Instructions for use Pylobact Neo combined set for oral use No. 42
Composition
active ingredients:
amoxicillin tablets – 1 film-coated tablet contains amoxicillin trihydrate equivalent to amoxicillin 1000 mg;
Clarithromycin tablets – 1 film-coated tablet contains 500 mg of clarithromycin;
omeprazole capsules – 1 capsule contains omeprazole 20 mg;
excipients:
amoxicillin tablets: microcrystalline cellulose, sodium starch glycolate, colloidal anhydrous silica, talc, magnesium stearate; shell composition: hydroxypropylmethylcellulose, titanium dioxide (E 171), parmasyl, sunset yellow FCF dye (E 110), polyethylene glycol;
Clarithromycin tablets: microcrystalline cellulose, povidone, magnesium stearate, stearic acid, talc, colloidal anhydrous silica, croscarmellose sodium; shell composition: hydroxypropylmethylcellulose, hydroxypropylcellulose, propylene glycol, sorbitan oleate, titanium dioxide (E 171), quinoline yellow dye (E 104), vanillin, opacod (black) contains: (shellac, black iron oxide, propylene glycol);
Omeprazole capsules: starch, dextrin, powdered sugar, talc, cane sugar, sodium carboxymethyl starch, sodium carboxymethylcellulose, disodium hydrogen phosphate, anhydrous sodium sulfite, hypromellose, titanium dioxide (E 171), polyethylene glycol 4000, sodium citrate, polyacrylic acid gum emulsion, non-parel granules, empty hard gelatin capsule size "2" contains: (diamond blue, carmoisine, gelatin, methylparaben, propylparaben).
Dosage form
Amoxicillin – film-coated tablets. Clarithromycin – film-coated tablets. Omeprazole – capsules.
Main physicochemical properties:
Amoxicillin tablets - orange-coated, capsule-shaped, biconvex tablets;
Clarithromycin tablets - film-coated, light yellow, oval, biconvex tablets, marked "SHT500" in black ink on one side;
Omeprazole capsules are self-closing hard gelatin capsules with a blue cap and a transparent pink body, size "2", containing white or almost white spherical granules.
Pharmacotherapeutic group
Combinations for eradication of Helicobacter pylori. ATX code A02B D05.
Pharmacological properties
Pharmacodynamics
Pylobact Neo is a combination kit containing omeprazole, clarithromycin and amoxicillin. Pylobact Neo is a triple regimen for the first-line eradication therapy of Helicobacter pylori (H. pylori), designed for 7 days of treatment.
Omeprazole is a proton pump inhibitor. Omeprazole reduces the secretion of hydrochloric acid in the stomach by inhibiting the activity of H+-K+-ATPase, which causes blocking of the final stage of hydrochloric acid secretion. This leads to a decrease in the level of basal and stimulated secretion regardless of the nature of the stimulus. The duration of inhibition of hydrochloric acid secretion in the stomach is more than 24 hours. Omeprazole increases the pH level in the stomach, thereby providing an optimal environment for antimicrobial activity. Omeprazole significantly reduces the volume of gastric juice and thus increases the concentrations of clarithromycin and amoxicillin in the gastric mucosa.
Clarithromycin is a macrolide antibiotic that exhibits 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 ribosomal subunit of susceptible bacteria. The minimum inhibitory concentration (MIC90) of clarithromycin and its active metabolite 14-hydroxyclarithromycin against H. pylori is 0.03 μg/ml and 0.06 μg/ml, respectively. Clarithromycin is resistant to the acidic environment of the stomach. Amoxicillin is an antibiotic from the group of semi-synthetic penicillins with a broad spectrum of bactericidal activity associated with the ability to inhibit the synthesis of the bacterial cell wall. Active against H. pylori, amoxicillin-resistant strains of H. pylori have not yet been identified.
Pharmacokinetics
All three drugs included in the set are well absorbed after oral administration. Omeprazole is rapidly absorbed, with an absolute bioavailability of approximately 40%. The half-life of the drug from blood plasma is 0.5-1 hour. 90-95% of omeprazole is bound to blood plasma proteins. Omeprazole undergoes extensive metabolism in the liver. Almost 80% of omeprazole is excreted by the kidneys in the form of metabolites.
Amoxicillin after oral administration is rapidly and almost completely absorbed in the gastrointestinal tract; it is not destroyed in the acidic environment of the stomach. Food does not affect the adsorption of amoxicillin. The maximum concentration of amoxicillin in the blood plasma is reached after 1-2 hours. Binding to plasma proteins is 20%. Amoxicillin is widely distributed in tissues, mucous membranes and body fluids. The half-life of amoxicillin is 1-1.5 hours. 60% of the dose taken is excreted unchanged in the urine by tubular secretion and glomerular filtration.
Indication
All three drugs included in the set are well absorbed after oral administration. Omeprazole is rapidly absorbed, with an absolute bioavailability of approximately 40%. The half-life of the drug from blood plasma is 0.5-1 hour. 90-95% of omeprazole is bound to blood plasma proteins. Omeprazole undergoes extensive metabolism in the liver. Almost 80% of omeprazole is excreted by the kidneys in the form of metabolites.
Clarithromycin is widely distributed in body tissues, including the mucous membranes of the stomach and duodenum. Clarithromycin concentrations in tissues and body fluids are 10 times higher than those in serum. Food intake does not affect the bioavailability of the drug. Approximately 20% of clarithromycin is metabolized to the main metabolite, 14-hydroxyclarithromycin. The half-life of clarithromycin is 5-7 hours. Approximately 20% of clarithromycin is eliminated by the kidneys unchanged, and 15% as 14-hydroxyclarithromycin. It has been proven that simultaneous administration of omeprazole and clarithromycin has a beneficial effect on the pharmacokinetic properties of clarithromycin.
Amoxicillin after oral administration is rapidly and almost completely absorbed in the gastrointestinal tract; it is not destroyed in the acidic environment of the stomach. Food does not affect the adsorption of amoxicillin. The maximum concentration of amoxicillin in the blood plasma is reached after 1-2 hours. Binding to plasma proteins is 20%. Amoxicillin is widely distributed in tissues, mucous membranes and body fluids. The half-life of amoxicillin is 1-1.5 hours. 60% of the dose taken is excreted unchanged in the urine by tubular secretion and glomerular filtration.
Contraindication
Eradication of Helicobacter pylori in patients with gastric and duodenal ulcers.
Hypersensitivity to omeprazole, clarithromycin, other macrolides, amoxicillin, other beta-lactam antibiotics and substituted benzimidazoles or other components of the drug.
Omeprazole, like other proton pump inhibitors, should not be taken with atazanavir and nelfinavir.
Concomitant use of clarithromycin with one of the following drugs is contraindicated: cisapride, astemizole, ergotamine or dihydroergotamine, pimozide, terfenadine.
Concomitant administration of clarithromycin with one of the following drugs is contraindicated: HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) due to an increased risk of myopathy, including rhabdomyolysis. Concomitant administration of clarithromycin and oral midazolam (see Interactions with other medicinal products and other forms of interaction).
Contraindicated in patients with a history of QT prolongation or ventricular cardiac arrhythmias, including torsades de pointes (see "Special warnings and precautions for use", "Interaction with other medicinal products and other types of interactions").
Hypokalemia (risk of QT prolongation).
Severe hepatic insufficiency and concomitant renal insufficiency.
Concomitant use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine in patients with renal or hepatic impairment (see "Special warnings and precautions for use", "Interaction with other medicinal products and other types of interactions").
Concomitant use of clarithromycin and any of the following: astemizole, cisapride, pimozide, terfenadine (as this may lead to QT prolongation and the development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsades de pointes). Ergot alkaloids, e.g. ergotamine, dihydroergotamine (as this may lead to ergotoxicity).
Concomitant use of clarithromycin with sticagrelor or ranolazine.
Interaction with other medicinal products and other types of interactions
Amoxicillin
Probenecid, phenylbutazone, oxyphenbutazone, and to a lesser extent, acetylsalicylic acid and sulfinpyrazone inhibit the tubular secretion of penicillin drugs, which leads to an increase in the half-life and concentration of amoxicillin in blood plasma.
Bacteriostatic drugs (tetracycline antibiotics, macrolides, chloramphenicol) can neutralize the bactericidal effect of amoxicillin. Parallel use of aminoglycosides is possible (synergistic effect).
Not recommended combinations
Allopurinol. Simultaneous use with amoxicillin contributes to the occurrence of allergic skin reactions.
Digoxin. The absorption of digoxin increases, therefore its dose adjustment is necessary.
Anticoagulants. Concomitant use of amoxicillin and coumarin anticoagulants may prolong bleeding time. Dose adjustment of anticoagulants may be necessary. There have been reports of increased activity of oral anticoagulants in patients receiving amoxicillin.
Methotrexate. The use of amoxicillin with methotrexate leads to an increase in the toxic effect of the latter. Amoxicillin reduces the renal clearance of methotrexate, therefore its serum concentration should be monitored.
Amoxicillin should be used with caution in combination with oral hormonal contraceptives, as plasma levels of estrogen and progesterone may be temporarily reduced, which may reduce the effectiveness of hormonal contraceptives. Therefore, the use of additional non-hormonal contraceptives is recommended.
Other types of interactions
Forced diuresis leads to a decrease in the concentration of amoxicillin in the blood plasma by increasing its elimination.
The occurrence of diarrhea may lead to a decrease in the absorption of other drugs and adversely affect their effectiveness.
Impact on the results of diagnostic laboratory tests: when determining the presence of glucose in urine, it is recommended to use the enzymatic glucose oxidase method. When using chemical methods, false-positive results are usually observed.
Amoxicillin may reduce the amount of estriol in the urine of pregnant women.
At high concentrations, amoxicillin may reduce serum glycemia. Amoxicillin may interfere with colorimetric protein determination.
Clarithromycin
Clarithromycin does not interact with oral contraceptives.
The use of the following drugs is strictly contraindicated due to the possible development of severe interaction effects.
Cisapride, pimozide, astemizole, terfenadine. Increased serum levels of cisapride, pimozide, and terfenadine have been observed when co-administered with clarithromycin, which may lead to QT prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been observed with the concomitant use of astemizole and other macrolides.
Ergot alkaloids: 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.
Effect of other drugs on the pharmacokinetics of clarithromycin
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. 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 medicinal products are known or suspected to affect clarithromycin blood concentrations and may require dose adjustment or alternative therapy.
Efavirenz, nevirapine, rifampicin, rifabutin, and 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 is different against different bacteria, the expected therapeutic effect may not be achieved due to the concomitant use of clarithromycin and inducers of cytochrome P450 enzymes.
Etravirine: Clarithromycin activity was attenuated by etravirine, but concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against MAS, overall activity against this pathogen may be altered. Therefore, alternative agents to clarithromycin should be considered for the treatment of MAS.
Fluconazole: Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered by co-administration with fluconazole. No dose adjustment of clarithromycin is required.
Ritonavir. The use of ritonavir and clarithromycin resulted in significant inhibition of clarithromycin metabolism. Clarithromycin Cmax was 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 necessary in patients with normal renal function. However, dose adjustment is necessary in patients with renal insufficiency: for patients with CLCR 30-60 mL/min, the clarithromycin dose should be reduced by 50%. For patients with severe renal insufficiency (CLCR < 30 mL/min), the clarithromycin dose should be reduced by 75%. Doses of clarithromycin exceeding 1 g/day should not be used with ritonavir.
Effect of clarithromycin on the pharmacokinetics of other drugs
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.
CYP3A: 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 in turn 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 CYP3A substrate drugs, especially if the CYP3A substrate has a narrow therapeutic range (e.g. carbamazepine) and/or is extensively metabolized by this enzyme.
Dose adjustment and, if possible, close monitoring of serum concentrations of a drug metabolized by CYP3A may be necessary for patients receiving concomitant clarithromycin.
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), 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.
Omeprazole: The use of clarithromycin in combination with omeprazole resulted in an increase in the equilibrium concentrations of omeprazole. When using omeprazole alone, the average pH of gastric juice measured over 24 hours was 5.2, when using omeprazole with clarithromycin, it was 5.7.
Sildenafil, tadalafil and vardenafil: There is a potential for increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil and vardenafil) when co-administered with clarithromycin, which may require a reduction in the dose of the phosphodiesterase inhibitor.
Theophylline, carbamazepine: There is a small but statistically significant increase in theophylline or carbamazepine plasma concentrations when co-administered with clarithromycin.
Tolterodine. Tolterodine is primarily metabolized by CYP2D6. However, in a population of patients lacking CYP2D6, metabolism occurs via CYP3A4. In this population, inhibition of CYP3A4 results in significantly increased plasma concentrations of tolterodine. In such patients, a reduction in the dose of tolterodine may be necessary when administered with clarithromycin.
Triazolebenzodiazepines (e.g. alprazolam, midazolam, triazolam). The combined use of oral midazolam and clarithromycin should be avoided. When intravenous midazolam is used with clarithromycin, the patient's condition should be carefully monitored for timely dose adjustment.
The same precautions should be observed when using other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines that are not eliminated by CYP3A (temazepam, nitrazepam, lorazepam), the development of clinically significant interactions with clarithromycin is unlikely.
There is evidence of drug interactions and the development of CNS adverse events (such as drowsiness and confusion) with the combined use of clarithromycin and triazolam. The patient should be monitored, taking into account the possibility of increased CNS pharmacological effects.
Other types of interactions
Colchicine. Colchicine is a substrate of CYP3A and P-glycoprotein (P-gp). Clarithromycin and other macrolides are known to inhibit CYP3A and P-gp. When clarithromycin and colchicine are coadministered, inhibition of P-gp and 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.
Zidovudine. Concomitant administration of clarithromycin and zidovudine in HIV-infected patients may result in decreased steady-state serum concentrations of zidovudine. Since clarithromycin may interfere with the absorption of oral zidovudine when administered concomitantly, a 4-hour interval should be maintained between the administration of clarithromycin and zidovudine. No such interaction has been reported with clarithromycin suspension and zidovudine or dideoxynazine in children.
Phenytoin and valproate. There have been 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 serum levels of these drugs be monitored when co-administered with clarithromycin. Increased serum levels have been reported.
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 for patients with normal renal function. The clarithromycin dose should be reduced by 50% for patients with CLCR 30-60 mL/min and by 75% for patients with CLCR <30 mL/min. Doses of clarithromycin 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 clarithromycin is administered concomitantly with calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem). The interaction may result in increased plasma concentrations of both clarithromycin and the calcium channel blocker. Hypotension, bradyarrhythmia, and lactic acidosis have been observed with concomitant administration of clarithromycin and verapamil.
Oral hypoglycemic agents/insulin. Concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin may result in severe hypoglycemia. When used concomitantly with hypoglycemic agents such as nateglinide, pioglitazone, repaglinide, and rosiglitazone, clarithromycin may inhibit the CYP3A enzyme, which may result in hypoglycemia. Close monitoring of glucose levels is recommended.
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 an enhanced or prolonged pharmacological effect.
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 and a 187% increase in Cmax 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 doses and dosage forms mentioned above. The results of a drug interaction study with the soft gelatin capsules may not be consistent with the effects observed with saquinavir as a hard gelatin capsule. The results of a drug interaction study with saquinavir alone may not be consistent with the effects observed with saquinavir and ritonavir. When saquinavir is used with ritonavir, the possible effects of ritonavir on clarithromycin should be considered (see above).
Oral anticoagulants: Concomitant use of clarithromycin with warfarin has been associated with a risk of serious bleeding, significant elevations in INR (international normalized ratio) and prothrombin time. While patients are receiving concomitant clarithromycin and oral anticoagulants, INR and prothrombin time should be monitored frequently.
HMG-CoA reductase inhibitors. The combined use of clarithromycin with lovastatin or simvastatin is contraindicated. Like other macrolides, clarithromycin has been shown to increase the concentration of HMG-CoA reductase inhibitors. Rhabdomyolysis has been reported rarely in patients receiving these drugs concomitantly. Patients should be monitored for signs and symptoms of myopathy.
Rhabdomyolysis has been reported rarely in patients receiving clarithromycin concomitantly with atorvastatin. In the event of concomitant use, the dose of atorvastatin should be reduced as much as possible. Appropriate decisions should be made regarding dose adjustment of the statin or the use of a statin that is not dependent on CYP3A metabolism (e.g., fluvastatin or pravastatin).
Omeprazole
Effect of omeprazole on the pharmacokinetics of other drugs
Absorption. Reduced gastric acidity during treatment with omeprazole may increase or decrease the absorption of drugs whose absorption depends on the pH of gastric juice.
As with other drugs that inhibit gastric acidity, the absorption and therefore the clinical efficacy of drugs such as posaconazole, erlotinib, ketoconazole, itraconazole may be reduced during the use of omeprazole. The concomitant use of omeprazole with posaconazole and erlotinib should be avoided.
Digoxin
Concomitant treatment with omeprazole (20 mg daily) and digoxin increases the bioavailability of digoxin by 10%. Rare cases of digoxin-induced toxicity have been reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified.
Clopidogrel
As a precautionary measure, the concomitant use of omeprazole and clopidogrel should be avoided. With concomitant use, the mean platelet aggregation is reduced by 47% (after 24 hours) and by 30% (on day 5).
Metabolism
Omeprazole inhibits CYP2C19, the main omeprazole-metabolizing enzyme.
Therefore, the metabolism of concomitant drugs that are also metabolized by CYP2C19, such as diazepam, phenytoin, warfarin (R-warfarin) or other vitamin K antagonists and cilostazol, may be slowed.
Monitoring of phenytoin plasma concentrations is recommended during the first two weeks after starting omeprazole treatment; and if phenytoin dose adjustment has been made, monitoring and further dose adjustment should be performed after omeprazole treatment has been discontinued.
Monitoring of MNH is recommended in patients taking warfarin or other vitamin K antagonists; dose reduction of warfarin (or other vitamin K antagonist) may be necessary.
Concomitant use of 20 mg omeprazole per day, however, does not alter coagulation time in patients on long-term warfarin therapy.
There is evidence that the use of 40 mg of omeprazole increases the Cmax and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%, respectively.
Omeprazole is also partially metabolized by CYP3A4, but does not inhibit this enzyme.
Thus, omeprazole does not affect the metabolism of drugs metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin and budesonide.
Omeprazole at a dose of 20-40 mg per day does not significantly affect any other CYP enzymes.
Unknown mechanism
Tacrolimus
There is evidence that concomitant use of omeprazole increases serum levels of tacrolimus. Increased monitoring of tacrolimus and renal function (creatinine clearance) is required, and if necessary, the dosage of tacrolimus should be adjusted.
Methotrexate
There are reports of increased methotrexate levels in some patients when co-administered with proton pump inhibitors. If high doses of methotrexate are necessary, temporary withdrawal of omeprazole should be considered.
Atazanavir and nelfinavir
Omeprazole has been reported to interact with some antiretroviral agents. The clinical significance and mechanism of this interaction are not always known. The increase in gastric pH during omeprazole use may alter the absorption of antiretroviral agents. Another possible mechanism of interaction is via CYP 2C19. In the case of some antiretroviral agents, such as atazanavir and nelfinavir, reduced serum levels of the latter have been observed when co-administered with omeprazole. Therefore, concomitant use of omeprazole and such agents as atazanavir and nelfinavir is contraindicated.
Saquinavir
There are reports of increased serum levels of other antiretroviral agents, such as saquinavir. There are also other antiretroviral agents whose serum levels remain unchanged when co-administered with omeprazole.
Effect of other drugs on the pharmacokinetics of omeprazole
CYP2C19 and CYP3A4 inhibitors
Metabolism: Since omeprazole is metabolized by CYP2C19 and CYP3A4, drugs that inhibit CYP2C19, CYP3A4, or both enzymes (such as clarithromycin and voriconazole) may increase omeprazole serum levels by slowing its metabolism. Concomitant use of voriconazole may result in a more than two-fold increase in omeprazole exposure. Since high doses of omeprazole are well tolerated, no dose adjustment is necessary during temporary co-administration. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.
CYP2C19, CYP3A4 inducers
Drugs that induce CYP2C19, CYP3A4 or both enzymes (such as rifampicin, St. John's wort) may lead to decreased serum levels of omeprazole by accelerating its metabolism.
Application features
Amoxicillin
Before starting therapy with amoxicillin, it is necessary to perform a preliminary test for the possibility of a hypersensitivity reaction to penicillins and cephalosporins.
Severe and sometimes fatal cases of hypersensitivity (anaphylactic reaction) have been reported in patients receiving penicillin therapy. Such reactions occur more frequently in patients with a known history of severe allergic reactions. Treatment with the drug should be discontinued and appropriate therapy instituted. Treatment of symptoms of anaphylactic reaction may be necessary, such as immediate administration of adrenaline, steroids (intravenously) and emergency treatment for respiratory failure.
Patients with severe gastrointestinal disorders accompanied by diarrhea and vomiting should not use the drug due to the risk of reduced absorption.
In patients with impaired renal function, the excretion of amoxicillin is slowed down, therefore, depending on the degree of impairment, treatment with amoxicillin should either be discontinued or the total daily dose of the drug should be reduced.
Prolonged use of the drug may lead to the development of colonization with resistant microorganisms or yeasts. Superinfection is possible, which requires careful monitoring of such patients.
When using high doses of the drug, it is necessary to drink a sufficient amount of fluid to prevent crystalluria, which can be caused by amoxicillin. The presence of high concentrations of amoxicillin in the urine may cause the drug to precipitate in the urinary catheter, so it should be visually checked at certain intervals.
If severe diarrhea occurs, typical of pseudomembranous colitis (most often caused by Clostridium difficile), it is recommended to discontinue use of the drug and take appropriate measures. The use of agents that inhibit peristalsis is contraindicated.
Amoxicillin is not recommended for the treatment of patients with viral infections, acute lymphocytic leukemia, or infectious mononucleosis due to an increased risk of erythematous skin rashes.
A non-allergic, crusted rash may occur in individuals with infectious mononucleosis. Therefore, amoxicillin should not be prescribed for the treatment of clinically streptococcal angina unless confirmed by bacteriological studies.
During high-dose therapy, blood counts should be monitored regularly.
High-dose amoxicillin therapy in patients with renal insufficiency or in patients with a history of epilepsy and meningitis may in isolated cases lead to convulsions. The occurrence of generalized erythema with fever and pustules at the beginning of treatment may indicate the development of acute generalized eczematous pustulosis, which requires discontinuation of amoxicillin therapy.
Clarithromycin
Prolonged or repeated use of antibiotics may result in overgrowth of nonsusceptible bacteria and fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy initiated.
The drug is excreted by the liver and kidneys. Caution should be exercised when using the drug in patients with impaired hepatic function, with moderate or severe renal impairment. Caution should be exercised in patients with severe renal impairment. Hepatic dysfunction, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis with or without jaundice, have been reported with clarithromycin. These hepatic dysfunctions may be severe and are usually reversible. In some cases, fatal hepatic failure has been reported, which was mainly associated with serious underlying diseases and/or concomitant medication. Clarithromycin should be discontinued immediately if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, itching, or abdominal pain occur.
Diarrhea, ranging from mild to fatal, caused by Clostridium difficile, has been reported with virtually all antibacterial agents, including clavulanic acid.
