Binoclar (Tablets) Instructions for Use

Marketing Authorization Holder

Sandoz, GmbH (Austria)

Manufactured By

Novartis (Bangladesh) Ltd. (Bangladesh)

ATC Code

J01FA09 (Clarithromycin)

Active Substance

Clarithromycin (Rec.INN registered by WHO)

Dosage Form

Binoclar

Film-coated tablets, 250 mg: 10 pcs.

Dosage Form, Packaging, and Composition

10 pcs. – blister packs (1) – cardboard packs.

Clinical-Pharmacological Group

Antibiotic of the macrolide group

Pharmacotherapeutic Group

Antibiotic-macrolide

Pharmacological Action

A semisynthetic antibiotic of the macrolide group. Suppresses protein synthesis in the microbial cell by interacting with the 50S ribosomal subunit of bacteria. Acts mainly bacteriostatically, as well as bactericidally.

Active against gram-positive aerobic microorganisms – Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumonia, Listeria monocytogenes; aerobic gram-negative microorganisms – Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila, Helicobacter pylori; predominantly intracellular microorganisms – Mycoplasma pneumonia, Chlamydia pneumonia (TWAR), Mycobacterium leprae, Mycobacterium kansaii, Mycobacterium chelonae, Mycobacterium fortitum, Mycobacterium avium complex (MAC) – a complex including Mycobacterium avium, Mycobacterium intracellulare.

Under in vitro conditions, Clarithromycin exhibits activity against most strains of the following microorganisms: aerobic gram-positive microorganisms – Streptococcus agalactiae, Streptococcaceae (groups C, F, G), Streptococcus viridans; aerobic gram-negative microorganisms – Bordetella pertussis, Pasteurella multocida, Campylobacter jejuni; anaerobic gram-positive microorganisms – Clostridium perfringens, Peptococcus niger, Propionibacterium acnes; anaerobic gram-negative microorganisms – Bacteroides melaninogenicus; spirochetes – Borrelia burgdorferi, Treponema pallidum.

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

Pharmacokinetics

When taken orally, Clarithromycin is well absorbed from the gastrointestinal tract. Food intake slows down absorption but does not affect the bioavailability of the active substance.

Clarithromycin penetrates well into biological fluids and body tissues, where it reaches concentrations 10 times higher than in plasma.

Approximately 20% of clarithromycin is immediately metabolized to form the main metabolite 14-hydroxyclarithromycin.

At a dose of 250 mg, T_1/2 is 3-4 hours, at a dose of 500 mg – 5-7 hours.

It is excreted in the urine unchanged and in the form of metabolites.

Indications

Treatment of infectious and inflammatory diseases caused by pathogens sensitive to clarithromycin: infections of the upper respiratory tract and ENT organs (tonsillopharyngitis, otitis media, acute sinusitis); infections of the lower respiratory tract (acute bronchitis, exacerbation of chronic bronchitis, community-acquired bacterial and atypical pneumonia); odontogenic infections; skin and soft tissue infections; mycobacterial infections (M.avium complex, M.kansasii, M.marinum, M.leprae) and their prevention in AIDS patients; eradication of Helicobacter pylori in patients with duodenal or gastric ulcer (only as part of combination therapy).

ICD codes

Dosage Regimen

Individual. When taken orally for adults and children over 12 years of age, a single dose is 0.25-1 g, frequency of administration is 2 times/day.

For children under 12 years of age, the daily dose is 7.5-15 mg/kg/day in 2 divided doses.

In children, Clarithromycin should be used in the appropriate dosage form intended for this category of patients.

The duration of treatment depends on the indications.

For patients with impaired renal function (creatinine clearance less than 30 ml/min or serum creatinine level more than 3.3 mg/dl), the dose should be reduced by half or the interval between doses should be doubled.

Maximum daily doses for adults – 2 g, for children – 1 g.

Adverse Reactions

From the digestive system: often – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; infrequently – esophagitis, gastroesophageal reflux disease, gastritis, proctalgia, stomatitis, glossitis, abdominal distension, constipation, dry mouth, belching, flatulence, increased blood bilirubin concentration, increased activity of ALT, AST, GGT, ALP, LDH, cholestasis, hepatitis, including cholestatic and hepatocellular; frequency unknown – acute pancreatitis, discoloration of tongue and teeth, liver failure, cholestatic jaundice.

Allergic reactions: often – rash; infrequently – anaphylactoid reaction, hypersensitivity, bullous dermatitis, pruritus, urticaria, maculopapular rash; frequency unknown – anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

From the nervous system: often – headache, insomnia; infrequently – loss of consciousness, dyskinesia, dizziness, drowsiness, tremor, anxiety, increased excitability; frequency unknown – convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, paresthesia, mania.

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

From the sensory organs: often – dysgeusia; infrequently – vertigo, hearing impairment, tinnitus; frequency unknown – deafness, ageusia, parosmia, anosmia.

From the cardiovascular system: often – vasodilation; infrequently – cardiac arrest, atrial fibrillation, QT interval prolongation on ECG, extrasystole, atrial flutter; frequency unknown – ventricular tachycardia, including torsades de pointes.

From the urinary system: infrequently – increased creatinine concentration, change in urine color; frequency unknown – renal failure, interstitial nephritis.

From metabolism and nutrition: infrequently – anorexia, decreased appetite, increased urea concentration, change in albumin-globulin ratio.

From the musculoskeletal system: infrequently – muscle spasm, musculoskeletal stiffness, myalgia; frequency unknown – rhabdomyolysis, myopathy.

From the respiratory system: infrequently – asthma, epistaxis, pulmonary embolism.

From the hematopoietic system: infrequently – leukopenia, neutropenia, eosinophilia, thrombocythemia; frequency unknown – agranulocytosis, thrombocytopenia.

From the blood coagulation system: infrequently – increased INR value, prolonged prothrombin time.

Infectious and parasitic diseases: infrequently – cellulitis, candidiasis, gastroenteritis, secondary infections (including vaginal); frequency unknown – pseudomembranous colitis, erysipelas.

Local reactions: very often – phlebitis at the injection site, often – pain at the injection site, inflammation at the injection site.

From the body as a whole: infrequently – malaise, hyperthermia, asthenia, chest pain, chills, fatigue.

Contraindications

History of QT interval prolongation, ventricular arrhythmia, or torsades de pointes ventricular tachycardia; hypokalemia (risk of QT interval prolongation); severe hepatic impairment occurring concurrently with renal impairment; cholestatic jaundice/hepatitis in history, developed during the use of clarithromycin; porphyria; first trimester of pregnancy; lactation period (breastfeeding); simultaneous administration of clarithromycin with astemizole, cisapride, pimozide, terfenadine; with ergot alkaloids, e.g., ergotamine, dihydroergotamine; with orally administered midazolam; with HMG-CoA reductase inhibitors (statins) that are largely metabolized by the CYP3A4 isoenzyme (lovastatin, simvastatin), with colchicine; with ticagrelor or ranolazine; hypersensitivity to clarithromycin and other macrolides.

Use in Pregnancy and Lactation

Use in the first trimester of pregnancy is contraindicated.

Use in the second and third trimesters of pregnancy is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus.

If it is necessary to use during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency, hepatitis (in history).

Use in Renal Impairment

For patients with impaired renal function (creatinine clearance less than 30 ml/min or serum creatinine level more than 3.3 mg/dl), the dose should be reduced by half or the interval between doses should be doubled.

Pediatric Use

Currently, there is insufficient data on the efficacy and safety of clarithromycin use in children under 6 months of age.

Special Precautions

Clarithromycin should be used with caution in patients with moderate and severe renal failure; moderate and severe hepatic failure, with coronary artery disease, severe heart failure, hypomagnesemia, marked bradycardia (less than 50 beats/min); simultaneously with benzodiazepines such as alprazolam, triazolam, intravenously administered midazolam; simultaneously with other ototoxic drugs, especially aminoglycosides; simultaneously with drugs that are metabolized by CYP3A isoenzymes (including carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants, quinidine, rifabutin, sildenafil, tacrolimus, vinblastine; simultaneously with CYP3A4 inducers (including rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort); simultaneously with statins whose metabolism does not depend on the CYP3A isoenzyme (including fluvastatin); simultaneously with slow calcium channel blockers that are metabolized by the CYP3A4 isoenzyme (including verapamil, amlodipine, diltiazem); simultaneously with class I A antiarrhythmic drugs (quinidine, procainamide) and class III antiarrhythmic drugs (dofetilide, amiodarone, sotalol).

Cross-resistance is observed among antibiotics of the macrolide group.

Treatment with antibiotics alters the normal intestinal flora, so the development of superinfection caused by resistant microorganisms is possible.

It should be borne in mind that severe persistent diarrhea may be due to the development of pseudomembranous colitis.

Prothrombin time should be periodically monitored in patients receiving Clarithromycin simultaneously with warfarin or other oral anticoagulants.

Drug Interactions

Clarithromycin inhibits the activity of the CYP3A4 isoenzyme, which leads to a slowdown in the metabolism rate of astemizole when used simultaneously. As a result, the QT interval increases and the risk of developing torsades de pointes ventricular arrhythmia increases.

Simultaneous administration of clarithromycin with lovastatin or simvastatin is contraindicated because 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. Cases of rhabdomyolysis have been reported in patients taking Clarithromycin together with these drugs. If it is necessary to use clarithromycin, lovastatin or simvastatin should be discontinued during therapy.

Clarithromycin should be used with caution in combination therapy with other statins. It is recommended to use statins that do not depend on the metabolism of CYP3A isoenzymes (for example, fluvastatin). If concomitant administration is necessary, the lowest dose of the statin is recommended. The development of signs and symptoms of myopathy should be monitored. When used concomitantly with atorvastatin, the plasma concentration of atorvastatin moderately increases, and the risk of myopathy increases.

Drugs that are inducers of CYP3A (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) can induce the metabolism of clarithromycin, which can lead to subtherapeutic concentration of clarithromycin and reduce its effectiveness. It is necessary to monitor the plasma concentration of the CYP3A inducer, which may increase due to inhibition of CYP3A by clarithromycin.

When used concomitantly with rifabutin, the plasma concentration of rifabutin increases, the risk of uveitis increases, and the plasma concentration of clarithromycin decreases.

When used concomitantly with clarithromycin, plasma concentrations of phenytoin, carbamazepine, and valproic acid may increase.

Strong inducers of cytochrome P450 isoenzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, can accelerate the metabolism of clarithromycin and thus lower the plasma concentration of clarithromycin and weaken its therapeutic effect, while simultaneously increasing the concentration of 14-OH-clarithromycin – a metabolite that is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against different bacteria, the therapeutic effect may decrease when clarithromycin and enzyme inducers are used together.

The plasma concentration of clarithromycin decreases when etravirine is used, while the concentration of the active metabolite 14-OH-clarithromycin increases. Since 14-OH-Clarithromycin has low activity against MAC infections, the overall activity against their pathogens may change, so alternative treatment for MAC should be considered.

A pharmacokinetic study showed that co-administration of ritonavir at a dose of 200 mg every 8 hours and clarithromycin at a dose of 500 mg every 12 hours led to a marked suppression of clarithromycin metabolism. When co-administered with ritonavir, the C_max of clarithromycin increased by 31%, C_min increased by 182%, and AUC increased by 77%, while the concentration of its metabolite 14-OH-clarithromycin significantly decreased. Ritonavir should not be co-administered with clarithromycin at doses exceeding 1 g/day.

Clarithromycin, atazanavir, saquinavir are substrates and inhibitors of CYP3A, which determines their bidirectional interaction. When taking saquinavir together with ritonavir, the potential effect of ritonavir on Clarithromycin should be taken into account.

When used concomitantly with zidovudine, the bioavailability of zidovudine is slightly reduced.

Colchicine is a substrate for both CYP3A and P-glycoprotein. Clarithromycin and other macrolides are known to be inhibitors of CYP3A and P-glycoprotein. When clarithromycin and colchicine are taken together, inhibition of P-glycoprotein and/or CYP3A may lead to an increased effect of colchicine. The development of clinical symptoms of colchicine poisoning should be monitored. Post-marketing reports of cases of colchicine poisoning when taken concomitantly with clarithromycin have been registered, more frequently in elderly patients. Some of the described cases occurred in patients with renal failure. Some cases were reported to be fatal. Concomitant use of clarithromycin and colchicine is contraindicated.

When midazolam and clarithromycin (orally at 500 mg twice daily) were used concomitantly, an increase in the AUC of midazolam was noted: 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant use of clarithromycin with orally administered midazolam is contraindicated. If the intravenous form of midazolam is used together with clarithromycin, the patient’s condition should be carefully monitored for possible dose adjustment. The same precautions should be applied to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

When clarithromycin and triazolam are used concomitantly, effects on the CNS, such as drowsiness and confusion, are possible. With this combination, it is recommended to monitor for symptoms of CNS impairment.

When used concomitantly with warfarin, the anticoagulant effect of warfarin may be enhanced and the risk of bleeding may increase.

Digoxin is presumed to be a substrate for P-glycoprotein. Clarithromycin is known to inhibit P-glycoprotein. When used concomitantly with digoxin, a significant increase in the plasma concentration of digoxin and the risk of digitalis intoxication are possible.

Ventricular tachycardia of the “torsades de pointes” type may occur with the concomitant use of clarithromycin and quinidine or disopyramide. When clarithromycin is taken concomitantly with these drugs, regular ECG monitoring for QT interval prolongation should be performed, and serum concentrations of these drugs should be monitored. In post-marketing use, cases of hypoglycemia have been reported with the concomitant use of clarithromycin and disopyramide. Blood glucose concentrations should be monitored when clarithromycin and disopyramide are used concomitantly. It is believed that an increase in the plasma concentration of disopyramide is possible due to inhibition of its metabolism in the liver under the influence of clarithromycin.

Concomitant administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg twice daily resulted in an increase in the mean minimum steady-state concentration (C_min) and AUC of clarithromycin by 33% and 18%, respectively. In this case, concomitant administration did not significantly affect the mean steady-state concentration of the active metabolite 14-OH-clarithromycin. Dose adjustment of clarithromycin in case of concomitant administration of fluconazole is not required.

Clarithromycin and itraconazole are both substrates and inhibitors of CYP3A, which determines their bidirectional interaction. Clarithromycin may increase the plasma concentration of itraconazole, while itraconazole may increase the plasma concentration of clarithromycin.

When used concomitantly with methylprednisolone – the clearance of methylprednisolone decreases; with prednisone – cases of acute mania and psychosis have been described.

When used concomitantly with omeprazole – the concentration of omeprazole increases significantly and the concentration of clarithromycin in plasma increases slightly; with lansoprazole – glossitis, stomatitis and/or dark discoloration of the tongue are possible.

When used concomitantly with sertraline – the development of serotonin syndrome cannot be theoretically excluded; with theophylline – an increase in the plasma concentration of theophylline is possible.

When used concomitantly with terfenadine, a decrease in the rate of metabolism of terfenadine and an increase in its plasma concentration are possible, which may lead to QT interval prolongation and an increased risk of ventricular arrhythmia of the “torsades de pointes” type.

Inhibition of the CYP3A4 isoenzyme activity under the influence of clarithromycin leads to a decrease in the rate of metabolism of cisapride when used concomitantly. As a result, the plasma concentration of cisapride increases and the risk of life-threatening cardiac arrhythmias, including ventricular arrhythmias of the “torsades de pointes” type, increases.

The primary metabolism of tolterodine is mediated by CYP2D6. However, in a part of the population lacking CYP2D6, metabolism occurs via CYP3A. In this population group, suppression of CYP3A leads to significantly higher serum concentrations of tolterodine. Therefore, in patients with a low level of CYP2D6-mediated metabolism, a dose reduction of tolterodine may be required in the presence of CYP3A inhibitors such as Clarithromycin.

When clarithromycin and oral hypoglycemic agents (e.g., sulfonylurea derivatives) and/or insulin are used concomitantly, severe hypoglycemia may be observed. Concomitant use of clarithromycin with certain hypoglycemic drugs (e.g., nateglinide, pioglitazone, repaglinide, and rosiglitazone) may lead to inhibition of CYP3A isoenzymes by clarithromycin, which may result in hypoglycemia. It is believed that when used concomitantly with tolbutamide, there is a possibility of hypoglycemia.

A case of toxic effects due to the action of fluoxetine has been described when used concomitantly with fluoxetine.

When clarithromycin is taken concomitantly with other ototoxic drugs, especially aminoglycosides, caution should be exercised and the functions of the vestibular and auditory apparatus should be monitored both during therapy and after its completion.

When used concomitantly with cyclosporine, the plasma concentration of cyclosporine increases, and there is a risk of increased adverse effects.

Cases of increased adverse effects of ergotamine and dihydroergotamine have been described when used concomitantly with ergotamine and dihydroergotamine. Post-marketing studies show that when clarithromycin is used concomitantly with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with ergotamine group drugs are possible: vascular spasm, ischemia of the extremities and other tissues, including the CNS. Concomitant use of clarithromycin and ergot alkaloids is contraindicated.

Each of these PDE inhibitors is metabolized, at least partially, by CYP3A. At the same time, Clarithromycin is capable of inhibiting CYP3A. Concomitant use of clarithromycin with sildenafil, tadalafil, or vardenafil may lead to an increase in the inhibitory effect on PDE. With these combinations, the possibility of reducing the dose of sildenafil, tadalafil, and vardenafil should be considered.

Caution should be exercised when clarithromycin and calcium channel blockers that are metabolized by the CYP3A4 isoenzyme (e.g., verapamil, amlodipine, diltiazem) are used concomitantly, as there is a risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as calcium channel blockers, may increase with concomitant use. Arterial hypotension, bradyarrhythmia, and lactic acidosis are possible with the concomitant use of clarithromycin and verapamil.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.