Biotericin - instructions for use, dose, side effects, contraindications

composition of the tablet shell: hypromellose 15 mg, propylene glycol 1.5 mg, sorbitan oleate 1.2 mg, titanium dioxide (E171) 5.25 mg, vanillin 0.5 mg, dye quinoline yellow (E104) 1.2 mg.

Description:

Biconvex tablets of oval form, film-coated, yellow, with engraving "CLARITT XL" on one side.

Pharmacotherapeutic group:Antibiotic-macrolide

ATX: & nbsp

J.01.F.A.09 Clarithromycin

Pharmacodynamics:

Semisynthetic macrolide antibiotic of broad spectrum of action. It breaks the synthesis of the protein of microorganisms (binds to the 50S subunit of the microbial cell ribosome membrane). It acts on extra- and intracellularly located microorganisms. The activity of clarithromycin against most strains of the following microorganisms is proved both in vitro and in clinical practice:

- aerobic Gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes;

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

- other microorganisms Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR-Taiwan Acute Respiratory Agent);

- mycobacteria: Mycobacterium avium complex (MAC) - complex, including: Mycobacterium avium, Mycobacterium intracellulare.

Clarithromycin exerts its action in vitro and for most strains of the following microorganisms:

- aerobic Gram-positive microorganisms: Streptococcus agalactiae, Streptococcus spp. groups C, F, G, Streptococcus spp. groups Viridans, Listeria monocytogenes;

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

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

- anaerobic gram-negative microorganisms: Bacteroides melaninogenicus;

- Spirochetes: Borrelia burgdorferi, Treponema pallidum;

- mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum;

- Campylobacteria: Campylobacter jejuni.

The microbiologically active metabolite of clarithromycin in the human body is 14 (R) -hydroxyclarithromycin. The microbiological activity of the metabolite is the same as that of the starting material, or 1-2 times weaker in respect of most microorganisms.

Clarithromycin and its metabolite in combination can have both additive and synergistic effects on Haemophilus influenzae in conditions in vitro and in vivo, depending on the strain of the bacteria.

The production of beta-lactamase does not affect the activity of clarithromycin.

Most strains of staphylococci, resistant to methicillin and oxacillin, are resistant to clarithromycin.

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

Clarithromycin insensitive Enterobacteriaceae spp., Pseudomonas spp., as well as other non-fermenting lactose, gram-negative bacteria.

Pharmacokinetics:

Tablets of prolonged action when passing through the gastrointestinal tract provide a sustained release of the active substance. Clarithromycin quickly absorbed from the gastrointestinal tract. Food slows down absorption, without significantly affecting bioavailability.

Absolute bioavailability is about 50%. After a single dose, 2 peaks of the maximum concentration (Cmax) in the blood plasma are recorded. The second peak is due to the ability of the drug to accumulate in the gallbladder, followed by a gradual or rapid intake into the intestine and absorption.

With repeated intake of a dose of the cumulation drug is not detected and the nature of metabolism in the human body does not change.

Clarithromycin accumulates in therapeutic concentrations in the lungs, skin and soft tissues (concentrations 10 times higher than plasma ones).

After oral administration, the concentration of clarithromycin in the cerebrospinal fluid remains low (in patients with intact blood-brain barrier is 1-2% of the concentration in the blood plasma).

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

Reception of clarithromycin prolonged action inside at a dose of 500 mg per day allows maintaining equilibrium maximum concentrations (Cmah) clarithromycin and 14 (R) -hydroxyclarithromycin in the blood plasma. The equilibrium maximum concentrations (Cmah) clarithromycin and 14 (R) -hydroxyclarithromycin in the blood plasma are 1.3 μg / ml and 0.48 μg / ml, respectively.

After oral administration of 20-30% of the accepted dose of clarithromycin is rapidly hydroxylated in the liver by cytochrome - CYP3A4, CYP3A5 and CYP3A7 isoenzymes with the formation of the main metabolite - 14 (R) -hydroxyclamirithromycin. Clarithromycin is an inhibitor of CYP3A4 isoenzymes; CYP3A5 and CYP3A7.

The half-life (T1 / 2) of the parent drug and its main metabolite for long-acting dosage forms (500 mg per day) is 5.3 hours and 7.7 hours, respectively; 1000 mg per day - 5.8 hours and 8.9 hours, respectively. When taking clarithromycin prolonged action inside at a dose of 1000 mg per day (2 tablets of 500 mg) the equilibrium maximum concentrations (Cmah) clarithromycin and 14 (R) -hydroxyclarithromycin averages 2.4 μg / ml and 0.67 μg / ml, respectively. The time to reach the maximum concentration (TCmah) when taking doses of 500 mg and 1000 mg per day is about 6 hours. At equilibrium, the concentration of 14 (R) -hydroxyclarithromycin does not increase in proportion to the doses of clarithromycin, and the half-lives of clarithromycin and its main metabolite increase with increasing doses. The nonlinear character of the pharmacokinetics of clarithromycin is associated with a decrease in the formation of 14 (R) -hydroxylated and N-demethylated metabolites when higher doses are used, which indicates the non-linearity of clarithromycin metabolism when taking high doses.

It is excreted by the kidneys and intestines (20-30% - in unchanged form, the rest - in the form of metabolites).

Dysfunction of the liver

In patients with moderate and severe impairment of liver function, but with preserved renal function, correction of the dose of clarithromycin is not required. The equilibrium concentration in the blood plasma and the systemic clearance of clarithromycin do not differ from these parameters in healthy patients. The equilibrium concentration is 14 (R) -hydroxyclarithromycin in people with impaired liver function is lower than in healthy people.

Renal impairment

If the renal function is impaired, the minimum and maximum concentrations of clarithromycin in the blood plasma increase, the half-life, the area under the concentration-time curve of clarithromycin and 14 (R) -hydroxyclamirithromycin. The elimination constant and excretion by the kidneys decrease. The degree of changes in these parameters depends on the degree of impaired renal function.

HIV infection

The equilibrium concentration of clarithromycin 14 (R) -hydroxyclarithromycin in patients with HIV infection who received clarithromycin in usual doses (500 mg once a day) were similar to those in healthy people. However, when using clarithromycin at higher doses that may be required for treatment Mycobacterial infections, the concentration of antibiotic can significantly exceed the usual. In patients with HIV infection who took clarithromycin in a dose of 1000 mg / day and 2000 mg / day in 2 divided doses, the maximum equilibrium concentration was usually 2-4 μg / ml and 5-10 μg / ml, respectively. When the drug was used at higher doses, the half-life was longer than in healthy people who received clarithromycin in usual doses.

Elderly patients

In elderly patients, the concentration of clarithromycin and its metabolite in the blood plasma was higher, and excretion was slower than in a group of young people. It is believed that the changes in pharmacokinetics in elderly patients are primarily related to changes in creatinine clearance and the functional state of the kidneys, rather than with the age of the patients.

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to clarithromycin:

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

- infections of the upper respiratory tract and ENT organs (such as pharyngitis, sinusitis);

- infections of the skin and subcutaneous tissue (such as folliculitis, erysipelas).

Contraindications:

- Hypersensitivity to clarithromycin or any other component of the drug;

- severe renal failure - creatinine clearance less than 30 ml / min (such patients are prescribed clarithromycin immediate release: tablets of 250 mg or 500 mg);

- porphyria;

- simultaneous reception of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine, ergotamine and other ergot alkaloids, midazolam (for oral administration), alprazolam, triazolam;

- children's age (up to 18 years);

- I trimester of pregnancy;

- lactation period;

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

Carefully:

Hepatic and / or renal failure (creatinine clearance more than 30 ml / min), myasthenia gravis, concurrent administration of drugs metabolized by the liver (it is recommended to measure their concentration in the blood plasma), simultaneous reception of colchicine.

Pregnancy and lactation:

Clarithromycin can be used in the II and III trimesters of pregnancy only if the expected benefit to the mother exceeds the potential risk to the fetus.

If it is necessary to use the drug during lactation, it is necessary to interrupt breastfeeding.

Dosing and Administration:

Inside.It is recommended to take the drug during meals, do not chew, swallow whole.

Adults: 500 mg once a day with meals. With a more severe infection, the dose is increased to 1000 mg once a day. Duration of treatment 5-14 days; Community-acquired pneumonia and sinusitis - 6-14 days.

Patients with renal insufficiency (clearance of creatinine 30-60 ml / min), only in severe infections, the administration of the drug at a dose of 500 mg once a day (i.e., a reduction in the daily dose by 50%) is possible.

Side effects:

Very frequent -> 10%; frequent -> 1% and <10%; infrequent -> 0.1% and <1%; rare -> 0.01% and <0.1%; very rare - <0.01%.

From the nervous system: headache, dizziness, anxiety, insomnia, "nightmarish" dreams, convulsions, depression; disorientation, hallucinations, psychosis, depersonalization, confusion.

From the hematopoiesis: rarely - thrombocytopenia (unusual bleeding, hemorrhage).

From the side of the cardiovascular system: ventricular tachycardia, including the type of "pirouette", flutter and fibrillation of the ventricles, prolongation of the QT interval on the electrocardiogram (ECG).

From the sense organs: noise, ringing in the ears, change in taste (dysgeusia); in isolated cases - hearing loss, which occurs after the drug is discontinued, impaired sense of smell.

From the digestive systemdyspepsia, nausea, vomiting, gastralgia, diarrhea, stomatitis, glossitis, candidiasis of the oral mucosa, discoloration of the tongue and teeth, acute pancreatitis, increased activity of "liver" transaminases, hepatocellular and cholestatic hepatitis, cholestatic jaundice, rarely - pseudomembranous colitis, hepatic insufficiency with a lethal outcome mainly on the background of severe comorbidities and / or concomitant drug therapy.

From the side of the musculoskeletal system: myalgia.

From the side of the urinary system: interstitial nephritis.

Allergic reactions: skin rash, itching, urticaria, skin hyperemia, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis, anaphylactic reactions.

Laboratory indicators: leukopenia, hypercreatininaemia, hypoglycemia (including the simultaneous use of hypoglycemic drugs).

Other: secondary infections (development of resistance of microorganisms).

Overdose:

Symptoms: nausea, vomiting, diarrhea, abdominal pain, headache, confusion.

Treatment: gastric lavage, later carry out symptomatic therapy. Clarithromycin is not removed by hemo- or peritoneal dialysis.

Interaction:

When prescribing a drug, consideration should be given to the possibility of developing cross-resistance between clarithromycin and other drugs of the macrolide group, such as lincomycin and clindamycin.

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

Cisapride, pimozide

When applied simultaneously with clarithromycin are possible: Increasing concentrations of cisapride blood plasma, increased QT interval on the ECG, arrhythmias, ventricular tachycardia, fibrillation and torsades de pointes.

Terfenadine, astemizole

When applied simultaneously with clarithromycin are possible: Increasing concentrations of astemizole and terfenadine in the blood plasma, arrhythmia, increased QT interval on the ECG, ventricular tachycardia, fibrillation and torsades de pointes.

Ergotamine, dihydroergotamine

With simultaneous use with clarithromycin, the following side effects may develop,associated with acute poisoning with drugs of the group ergotamine: vascular spasm, ischemia of limbs and other tissues, including the central nervous system.

The effect of other drugs on clarithromycin

The following drugs have a proven or suspected effect on the concentration of clarithromycin; In the case of their simultaneous use with clarithromycin, dosage adjustment or alternate treatment may be required

Efavirenz, nevirapine, rifampicin, rifabutin, rifapentin

Strong inductors of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin are: to accelerate the metabolism of clarithromycin and thus lower the concentration of clarithromycin in plasma and reduce the therapeutic effect and at the same time increase the concentration of 14 (R) -gidroksiklaritromitsina plasma - metabolite, which is also microbiologically active.

Ritonavir

With the simultaneous administration of ritonavir, the metabolism of clarithromycin is significantly slowed down. The maximum concentration (Сmах) of clarithromycin in the blood plasma increases by 31%, the minimum concentration (Cmin) by 182%, and the area under the concentration-time curve (AUC) by 77%.There is a significant slowdown in the formation of 14 (R) -hydroxyclarithromycin. In this case, in patients without impaired renal function, there is no need to adjust the dose of clarithromycin. In patients with renal insufficiency it is advisable to consider the following options for dose adjustment: with creatinine clearance of 30-60 ml / min, the dose of clarithromycin should be reduced by 50% to a maximum dose of 500 mg (1 film-coated tablet) once a day. Patients with severe renal insufficiency (creatinine clearance less than 30 ml / min) should not take the drug due to the inability to adequately correct (reduce) the dose. When taking ritonavir should not simultaneously prescribe a dosage of clarithromycin more than 1000 mg per day.

Action of clarithromycin on other drugs

Quinidine, disopyramide

Possible development of tachycardia such as "pirouette" with the simultaneous use of clarithromycin and quinidine or disopyramide. When taking clarithromycin concomitantly with these drugs, ECG monitoring should be performed regularly to increase the QT interval, and the concentrations of these drugs should be monitored in blood plasma.

Interactions caused by cytochrome P450 (CYP3A)

Simultaneous reception of clarithromycin with drugs metabolized with the participation of cytochrome P450 (CYP3A) can lead to an increase in their concentrations in the blood plasma, which can enhance or prolong both the therapeutic and side effects. Clarithromycin should be administered with caution to patients receiving drugs that are substrates of CYP3A isoenzymes, especially if the substrate of CYP3A isoenzymes has a narrow therapeutic range (for example, carbamazepine), and / or is extensively metabolized by these enzymes. If necessary, a dose adjustment of the drug taken concomitantly with clarithromycin should be performed. Also, concentrations of drugs in blood plasma, primarily metabolized by CYP3A isoenzymes, should be monitored.

Metabolism of the following drugs / classes is carried out by the same isozymes of CYP3A as the metabolism of clarithromycin: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, ciclosporin, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (for example, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine.

To drugs interacting in a similar way through other isoenzymes within the cytochrome P450 system, phenytoin, theophylline and valproic acid.

Hydromethylglutaryl-CoA (HMG-CoA) reductase inhibitors

Like other macrolides, clarithromycin increases concentrations of HMG-CoA reductase inhibitors (lovastatin, simvastatin) in the blood plasma. Rare cases of rhabdomyolysis in patients taking these drugs concomitantly with clarithromycin are described.

Omeprazole

With the simultaneous use of clarithromycin and omeprazole, an increase in the maximum concentration (C max) in blood plasma, the area under the concentration-time curve (AUC) and the half-life (T1 / 2) of omeprazole by 30%, 89% and 34%, respectively. The average pH in the stomach for 24 hours was 5.2 with only omeprazole and 5.7 with omeprazole together with clarithromycin.

Oral anticoagulants

It is possible to enhance the effect of oral anticoagulants. If patients simultaneously receive clarithromycin and oral anticoagulants, prothrombin time should be carefully monitored.

Sildenafil, tadalafil, vardenafil

Each of these inhibitors of phosphodiesterase-5 (PDE-5) is metabolized, at least in part, with the participation of CYP3A isoenzymes. At the same time, CYP3A isoenzymes can be inhibited in the presence of clarithromycin. The combined use of clarithromycin with PDE5 inhibitors can lead to an increase in the inhibitory effect on PDE-5. When using these drugs, you should jointly consider the possibility of reducing the dose of sildenafil, tadalafil or vardenafil.

Theophylline, carbamazepine

It is possible to increase the concentration of theophylline or carbamazepine in blood plasma with simultaneous reception with clarithromycin.

Triazolobenzodiazepines (alprazolam, midazolam, triazolam)

With the simultaneous use of midazolam and clarithromycin (500 mg twice daily), there was an increase in the area under the concentration-time curve (AUC) of midazolam: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. It is necessary to avoid simultaneous oral administration of midazolam and clarithromycin.If intravenous administration of midazolam is simultaneously assigned clarithromycin, the patient's condition should be carefully monitored for possible dose adjustment.

The same precautions should also be applied to other benzodiazepines that are metabolized by CYP3A isoenzymes, including triazolam and alprazolam.

For benzodiazepines, the removal 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, it is possible to influence the central nervous system, for example: drowsiness and confusion.

Interaction with other drugs

Colchicine

Colchicine is a substrate for both the CYP3A isoenzymes and the carrier protein responsible for excretion of the drug, P-glycoprotein. Clarithromycin and other macrolides inhibit the isoenzymes CYP3A and P-glycoprotein. With concurrent administration of clarithromycin and colchicine, inhibition of the P-glycoprotein and / or isoenzymes CYP3A can lead to an enhanced colchicine effect. It is necessary to control the possible development of clinical symptoms of colchicine intoxication, especially in elderly patients.

Digoxin

With concurrent administration of clarithromycin and digoxin, inhibition of the P-glycopeptide with clarithromycin may lead to an increase in the action of digoxin. Joint reception of digoxin and clarithromycin can also lead to an increase in the concentration of digoxin in the blood plasma, to the development of clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias. With concurrent administration of clarithromycin and digoxin, the concentration of digoxin in the blood plasma should be carefully monitored.

Zidovudine

Simultaneous oral administration of clarithromycin and zidovudine by adult HIV-infected patients may lead to a decrease in the equilibrium concentration of zidovudine. Because the clarithromycin affects the absorption of zidovudine, taking these two drugs should be separated in time. Bi-directional interaction of drugs.

Atazanavir

Clarithromycin and atazanavir are substrates and inhibitors of CYP3A isoenzymes. The simultaneous use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once a day) may increase the area under the concentration-time curve (AUC) of atazanavir by 28%two-fold increase in the area under the concentration-time curve (AUC) of clarithromycin, a decrease in the area under the concentration-time curve (AUC) of 14 (11) -hydroxyclarithromycin by 70%.

Due to the wide therapeutic range of clarithromycin in patients with normal renal function, a dose reduction is not required. In patients with moderate renal insufficiency (creatinine clearance 30-60 ml / min), the dose of clarithromycin should be reduced by 50%. Clarithromycin in doses exceeding 1000 mg per day, can not be administered simultaneously with protease inhibitors.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of CYP3A isoenzymes. Clarithromycin can increase the concentration of itraconazole in the blood plasma, while itraconazole can increase the 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 CYP3A isoenzymes.The simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg 3 times a day) can cause an increase in the area under the concentration-time curve (AUC) and maximal concentration (Cmax) in saquinavir plasma by 177% and 187%, respectively, compared with the administration of saquinavir alone. The area values under the concentration-time curve (AUC) and the maximum concentration (Cmax) in the blood plasma of clarithromycin were approximately 40% higher than when taking clarithromycin alone. If these two drugs are used together for a limited time, the dosage indicated above should not be adjusted. 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. The results of the study of drug interactions in the isolated use of saquinavir may not correspond to the effects observed with saquinavir / ritonavir therapy. When taking saquinavir concomitantly with ritonavir, the potential effect of ritonavir on clarithromycin.

Verapamil

With simultaneous reception with clarithromycin, it is possible: lowering blood pressure, bradyarrhythmia and lactic acidosis.

Special instructions:

If a severe and prolonged diarrhea occurs during or after treatment, the diagnosis of pseudomembranous colitis should be deleted, which requires immediate discontinuation of the drug and the appointment of appropriate treatment.

When developing a secondary infection, adequate therapy should be prescribed.

Clarithromycin with caution is prescribed against a background of drugs metabolized by the liver (see section "Interaction with other medicinal products").

With the combined use of clarithromycin with indirect anticoagulants (including warfarin), prothrombin time should be monitored.

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

Patients with impaired liver function of mild to moderate severity do not need to reduce the dose of the drug if the kidney function is normal.

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

During the treatment period, care must be taken when driving vehicles and practicing other potentially hazardous activities, taking into account possible side effects from the central nervous system. The drug has no effect on the rate of psychomotor reactions.

Form release / dosage:

Tablets of prolonged action, film-coated, 500 mg.

Packaging:

For 7 tablets in a blister of PVC-PVDH film / aluminum foil.

For 1, 2 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:

In dry, dark place at a temperature of 15 ° C to 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000752

Date of registration:29.09.2011 / 10.11.2014

Expiration Date:21.11.2016

The owner of the registration certificate:M.Biotek LimitedM.Biotek Limited United Kingdom

Manufacturer: & nbsp

TABUK PHARMACEUTICALS, MFG. Co. Saudi Arabia

Representation: & nbspSharan Pharma, LLCSharan Pharma, LLC

Information update date: & nbsp12.02.2017

Illustrated instructions

Instructions

Biotericin (Biothercin)