Clatynol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLATINOL® (CLATINOL®)

Composition:

Active substances: clarithromycin, tinidazole, lansoprazole;

1 tablet contains clarithromycin 250 mg;

Excipients: microcrystalline cellulose, povidone (K30), magnesium stearate, colloidal anhydrous silicon dioxide, sodium croscarmellose, 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, Opadry white 58920 film coating: polyethylene glycol 6000, tartrazine colorant (E 102), talc;

1 capsule contains lansoprazole pellets equivalent to lansoprazole 30 mg;

Excipients: sugar, methacrylate copolymer, starch, hypromellose, disodium hydrogen phosphate dihydrate, titanium dioxide, polyethylene glycol, talc, sodium lauryl sulfate, polysorbate-80, sodium hydroxide.

Pharmaceutical form. Coated tablets; capsules.

Main physicochemical properties.

Tinidazole tablets: coated, biconvex, round-shaped tablets, yellow in color;

Clarithromycin tablets: yellow-colored, oval-shaped, biconvex, coated tablets with a score line on one side;

Lansoprazole capsules: hard gelatin capsules with an orange-colored body and a white cap, marked with the letter "S" on both cap and body, containing white-colored granules.

Pharmacotherapeutic group. Combinations for eradication of H. pylori. Lansoprazole, clarithromycin and tinidazole. ATC code A02BD09.

Pharmacological Properties

Pharmacodynamics

Clarithromycin is a macrolide antibiotic with 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 through binding to the 50S subunit of the bacterial ribosomal membrane. The minimum inhibitory concentration (MIC90) of clarithromycin and its active metabolite, 14-hydroxyclarithromycin, against H. pylori is 0.06 mcg/mL.

Lansoprazole blocks the final stage of hydrochloric acid production. In the canaliculi of gastric parietal cells, it is transformed into its active form – sulfenamide, which irreversibly interacts with the SH-groups of H+-K+-ATPase (proton pump). It reduces both basal and stimulated (by food, pentagastrin, insulin) acid secretion and volume of gastric juice. Reactivation of H+-K+-ATPase occurs with a half-life of 30–48 hours. The mean daily gastric juice pH increases to 2.9 (the percentage of time with pH > 3 is 47.6%). After discontinuation of treatment, acid levels remain below 50% of baseline for up to 39 hours, with no rebound increase in secretion observed. The effect is prolonged in patients with Zollinger-Ellison syndrome. Lansoprazole inhibits pepsin production (serum pepsinogen levels increase). It exhibits gastroprotective effects: improved mucosal oxygenation and increased bicarbonate secretion. It suppresses the growth of H. pylori (minimum inhibitory concentration ranges from 0.78 to 6.25 mg/L) and promotes the formation of specific immunoglobulins A in the gastric mucosa. It reduces blood flow in the gastric antrum, pylorus, and duodenal bulb by an average of 17%, and inhibits gastric motor and evacuatory function. Suppression of acid secretion is accompanied by an increase in nitrosobacteria and elevated nitrate concentrations in gastric secretions. Serum gastrin concentration increases by 50–100%. It ensures faster symptom relief and ulcer healing in duodenal ulcer disease. It is effective in treating gastric and duodenal ulcers resistant to H2-receptor blockers. Concurrent use of clarithromycin and lansoprazole enhances the pharmacokinetic parameters of both drugs. The eradication rate of H. pylori significantly increases when tinidazole is added to this combination. Tinidazole belongs to the nitroimidazole class and has antimicrobial activity against anaerobic bacteria, protozoa, and H. pylori. Due to its high lipophilicity, tinidazole readily penetrates anaerobic microorganisms, where it is reduced by nitroreductase, leading to disruption of the DNA helical structure.

Thus, lansoprazole in combination with antibiotic therapy ensures rapid symptom relief and ulcer healing. Clarithromycin and lansoprazole have not shown mutagenic properties in various tests.

Pharmacokinetics

Clarithromycin is rapidly and adequately absorbed after oral administration. Food slows absorption but does not significantly affect bioavailability. After single-dose administration, two peaks in serum concentration are observed. The second peak is attributed to the drug's ability to accumulate in the gallbladder, followed by gradual or rapid release. In plasma, it binds to serum proteins (over 90%). Approximately 20% of the administered dose is immediately oxidized in the liver to form the main active metabolite, 14-hydroxyclarithromycin. This biotransformation is catalyzed by cytochrome P450 enzyme system. Clarithromycin distributes well into body fluids and tissues, achieving concentrations up to 10 times higher than plasma levels. The elimination half-life after a 500 mg dose is 7–9 hours. Up to 30% of the dose is excreted unchanged in urine, and the remainder is excreted as metabolites.

Lansoprazole is rapidly absorbed, with an absolute bioavailability of approximately 40%. Food does not affect its absorption. It undergoes extensive hepatic metabolism. The elimination half-life from plasma is 0.5–1 hour. Approximately 80% of lansoprazole is excreted by the kidneys. After oral administration, the onset of antisecretory action occurs within 1 hour. The duration of inhibition of gastric acid secretion lasts nearly 24 hours. With repeated administration of 20 mg/day, daily intragastric acidity is reduced by 97%.

It has been demonstrated that concomitant use of lansoprazole and clarithromycin favorably affects the pharmacokinetic properties of the latter. The mean maximum concentration (Cmax) was 10% higher, the mean minimum concentration (Cmin) was 27% higher, and the mean AUC (area under the curve) was 15% greater compared to clarithromycin administered alone. Clarithromycin concentrations in gastric tissue and mucus also increased when administered concurrently with lansoprazole.

Tinidazole is rapidly absorbed after oral administration, with an absorption rate of approximately 90%. It accumulates in the blood, and Cmax is reached within 2 hours. Plasma protein binding is 10%. It readily penetrates various tissues and body fluids and crosses the blood-brain barrier. It undergoes biotransformation, with the main metabolites being pharmacologically active hydroxylated compounds (which inhibit the growth of anaerobic microorganisms and may enhance the effect of tinidazole). It is slowly excreted (including metabolites) by the kidneys (with intense tubular reabsorption). The elimination half-life in adults is 10–14 hours.

Clinical characteristics.

Indications.

Peptic ulcer of the stomach and duodenum, chronic gastritis associated with H. pylori.

Contraindications.

Hypersensitivity to lansoprazole, clarithromycin, or other macrolide antibiotics, tinidazole or other 5-nitroimidazole derivatives. Concomitant use with the following medicinal products: atazanavir, astemizole, cisapride, pimozide, terfenadine (due to risk of QT interval prolongation and development of cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsades de pointes); ergot alkaloids, e.g. ergotamine, dihydroergotamine (due to risk of ergot toxicity); HMG-CoA reductase inhibitors (statins) predominantly metabolized by CYP3A4, such as lovastatin or simvastatin (due to increased risk of myopathy, including rhabdomyolysis). Blood disorders. Organic lesions of the nervous system. Concomitant use of clarithromycin (and other potent 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 lomitapide. History of QT interval prolongation or ventricular arrhythmias, including torsades de pointes. Severe hepatic impairment with concomitant renal impairment. Electrolyte imbalance: hypokalemia or hypomagnesemia (due to risk of QT interval prolongation).

Interaction with other medicinal products and other types of interactions.

The use of the following medicinal products is strictly contraindicated due to the potential for severe interaction consequences.

Cisapride, pimozide, astemizole, terfenadine. Increased serum levels of cisapride have been observed when used concomitantly with clarithromycin, which may cause QT interval prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been reported with concomitant use of pimozide and clarithromycin. Macrolides have been shown to alter the metabolism of terfenadine, leading to increased serum levels of terfenadine, sometimes associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes. During concomitant use of terfenadine and clarithromycin, serum levels of terfenadine's acid metabolite increased 2–3 times and QT interval was prolonged, although no clinically evident effect was observed. Similar effects have been noted with concomitant use of astemizole and other macrolides.

Ergot alkaloids. Post-marketing reports indicate that concomitant use of clarithromycin with ergotamine or dihydroergotamine has been associated with signs of acute ergotism, characterized by vasospasm and ischemia of extremities and other tissues, including the central nervous system.

HMG-CoA reductase inhibitors (statins). Combined use of clarithromycin with lovastatin or simvastatin is contraindicated, as these statins are predominantly metabolized by CYP3A4, and concomitant use with clarithromycin increases their plasma concentration, thereby increasing the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients receiving concomitant clarithromycin and these statins. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin must be discontinued during the course of treatment.

Clarithromycin should be used with caution when administered concomitantly with other statins. In situations where concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin not dependent on CYP3A metabolism (e.g., fluvastatin) may be considered. 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 increase in transaminase levels (see section "Contraindications").

Concomitant use of clarithromycin is also contraindicated with ergot alkaloids, oral midazolam, HMG-CoA reductase inhibitors predominantly metabolized by CYP3A4 (e.g., lovastatin and simvastatin), colchicine, ticagrelor, ivabradine, and ranolazine (see section "Special precautions for use").

Effect of other medicinal products on the pharmacokinetics of clarithromycin.

CYP3A-related interactions. Medicinal products that are CYP3A inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) may induce clarithromycin metabolism. This may lead to subtherapeutic levels of clarithromycin and reduced efficacy. Additionally, monitoring of plasma levels of the CYP3A inducer may be required, as they may be increased due to CYP3A inhibition by clarithromycin (see also the prescribing information for the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has led to increased rifabutin levels and decreased clarithromycin serum levels, with an increased risk of uveitis.

The effect of the following medicinal products on clarithromycin blood concentration is known or suspected, thus dose adjustment or alternative therapy may be required.

Efavirenz, nevirapine, rifampicin, rifabutin, rifapentine. Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, may accelerate clarithromycin metabolism, reducing its plasma concentration but increasing the concentration of 14-OH-clarithromycin – a microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against various bacteria, the expected therapeutic effect may not be achieved with concomitant use of clarithromycin and cytochrome P450 enzyme inducers.

Etravirine. The effect of clarithromycin was diminished 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 MAC treatment.

Fluconazole. Concomitant use of fluconazole 200 mg daily and clarithromycin 500 mg twice daily resulted in an average 33% increase in steady-state Cmin of clarithromycin and 18% increase in AUC. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered with concomitant fluconazole. Dose adjustment of clarithromycin is not required.

Ritonavir. A pharmacokinetic study showed that administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. Cmax of clarithromycin increased by 31%, Cmin by 182%, and AUC by 77%. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic window, dose reduction of clarithromycin is not required in patients with normal renal function. Dose adjustment is required in patients with renal impairment: for CLCR 30–60 mL/min, clarithromycin dose should be reduced by 50% to a maximum of one prolonged-release tablet daily; for CLCR < 30 mL/min, clarithromycin dose should be reduced by 75%. In this case, this formulation should not be used, as it does not allow adequate dose reduction. Doses of clarithromycin exceeding 1 g/day should not be used concomitantly with ritonavir.

The same dose adjustments should be applied for patients with impaired renal function when ritonavir is used as a pharmacokinetic booster with other HIV protease inhibitors, including atazanavir and saquinavir.

Effect of clarithromycin on the pharmacokinetics of other medicinal products.

Antiarrhythmic agents. Post-marketing reports indicate the development of torsades de pointes with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended for early detection of QT interval prolongation. Serum concentrations of these agents should be monitored during clarithromycin therapy. Post-marketing reports have also noted hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, blood glucose monitoring is necessary when these agents are used together.

Hydroxychloroquine and chloroquine: Clarithromycin should be used with caution in patients receiving these agents, which are known to prolong the QT interval, due to the 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, potentially causing hypoglycemia. Close monitoring of glucose levels is recommended.

CYP3A-related interactions. Concomitant use of clarithromycin, a known CYP3A enzyme inhibitor, with a medicinal product predominantly metabolized by CYP3A, may lead to increased plasma concentrations of the latter, thereby enhancing or prolonging its therapeutic effect and increasing the risk of adverse reactions. Caution is advised when using clarithromycin in patients receiving CYP3A substrate drugs, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine) and/or is predominantly metabolized by this enzyme. Dose adjustment and, if possible, careful monitoring of serum concentrations of the CYP3A-metabolized drug may be required for patients receiving clarithromycin concomitantly.

It is known (or suspected) that the following medicinal products or groups of products are 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, although this list is not exhaustive. A similar interaction mechanism has been observed with phenytoin, theophylline, and valproate, which are metabolized by other cytochrome P450 isoenzymes.

Direct oral anticoagulants. Direct oral anticoagulants dabigatran and edoxaban are substrates of the efflux transporter P-glycoprotein (Pgp). Rivaroxaban and apixaban are metabolized by CYP3A4 and are also Pgp substrates. Concomitant use of direct oral anticoagulants such as dabigatran, rivaroxaban, and apixaban with clarithromycin requires caution, especially in patients at high risk of bleeding (see section "Special precautions for use").

Omeprazole. Administration of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers resulted in increased steady-state concentrations of omeprazole (Cmax, AUC0–24, t1/2 increased by 30%, 89%, and 34%, respectively). When omeprazole was used alone, the mean gastric pH measured over 24 hours was 5.2; with concomitant use of omeprazole and clarithromycin, it was 5.7.

Sildenafil, tadalafil, and vardenafil. Concomitant administration of clarithromycin with sildenafil, tadalafil, or vardenafil, which are at least partially metabolized by CYP3A, is likely to increase exposure to the phosphodiesterase inhibitor, potentially requiring dose reduction of the phosphodiesterase inhibitor.

Theophylline, carbamazepine. Clinical studies have shown a slight but statistically significant (p ≤ 0.05) increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.

Solifenacin. Solifenacin is primarily metabolized by the cytochrome P450 2D6 isoenzyme (CYP2D6). However, in the population of patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in solifenacin plasma concentrations. Dose reduction of solifenacin may be necessary in such patients when used with CYP3A inhibitors such as clarithromycin.

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam). When midazolam and clarithromycin (500 mg twice daily) were co-administered, AUC of midazolam increased 2.7-fold after intravenous administration and 7-fold after oral administration. Combined use of oral midazolam and clarithromycin should be avoided. With intravenous midazolam and clarithromycin, careful patient monitoring is required for timely dose adjustment. The same precautions should be followed when using other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is independent of CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

Post-marketing reports describe drug interactions and adverse effects on the central nervous system (e.g., somnolence and confusion) with concomitant use of clarithromycin and triazolam. Patients should be observed for possible enhancement of pharmacological effects on the CNS.

Bidirectional drug interactions.

Atazanavir. Concomitant use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, resulted in a doubling of clarithromycin exposure and a 70% reduction in 14-OH-clarithromycin exposure, with a 28% increase in AUC of atazanavir. Since clarithromycin has a wide therapeutic range, dose reduction is not necessary in patients with normal renal function. Clarithromycin dose should be reduced by 50% in patients with creatinine clearance of 30–60 mL/min and by 75% in patients with creatinine clearance < 30 mL/min, using an appropriate dosage form. Clarithromycin doses exceeding 1000 mg daily should not be used concomitantly with protease inhibitors.

Calcium channel blockers. Clarithromycin should be used with caution concomitantly with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem) due to the risk of arterial hypotension. Plasma concentrations of both clarithromycin and calcium channel blockers may increase during interaction. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving clarithromycin with verapamil.

Itraconazole. Clarithromycin and itraconazole are both substrates and inhibitors of CYP3A, thus clarithromycin may increase plasma levels of itraconazole and vice versa. Patients receiving itraconazole with clarithromycin should be closely monitored for signs or symptoms of enhanced or prolonged pharmacological effect.

Saquinavir. Concomitant use 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 AUC and 187% increase in Cmax of saquinavir at steady state compared to saquinavir alone. AUC and Cmax of clarithromycin increased by approximately 40% compared to clarithromycin alone. Dose adjustment is not necessary if both drugs are used concomitantly for a limited period and at the above-mentioned doses/forms. Results from drug interaction studies using soft gelatin capsules may not reflect effects observed with hard gelatin capsules of saquinavir. Results from drug interaction studies using saquinavir alone may not reflect effects observed with saquinavir/ritonavir therapy. If saquinavir is used with ritonavir, possible effects of ritonavir on clarithromycin should be considered (see above).

Other types of interactions.

Aminoglycosides. Clarithromycin should be used with caution concomitantly 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. Concomitant use of clarithromycin and colchicine may lead to increased colchicine exposure due to inhibition of Pgp and/or CYP3A by clarithromycin. Patients should be monitored for clinical signs of colchicine toxicity. Colchicine dose should be reduced when used concomitantly with clarithromycin in patients with normal renal and hepatic function. Concomitant use of clarithromycin with colchicine in patients with renal or hepatic impairment is contraindicated.

Digoxin. Digoxin is considered a substrate of P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. Concomitant use may lead to increased digoxin exposure due to Pgp inhibition. Post-marketing reports have noted increased digoxin plasma concentrations in patients receiving clarithromycin with digoxin. In some patients, signs of digoxin toxicity developed, including potentially fatal arrhythmias. Digoxin plasma concentrations should be carefully monitored in patients receiving digoxin with clarithromycin.

Zidovudine. Concomitant use of clarithromycin and zidovudine in HIV-infected patients may lead to decreased steady-state plasma concentrations of zidovudine. Clarithromycin may interfere with the absorption of oral zidovudine when administered concomitantly; this can largely be avoided by maintaining a 4-hour interval between doses of clarithromycin and zidovudine. Such interaction has not been reported with clarithromycin suspension and zidovudine or didanosine in children. This interaction is unlikely with intravenous clarithromycin.

Phenytoin and valproate. There are spontaneous and published reports of interaction between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Plasma levels of these drugs should be monitored when co-administered with clarithromycin. Increased plasma levels have been reported.

Corticosteroids. Caution is advised when using clarithromycin concomitantly with systemic and inhaled corticosteroids predominantly metabolized by CYP3A, as systemic exposure to corticosteroids may increase. Close monitoring for adverse effects of systemic corticosteroids is required when used concomitantly.

Lansoprazole.

Atazanavir. Lansoprazole, like other proton pump inhibitors, reduces the concentration of atazanavir (an HIV protease inhibitor), whose absorption is acid-dependent, potentially affecting atazanavir’s therapeutic effect and promoting HIV resistance. Concomitant use of atazanavir and lansoprazole is contraindicated.

Medicinal products metabolized by the cytochrome P450 system. Lansoprazole may increase plasma concentrations of drugs metabolized by CYP3A4 (warfarin, antipyrine, indometacin, ibuprofen, phenytoin, propranolol, prednisolone, diazepam, clarithromycin, or terfenadine).

Medicinal products inhibiting CYP2C19 (fluvoxamine). Fluvoxamine causes a significant (4-fold) increase in lansoprazole plasma concentration. Dose adjustment of lansoprazole is required when used concomitantly.

Medicinal products inducing CYP2C19 and CYP3A4 (rifampicin, St. John’s wort). Inducers of CYP2C19 and CYP3A4 may significantly reduce lansoprazole plasma concentrations. Dose adjustment of lansoprazole is required when used concomitantly.

Medicinal products whose absorption depends on pH. Lansoprazole causes prolonged inhibition of gastric acid secretion, thus theoretically affecting the bioavailability of drugs whose absorption is pH-dependent (e.g., itraconazole, ampicillin esters).

Amoxicillin. No clinical evidence of interaction between lansoprazole and amoxicillin has been observed.

Sucralfate and antacid medicinal products may reduce lansoprazole bioavailability; therefore, lansoprazole should be taken at least 1 hour after these agents.

Nonsteroidal anti-inflammatory medicinal products. No clinically significant interaction between lansoprazole and nonsteroidal anti-inflammatory drugs has been identified.

Theophylline. When lansoprazole is used concomitantly with theophylline (CYP1A2, CYP3A), a moderate increase (10%) in theophylline clearance is observed, but clinical significance of the interaction is unlikely. However, dose adjustment of theophylline may be required at the start or discontinuation of lansoprazole therapy to maintain clinically effective theophylline concentrations.

Warfarin. Lansoprazole does not affect warfarin pharmacokinetics or prothrombin time. However, increased INR and prothrombin time may lead to bleeding and even fatal outcomes.

Digoxin. Increased digoxin plasma levels have been observed with concomitant use of digoxin and lansoprazole.

Tacrolimus. Plasma concentrations of tacrolimus may increase when used concomitantly with lansoprazole, especially in transplant patients.

Tinidazole.

Tinidazole is compatible with sulfonamides and antibiotics (aminoglycosides, erythromycin, rifampicin, cephalosporins).

Not recommended to be prescribed together with ethionamide.

Phenobarbital accelerates hepatic inactivation.

Tinidazole potentiates the effect of indirect coagulants (to reduce bleeding risk, it is recommended to reduce their dose by 50%).

Alcohol. Concomitant use of tinidazole and alcohol may cause a disulfiram-like reaction; therefore, this combination should be avoided.

Anticoagulants. Medicinal products with similar chemical structure potentiate the effects of oral anticoagulants. Prothrombin time should be frequently checked and, if necessary, anticoagulant dose adjusted.

Special precautions for use.

Prolonged or repeated use of antibiotics, including clarithromycin, may lead to overgrowth of resistant bacteria and fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy initiated.

The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection may result in the development of microbial resistance. In a small number of patients, resistance of H. pylori microorganisms to clarithromycin may develop.

Abnormal liver function, including elevated liver enzymes, hepatocellular and/or cholestatic hepatitis with or without jaundice, has been reported during clarithromycin treatment. Liver dysfunction may be severe but is usually reversible. There have been reports of fatal hepatic failure, primarily associated with severe underlying diseases and/or concomitant medications. Clarithromycin should be discontinued immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Diarrhea, ranging from mild to severe pseudomembranous colitis, including fatal cases caused by Clostridium difficile, has been reported with nearly all antibacterial agents, including clarithromycin. Clostridium difficile-associated diarrhea should always be considered in all patients presenting with diarrhea following antibiotic use. Furthermore, careful medical history is essential, as cases of Clostridium difficile-associated diarrhea have been reported up to 2 months after antibiotic administration.

In the event of severe acute hypersensitivity reactions such as anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome, or Henoch-Schönlein purpura, clarithromycin therapy should be discontinued immediately and appropriate treatment initiated.

Exacerbation of symptoms of myasthenia gravis has been reported in patients receiving clarithromycin.

Caution is advised when clarithromycin is used concomitantly with direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban, especially in patients at high risk of bleeding (see section "Interaction with other medicinal products and other types of interactions").

Tinidazole may cause darkening of urine.

The drug is eliminated via both the liver and kidneys. Caution is advised when administering the drug to patients with hepatic impairment or moderate to severe renal impairment.

Due to the risk of QT interval prolongation, the drug should be used with caution in patients with ischemic heart disease, severe heart failure, bradycardia (<50 beats/min), or when used concomitantly with other drugs known to prolong the QT interval (see "Interaction with other medicinal products and other types of interactions").

The drug should be used with caution when administered concomitantly with triazolobenzodiazepines (e.g., triazolam), intravenous midazolam, ototoxic agents (particularly aminoglycosides), inducers of cytochrome CYP3A4 enzyme, statins (concomitant use with lovastatin and simvastatin is contraindicated), oral hypoglycemic agents (e.g., sulfonylureas) and/or insulin, and oral anticoagulants (see section "Interaction with other medicinal products and other types of interactions").

Alcohol consumption is prohibited during treatment due to the potential for a disulfiram-like reaction (abdominal cramps, nausea, vomiting).

Drugs with a chemical structure similar to tinidazole may potentiate the effects of oral anticoagulants. Prothrombin time should be monitored frequently, and the anticoagulant dose adjusted as necessary.

Cross-resistance between clarithromycin and other macrolides, as well as with clindamycin and lincomycin, should be considered.

The drug is recommended for patients who have not previously received nitroimidazole group agents.

Lansoprazole capsules contain sugar, which should be taken into account in patients with diabetes mellitus.

Use during pregnancy or breastfeeding.

Klatinol® is contraindicated during pregnancy and breastfeeding.

The safety of clarithromycin use during pregnancy or breastfeeding has not been established. Based on animal studies and human experience, a harmful effect on embryonic and fetal development cannot be excluded. Some observational studies assessing the impact of clarithromycin during the first and second trimesters of pregnancy have shown an increased risk of pregnancy loss compared to no antibacterial therapy or use of other antibacterial agents during the same period. Available epidemiological studies on the risk of congenital malformations associated with macrolide use, including clarithromycin, during pregnancy have yielded conflicting results. Clarithromycin should not be used during pregnancy without careful assessment of the benefit-risk ratio.

Clarithromycin passes into breast milk in small amounts. The amount of clarithromycin received by an exclusively breastfed infant has been estimated to be approximately 1.7% of the maternal dose adjusted for body weight.

Ability to affect reaction speed when driving or operating machinery.

The use of the drug does not affect the ability to drive or operate machinery or engage in activities requiring rapid reaction and coordination. However, due to the possibility of adverse effects, caution should be exercised during Klatinol® treatment.

Dosage and Administration.

The decision regarding the treatment regimen, drug dosages, and duration of therapy should be made by a physician. The recommended dosage regimen is 1 strip or blister containing 2 capsules of lansoprazole, 2 tablets of clarithromycin, and 2 tablets of tinidazole, sufficient for 1 day of treatment. In the morning, take 1 capsule of lansoprazole and 1 tablet each of clarithromycin and tinidazole; repeat the same doses in the evening.

In addition to the combined daily pack, it is necessary to take 250 mg of clarithromycin twice daily, together with the proposed regimen.

A 14-day therapy is recommended, consistent with current standards.

Children.

Not to be used in pediatric practice.

Overdose.

Clarithromycin.

Symptoms: gastrointestinal reactions (nausea, vomiting, diarrhea) may occur. In one patient with a history of bipolar disorder who ingested 8 grams of clarithromycin, disturbances in mental status, paranoid behavior, hypokalemia, and hypoxemia developed.

Treatment: immediate gastric lavage and symptomatic therapy are required. Hemodialysis and dialysis do not significantly alter the blood levels of clarithromycin.

Lansoprazole.

Symptoms: not reported (single oral doses up to 600 mg have not been associated with clinical manifestations of overdose).

Treatment: supportive and symptomatic therapy is recommended in case of suspected overdose. Hemodialysis is not effective.

Tinidazole.

Cases of overdose have not been reported.

There is no specific antidote. Tinidazole is removed by hemodialysis.

Adverse Reactions.

Clarithromycin.

Infections and infestations: candidiasis, gastroenteritis, infection, vaginal infection; pseudomembranous colitis, esophagitis.

Blood and lymphatic system disorders: leukopenia, neutropenia, thrombocytosis, eosinophilia, agranulocyt inflammatio.

Immune system disorders: hypersensitivity reactions, including anaphylactic and anaphylactoid reactions, angioneurotic edema.

Metabolism and nutrition disorders: anorexia, decreased appetite, hypoglycemia.

Psychiatric disorders: insomnia, anxiety, nervousness, agitation, psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.

Nervous system disorders: dysgeusia (disturbance of taste sensation), headache, taste distortion; somnolence, tremor, convulsions, ageusia (loss of taste sensation), parosmia, anosmia, paresthesia.

Ear and labyrinth disorders: dizziness, hearing impairment, tinnitus, hearing loss.

Cardiac disorders: QT interval prolongation, palpitations, ventricular tachycardia, including torsades de pointes, hemorrhage.

Respiratory, thoracic and mediastinal disorders: epistaxis.

Gastrointestinal disorders: dyspepsia, gastroesophageal reflux disease, gastritis, proctalgia, abdominal distension, constipation, dry mouth, eructation, acute pancreatitis, tongue discoloration, tooth discoloration, nausea, vomiting, altered taste sensation, epigastric pain, diarrhea, stomatitis, glossitis.

Hepatobiliary disorders: abnormal liver function tests, cholestasis, hepatitis, increased levels of ALT, AST, GGT, liver failure, cholestatic jaundice, hepatocellular jaundice.

Skin and subcutaneous tissue disorders: rash, hyperhidrosis, pruritus, maculopapular rash, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acne, cellulitis, Henoch-Schönlein purpura, erythrasma, urticaria, Stevens-Johnson syndrome, anaphylactoid reactions.

Musculoskeletal and connective tissue disorders: muscle spasms, myalgia, rhabdomyolysis (in some reports of rhabdomyolysis, clarithromycin was used concomitantly with other medicinal products known to be associated with rhabdomyolysis (e.g., statins, fibrates, colchicine, or allopurinol)), myopathy, arthralgia.

Renal and urinary disorders: renal failure, interstitial nephritis.

General disorders: malaise, fever, asthenia, chest pain, chills, fatigue.

Investigations: increased plasma levels of alkaline phosphatase and lactate dehydrogenase, increased international normalized ratio, prolonged prothrombin time, change in urine color.

When clarithromycin powder for solution for infusion was used, the following adverse reactions have been reported: loss of consciousness, dyskinesia, cardiac arrest, atrial fibrillation, extrasystoles, vasodilation, asthma, pulmonary embolism, esophagitis, bullous dermatitis, cellulitis, skeletal muscle rigidity, increased plasma creatinine and urea levels.

Patients with impaired immune system.

In patients with AIDS and other patients with impaired immune system who received high doses of clarithromycin for prolonged periods beyond the recommended duration for treatment of mycobacterial infections, it was often difficult to distinguish adverse reactions related to the drug from symptoms of the underlying or concomitant diseases.

Tinidazole.

Gastrointestinal disorders: dyspeptic disorders such as decreased appetite, nausea, occasionally vomiting, diarrhea, abdominal pain, anorexia, tongue coating, glossitis, stomatitis.

Nervous system and sensory organ disorders: dizziness, headache, locomotor ataxia, dysarthria, paresthesia, hypesthesia, peripheral neuropathy, vertigo, sensory disturbances, metallic taste in the mouth, flushing.

General disorders: increased fatigue, elevated body temperature.

Blood and lymphatic system disorders: transient leukopenia.

Musculoskeletal and connective tissue disorders: convulsive reactions.

Renal and urinary disorders: darkening of urine color.

Immune system disorders: hypersensitivity reactions, urticaria, rash, pruritus (isolated cases), angioneurotic edema.

Lansoprazole.

Cardiac disorders: angina pectoris, arrhythmia, bradycardia, cardiac pain, cerebrovascular events (stroke), arterial hypertension, arterial hypotension, migraine, myocardial infarction, palpitations, shock (circulatory collapse), vasodilation, syncope, tachycardia.

Blood and lymphatic system disorders: leukopenia, thrombocytopenia, eosinophilia, pancytopenia or agranulocytosis, aplastic anemia, hemolytic anemia, neutropenia, thrombotic and thrombocytopenic purpura.

Nervous system disorders: headache; rarely: somnolence, dizziness, vertigo, hemiplegia, tremor, paresthesia.

Psychiatric disorders: anxiety, depression, agitation, amnesia, excitement, apathy, hallucinations, hostility, nervousness, insomnia, thought disorders, confusion.

Respiratory, thoracic and mediastinal disorders: asthma, bronchitis, severe cough, pharyngitis, rhinitis, hiccups, epistaxis, pulmonary hemorrhage, pneumonia, inflammation or infection of upper respiratory tract.

Eye disorders: eye pain, visual disturbances, blurred vision, visual field defects.

Ear and labyrinth disorders: tinnitus, deafness, otitis media.

Gastrointestinal disorders: constipation; abdominal pain; diarrhea; nausea; dyspepsia; taste disturbances; bad breath; dry mouth/thirst; dysphagia; cardiospasm; eructation; vomiting; esophageal stricture; esophageal ulcer; esophagitis; change in stool color; flatulence; gastric polyps; gastroenteritis; colitis; gastrointestinal hemorrhage, including rectal; vomiting with blood (hematemesis); increased or decreased appetite; anorexia; increased salivation; melena; stomatitis; glossitis; pancreatitis; tenesmus.

Hepatobiliary disorders: jaundice, hepatitis, cholelithiasis.

Endocrine disorders: diabetes mellitus, goiter, hyperglycemia/hypoglycemia, hypothyroidism.

Skin and subcutaneous tissue disorders: frequently – skin rash; rarely – pruritus, urticaria, purpura, angioneurotic edema, petechiae or hair loss, hyperhidrosis, acne, photosensitivity; very rarely – severe generalized reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.

Musculoskeletal and connective tissue disorders: joint, muscle, or bone pain, arthritis/arthralgia, myalgia.

Renal and urinary disorders: interstitial nephritis, which may lead to renal failure, glucosuria, hematuria, albuminuria, kidney stones, urinary retention.

Reproductive system disorders: urogenital disorders, impotence, decreased libido, breast enlargement or gynecomastia, breast tenderness, menstrual disorders.

General disorders: anaphylactoid/anaphylactic reactions, anaphylactic shock, abdominal distension, allergic reactions, asthenia, candidiasis, carcinoma, back pain, neck rigidity, chest pain (not always specific), pelvic pain, facial flushing, speech disorders, edema, chills, dyspnea, fever, influenza-like syndrome, infections (nonspecific), weakness.

Investigations: increased levels of AST, ALT, alkaline phosphatase, creatinine, globulins, gamma-glutamyl transferase, increased/decreased white blood cell count, altered A/G ratio, changes in red blood cell count, bilirubinemia, eosinophilia, hyperlipidemia, increased/decreased electrolytes, increased/decreased cholesterol, decreased hemoglobin, increased potassium, urea, and salt in urine, increased glucocorticoid levels, increased low-density lipoprotein levels, increased/decreased platelet count, increased gastrin levels, positive occult blood test, albuminuria, glucosuria, hematuria.

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store in a place inaccessible to children, dry, protected from light, at a temperature not exceeding 30°C.

Packaging.

Combined oral dosage set No. 42: 2 yellow round tablets (tinidazole) + 2 yellow oval tablets (clarithromycin) + 2 capsules (lansoprazole) – in a strip; 7 strips per cardboard box labeled in Ukrainian.

Combined oral dosage set No. 42: 2 yellow round tablets (tinidazole) + 2 yellow oval tablets (clarithromycin) + 2 capsules (lansoprazole) – in a blister; 7 blisters per cardboard box labeled in Ukrainian.

Prescription status. Prescription only.

Manufacturer.

Evertogen Life Sciences Limited / Evertogen Life Sciences Limited.

Manufacturer's location and address of its business activity.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India /
Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.