Clacid Granules for preparation of suspension 250mg/5ml, 49.5g 70ml vials

Pharmacological action

Bacteriostatic, antibacterial.

Pharmacokinetics

The drug is rapidly absorbed in the gastrointestinal tract. Absolute bioavailability is about 50%. With repeated use of the drug dose, no accumulation was detected, and the nature of metabolism in the human body did not change. Food intake immediately before taking the drug increased the bioavailability of the drug by an average of 25%.

Clarithromycin can be used before or during meals.

In vitro

In vitro studies showed a 70% binding of clarithromycin to plasma proteins at concentrations ranging from 0.45 to 4.5 mcg / ml. At a concentration of 45 micrograms/ml, binding decreases to 41%, probably as a result of saturation of the binding sites. This is observed only at concentrations that are many times higher than the therapeutic value.

Healthy ones

When clarithromycin was administered at a dose of 250 mg 2 times a day, the maximum Css of clarithromycin and 14-hydroxyclarithromycin in plasma was reached after 2-3 days and amounted to 1 and 0.6 mcg / ml, respectively. T1 / 2 of the initial drug and its main metabolite were 3-4 and 5-6 hours, respectively.

When clarithromycin was administered at a dose of 500 mg 2 times a day, the maximum Css of clarithromycin and 14-hydroxyclarithromycin in plasma was reached after taking the 5th dose and averaged 2.7–2.9 and 0.88–0.83 mcg / ml, respectively. T1 / 2 of the initial drug and its main metabolite were 4.5–4.8 hours and 6.9–8.7 hours, respectively.

At steady state, the level of 14-hydroxyclarithromycin does not increase in proportion to the dose of clarithromycin, and T1/2 of clarithromycin and its main metabolite increase with increasing dose.

The non-linear nature of clarithromycin pharmacokinetics is associated with a decrease in the formation of 14-OH – and N-demethylated metabolites at higher doses, which indicates a non-linear metabolism of clarithromycin at high doses.

About 37.9% is excreted in the urine after taking 250 mg and 46% after taking 1200 mg of clarithromycin, and about 40.2% and 29.1% are excreted through the intestines, respectively.

Clarithromycin and its 14-OH metabolite are well distributed in body tissues and fluids. After oral use of clarithromycin, its content in the cerebrospinal fluid remains low (with normal BBB permeability of 1-2% of the blood serum level). The content in the tissues is usually several times higher than the content in the blood serum.

The table shows examples of tissue and serum concentrations.

Concentrations (250 mg every 12 hours)

Liver function disorders

In patients with moderate to severe hepatic impairment, but with preserved renal function, no dose adjustment of clarithromycin is required. Css in blood plasma and systemic clearance of clarithromycin do not differ in patients of this group and healthy patients. The Css of 14-hydroxyclarithromycin in people with impaired liver function is lower than in healthy people.

Impaired renal function

With impaired renal function, the minimum and maximum plasma concentrations of clarithromycin, T1/2, and AUC of clarithromycin and the 14-OH metabolite increase. The elimination constant and urinary excretion are reduced. The degree of changes in these parameters depends on the degree of impaired renal function.

Elderly patients

In elderly patients, the level of clarithromycin and its 14-OH metabolite in the blood was higher, and excretion was slower than in the group of young people. It is believed that changes in pharmacokinetics in elderly patients are primarily associated with changes in creatinine clearance and renal function, and not with the age of patients.

Patients with mycobacterial infections of

Css clarithromycin and 14-OH-clarithromycin in HIV-infected patients treated with clarithromycin in normal doses (500 mg 2 times a day) were similar to those in healthy people. However, when clarithromycin is used in higher doses, which may be required for the treatment of mycobacterial infections, the antibiotic concentrations may significantly exceed the usual ones.

In patients with HIV infection who received clarithromycin at a dose of 1000 and 2000 mg/day in 2 doses, Css was usually 2-4 and 5-10 mcg / ml, respectively.

When using the drug in higher doses, there was an elongation of T1/2 compared to that in healthy people who received clarithromycin in normal doses. The increase in plasma concentrations and T1/2 duration when clarithromycin is administered at higher doses is consistent with the known non-linearity of the drug’s pharmacokinetics.

Combination treatment with omeprazole

Clarithromycin 500 mg 3 times a day in combination with omeprazole at a dose of 40 mg / day increases the T1/2 and AUC0–24 of omeprazole. In all patients treated with combination therapy, compared with those treated with omeprazole alone, an 89% increase in AUC0–24 and 34% increase in T1/2 of omeprazole was observed.

In clarithromycin, Cmax, Cmin, and AUC0-8 increased by 10,27, and 15%, respectively, compared to data when clarithromycin alone was used without omeprazole. At steady state, clarithromycin concentrations in the gastric mucosa 6 hours after use in the group receiving the combination were 25 times higher than those in the group receiving clarithromycin alone.

Clarithromycin concentrations in gastric tissues 6 hours after taking 2 drugs were 2 times higher than those obtained in the group of patients receiving clarithromycin alone.

Pharmacodynamics

Clarithromycin is a semi-synthetic antibiotic of the macrolide group and has an antibacterial effect, interacting with the 50S ribosomal subunit of sensitive bacteria and suppressing protein synthesis.

Clarithromycin showed high activity in vitro against standard and isolated bacterial cultures. Highly effective against many aerobic and anaerobic, gram-positive and gram-negative microorganisms.

Clarithromycin is highly effective in vitro against Legionella pneumophila, Mycoplasma pneumoniae and Helicobacter (CamPylobacter) pylori. Enterobacteriaceae and Pseudomonas as well as other non-lactose-degrading gram-negative bacteria are not sensitive to clarithromycin.

Clarithromycin has been shown to have an antibacterial effect against the following pathogens: aerobic gram — positive microorganisms — Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes; aerobic gram — negative microorganisms: Haemophilus influenzae, Haemophilus parainftuenzae, Moraxella catarrhalis, Legionella pneumophila, Neisseria gonorrhoeae; other microorganisms — Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR), Chlamydia trachomatis; Mycobacteria-Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum; Mycobacterium avium complex (MAC) – complex, including: Mycobacterium avium, Mycobacterium intracellulare.

Beta-lactamase production does not affect the activity of clarithromycin.

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

Helicobacter pylori. The sensitivity of H. pylori to clarithromycin was studied on H. pylori isolates isolated from 104 patients before starting therapy with the drug. Clarithromycin — resistant H. pylori strains were isolated in 4 patients, intermediate-resistant strains were isolated in 2 patients, and H. pylori isolates were sensitive to clarithromycin in the remaining 98 patients.

Clarithromycin has an in vitro effect on most strains of the following microorganisms (however, the safety and efficacy of clarithromycin in clinical practice has not been confirmed by clinical studies and the practical 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 bacteria — Bacteroides melaninogenicus;
• spirochaetes — Borrelia burgdorferi, Treponema pallidum;
• Campylobacter — 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 parent substance, or 1-2 times weaker against most microorganisms.

The exception is H. influenzae, for which the effectiveness of the metabolite is 2 times higher. The parent substance and its main metabolite have either an additive or synergistic effect against H. influenzae in vitro and in vivo, depending on the bacterial culture.

Sensitivity studies

Quantitative methods that require measuring the diameter of the microbial growth retardation zone provide the most accurate estimates of the sensitivity of bacteria to antimicrobial agents.

One of the recommended sensitivity testing procedures uses discs soaked in 15 micrograms of clarithromycin (Kirby-Bauer diffusion test); the test results are interpreted depending on the diameter of the microbial growth retardation zone and the clarithromycin BMD value. The MPC value is determined by dilution of the medium or diffusion in agar.

Laboratory tests give one of 3 results:

• stable — it can be considered that the infection does not respond to treatment with this drug;
• medium sensitive — the therapeutic effect is ambiguous, and an increase in dosage may lead to sensitivity;
• sensitive — it can be considered that the infection can be treated with clarithromycin.

Indications

Infectious and inflammatory diseases caused by clarithromycin-sensitive microorganisms: lower respiratory tract infections (such as bronchitis, pneumonia); upper respiratory tract infections (such as pharyngitis, sinusitis); skin and soft tissue infections (such as folliculitis, subcutaneous tissue inflammation, erysipelas); disseminated or localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare; localized infections caused by caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii; acute otitis media.

Use during pregnancy and lactation

The use of clarithromycin during pregnancy (especially in the first trimester) is possible only in the absence of alternative therapy, and the potential benefit to the mother exceeds the potential risk to the fetus. Clarithromycin is excreted in breast milk. If it is necessary to take it during lactation, breastfeeding should be discontinued.

Contraindications

Hypersensitivity to the components of the drug and other macrolides; concomitant use of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine; concomitant use of clarithromycin with ergot alkaloids, for example, ergotamine, dihydroergotamine; concomitant use of clarithromycin with midazolam for oral use; patients with a history of QT prolongation, ventricular arrhythmia arrhythmia or ventricular tachycardia of the “pirouette” type; patients with hypokalemia (risk of prolongation of the QT interval); patients with severe hepatic insufficiency occurring simultaneously with renal insufficiency; concomitant use of clarithromycin with HMG-CoA reductase inhibitors (statins), which are largely metabolized by the CYP3A4 isoenzyme (lovastatin, simvastatin), due to an increased risk of myopathy, including rhabdomyolysis; concomitant use of clarithromycin with colchicine in patients with impaired liver or kidney function; patients with a history of cholestatic jaundice/hepatitis that developed with the use of clarithromycin; porphyria; breast-feeding period; patients with congenital fructose intolerance, sucrose-isomaltase insufficiency, glucose-galactose malabsorption syndrome.

With caution: moderate to severe renal insufficiency; moderate to severe hepatic insufficiency; myasthenia gravis (possibly increased symptoms); concomitant use of clarithromycin with benzodiazepines such as alprazolam, triazolam, midazolam for intravenous use; concomitant use with drugs that are metabolized by the CYP3A isoenzyme, for example, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine; concomitant use with drugs that induce the CYP3A4 isoenzyme, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort; concomitant use with calcium channel blockers that 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/min), as well as patients simultaneously taking class IA antiarrhythmic drugs (quinidine, procainamide) and class III antiarrhythmic drugs (dofetilide, amiodarone, sotalol); pregnancy; diabetes mellitus (the drug contains sucrose).

Composition

The most common side effects were gastrointestinal side effects, including diarrhea, vomiting, abdominal pain, and nausea. Other adverse reactions included headache, impaired taste, and a transient increase in liver enzyme activity.

Post-marketing experience

When treated with clarithromycin, liver function disorders, including increased activity of liver enzymes, and hepatocellular and/or cholestatic hepatitis, accompanied or not accompanied by jaundice, were infrequently observed. Hepatic dysfunction can be severe and usually reversible. In very rare cases, deaths from liver failure were recorded, which were usually observed in the presence of serious concomitant diseases and / or the simultaneous use of other drugs.

Individual cases of increased serum creatinine levels have been described, but their association with the drug has not been established.

When clarithromycin is administered orally, allergic reactions have been described, which ranged from urticaria and small rashes to anaphylaxis and Stevens-Johnson syndrome/toxic epidermal necrolysis.

Transient effects on the central nervous system have been reported, including dizziness, anxiety, insomnia, nightmares, tinnitus, confusion, disorientation, hallucinations, psychosis, and depersonalization; no causal relationship has been established with the drug.

Cases of hearing loss have been reported during treatment with clarithromycin; after discontinuation of treatment, hearing was usually restored. There are also known cases of olfactory disorders, which were usually combined with a perversion of taste.

Glossitis, stomatitis, oral thrush, and discoloration of the tongue have been reported with clarithromycin. There are known cases of discoloration of teeth in patients treated with clarithromycin. These changes are usually reversible and can be corrected by a dentist.

Rare cases of hypoglycemia have been described, some of which have been reported in patients receiving oral hypoglycemic agents or insulin.

Isolated cases of leukopenia and thrombocytopenia have been reported.

When treated with clarithromycin, as with other macrolides, in rare cases, QT interval prolongation, ventricular tachycardia and ventricular tachycardia of the “pirouette” type were noted.

Rare cases of pancreatitis and seizures are described.

Interstitial nephritis has been reported in patients treated with clarithromycin.

In clinical practice, cases of toxicity of colchicine in combination with clarithromycin, especially in the elderly, have been described. Some of them have been observed in patients with renal insufficiency; several deaths have been reported in such patients.

Children with suppressed immune systems

In patients with AIDS and other immunodeficiency disorders who receive clarithromycin in higher doses for a long time to treat mycobacterial infections, it is often difficult to differentiate the undesirable effects of the drug from the symptoms of HIV infection or intercurrent diseases.

The main adverse events in patients taking oral clarithromycin at a dose of 1 g were nausea, vomiting, taste distortion, abdominal pain, diarrhea, rash, bloating, headache, hearing impairment, constipation, increased AST and ALT levels. Dyspnea, insomnia, and dry mouth were also less common.

In this group of patients with suppressed immunity, significant deviations of laboratory parameters from the standard values in specific tests were recorded (a sharp increase or decrease).

Based on this, approximately 2-3% of patients who took clarithromycin orally at a dose of 1 g/day had significant laboratory deviations from the norm, such as an increase in AST, ALT and a decrease in the number of white blood cells and platelets. A smaller number of patients also experienced an increase in blood urea nitrogen levels.

Interaction

Interaction with cytochrome P 450

Clarithromycin is metabolized in the liver by the cytochrome P 4503 A (CYP3A) isoenzyme. This mechanism determines many interactions with other drugs. Clarithromycin can inhibit the biotransformation of other drugs under the action of this system, which can lead to an increase in their serum levels.

The following drugs or classes are known or suspected to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e. g. warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine.

Similar mechanisms of interaction, which are mediated by other cytochrome P 450 isoenzymes, are typical for phenytoin, theophylline, and valproic acid. In clinical studies, when theophylline or carbamazepine were combined with clarithromycin, there was a small but statistically significant (p

In clinical practice, the following CYP3A-mediated interactions have been reported with erythromycin and/or clarithromycin preparations.

When clarithromycin was co-administered with HMG-CoA reductase inhibitors, such as lovastatin and simvastatin, rhabdomyolysis developed in rare cases.

When clarithromycin was co-administered with cisapride, an increase in the levels of the latter was observed. This can lead to prolongation of the QT interval and the development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and polymorphic ventricular tachycardia of the “pirouette” type. Similar effects were reported in patients treated with clarithromycin and pimozide.

Macrolides caused disruption of terfenadine metabolism, which led to an increase in its plasma levels and was sometimes associated with the development of arrhythmias, including prolongation of the QT interval, ventricular tachycardia, ventricular fibrillation and ventricular tachycardia of the “pirouette”type.

In one study in 14 healthy volunteers, the combined use of clarithromycin tablets and terfenadine resulted in a 2-3-fold increase in serum levels of the acidic metabolite of terfenadine and prolongation of the QT interval, which was not accompanied by any clinical effects.

In clinical practice, cases of ventricular tachycardia of the “pirouette” type have been reported when clarithromycin is combined with quinidine or disopyramide. When treated with clarithromycin, serum levels of these drugs should be monitored.

Ergotamine/dihydroergotamine. In clinical practice, when clarithromycin is combined with ergotamine or dihydroergotamine, cases of acute toxicity of the latter have been recorded, which is characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system.

Interaction with other drugs. In patients receiving clarithromycin tablets in combination with digoxin, an increase in serum concentrations of the latter was observed. Monitoring of serum digoxin levels is advisable.

Colchicine. It is a substrate for CYP3A and P-glycoprotein. Clarithromycin and other macrolides are inhibitors of CYP3A and P-glycoprotein. When colchicine and clarithromycin are co-administered, inhibition of P-glycoprotein and / or CYP3A may lead to an increase in the effect of colchicine. Patients should be carefully monitored for symptoms of colchicine toxicity.

Interaction with antiretroviral drugs. Concomitant oral use of clarithromycin tablets with zidovudine in HIV-infected adult patients may lead to a decrease in zidovudine Css. This interaction was not observed in HIV-infected children who received a pediatric suspension of clarithromycin with zidovudine or dideoxyinosine.

In a pharmacokinetic study, concomitant use of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant suppression of clarithromycin metabolism. Cmax of clarithromycin in combination with ritonavir increased by 31%, Cmin-by 182%, AUC-by 77%.

Virtually complete inhibition of the formation of 14-hydroxyclarithromycin was observed. Given the high therapeutic index of clarithromycin, no dose reduction is required in patients with normal renal function. However, in patients with impaired renal function, dose adjustment is advisable.

In patients with Cl creatinine 30-60 ml/min, the dose of clarithromycin is reduced by 50%, and in patients with Cl creatinine

How to take, course of use and dosage

For oral use. The finished suspension can be taken regardless of food intake, including with milk. Preparation for use: water is gradually added to the bottle to the mark and shaken to obtain 60 ml (125 mg / 5 ml) or 100 ml (250 mg/5 ml) of suspension. The recommended daily dose of clarithromycin suspension for non-mycobacterial infections in children is 7.5 mg / kg 2 times a day (the maximum is 500 mg 2 times a day). The usual duration of treatment is 5-10 days, depending on the pathogen and severity of the condition. In children with disseminated or localized mycobacterial infections (M. avium, M. intracellulare, M. chelonae, M. fortuitum, M. kansasii), the recommended daily dose of clarithromycin is 7.5-15 mg/kg 2 times a day. In children with creatinine clearance less than 30 ml/min, the dose of clarithromycin should be halved.

Overdose

Symptoms: taking a large dose of clarithromycin may cause symptoms of gastrointestinal disorders. One patient with a history of bipolar disorder after taking 8 g of clarithromycin described changes in mental state, paranoid behavior, hypokalemia and hypoxemia.

Treatment: in case of overdose, the unabsorbed drug should be removed from the gastrointestinal tract and symptomatic therapy should be performed. Hemodialysis and peritoneal dialysis do not significantly affect the level of clarithromycin in serum, which is typical for other drugs of the macrolide group.

Special instructions

In the presence of chronic liver diseases, it is necessary to conduct regular monitoring of serum enzymes.

With caution, it is prescribed against the background of drugs that are metabolized by the liver.

In the case of co-use with warfarin or other indirect anticoagulants, PV should be monitored.

In children, it is preferable to use Klacid in the dosage form of powder for the preparation of a suspension for oral use of 125 mg/5 ml and 250 mg/5 ml.

Active ingredient

Clarithromycin

Conditions of release from pharmacies

By prescription

Dosage form

Oral suspension