Instructions for use Klatinol combined oral use kit strip No. 42
Composition
active ingredients: clarithromycin, tinidazole, lansoprazole;
1 tablet contains clarithromycin 250 mg;
excipients: microcrystalline cellulose, povidone (K30), magnesium stearate, colloidal anhydrous silicon dioxide, croscarmellose sodium, sodium starch glycolate (type A), hypromellose, titanium dioxide (E 171), polyethylene glycol 6000, talc, quinoline yellow (E 104), isopropyl alcohol, dichloromethane;
1 tablet contains tinidazole 500 mg;
excipients: corn starch, povidone (K30), methylparaben (E 218), propylparaben (E 216), magnesium stearate, talc, sodium starch glycolate (type A), microcrystalline cellulose, colloidal anhydrous silicon dioxide, film coating Opadry white 58920: polyethylene glycol 6000, tartrazine dye (E 102), talc;
1 capsule contains lansoprazole pellets equivalent to lansoprazole 30 mg;
excipients: sugar, methacrylate copolymer, starch, hypromellose, sodium hydrogen phosphate dihydrate, titanium dioxide, polyethylene glycol, talc, sodium lauryl sulfate, polysorbate-80, sodium hydroxide.
Dosage form
Coated tablets; capsules.
Basic physicochemical properties.
tinidazole tablets: film-coated, biconvex, round, yellow tablets;
Clarithromycin tablets: yellow, oblong, biconvex, film-coated tablets with a score on one side;
Lansoprazole capsules: hard gelatin capsules No. 1, orange body, almost white cap, imprinted with "S" on the cap and body and containing white granules;
Pharmacotherapeutic group
Combinations for the eradication of H. pylori. Lansoprazole, clarithromycin and tinidazole. ATX code A02B D09.
Pharmacological properties
Pharmacodynamics
Clarithromycin is a macrolide antibiotic that has antibacterial activity against many aerobic and anaerobic Gram-positive and Gram-negative microorganisms, including H. pylori. Clarithromycin exerts its antibacterial effect by inhibiting protein synthesis by binding to the 50S subunit of the microbial cell ribosome membrane. The minimum inhibitory concentration (MIC90) of clarithromycin and its active metabolite 14-hydroxyclarithromycin against H. pylori is 0.06 μg/ml.
Lansoprazole blocks the final stage of hydrochloric acid formation. In the tubules of the parietal cells of the stomach, it is transformed into the active form - sulfenamide, which irreversibly interacts with the SH-groups of H+-K+-ATP-ase (proton pump). Reduces basal and stimulated (food, pentagastrin, insulin) secretion and volume of secretion. Restoration of H+-K+-ATP-ase activity occurs with a half-life of 30-48 hours. The average daily pH value of gastric juice increases to 2.9 (the percentage of time the pH is maintained above 3 is 47.6). After discontinuation of the drug, the acid level remains below 50% of the basal level for 39 hours, a rebound increase in secretion (not noted). In patients with Zollinger-Ellison syndrome, it acts longer. Inhibits the production of pepsin (the level of pepsinogen in the blood serum increases). It has a gastroprotective effect: increased oxygenation of the mucous membrane, increased secretion of bicarbonates. Inhibits the growth of H. pylori (minimum inhibitory concentration is 0.78-6.25 mg/l), promotes the formation of specific immunoglobulins A in the mucous membrane. Reduces blood flow in the antrum of the stomach, pylorus and duodenal bulb by an average of 17%, inhibits the motor-evacuation function of the stomach. Inhibition of secretion is accompanied by an increase in the number of nitrosobacteria and an increase in the concentration of nitrates in the gastric secretion. Increases the concentration of gastrin in the blood serum by 50-100%. Provides faster healing and relief of symptoms in duodenal ulcers. Effective in the treatment of gastric and duodenal ulcers resistant to H2 blockers. The simultaneous use of clarithromycin and lansoprazole potentiates the pharmacokinetics of both drugs. The rate of eradication of H. pylori increases significantly when tinidazole, a member of the nitroimidazole group with antimicrobial activity against anaerobic bacteria and protozoa, as well as against H. pylori, is included in this combination. Due to its high lipophilicity, tinidazole easily penetrates into anaerobic microorganisms, where it is reduced by nitroreductase and destroys the helical structure of DNA.
Thus, lansoprazole in combination with antibiotic therapy provides rapid relief of symptoms and ulcer healing. Clarithromycin and lansoprazole did not show mutagenic properties in various tests.
Clarithromycin is rapidly and fairly completely absorbed when taken orally. Food slows down absorption, without significantly affecting bioavailability. After a single dose, 2 peaks of serum concentration are recorded. The second peak is due to the ability to concentrate in the gallbladder with subsequent gradual or rapid release. In plasma, it binds to serum proteins (more than 90%). Approximately 20% of the dose taken is immediately oxidized in the liver with the formation of the main active metabolite 14-hydroxyclarithromycin. Biotransformation is catalyzed by enzymes of the cytochrome P450 complex. It penetrates well into body fluids and tissues, forming concentrations that are 10 times higher than the level in blood plasma. The half-life when taking a dose of 500 mg is 7-9 hours. Up to 30% is excreted in the urine unchanged, the rest is excreted as metabolites.
Lansoprazole is rapidly absorbed, with an absolute bioavailability of almost 40%. The absorption of lansoprazole is not affected by food. It undergoes extensive metabolism in the liver. The half-life of the drug from blood plasma is 0.5-1 hour. Approximately 80% of lansoprazole is excreted by the kidneys. After oral administration, the onset of antisecretory action of lansoprazole is noted after 1 hour. The duration of inhibition of hydrochloric acid secretion in the stomach is almost 24 hours. After repeated administration of the drug at a dose of 20 mg/day, daily intragastric acidity decreases by 97%.
Concomitant administration of lansoprazole and clarithromycin has been shown to have a beneficial effect on the pharmacokinetics of clarithromycin. The mean maximum concentration (Cmax) was 10% higher, the mean Cmin was 27% higher, and the mean AUC was 15% higher than when clarithromycin was administered alone. The concentration of clarithromycin in gastric tissue and mucus was also increased when co-administered with lansoprazole.
Tinidazole is rapidly absorbed when taken orally, the percentage of absorption is approximately 90%. It accumulates in the blood, Cmax is reached after 2 hours. Plasma protein binding is 10%. It easily penetrates into various tissues and body fluids, passes through the blood-brain barrier. It undergoes biotransformation, the main metabolites are pharmacologically active hydroxylated substances (inhibit the growth of anaerobic microorganisms and can enhance the effect of tinidazole). It is slowly excreted (including metabolites) by the kidneys (intensive reabsorption in the renal tubules). The half-life in adults is 10-14 hours.
Indication
Gastric and duodenal ulcers, chronic gastritis, associated with H. pylori.
Contraindication
Hypersensitivity to lansoprazole, clarithromycin or other macrolide antibiotics, tinidazole or other 5-nitroimidazole derivatives. Concomitant use with the following: atazanavir, astemizole, cisapride, pimozide, terfenadine (as this may lead to prolongation of the QT interval and the development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsades de pointes); ergot alkaloids, such as ergotamine, dihydroergotamine (as this may lead to ergotoxicity), HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4, such as lovastatin or simvastatin (due to increased risk of myopathy, including rhabdomyolysis). Blood abnormalities. Organic nervous system disorders. Concomitant use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine. Concomitant use of clarithromycin with ticagrelor, ivabradine or ranolazine. Concomitant use of clarithromycin and oral midazolam. Concomitant use of clarithromycin and lomitamide. History of QT prolongation or ventricular cardiac arrhythmias, including torsades de pointes. Severe hepatic impairment and concomitant renal impairment. Electrolyte imbalance: hypokalemia or hypomagnesemia (due to risk of QT prolongation).
Interaction with other medicinal products and other types of interactions
The use of the following drugs is strictly contraindicated due to the possible development of severe interaction effects.
Ergot alkaloids: Postmarketing reports indicate that concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with the development of signs of acute ergotism, characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system.
HMG-CoA reductase inhibitors (statins). The combined use of clarithromycin with lovastatin or simvastatin is contraindicated because these statins are extensively metabolized by CYP3A4 and co-administration with clarithromycin increases their plasma concentrations, which in turn increases the risk of myopathy, including rhabdomyolysis. Rhabdomyolysis has been reported in patients receiving concomitant clarithromycin and these statins. If clarithromycin treatment cannot be avoided, lovastatin or simvastatin should be discontinued during the course of treatment.
Caution should be exercised when prescribing clarithromycin concomitantly with other statins. In situations where concomitant use of clarithromycin with a statin cannot be avoided, it is recommended to use the lowest approved dose of the statin. A statin that is not metabolized by CYP3A (e.g. fluvastatin) may be used. Patients should be monitored for signs and symptoms of myopathy.
Lomitapide: Concomitant use of clarithromycin with lomitapide is contraindicated due to the potential for marked elevations in transaminase levels (see Contraindications).
The use of clarithromycin is also contraindicated with ergot alkaloids, oral midazolam, HMG-CoA reductase inhibitors that are primarily metabolized by CYP3A4 (e.g., lovastatin and simvastatin), colchicine, ticagrelor, ivabradine, and ranolazine (see section 4.4).
Effect of other drugs on the pharmacokinetics of clarithromycin.
CYP3A-related interactions. Medicinal products that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may lead to subtherapeutic levels of clarithromycin and reduced efficacy. In addition, monitoring of plasma levels of the CYP3A inducer, which may be increased due to inhibition of CYP3A by clarithromycin, may be necessary (see also the Summary of Product Characteristics of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has been shown to increase rifabutin levels and decrease clarithromycin serum levels, with a concomitant increase in the risk of uveitis.
The following drugs are known or suspected to affect clarithromycin blood concentrations and may require dose adjustment or alternative therapy.
Efavirenz, nevirapine, rifampicin, rifabutin, rifapentine. Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, may accelerate the metabolism of clarithromycin, decreasing its plasma concentration but increasing the concentration of 14-OH-clarithromycin, the microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against different bacteria, the expected therapeutic effect may not be achieved due to the combined use of clarithromycin and inducers of cytochrome P450 enzymes.
Etravirine. Clarithromycin activity was attenuated by etravirine; however, concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Therefore, alternative agents to clarithromycin should be considered for the treatment of MAC.
Fluconazole. Coadministration of fluconazole 200 mg daily with clarithromycin 500 mg twice daily resulted in an average increase in steady-state clarithromycin Cmin by 33% and AUC by 18%. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered by coadministration with fluconazole. No dose adjustment of clarithromycin is required.
Ritonavir A pharmacokinetic study showed that the use of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. Clarithromycin Cmax increased by 31%, Cmin by 182%, and AUC by 77%. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the large therapeutic window, no dose reduction of clarithromycin is required in patients with normal renal function. Dosage adjustment is required in patients with renal insufficiency: for CLCR 30-60 ml/min, the dose of clarithromycin should be reduced by 50% to a maximum dose of 1 prolonged-release tablet per day; for CLCR < 30 ml/min, the dose of clarithromycin should be reduced by 75%. In this case, this formulation should not be used because it does not allow for adequate dose reduction. Doses of clarithromycin exceeding 1 g/day should not be used with ritonavir.
Similar dose adjustments should be made for patients with impaired renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir.
Antiarrhythmics. There have been postmarketing reports of torsades de pointes associated with concomitant use of clarithromycin with quinidine or disopyramide. ECG monitoring is recommended for early detection of QT prolongation. Serum concentrations of these drugs should be monitored during clarithromycin therapy. Hypoglycemia has been reported in the postmarketing setting with concomitant use of clarithromycin and disopyramide, and blood glucose monitoring is recommended when these agents are used concomitantly.
Hydroxychloroquine and chloroquine: Clarithromycin should be used with caution in patients receiving these drugs known to prolong the QT interval, as there is a risk of cardiac arrhythmia and serious cardiovascular complications.
Oral hypoglycemic agents/insulin: When used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide, clarithromycin may inhibit the CYP3A enzyme, which may cause hypoglycemia. Close monitoring of glucose levels is recommended.
CYP3A-related interactions. Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, and a drug that is primarily metabolized by CYP3A may result in increased plasma concentrations of the latter, which may increase or prolong its therapeutic effect and the risk of adverse reactions. Caution should be exercised when administering clarithromycin to patients receiving therapy with drugs that are CYP3A substrates, especially if the CYP3A substrate has a narrow therapeutic index (e.g. carbamazepine) and/or is extensively metabolized by this enzyme. Dosage adjustment and, if possible, close monitoring of serum concentrations of the CYP3A-metabolized drug in patients receiving concomitant clarithromycin may be necessary.
The following drugs or drug 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, rivaroxaban, apixaban), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not exhaustive. A similar mechanism of interaction has been observed with phenytoin, theophylline and valproate, which are metabolized by a different cytochrome P450 isoenzyme.
Direct-acting oral anticoagulants. The direct-acting oral anticoagulants dabigatran and edoxaban are substrates for the efflux transporter P-glycoprotein (Pgp). Rivaroxaban and apixaban are metabolized by CYP3A4 and are also Pgp substrates. The concomitant use of direct-acting oral anticoagulants such as dabigatran, rivaroxaban and apixaban with clarithromycin requires caution, especially in patients at high risk of bleeding (see section 4.4).
Omeprazole: The use of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers resulted in an increase in steady-state concentrations of omeprazole (Cmax, AUC0-24, t1/2 increased by 30%, 89% and 34%, respectively). When omeprazole was used alone, the mean pH of gastric juice measured over 24 hours was 5.2, when omeprazole was used together with clarithromycin - 5.7.
Sildenafil, tadalafil, and vardenafil: Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil, which are at least partially metabolized by CYP3A, is likely to result in increased exposure to the phosphodiesterase inhibitor, which may require a reduction in the dose of the phosphodiesterase inhibitor.
Theophylline, carbamazepine. Clinical studies have shown that there is a slight but statistically significant (p≤ 0.05) increase in theophylline or carbamazepine plasma concentrations when co-administered with clarithromycin.
Tolterodine. Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoform (CYP2D6). However, in a population of patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A results in significantly increased plasma concentrations of tolterodine. In such patients, a reduction in the dose of tolterodine may be necessary when administered with CYP3A inhibitors such as clarithromycin.
There have been post-marketing reports of drug interactions and central nervous system adverse events (such as drowsiness and confusion) with concomitant use of clarithromycin and triazolam. The patient should be monitored for possible potentiation of CNS pharmacological effects.
Bidirectional drug interactions.
Atazanavir. Coadministration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, resulted in a 2-fold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic window, no dose reduction is necessary in patients with normal renal function. The clarithromycin dose should be reduced by 50% for patients with creatinine clearance 30-60 mL/min and by 75% for patients with creatinine clearance < 30 mL/min, using the appropriate dosage form. Clarithromycin doses greater than 1000 mg daily should not be administered with protease inhibitors.
Calcium channel blockers: Due to the risk of hypotension, caution should be exercised when administering clarithromycin concomitantly with calcium channel blockers metabolized by CYP3A4 (such as verapamil, amlodipine, diltiazem). The interaction may result in increased plasma concentrations of both clarithromycin and the calcium channel blocker. Hypotension, bradyarrhythmias, and lactic acidosis have been reported in patients receiving clarithromycin concomitantly with verapamil.
Itraconazole: Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, and therefore clarithromycin may increase plasma levels of itraconazole and vice versa. When itraconazole is used concomitantly with clarithromycin, patients should be closely monitored for signs or symptoms of enhanced or prolonged pharmacological effects.
Saquinavir. Coadministration of clarithromycin (500 mg twice daily) with saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, resulted in a 177% increase in steady-state AUC of saquinavir and a 187% increase in Cmax of saquinavir compared to saquinavir alone. The AUC and Cmax of clarithromycin were increased by approximately 40% compared to clarithromycin alone. No dose adjustment is necessary when both drugs are coadministered for a limited period of time and at the above-mentioned doses/formulations. The results of a drug interaction study with the soft gelatin capsules may not be consistent with the effects observed with the hard gelatin capsule formulation of saquinavir. The results of drug interaction studies with saquinavir alone may not be consistent with the effects observed with saquinavir/ritonavir therapy. If saquinavir is used with ritonavir, the potential effects of ritonavir on clarithromycin should be considered (see above).
Other types of interactions.
Aminoglycosides: Clarithromycin should be used with caution in combination with other ototoxic agents, especially aminoglycosides.
Colchicine. Colchicine is a substrate of CYP3A and P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are coadministered, inhibition of Pgp and/or CYP3A by clarithromycin may result in increased exposure to colchicine. Patients should be monitored for clinical signs of colchicine toxicity. The dose of colchicine should be reduced when coadministered with clarithromycin in patients with normal renal and hepatic function. Concomitant use of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment.
Digoxin. Digoxin is considered a substrate for P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. Concomitant use of Pgp inhibition may result in increased digoxin exposure. Increased plasma digoxin concentrations have been reported in postmarketing experience in patients receiving clarithromycin concomitantly with digoxin. Some patients have developed signs of digitalis toxicity, including potentially fatal arrhythmias. Patients should be closely monitored for digoxin plasma concentrations when clarithromycin is administered with digoxin.
Phenytoin and valproate. There have been spontaneous and published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). It is recommended that plasma levels of these drugs be monitored when co-administered with clarithromycin. Increased plasma levels have been reported.
Corticosteroids: Caution should be exercised when clarithromycin is coadministered with systemic and inhaled corticosteroids that are primarily metabolized by CYP3A, as systemic exposure to the corticosteroid may be increased. Patients should be closely monitored for adverse effects of systemic corticosteroids during concomitant use.
Lansoprazole.
Atazanavir. Lansoprazole, like other proton pump inhibitors, reduces the concentration of atazanavir (an HIV protease inhibitor), the absorption of which depends on gastric acidity, and therefore may affect the therapeutic effect of atazanavir and the development of resistance to HIV infection. The simultaneous use of atazanavir and lansoprazole is contraindicated.
Medicinal products metabolised by the cytochrome P450 system: Lansoprazole may increase the plasma concentrations of medicinal products metabolised by CYP3A4 (warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisolone, diazepam, clarithromycin or terfenadine).
Drugs that inhibit CYP2C19 (fluvoxamine). Fluvoxamine leads to a significant increase (4-fold) in the plasma concentration of lansoprazole. With simultaneous use, dose adjustment of lansoprazole is required.
Medicinal products that induce CYP2C19 and CYP3A4 (rifampicin, St. John's wort). CYP2C19 and CYP3A4 inducers may significantly reduce lansoprazole plasma concentrations. Lansoprazole dose adjustment is required when co-administered.
Drugs for which pH is important for absorption. Lansoprazole causes long-term inhibition of gastric secretion, therefore, theoretically, lansoprazole may affect the bioavailability of drugs for which pH is important for absorption (itraconazole, ampicillin esters).
Amoxicillin: No clinical interactions of lansoprazole with amoxicillin have been observed.
Sucralfate and antacids may reduce the bioavailability of lansoprazole, which is why lansoprazole should be taken at least 1 hour after taking these drugs.
Nonsteroidal anti-inflammatory drugs: No clinically significant interaction has been identified between lansoprazole and nonsteroidal anti-inflammatory drugs.
Theophylline: Concomitant administration of lansoprazole with theophylline (CYP1A2, CYP3A) has been shown to result in a modest increase (10%) in theophylline clearance, but the clinical significance of the interaction is unlikely. However, in order to maintain clinically effective theophylline concentrations, individual patients may require adjustment of theophylline dose when initiating or discontinuing lansoprazole therapy.
Warfarin. Lansoprazole does not affect the pharmacokinetics of warfarin and prothrombin time. An increase in MHO and prothrombin time can lead to bleeding and even death.
Digoxin: Concomitant use of digoxin and lansoprazole has been associated with an increase in plasma digoxin levels.
Tacrolimus: Concomitant use of lansoprazole and tacrolimus may increase plasma concentrations of tacrolimus, especially in transplant patients.
Tinidazole.
Tinidazole is compatible with sulfonamides and antibiotics (aminoglycosides, erythromycin, rifampicin, cephalosporins).
It is not recommended to prescribe it together with ethionamide.
Phenobarbital accelerates inactivation in the liver.
Tinidazole enhances the effect of indirect coagulants (to reduce the risk of bleeding, it is recommended to reduce their dose by 50%).
Alcohol. The simultaneous use of tinidazole and alcohol may lead to a disulfiram-like reaction, so this combination should be avoided.
Anticoagulants: Drugs with similar chemical structures potentiate the effects of oral anticoagulants. Prothrombin time should be monitored frequently and the anticoagulant dose adjusted if necessary.
Application features
Prolonged or repeated use of antibiotics, including clarithromycin, may result in overgrowth of nonsusceptible bacteria and fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy initiated.
Hepatic dysfunction, including elevated liver enzymes, hepatocellular and/or cholestatic hepatitis with or without jaundice, has been reported with clarithromycin. Liver dysfunction may be severe and is usually reversible. Fatal hepatic failure has been reported in some cases, and was generally associated with severe underlying medical conditions and/or concomitant medication. Clarithromycin should be discontinued immediately if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.
Clostridium difficile-associated diarrhea, ranging from mild to fatal, has been reported with nearly all antibacterial agents, including clarithromycin. The possibility of Clostridium difficile-associated diarrhea should be kept in mind in all patients presenting with diarrhea following antibiotic therapy. A careful history should also be taken, as Clostridium difficile-associated diarrhea has been reported up to 2 months after antibiotic therapy.
In the event of the development of severe acute hypersensitivity reactions such as anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, Henoch-Schonlein-Schönlein disease, clarithromycin therapy should be discontinued immediately and appropriate treatment initiated.
Exacerbation of myasthenia gravis symptoms has been reported in patients taking clarithromycin.
Caution should be exercised when clarithromycin is co-administered with direct-acting oral anticoagulants such as dabigatran, rivaroxaban, apixaban and edoxaban, especially in patients at high risk of bleeding (see section 4.5).
Tinidazole causes darkening of urine.
The drug is excreted by the liver and kidneys. Caution should be exercised when using the drug in patients with hepatic insufficiency, moderate or severe renal insufficiency.
Due to the risk of QT prolongation, the drug should be used with caution in patients with ischemic heart disease, severe heart failure, bradycardia (<50 beats/minute) or when used concomitantly with other drugs associated with QT prolongation (see "Interaction with other medicinal products and other types of interactions").
The drug should be used with caution simultaneously with triazolebenzodiazepines (e.g. triazolam), intravenous midazolam, ototoxic agents (especially aminoglycosides), cytochrome CYP3A4 enzyme inducers, statins (use with lovastatin and simvastatin is contraindicated), oral hypoglycemic agents (e.g. sulfonylureas) and/or insulin, oral anticoagulants (see section "Interaction with other medicinal products and other types of interactions").
During treatment with the drug, the consumption of alcoholic beverages is prohibited due to the possible development of a disulfiram-like reaction (abdominal cramps, nausea, vomiting).
Drugs with a similar chemical structure to tinidazole potentiate the effects of oral anticoagulants. Prothrombin time should be monitored frequently and the anticoagulant dose adjusted if necessary.
The potential for cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin, should be considered.
The drug is recommended for patients who have not previously used drugs from the nitroimidazole group.
Lansoprazole capsules contain sugar, which should be taken into account by diabetics.
Use during pregnancy or breastfeeding
Clatinol® is contraindicated during pregnancy or breastfeeding.
The safety of clarithromycin during pregnancy or lactation has not been established. Based on animal studies and human experience, a harmful effect on embryo-fetal development cannot be excluded. Some observational studies evaluating exposure to clarithromycin during the first and second trimesters of pregnancy have shown an increased risk of miscarriage compared with no antibacterial therapy or with the use of other antibacterial agents during the same period. Available epidemiological studies on the risk of congenital malformations with the use of macrolides, including clarithromycin, during pregnancy have shown conflicting results. Clarithromycin should not be used during pregnancy without careful benefit/risk assessment.
Clarithromycin is excreted in human milk in small amounts. It has been found that the amount of clarithromycin received by an exclusively breastfed infant is approximately 1.7% of the maternal weight-adjusted dose.
Ability to influence reaction speed when driving vehicles or other mechanisms
The use of the drug does not affect the ability to drive vehicles or work with potentially dangerous
