Pharmacological properties
Pharmacodynamics.
Clarithromycin is a semisynthetic macrolide antibiotic. The antibacterial effect of clarithromycin is determined by its binding to the 50s-ribosomal subunit of sensitive bacteria and inhibition of protein biosynthesis. the drug is highly effective in vitro against a wide range of aerobic and anaerobic gram-positive and gram-negative microorganisms, including hospital strains. The MIC of clarithromycin is usually 2 times lower than the MIC of erythromycin. Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumonie. It is bactericidal against H. pylori; the activity of clarithromycin is higher at neutral pH than at acidic pH. In vitro and in vivo data indicate the high effectiveness of clarithromycin against clinically significant strains of mycobacteria. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as gram-negative bacteria that do not produce lactase, are insensitive to clarithromycin.
Microbiology. Clarithromycin is active in vitro and in clinical practice against most strains of such microorganisms.
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.
Other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR).
Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC), which includes Mycobacterium avium, Mycobacterium intracellulare.
Beta-lactamases of microorganisms do not affect the effectiveness of clarithromycin.
Most methicillin- and oxacillin-resistant strains of staphylococci are not sensitive to clarithromycin.
Helicobacter: H. pylori.
Clarithromycin is active in vitro against most strains of such microorganisms, but the clinical effectiveness and safety of its use have not been established.
Aerobic gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groups C, F, G), Viridans group streptococci.
Aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida.
Other microorganisms: Chlamydia trachomatis.
Aerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.
Anaerobic gram-negative microorganisms: Bacteriodes melaninogenicus.
Spirochetes: Borrelia burgdorferi, Treponema pallidum.
Campylobacter: Campylobacter jejuni.
Clarithromycin has a bactericidal effect against several strains of bacteria: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori and Campylobacter spp. The main metabolite of clarithromycin in the human body is the microbiologically active 14-hydroxyclarithromycin (14-OH-clarithromycin). For most microorganisms, the microbiological activity of the metabolite is equal to or 1–2 times weaker than the parent substance, with the exception of H. influenzae, against which the effectiveness of the metabolite is 2 times higher. Under in vitro and in vivo conditions, the parent substance and its major metabolite have either an additive or synergistic effect against H. influenzae, depending on the strain of the microorganism.
Pharmacokinetics. Clarithromycin is quickly and well absorbed from the gastrointestinal tract after oral administration of the drug in tablet form. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first-pass metabolism. Clarithromycin can be taken with or without food since food does not affect the bioavailability of clarithromycin tablets. Food slightly delays the onset of absorption of clarithromycin and the formation of the 14-hydroxy metabolite. The pharmacokinetics of clarithromycin is nonlinear; however, steady-state concentrations are achieved within 2 days of taking the drug. When using 250 mg 2 times a day, 15–20% of the unchanged drug is excreted in the urine. At a dose of 500 mg 2 times a day, excretion of the drug in urine is more intense (approximately 36%). 14-Hydroxyclarithromycin is the main metabolite, which is excreted in the urine in an amount of 10-15% of the dose taken. Most of the remainder of the dose is excreted in the feces, mainly in bile. 5–10% of the original compound is determined in feces.
When using 500 mg of clarithromycin 3 times a day, the concentration of clarithromycin in the blood plasma increases compared to a dose of 500 mg 2 times a day.
The concentration of clarithromycin in tissues is several times higher than the concentration of the drug in the blood. Increased concentrations were detected in both tonsillar and lung tissue. Clarithromycin in therapeutic doses is 80% bound to plasma proteins.
Clarithromycin penetrates the gastric mucosa. The content of clarithromycin in the mucous membrane and tissue of the stomach is higher when clarithromycin is used in combination with omeprazole than when clarithromycin is used alone.
Indications
Treatment of infections caused by microorganisms sensitive to clarithromycin:
- upper respiratory tract infections (pharyngitis, sinusitis, tonsillitis);
- lower respiratory tract infections (bronchitis, pneumonia);
- infections of the skin and soft tissues (folliculitis, erysipeloid);
- disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum or Mycobacterium kansasii;
- prevention of disseminated infections caused by MAC in HIV-infected patients with a CD4 lymphocyte count of 100/mm3;
- eradication of H. pylori in patients with duodenal ulcers when the secretion of hydrochloric acid is suppressed, which is caused by omeprazole or lansoprazole (the activity of clarithromycin against H. pylori is higher at neutral pH than at acidic pH);
- treatment of odontogenic infections.
Application
The recommended dose of clarithromycin for adults and children over 12 years of age is 250 mg 2 times a day (since the tablets are not dispensable, if necessary they are prescribed in other dosage forms or a different dosage per tablet), for severe infections the dose can be increased to 500 mg 2 once a day. The usual duration of treatment is from 5 to 14 days, with the exception of treatment of community-acquired pneumonia and sinusitis, which require 6 to 14 days of therapy. Clerimed 500 can be used regardless of food intake, since food does not affect the bioavailability of clarithromycin.
Use in patients with mycobacterial infection. The recommended dose for adults is 500 mg 2 times a day. Treatment of MAC infections in AIDS patients continues as long as the clinical and microbiological effectiveness of the drug lasts. Clarithromycin should be used in combination with other antimycobacterial agents.
The duration of treatment for other non-tuberculous mycobacterial infections is determined by the doctor individually.
Prevention of MAC infections: The recommended dose of clarithromycin for adults is 500 mg 2 times a day.
Treatment of odontogenic infections. Use 250 mg 2 times a day for 5 days (since the tablets cannot be distributed, if necessary, they are prescribed in other dosage forms or a different dosage per tablet).
Eradication of H. pylori in patients with duodenal ulcer (adults)
Triple therapy (7–14 days): clarithromycin (500 mg) 2 times a day for 7–14 days is used in combination with lansoprazole and amoxicillin at the appropriate dosage.
Triple therapy (7 days): clarithromycin (500 mg) 2 times a day for 7 days, use in combination with lansoprazole and metronidazole in dosages appropriate to treatment regimens.
Triple therapy (7 days): clarithromycin (500 mg) 2 times a day for 7 days, use in combination with omeprazole and amoxicillin or metronidazole in dosages appropriate to treatment regimens.
Triple therapy (10 days): clarithromycin (500 mg) 2 times a day for 10 days is used in combination with amoxicillin and omeprazole in dosages appropriate to treatment regimens.
Dual therapy (14 days): The usual dose of clarithromycin is 500 mg 3 times daily for 14 days. Clarithromycin should be used together with omeprazole.
Use in the elderly: as for adults.
Use in patients with renal insufficiency: There is usually no need for dose adjustment, except in patients with severe renal insufficiency (creatinine clearance 30 ml/min). If correction is required, the dose should be reduced by half, for example 250 mg 1 time per day or 250 mg 2 times per day for severe infections. In such patients, the duration of treatment should not exceed 14 days.
Use of the drug Clerimed 500
The dosage and duration of treatment is determined by the doctor depending on the nature of the pathogen and the course of the disease. The usual dose for adults and children over 12 years of age is 250 mg 2 times a day, the course of treatment is 7 days. In case of severe infections, the dose can be increased to 500 mg 2 times a day, applied for 14 days. For peptic ulcers of the stomach and duodenum, in order to eradicate Helicobacter pylori, 500 mg of clarithromycin is prescribed 2 times a day in combination with proton pump inhibitor drugs. Treatment regimen with 3 drugs: 500 mg of clarithromycin 2 times a day simultaneously with taking a proton pump inhibitor (lansoprazole, pantoprazole, omeprazole) in an appropriate dose, amoxicillin 1000 mg 2 times a day for 7–10 days. Treatment regimen with 2 drugs: 500 mg clarithromycin 3 times a day simultaneously with taking a proton pump inhibitor (pantoprazole, omeprazole) at an appropriate dose for 14 days, then a proton pump inhibitor (for example, pantoprazole, omeprazole) at an appropriate dose for the next 14 days . In patients with severe renal impairment (creatinine clearance ≤30 ml/min), the drug is not used in this dosage.
Contraindications
Hypersensitivity to the components of the drug and other macrolide antibiotics. simultaneous use of clarithromycin and any of the following drugs: cisapride, pimozide, terfenadine, astemizole (this may lead to prolongation of the qt interval and the development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsades de pointes), ergotamine, dihydroergotamine (as this may cause ergotoxicity), lovastatin or simvastatin (due to the risk of rhabdomyolysis, treatment with these drugs should be discontinued during clarithromycin therapy) (see special instructions, interactions).
Patients with a history of QT prolongation or ventricular cardiac arrhythmias, including torsades de pointes.
In patients with renal or hepatic impairment who are taking P-glycoprotein (P-gp) or a strong CYP3A4 inhibitor (eg, clarithromycin), concomitant use of colchicine is contraindicated.
Side effects
Before using the drug, like all antibiotic drugs, it is necessary to determine whether the patient has hypersensitivity to antibiotics and lidocaine by performing a skin test.
Clarithromycin is generally well tolerated.
Frequent and common adverse reactions when treated with clarithromycin in adults and children are abdominal pain, diarrhea, nausea, vomiting and taste disturbances. These adverse reactions are usually mild and are consistent with the known safety profile of macrolide antibiotics.
The list contains all known side effects that may occur when using clarithromycin.
Infections and invasions: cellulitis1, oral candidiasis, gastroenteritis2, infection3, vaginal infection, pseudomembranous colitis, erysipelas, erythrasma.
From the blood and lymphatic system: leukopenia, neutropenia4, thrombocythemia3, eosinophilia4, agranulocytosis, thrombocytopenia.
From the immune system: anaphylactoid reactions1, hypersensitivity, anaphylactic reactions.
From the side of metabolism and nutrition: anorexia, loss of appetite, hypoglycemia.
From the mental side: insomnia, anxiety, nervousness, screaming3, psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares.
From the side of the central nervous system: dysgeusia (impaired taste sensitivity), headache, impaired taste, loss of consciousness1, dyskinesia1, dizziness, drowsiness, tremor, convulsions, ageusia (loss of taste sensitivity), parosmia, anosmia.
From the organ of hearing and labyrinth: dizziness, hearing loss, tinnitus, hearing loss.
Cardiac disorders: cardiac arrest1, atrial fibrillation1, prolongation of the QT interval, ecstasystoles1, palpitations, torsades de pointes, ventricular tachycardia.
Vascular disorders: vasodilation1, hemorrhage.
From the respiratory system, chest and mediastinal organs: asthma1, nosebleeds2, pulmonary embolism1.
From the digestive system: diarrhea, vomiting, dyspepsia, nausea, abdominal pain, esophagitis1, gastroesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, bloating4, constipation, dry mouth, belching, flatulence, acute pancreatitis, discoloration of the tongue , discoloration of teeth.
From the hepatobiliary system: abnormal liver function tests, cholestasis4, hepatitis4, increased levels of ALT, AST, γ-glutamyl transpeptidase4, liver failure, cholestatic jaundice, hepatocellular jaundice.
From the skin and subcutaneous tissue: rash, hyperhidrosis, bullous dermatitis1, itching, urticaria, maculopapular rash3, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction of the skin accompanied by eosinophilia and systemic manifestations (DRESS), acne, Henoch-Schönlein disease.
From the musculoskeletal system and connective tissue: muscle spasms3, musculoskeletal rigidity1, myalgia2, rhabdomyolysis2 (in some reports of rhabdomyolysis, clarithromycin was used in combination with statins, fibrates, colchicine or allopurinol), myopathy.
From the kidneys and urinary system: increased blood creatinine1, increased blood urea1, renal failure, interstitial nephritis.
General disorders at the injection site: phlebitis at the injection site1, pain, inflammation at the injection site1, malaise4, fever3, asthenia, chest pain4, chills4, fatigue4.
Laboratory tests: change in the albumin/globulin ratio1, increase in the level of ALP4, LDH in the blood4, increase in the international normalized ratio (INR), increase in prothrombin time, change in urine color.
1,2,3,4 These adverse reactions were reported only when using the drug in the form of: 1 - lyophilized powder for the preparation of solution for infusion; 2 - extended-release tablets; 3 - suspensions; 4 - immediate release tablets.
Paresthesia, arthralgia, and angioedema have been reported.
There have been very rare reports of uveitis, predominantly in patients taking rifabutin concomitantly. Most cases were reversible.
Colchicine toxicity (including death) has been reported with the combined use of clarithromycin and colchicine, especially in elderly patients, including those with renal failure.
Patients with a compromised immune system. In patients with AIDS and other patients with compromised immune systems who have used clarithromycin in high doses for longer than recommended for the treatment of mycobacterial infections, it is not always possible to distinguish between adverse reactions associated with the use of the drug and symptoms of the underlying or concomitant diseases.
In adult patients receiving clarithromycin at a daily dose of 1000 mg, the most common side effects were nausea, vomiting, taste disturbance, abdominal pain, diarrhea, rash, bloating, headache, constipation, hearing loss, increased ALT and AST levels. Dyspnoea, insomnia and dry mouth occurred infrequently. In 2–3% of patients, a significant increase in the levels of ALT and AST and a significant decrease in the number of leukocytes and platelets in the blood were noted. In several patients, an increase in urea levels in the blood was recorded.
Side effects of the drug Clerimed 500
From the gastrointestinal tract: nausea, vomiting, dyspepsia, diarrhea, abdominal pain; rarely - stomatitis, glossitis. Allergic reactions: rarely - skin rash, urticaria; in isolated cases - anaphylactoid reactions, Stevens-Johnson syndrome, reversible changes in the color of the tongue. From the side of the central nervous system: headache, dizziness, insomnia, anxiety, nightmares, hallucinations, psychosis, hearing loss (recovers after cessation of therapy) and taste. From the liver: as with the use of other macrolides, liver dysfunction was noted - increased levels of liver transaminases, hepatitis, cholestasis. This process is usually reversible, but liver dysfunction can be severe and cause death. Other : oral mycosis; in isolated cases - pseudomembranous colitis.
special instructions
Long-term or repeated use of antibiotics can cause overgrowth of non-susceptible bacteria and fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy should be initiated. the drug should be used with caution in patients with severe renal failure. Liver dysfunction, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis with or without jaundice have been reported with clarithromycin use. this impairment of liver function can be severe and is usually reversible. In some cases, fatal liver failure has been reported, which was mainly associated with serious underlying diseases and/or concomitant drug treatment. clarithromycin should be stopped immediately if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, itching or abdominal pain occur.
Mild to fatal diarrhea caused by Clostridium difficile has been reported with almost all antibacterial drugs, including clarithromycin. The possibility of developing Clostridium difficile diarrhea should always be kept in mind in all patients with diarrhea after antibiotic use. In addition, a careful history must be taken as diarrhea caused by Clostridium difficile has been reported even 2 months after the use of antibacterial drugs. There have been reports of increased symptoms of myasthenia gravis in patients taking clarithromycin.
Excreted by the liver and kidneys. Caution should be exercised when using the drug in patients with impaired liver function or moderate or severe renal impairment.
Colchicine toxicity (including death) has been reported with the combined use of clarithromycin and colchicine, especially in elderly patients, including those with renal failure.
Clarithromycin and triazolbenzodiazepines, such as triazolam, midazolam, should be used with caution (see INTERACTIONS).
Due to the risk of QT prolongation, clarithromycin should be administered with caution to patients with a tendency to develop QT prolongation and torsades de pointes.
Pneumonia. Because Streptococcus pneumoniae may be resistant to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin for the treatment of community-acquired pneumonia. In case of hospital-acquired pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.
Mild to moderate skin and soft tissue infections. These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important to conduct a sensitivity test. In cases where β-lactam antibiotics cannot be used (for example, for allergies), other antibiotics, such as clindamycin, should be used as first-line drugs. Currently, macrolides play a role only in the treatment of certain skin and soft tissue infections, such as those caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, erysipelas; and in situations where treatment with penicillins cannot be carried out.
In the event of severe acute hypersensitivity reactions, such as anaphylactic shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash accompanied by eosinophilia and systemic symptoms (DRESS syndrome), Henoch-Schönlein disease, clarithromycin therapy should be stopped immediately and start appropriate treatment.
Clarithromycin should be used with caution when co-administered with inducers of the cytochrome CYP3A4 enzyme (see INTERACTIONS).
Attention should be paid to the possibility of cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.
The use of any antimicrobial therapy, including clarithromycin for the treatment of H. pylori infection, can lead to the emergence of microbial resistance. A small number of patients may develop H. pylori resistance to clarithromycin.
The ability to influence reaction speed when driving vehicles or working with other mechanisms. Taking into account the fact that sensitive patients may experience adverse reactions when using the drug (dizziness, drowsiness), while taking the drug, you should refrain from driving vehicles and performing other work that requires concentration.
Use during pregnancy and lactation. The safety of clarithromycin during pregnancy and lactation has not been studied. Therefore, clarithromycin should not be used during pregnancy and lactation, unless the benefit to the pregnant woman outweighs the risk to the fetus. Clarithromycin passes into breast milk, so breastfeeding should be discontinued while using clarithromycin.
Children. The drug in this dosage in a tablet is not prescribed to children under the age of 12 years.
Special instructions for the use of the drug Clerimed 500
Caution should be used in patients with impaired liver and kidney function. With prolonged or repeated use of Clerimed, due to an increase in the number of resistant bacteria or fungi, superinfection may develop. In this case, taking Clerimed should be stopped and appropriate therapy should be applied. H. pylori may develop resistance to clarithromycin. Use during pregnancy and lactation. The drug should not be taken during pregnancy. Admission is possible only if the expected benefit to the mother outweighs the likely risk to the fetus. Breastfeeding should be stopped during treatment. Children. It is not recommended to use the drug in children under 12 years of age. Does not affect reaction speed when driving vehicles or operating other mechanisms.
Interactions
Clarithromycin does not interact with oral contraceptives.
The use of the following drugs is strictly contraindicated due to the possible development of severe consequences of interaction. Increased plasma levels of cisapride, pimozide and terfenadine have been observed when used concomitantly with clarithromycin, which may cause QT prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects were noted with the combined use of astemizole and other macrolides.
Ergotamine/dihydroergotamine. Concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with the appearance of signs of acute ergotism, which is characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system.
The influence of other drugs on the pharmacokinetics of clarithromycin. Medicines that are inducers of CYP 3A (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may result in subtherapeutic levels of clarithromycin and reduced effectiveness. In addition, plasma levels of the CYP3A inducer may need to be monitored, which may be increased by CYP3A inhibition with clarithromycin (see also prescribing information for the relevant CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin resulted in increased rifabutin levels and decreased clarithromycin plasma levels, while increasing the risk of uveitis.
The following drugs have known or suspected effects on clarithromycin blood concentrations, so dose adjustments or alternative therapy may be necessary. Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine. Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, can accelerate the metabolism of clarithromycin, reducing its plasma concentrations, but increasing the concentration of 14-OH-clarithromycin, a microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin is different in relation to different bacteria, the expected therapeutic effect may not be achieved due to the combined use of clarithromycin and inducers of cytochrome P450 enzymes.
Etravirine. The effect of clarithromycin was weakened by etravirine, but the concentrations of the active metabolite 14-OH-clarithromycin increased. Because 14-OH-clarithromycin has reduced activity against MAC, overall activity against this pathogen may be affected. Therefore, alternative drugs to clarithromycin should be considered for the treatment of MAC.
Fluconazole. Steady-state concentrations of the active metabolite 14-OH-clarithromycin did not change significantly when administered concomitantly with fluconazole. No change in the dose of clarithromycin is required.
Ritonavir. The use of ritonavir and clarithromycin resulted in significant suppression of the metabolism of clarithromycin. Cmax of clarithromycin increased by 31%, Cmin by 182% and AUC by 77%. There was complete inhibition of the formation of 14-OH-clarithromycin. Due to the large therapeutic window, no dose reduction of clarithromycin is required in patients with normal renal function. However, for patients with renal failure, dose adjustment is necessary: for patients with a creatinine clearance (CLcr) of 30-60 ml/min, the dose of clarithromycin should be reduced by 50%. In patients with severe renal impairment (CLcr 30 ml/min), the dose of clarithromycin should be reduced by 75%. Doses of clarithromycin exceeding 1 g/day should not be used together with ritonavir.
The same dose adjustments should be made in patients with renal impairment when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir.
Effect of clarithromycin on the pharmacokinetics of other drugs. Antiarrhythmic drugs (quinidine or disopyramide). There are post-marketing reports of torsades de pointes (TdP) occurring during concomitant use of clarithromycin with quinidine or disopyramide. It is recommended to carry out ECG monitoring for timely detection of prolongation of the QT interval. Plasma concentrations of these drugs should be monitored during clarithromycin therapy.
CYP 3A. The combined use of clarithromycin, a known inhibitor of the CYP3A enzyme, and a drug primarily metabolized by CYP3A, may lead to increased plasma concentrations of the latter, which in turn may enhance or prolong its therapeutic effect and the risk of adverse reactions.
Caution should be exercised when using clarithromycin in patients receiving therapy with drugs that are CYP3A substrates, especially if the CYP3A substrate has a narrow therapeutic range (for example, carbamazepine) and/or is extensively metabolized by this enzyme.
Dose adjustments and, if possible, close monitoring of plasma concentrations of a drug that is metabolized by CYP3A may be necessary in patients taking clarithromycin concomitantly.
The following drugs or groups of drugs are known (or suspected) to be metabolized by the same CYP 3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine.
A similar mechanism of interaction was noted with the use of phenytoin, theophylline and valproate, which are metabolized by another isoenzyme of the cytochrome P450 system.
Omeprazole. The use of clarithromycin in combination with omeprazole in healthy adult volunteers resulted in increased steady-state concentrations of omeprazole. When using omeprazole alone, the average pH value of gastric juice when measured over 24 hours was 5.2, when omeprazole was used simultaneously with clarithromycin - 5.7.
Sildenafil, tadalafil and vardenafil. There is a possibility of increased plasma concentrations of PDE inhibitors (sildenafil, tadalafil and vardenafil) when combined with clarithromycin, which may require a reduction in the dose of PDE inhibitors.
Theophylline, carbamazepine. There is a slight but statistically significant increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.
Tolterodine. A dose reduction of tolterodine may be necessary when used with clarithromycin.
Triazolbenzodiazepines (eg alprazolam, midazolam, triazolam). Concomitant use of oral midazolam and clarithromycin should be avoided. When using midazolam with clarithromycin, the patient should be carefully monitored for timely dose adjustment.
The same precautions should be taken when using other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination does not depend on CYP3A (temazepam, nitrazepam, lorazepam), the development of a clinically significant interaction with clarithromycin is unlikely.
There are post-marketing reports of drug interactions and CNS side effects (such as drowsiness and confusion) with concomitant use of clarithromycin and triazolam. The patient should be monitored for possible increased pharmacological effects on the central nervous system.
Other types of interactions
Colchicine. Colchicine is a CYP3A and P-gp substrate. Clarithromycin and other macrolides are known to inhibit CYP 3A and P-gp. When clarithromycin and colchicine are used concomitantly, inhibition of P-gp and CYP3A by clarithromycin may lead to increased colchicine exposure. Patients should be monitored for clinical signs of colchicine toxicity.
Digoxin. Some patients developed signs of digitalis toxicity, including potentially fatal arrhythmias. The concentration of digoxin in the blood plasma of patients should be carefully monitored when it is used with clarithromycin.
Zidovudine. Concomitant use of clarithromycin immediate-release tablets and zidovudine in HIV-infected patients may cause a decrease in the steady-state plasma concentrations of zidovudine. This can be largely avoided by observing the interval between doses of clarithromycin and zidovudine. This interaction has not been reported with clarithromycin suspension and zidovudine or dideoxinazine in children.
Phenytoin and valproate. There have been reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs that are not metabolized by CYP3A (eg, phenytoin and valproate). It is recommended to determine plasma levels of these drugs when coadministering them with clarithromycin. Increases in their plasma levels have been reported.
Bilateral drug interactions between clarithromycin and atazanovir, intraconazole, and saquinavir are also possible.
Verapamil. The development of arterial hypotension, bradyarrhythmia and lactic acidosis has been reported with the combined use of clarithromycin and verapamil.
Oral hypoglycemic agents/insulin. The combined use of clarithromycin and oral antidiabetic agents and/or insulin may cause severe hypoglycemia. When used in combination with hypoglycemic agents such as nateglinide, pioglitazone, repaglinide and rosiglitazone, clarithromycin may inhibit the CYP3A enzyme, which may cause hypoglycemia. Close monitoring of blood glucose levels is recommended.
Oral anticoagulants. When clarithromycin is used concomitantly with warfarin, there is a risk of serious bleeding, increased INR and prothrombin time. While patients are receiving clarithromycin and oral anticoagulants concomitantly, the INR and prothrombin time should be monitored frequently.
HMG-CoA reductase inhibitors. The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see CONTRAINDICATIONS).
Like other macrolides, clarithromycin caused an increase in the concentration of HMG-CoA reductase inhibitors. Rarely, rhabdomyolysis has been reported in patients using these drugs in combination. Monitor patients for signs and symptoms of myopathy.
Rarely, the development of rhabdomyolysis has been reported in patients when clarithromycin was combined with atorvastatin. In case of simultaneous use, the dose of atorvastatin should be reduced as much as possible. An appropriate decision should be made to adjust the dose of the drug or use a statin that is not dependent on CYP3A metabolism (for example, fluvastatin or pravastatin).
Interactions of the drug Clerimed 500
When taken simultaneously with drugs that are metabolized through the cytochrome P450 system, such as cyclosporine, disopyramide, ergot alkaloids, lovastatin, midazolam, phenytoin, triazolam, warfarin, clarithromycin, the level of these drugs in the blood plasma may increase. It is also possible to increase the plasma levels of theophylline and carbamazepine when taken simultaneously with Clerimed. When taking clarithromycin and warfarin in combination, the effect of warfarin may be enhanced. Concomitant use of clarithromycin and digoxin may lead to an increase in the concentration of digoxin in the blood plasma and an increase in its therapeutic and side effects. With the simultaneous use of clarithromycin and zidovudine in HIV-infected patients, a decrease in the constant concentration of zidovudine is possible, so these drugs should be taken at intervals of 1–2 hours. Simultaneous use of clarithromycin with omeprazole or ranitidine can lead to an increase in their concentration in the blood plasma, while reducing no doses required. Thus, patients taking drugs in the listed combinations should be under clinical supervision; if necessary, the treatment regimen should be changed.
Note!
Description of the drug Clerimed 500 tablets. p/o 500 mg No. 14 on this page is a simplified author’s version of the apteka911 website, created on the basis of the instructions for use.
Before purchasing or using the drug, you should consult your doctor and read the manufacturer's original instructions (attached to each package of the drug). Information about the drug is provided for informational purposes only and should not be used as a guide to self-medication. Only a doctor can decide to prescribe the drug, as well as determine the dose and methods of its use.
