colitis, anorexia, constipation, dryness of the oral mucosa, eructation, flatulence, gastritis; very rarely reported cases of hepatic insufficiency with a fatal outcome, mainly against the backdrop of severe co-morbidities and / or concomitant drug therapy.
From the skin and subcutaneous tissue: often - increased sweating;
frequency unknown - drug rash with eosinophilia and systemic symptoms, acne, erysipelas, erythrasma.
From the nervous system: often - headache;
infrequently - paresthesia, drowsiness, anxiety, hallucinations, convulsions, psychosis, dizziness, confusion, a sense of fear, insomnia, nightmares, depersonalization, disorientation, tremor, depression; frequency is unknown - mania.
From the senses: often - distortion or loss of taste sensations (dysgeusia);
infrequent - noise, ringing in the ears, individual cases of hearing loss (after hearing the drug the hearing is restored), vertigo; very rarely - cases of olfactory change.
From the cardiovascular system: infrequently - ventricular tachycardia, incl.
type "pirouette", flutter and fibrillation of the ventricles, prolongation of the QT interval on the ECG.
From the hemopoietic system: rarely - thrombocytopenia (unusual bleeding, hemorrhage), leukopenia;
frequency is unknown - agranulocytosis.
From the musculoskeletal system: infrequently - myalgia, arthralgia;
frequency is unknown - myopathy.
From the urinary system: infrequently - interstitial nephritis;
frequency unknown - renal failure.
Allergic reactions: infrequent - skin rash, itching, urticaria, skin hyperemia, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), anaphylactic reactions;
frequency is unknown - Sheinlein-Henoch purpura.
Laboratory indicators: infrequently - increased concentration of creatinine, hypoglycemia (including with the simultaneous use of hypoglycemic drugs), increased activity of alkaline phosphatase, increased bilirubin content;
frequency unknown - increase in INR, prolongation of prothrombin time.
Other: secondary infections (development of resistance to microorganisms);
infrequently, asthenia.
CONTRAINDICATIONS

- chronic renal failure of severe degree (CK <30 ml / min);

- episodes of cholestatic jaundice and / or liver function abnormalities that occurred with the use of clarithromycin (in anamnesis);

- porphyria;

- I trimester of pregnancy;

- the period of lactation (breastfeeding);

- age under 18 years (effectiveness and safety not established);

- simultaneous application with astemizole, cisapride, pimozide, terfenadine, ergotamine and other ergot alkaloids, midazolam, alprazolam, triazolam;

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

- Hypersensitivity to clarithromycin and other components of the drug;

- hypersensitivity to other antibiotics from the macrolide group.

With caution: II-III trimesters of pregnancy, renal failure of mild and moderate severity (CK> 30 ml / min), hepatic insufficiency, myasthenia gravis, simultaneous use of drugs metabolized in the liver.

PREGNANCY AND LACTATION

The use of the drug in the first trimester of pregnancy is contraindicated.
The use of the drug Frromilide ® uno in the II and III trimesters of pregnancy is possible only if the intended benefit to the mother exceeds the potential risk to the fetus.
Clarithromycin excreted in breast milk, so if you need to use the drug during lactation, breastfeeding should be discontinued.

APPLICATION FOR FUNCTIONS OF THE LIVER

Do not use Lemylid ® uno at CC <30 ml / min .

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Contraindicated use of the drug for severe hepatic insufficiency;
hepatitis (in history); porphyria.
APPLICATION FOR CHILDREN

The drug is prescribed for children over 12 years of age.

APPLICATION IN ELDERLY PATIENTS

In elderly patients, there is no need to change the dose of clarithromycin, except in cases of severe renal dysfunction.

SPECIAL INSTRUCTIONS

Most strains of Staphylococcus spp., Resistant to methicillin and oxacillin, are resistant to clarithromycin.

Among macrolide antibiotics, there is cross-resistance.

Treatment with antibiotics changes the normal intestinal microflora, so there may be a superinfection caused by resistant microorganisms.
When developing a secondary infection, adequate therapy should be prescribed.
If a severe and prolonged diarrhea occurs during or after treatment, the diagnosis of pseudomembranous colitis should be ruled out, which requires immediate discontinuation of the drug and the appropriate treatment.

In the presence of chronic liver diseases, it is necessary to regularly monitor the activity of liver enzymes in the blood plasma.

With the simultaneous use of drugs metabolized in the liver, it is recommended to measure their concentration in the blood serum.

In the case of concomitant use with warfarin or other indirect anticoagulants, prothrombin time should be monitored.

Impact on the ability to drive vehicles and manage mechanisms

Data on the effect of the preparation of Formylid ® uno on the ability to manage motor vehicles and other technical devices are not available.
However, given the possible development of side effects, patients should be careful in carrying out work that requires increased concentration and speed of psychomotor reactions.
OVERDOSE

Symptoms: abdominal pain, nausea, vomiting, diarrhea, headache, impaired consciousness, paranoid behavior, hypokalemia, hypoxemia.

Treatment: gastric lavage, symptomatic therapy.
Hemodialysis and peritoneal dialysis are ineffective.
DRUG INTERACTION

Cisapride, pimozide, terfenadine and astemizole

With simultaneous use with clarithromycin, an increase in the concentration of drugs in the blood, an increase in the QT interval on the ECG, arrhythmias, including ventricular tachycardia, ventricular fibrillation, ventricular pirouette tachycardia is possible.

Ergotamine, a diergotamine

With simultaneous application, it is possible to develop effects associated with acute poisoning with drugs of the dihydroergotamine group: vasospasm, limb ischemia, CNS disorders.

Efavinerz, nevirapine, rifampicin, rifabutin and rifapentin

These drugs are strong inducers of the cytochrome P450 isoenzyme system, which can cause an increase in the metabolism of clarithromycin and, consequently, a decrease in its concentration in the blood plasma, a weakening of the therapeutic effect.
At the same time, the level of the microbiologically active metabolite of 14-hydroxyclarithromycin is increasing.
Fluconazole

Despite an increase in the minimum C ss of clarithromycin when used concomitantly with fluconazole, the average C ss of the active metabolite of clarithromycin remains virtually unchanged.
Therefore, correction of the dose of clarithromycin in the case of its simultaneous application with fluconazole is not required.
Ritonavir

Due to the wide therapeutic range of clarithromycin, a dose reduction in patients with normal renal function is not required.
In patients with KK of 30-60 ml / min, the dose of clarithromycin can be reduced by 50% (not more than 1 tablet of the preparation Ofromilide ® uno per day). Patients with severe renal insufficiency (CC <30 mL / min) should not take long-acting clarithromycin in connection with the inability to adequately adjust the dose.
Antiarrhythmic drugs (quinidine and disopyramide)

Possible occurrence of tachycardia such as "pirouette" with the simultaneous use of clarithromycin and quinidine or disopyramide.
Regular ECG monitoring should be performed to increase the QT interval, as well as control the concentration of these drugs in the serum.
Interaction due to CYP3A isoenzymes

Simultaneous use of clarithromycin and drugs primarily metabolized by CYP3A isoenzymes may be associated with a mutual increase in their concentrations, which may enhance or prolong both the therapeutic and side effects.
If necessary, a dose adjustment of the drug taken together with clarithromycin of prolonged action should be performed.
The same CYP3A isozymes as the metabolism of clarithromycin metabolize alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants, pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine.
To drugs interacting in a similar way through other isoenzymes within the cytochrome P450 isoenzyme system, phenytoin, theophylline and valproic acid are included.
Inhibitors of HMG-CoA reductase

Like other macrolides, clarithromycin increases the concentration of HMG-CoA reductase inhibitors (eg lovastatin and simvastatin).
In rare cases, the development of rhabdomyolysis in patients taking these drugs simultaneously is possible.
Indirect anticoagulants

Perhaps strengthening their action.
Prothrombin time should be carefully monitored in case of simultaneous use of these drugs.
Sildenafil, tadalafil and vardenafil

Each of these PDE5 inhibitors is metabolized, at least in part, with the participation of CYP3A isoenzymes.
At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin. Simultaneous use of clarithromycin with these drugs may lead to an increase in the inhibitory effect on PDE5, so the possibility of reducing the dose of sildenafil, tadalafil and vardenafil should be considered.
Theophylline, carbamazepine

It is possible to increase the concentration of theophylline or carbamazepine in the systemic circulation.

Tolterodin

In a portion of the population characterized by a low activity of the CYP2D6 isoenzyme, a dose reduction of tolterodine in the presence of inhibitors of the CYP3A isoenzyme, such as clarithromycin, may be required.

Triazolobenzodiazepines

It is necessary to avoid simultaneous use with oral benzodiazepines, which are metabolized by CYP3A and clarithromycin.
In the case of their intravenous administration with simultaneous application with clarithromycin, the patient's condition should be carefully monitored for possible dose adjustment. For benzodiazepines, excretion of which does not depend on CYP3A isozymes (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.
With the simultaneous use of clarithromycin and triazolam, exposure to the central nervous system (drowsiness, confusion) is possible.

Colchicine

With the simultaneous use of clarithromycin and colchicine, inhibition of P-glycoprotein (P-gp) and / or CYP3A can lead to an increased colchicine effect.
In some cases, colchicine can be poisoned when used concomitantly with colchicine, mainly in elderly patients; In the presence of kidney failure, such cases ended in a fatal outcome.
Digoxin

With simultaneous use of clarithromycin and digoxin, inhibition of P-gp with clarithromycin may lead to an increase in the action of digoxin, an increase in the serum concentration of digoxin in patients, and the development of clinical symptoms of digoxin poisoning.

Zidovudine

The interaction of tablets of clarithromycin with delayed release with zidovudine was not conducted.

Bi-directional drug interactions

Atazanavir.
Being substrates and inhibitors of CYP3A, these drugs interact bidirectionally: the AUC of atazanavir and clarithromycin increases, the AUC of 14-hydroxyclarithromycin decreases. Due to the wide range of therapeutic clarithromycin in patients with normal renal function of patients required a dose reduction, and the average severity of renal failure (creatinine clearance of 30-60 ml / min), the dose should be halved clarithromycin. The maximum daily dose of clarithromycin while the use of protease inhibitors, should not exceed 1000 mg / day.
Itraconazole. Clarithromycin can increase itraconazole in plasma levels, while itraconazole can increase the concentration of clarithromycin. Patients simultaneously taking itraconazole and clarithromycin, should be carefully examined for the presence of increased symptoms or increase the duration of the pharmacological effects of these drugs.
Saquinavir.While the use of clarithromycin for a limited time correction dose is not required. When applied together with ritonavir, saquinavir should consider the potential influence of ritonavir on clarithromycin.
Verapamil. While the use of clarithromycin may increase blood pressure, bradyarrhythmias and lactic acidosis.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children, dry place at a temperature of no higher than 25 ° C.
Shelf life - 3 years.
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