Pilobact® [Amoxicillin, Clarithromycin, Omeprazole]

Pharmacological properties

Pilobact Neo is a combination drug that contains omeprazole, clarithromycin and amoxicillin. neuropilobact - a triple first-line regimen for eradication therapy h. pylori, designed for 7 days of treatment.

Pharmacodynamics Omeprazole is a proton pump inhibitor. Omeprazole reduces the secretion of hydrochloric acid in the stomach, inhibiting the activity of H⁺-TO⁺-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 the secretion of hydrochloric acid 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, thus increasing the concentrations of clarithromycin and amoxicillin in the gastric mucosa.

Clarithromycin is a macrolide antibiotic with antibacterial activity against many aerobic and anaerobic gram-positive and gram-negative microorganisms, including H. pylori. Clarithromycin has an antibacterial effect by inhibiting protein synthesis by binding to the subunit 50_s ribosome-sensitive bacteria. Minimum Inhibitory Concentration (MIC)₉₀) clarithromycin and its active metabolite 14-hydroxyclarithromycin relative to H. pylori is 0.03 and 0.06 μg / ml, respectively. Clarithromycin is resistant to the acidic environment of the stomach. Amoxicillin is an antibiotic from the group of semisynthetic penicillins with a wide spectrum of bactericidal action associated with the ability to inhibit the synthesis of bacterial cell wall. Active against H. pylori. Amoxicillin-resistant strains of H. pylori have not yet been identified.

Pharmacokinetics All 3 substances that make up the drug are well absorbed after oral administration. Omeprazole is rapidly absorbed, having an absolute bioavailability of ≈40%. T_½ a drug from blood plasma is 0.5–1 hours. 90–95% of omeprazole binds to plasma proteins. Omeprazole undergoes extensive metabolism in the liver. About 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. Concentrations of clarithromycin in tissues and body fluids are 10 times higher than those in blood plasma. Eating does not affect the bioavailability of the drug. About 20% of clarithromycin is metabolized to form the main metabolite, 14-hydroxyclarithromycin. T_½ clarithromycin is 5–7 hours. About 20% of clarithromycin is eliminated by the kidneys unchanged, and 15% as 14-hydroxyclarithromycin. It has been proven that the simultaneous administration of omeprazole and clarithromycin favorably affects the pharmacokinetic properties of clarithromycin.

Amoxicillin after oral administration is rapidly and almost completely absorbed in the digestive tract; it does not break down in the acidic environment of the stomach. Food does not affect the absorption of amoxicillin. C_max amoxicillin in 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. T_½ Amoxicillin is 1–1.5 hours. 60% of the dose taken is excreted unchanged in the urine by tubular secretion and glomerular filtration.

Indications

Eradication h. pylori in patients with gastric and duodenal ulcers.

Application

Pilobact Neo is a combination kit that contains omeprazole, clarithromycin and amoxicillin. neuropilobact - a triple first-line regimen for eradication therapy h. pylori, designed for 7 days of treatment.

1 blister, which contains 2 capsules of omeprazole, 2 tablets of clarithromycin and 2 tablets of amoxicillin, is designed for 1 day of treatment for adults. In the morning, take 1 capsule of omeprazole and 1 tablet of clarithromycin and amoxicillin, in the evening they repeat the intake of these drugs. The total duration of therapy is 7 days.

Contraindications

Hypersensitivity to omeprazole, clarithromycin, other macrolides, amoxicillin, other β-lactam antibiotics and substituted benzimidazoles or other components of the drug.

Omeprazole, like other proton pump inhibitors, should not be taken simultaneously with atazanavir and nelfinavir.

Concomitant use of clarithromycin with one of the drugs is contraindicated: cisapride, astemizole, ergotamine or dihydroergotamine, pimozide, terfenadine.

Concomitant use of clarithromycin with one of the drugs is contraindicated: HMG-CoA reductase inhibitors (statins), which are significantly metabolized by CYP 3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis. Concomitant use of clarithromycin and oral midazolam (see INTERACTIONS).

Contraindicated in patients with a history of Q-T interval prolongation or ventricular arrhythmia, including ventricular tachycardia of the pirouette type (torsades de pointes) (see SPECIAL INSTRUCTIONS).

Hypokalemia (risk of prolonged Q – T interval).

Severe liver failure and concomitant renal failure.

Concomitant use of clarithromycin (and other powerful CYP 3A4 inhibitors) with colchicine in patients with renal or hepatic insufficiency (see SPECIAL INSTRUCTIONS, INTERACTIONS).

The simultaneous use of clarithromycin and any of the following drugs: astemizole, cisapride, pimozide, terfenadine (this can lead to a prolongation of the Q – T interval and the development of arrhythmias, including ventricular tachycardia, ventricular fibrillation and pirouette ventricular tachycardia (torsades de pointes, Alcoa). ergotamine, dihydroergotamine (this can lead to ergotoxicity).

Concomitant use of clarithromycin with ticagrelor or ranolazine.

Side effects

The substances that make up the combination kit are well tolerated, and unwanted reactions usually proceed to a mild degree and are reversible.

Amoxicillin

From the side of the central nervous system and peripheral nervous system: rarely - hyperkinesia, dizziness and convulsions. Seizures can occur in patients with impaired renal function or in individuals using high doses of amoxicillin.

From the digestive system: nausea, vomiting, diarrhea, flatulence, pain in the stomach, soft stools, itching in the anus; in some cases - pseudomembranous and hemorrhagic colitis, enanthema (especially on the mucous membrane of the oral cavity), dry mouth, taste disturbance, intestinal candidiasis, staining of the teeth, staining of the tongue black (these side effects are mostly mild and go away during treatment or immediately after completion of therapy, the occurrence of such phenomena can be avoided if amoxicillin is used during meals).

From the hepatobiliary system: hepatitis, cholestatic jaundice, a moderate and short-term increase in the concentration of liver enzymes (AlAT, AsAT).

On the part of the skin and subcutaneous tissue: skin rash, exanthema, toxic epidermal necrolysis, bullous or exfoliative dermatitis, and acute generalized exanthematous pustulosis.

Allergic reactions: skin reactions in the form of a specific maculopapular rash, very rarely - itching, urticaria, erythema multiforme, Stevens-Johnson syndrome, anaphylactic shock and angioedema, severe allergic reactions, including anaphylaxis, serum sickness, allergic vasculitis, laryngeal edema. The sudden occurrence of urticaria indicates an allergic reaction to amoxicillin and requires immediate termination of therapy.

From the urinary system: rarely - interstitial nephritis, crystalluria.

On the part of the blood system and lymphatic system: hemolytic anemia, thrombocytopenia, leukopenia, eosinophilia, severe neutropenia, pancytopenia, myelosuppression, granulocytopenia, agranulocytosis, as well as lengthening bleeding time and prothrombin time.

Prolonged or repeated use of the drug can lead to the development of superinfection and colonization of resistant microorganisms or yeasts that cause oral or vaginal candidiasis, fever.

Clarithromycin

From the side of the central nervous system: headache, taste change, convulsions, dizziness, ageusia, anosmia, parosmia, insomnia, confusion, hallucinations, vertigo, anxiety, insomnia, nightmares, tinnitus, disorientation, hallucinations, psychosis and depersonalization, hearing loss , which usually recovered after discontinuation of therapy; nervousness, crying out; mania, loss of consciousness, dyskinesia, drowsiness, tremor of paresthesia, hearing impairment.

From the digestive system: diarrhea, nausea, abdominal pain, dyspepsia, vomiting, anorexia, loss of appetite, gastroenteritis, acute pancreatitis, glossitis, stomatitis, discoloration of the tongue, discoloration of the teeth (discoloration of the teeth is usually eliminated by a professional dental cleansing), oral candidiasis, smell disturbance, usually in combination with changes in taste, pseudomembranous colitis, oral candidiasis, gastroesophageal reflux disease, gastritis, proctalgia, bloating, constipation dry mouth, belching, flatulence, esophagitis.

From the hepatobiliary system: liver failure, hepatitis, cholestatic hepatitis, cholestatic jaundice, hepatocellular jaundice, impaired liver function, cholestasis.

On the part of the skin and subcutaneous tissue: Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, a slight skin rash, bullous dermatitis, pruritus, maculopapular rash, drug-related skin reaction accompanied by eosinophilia and systemic manifestations (DRESS), acne, Schleens disease, acne, , erysipelas, erythrasma.

From the musculoskeletal system and connective tissue: muscle cramps, musculoskeletal rigidity, myalgia rhabdomyolysis (in some reports of rhabdomyolysis, clarithromycin was used simultaneously with other drugs that are known to be associated with rhabdomyolysis (such as statins, fibrates , colchicine or allopurinol)), myopathy.

From the urinary system: interstitial nephritis, renal failure, discoloration of urine.

On the part of the blood and lymphatic system: leukopenia, thrombocytopenia, neutropenia, thrombocythemia, eosinophilia; agranulocytosis, an increase in the level of urea, an increase in the level of LDH in the blood, a change in the ratio of albumin-globulin, an increase in the level of alkaline phosphatase in the blood.

From the side of the immune system: anaphylactic reactions (angioedema in anaphylaxis), hypersensitivity.

Metabolic disorders: hypoglycemia, hyperhidrosis.

Mental disorder: psychoses, hallucinations, disorientation, depression, anxiety, insomnia, nightmares.

On the part of the organ of hearing and the labyrinth: hearing loss (usually recovered after discontinuation of therapy), dizziness, tinnitus.

From the cardiovascular system: ventricular tachycardia of the pirouette type (torsade de pointes), lengthening of the Q – T interval, ventricular tachycardia, cardiac arrest, atrial fibrillation, extrasystoles, palpitations; vasodilation, hemorrhage.

On the part of the respiratory system: AD, epistaxis, pulmonary embolism, chest pain.

Laboratory studies: increasing the activity of liver enzymes, increasing blood creatinine, increasing the international normalized ratio, increasing prothrombin time, changing the color of urine.

Other: cellulitis, infection, vaginal infection, malaise, fever, asthenia, chills, fatigue.

There were very rare reports of uveitis, mainly in patients who took rifabutin at the same time. Most reactions were reversible.

The development of colchicine toxicity (including death) has been reported with the combined use of clarithromycin and colchicine, especially in elderly patients, including against the background of renal failure.

It is expected that the frequency, type and severity of adverse reactions in children will be the same as in adults.

Patients with impaired immune system.In AIDS patients and patients with impaired immune systems who have used high doses of clarithromycin for longer than recommended for the treatment of mycobacterial infections, it is not always possible to distinguish between adverse reactions associated with the use of the drug and symptoms of the underlying or concomitant disease.

In adult patients who received clarithromycin at a dose of 1000 mg, the most common side effects were nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, bloating, headache, constipation, hearing impairment, increased levels of AlAT and AcAT. Infrequent shortness of breath, insomnia, and dry mouth occurred. In 2-3% of patients, a significant increase in the levels of AlAT and AcAT and a significant decrease in the number of leukocytes and platelets in the blood were revealed. Several patients had an increase in urea.

Omeprazole

From the side of the central nervous system and peripheral nervous system: headache dizziness, paresthesia, drowsiness, insomnia, vertigo, fatigue, weakness, sleep disturbance; in isolated cases - reversible confusion, agitation, depression or hallucinations, slight disorientation, aggression, agitation, visual impairment mainly in seriously ill patients. Seizures may occur in patients with impaired renal function.

From the digestive tract: diarrhea, nausea, vomiting, constipation, abdominal pain, flatulence in some cases - dry mouth, stomatitis and gastrointestinal candidiasis, microscopic colitis.

From the hepatobiliary system: rarely - increased levels of liver enzymes; in some cases - encephalopathy in severe liver diseases, hepatitis, which is accompanied or not accompanied by jaundice, liver failure.

Endocrine disorders: in some cases - gynecomastia.

On the part of the blood system and lymphatic system: leukopenia, thrombocytopenia, agranulocytosis and pancytopenia, hypomagnesemia, hypocalcemia, hypokalemia.

From the skin and subcutaneous tissue: rash, itching, erythema multiforme, Stevens-Johnson syndrome, alopecia, photosensitivity, dermatitis, hyperemia, toxic epidermal necrolysis.

From the musculoskeletal system and connective tissue: symptoms of arthritis and myalgia, muscle weakness, pain in the joints and muscles, arthralgia.

Other: rarely - general weakness, hypersensitivity reactions, including anaphylactic reactions, urticaria rash, Quinckes edema, fever, bronchospasm, interstitial nephritis, anaphylactic shock; in some cases - increased sweating, peripheral edema, blurred vision, impaired taste, a decrease in the concentration of sodium in the blood, impotence, malaise.

The profile of adverse events observed in children coincides with the profile in adults with both short-term and long-term therapy.

The product contains an orange-yellow dye (E110), which can cause allergic reactions.

special instructions

Amoxicillin. Before starting amoxicillin therapy, it is necessary to make a preliminary test for the possibility of a hypersensitivity reaction to penicillins and cephalosporins.

Cross-hypersensitivity and cross-resistance (10–15%) may exist between penicillins and cephalosporins.

Severe and sometimes fatal cases of hypersensitivity (anaphylactic reactions) were noted in patients receiving penicillin therapy. Such reactions occur more often in patients with a history of severe allergic reactions. Treatment with the drug must be discontinued and replaced with another appropriate treatment. Treatment for symptoms of an anaphylactic reaction may be required, such as the immediate administration of adrenaline, steroids (iv) and emergency treatment of respiratory failure.

Patients with severe gastrointestinal disorders, accompanied by diarrhea and vomiting, should not use the drug because of the risk of reduced absorption.

In patients with impaired renal function, the release of amoxicillin slows down, so depending on the degree of violation, treatment with amoxicillin should be discontinued or the daily dose should be reduced.

Long-term use of the drug can lead to the development of colonization of resistant microorganisms or yeast. Superinfection may occur, which requires careful monitoring of such patients.

When using high doses of the drug, it is necessary to use a sufficient amount of liquid to prevent crystalluria, which can be caused by amoxicillin. The presence of a high concentration of the drug in the urine can cause precipitation of the drug in the urinary catheter, so it should be visually checked at certain intervals.

In case of severe diarrhea characteristic of pseudomembranous colitis (in most cases caused by Clostridium difficile), it is recommended to stop using the drug and take appropriate measures. The use of drugs 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 the increased risk of erythematous skin rashes.

People with infectious mononucleosis may experience measles-like rashes of non-allergic origin. Therefore, amoxicillin should not be prescribed for the treatment of angina, clinically similar to streptococcal, if this is not confirmed by bacteriological studies.

During high-dose therapy, blood counts should be regularly monitored.

Therapy with high doses of amoxicillin in patients with renal failure or patients with a history of epilepsy and meningitis can in rare cases lead to seizures. 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 cancellation of amoxicillin therapy.

Clarithromycin Prolonged or repeated use of antibiotics can cause excessive growth of insensitive bacteria and fungi. If superinfection occurs, discontinue use of clarithromycin and begin appropriate therapy.

The drug is excreted by the liver and kidneys. Caution should be exercised when using the drug in patients with impaired liver function, with moderate or severe renal impairment. Caution should be used in patients with severe renal failure. When clarithromycin was used, a dysfunction of the liver was reported, including an increase in the level of liver enzymes, as well as hepatocellular and / or cholestatic hepatitis with or without jaundice. This impaired liver function can be severe and is usually reversible. In some cases, fatal liver failure has been reported, which has been mainly associated with serious underlying diseases and / or concomitant medication. Clarithromycin should be discontinued immediately if hepatitis symptoms and symptoms such as anorexia, jaundice, dark urine, itching, or abdominal pain occur.

The development of diarrhea from mild to fatal pseudomembranous colitis caused by Clostridium difficile has been reported with virtually all antibacterial drugs, including clarithromycin. You should always remember the possibility of developing diarrhea caused by C. difficile in all patients with diarrhea after using antibiotics. In addition, it is necessary to carefully collect an anamnesis, since the development of diarrhea caused by C.difficile has been reported even 2 months after the use of antibacterial drugs. Increased symptoms of miastenia gravis have been reported in patients taking clarithromycin.

The development of colchicine toxicity (including death) has been reported with the combined use of clarithromycin and colchicine, especially in elderly patients, including against the background of renal failure. If simultaneous use of colchicine and clarithromycin is necessary, patients should be monitored to identify possible clinical symptoms of colchicine toxicity. The dose of colchicine must be reduced for all patients receiving both colchicine and clarithromycin. The combined use of clarithromycin with colchicine in patients with renal or hepatic insufficiency is contraindicated.

With caution, clarithromycin and triazolbenzodiazepines, for example triazolam, midazolam for iv administration, should be used simultaneously.

Due to the risk of prolonging the Q – T interval, clarithromycin should be used with caution in patients with coronary artery disease, severe heart failure, hypomagnesemia, bradycardia (50 beats / min) or when combined with other drugs that are associated with prolongation of the Q – T interval. Clarithromycin should not be used in patients with a congenital or history of prolongation of the Q – T interval or with a history of ventricular arrhythmia.

Pneumonia. Since there may be resistance of Streptococcus pneumoniae to macrolides, it is important to conduct a sensitivity test when prescribing clarithromycin for the treatment of community-acquired pneumonia. In the case of hospital pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.

Infections of the skin and soft tissues of mild to moderate severity. These infections are most often caused by the microorganisms Staphylococcus aureus and Streptococcus pyogenes, which may be resistant to macrolides. Therefore, it is important to conduct a sensitivity test. In cases where it is impossible to use β-lactam antibiotics (for example, allergy), other antibiotics, such as clindamycin, can be used as first-choice drugs. Currently, macrolides play a role only in the treatment of certain infections of the skin and soft tissues (for example, infections caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, erysipelas) and in situations where penicillin treatment cannot be used.

In the case of severe acute hypersensitivity reactions, such as anaphylactic shock, Stevens-Johnson syndrome, Lyell syndrome, drug rash, which are accompanied by eosinophilia and the occurrence of systemic symptoms (DRESS), Shenlein-Genoch disease, clarithromycin therapy should be stopped immediately and the appropriate treatment should be started immediately treatment.

Clarithromycin should be used with caution when given concomitantly with CYP 3A4 enzyme inducers.

Attention should be paid to the possibility of cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.

The use of any antimicrobial therapy, including clarithromycin, to treat H. pylori infection can lead to microbial resistance. In a small number of patients, H. pylori microorganisms may develop resistance to clarithromycin.

Omeprazole In the presence of any alarming symptom (for example, a clear decrease in body weight, recurring vomiting, dysphagia, bloody vomiting or melena) and if there is a suspicion or presence of a stomach ulcer, it is necessary to exclude malignant processes, since treatment can reduce the severity of symptoms and complicate the diagnosis.

The simultaneous use of atazanavir with proton pump inhibitors is not recommended.If the combination of atazanavir with proton pump inhibitors cannot be avoided, careful clinical monitoring (eg viral load) in combination with increasing the dose of atazavir to 400 mg with 100 mg of ritonavir is recommended; the dose of omeprazole should not exceed 20 mg.

Omeprazole, like all drugs that suppress the secretion of hydrochloric acid in the stomach, can reduce the absorption of vitamin B₁₂ (cyancobalamin) due to hypo- or achlorhydria. This should be considered in patients with cachexia or risk factors for reduced vitamin B absorption.₁₂ with prolonged therapy.

Omeprazole is an inhibitor of CYP 2C19. At the beginning or at the end of treatment with the drug, it is necessary to consider the possibility of interaction with drugs that are metabolized with 2C19. The interaction observed between clopidogrel and this drug. The clinical significance of this interaction has not been determined. As a preventive measure, the simultaneous use of omeprazole and clopidogrel should be avoided.

Treatment with proton pump inhibitors can lead to a slightly increased risk of gastrointestinal infections caused by Salmonella and Campylobacter.

As with any long-term treatment, especially if the period exceeds 1 year, it is necessary to monitor the patients condition.

There is conflicting evidence of a causal relationship between the use of proton pump inhibitors and an increased risk of fractures associated with osteoporosis. Therefore, patients with progressive osteoporosis and a risk of fracture associated with osteoporosis should be recommended for clinical observation in accordance with current clinical guidelines for this condition.

The drug contains sucrose (as part of sugar spheres) as an excipient, therefore, patients with rare hereditary forms of fructose intolerance, impaired glucose / galactose absorption or sucrose-isomaltase deficiency should not use the drug.

The drug contains lactose as an auxiliary substance, therefore, the drug should not be used in patients with galactose intolerance, lactase deficiency or impaired glucose / galactose absorption.

Use during pregnancy and lactation. Pilobact Neo is contraindicated during pregnancy and lactation.

Children. The combined drug is contraindicated in children under 16 years of age.

The ability to influence the reaction rate when driving a vehicle or working with machinery. When using the drug, it is necessary to refrain from driving vehicles and working with other mechanisms.

When driving vehicles or working with other mechanisms, the possible occurrence of adverse reactions from the nervous system, such as cramps, dizziness, hallucinations, confusion, disorientation, should be considered.

Interactions

Amoxicillin

Probenecid, phenylbutazone, oxyphenbutazone, to a lesser extent acetylsalicylic acid and sulfinpyrazone inhibit the tubular secretion of penicillin preparations, which leads to an extension of T_½ and increasing the concentration of amoxicillin in blood plasma.

Drugs that have a bacteriostatic effect (tetracycline antibiotics, macrolides, chloramphenicol) can neutralize the bactericidal effect of amoxicillin. The simultaneous use of aminoglycosides is possible (synergistic effect).

Not recommended combinations

Allopurinol Concomitant use with amoxicillin causes the occurrence of allergic reactions.

Digoxin. Digoxin absorption increases, therefore dose adjustment is necessary.

Disulfiram. Concomitant use with amoxicillin is contraindicated.

Anticoagulants.The simultaneous use of amoxicillin and coumarin class anticoagulants may prolong bleeding time. A dose adjustment of anticoagulants is 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 severity of the toxic effect of the latter. Amoxicillin reduces renal clearance of methotrexate, therefore, its plasma level should be monitored.

Amoxicillin should be used with caution simultaneously with oral hormonal contraceptives, since the plasma levels of estrogen and progesterone may temporarily decrease, which may reduce the effectiveness of hormonal contraceptives. Therefore, it is recommended to use additional non-hormonal contraceptives.

Other types of interaction. Forced diuresis leads to a decrease in the concentration of the drug in blood plasma by increasing its elimination.

The occurrence of diarrhea can lead to a decrease in the absorption of other drugs and adversely affect their effectiveness.

Influence on the results of diagnostic laboratory tests: when determining the presence of glucose in the urine, it is recommended to use the enzymatic glucose oxidase method. When applying chemical methods, false-positive results are usually observed.

Amoxicillin may reduce the amount of estriol in pregnant women.

In high concentrations, amoxicillin can lower glycemia. Amoxicillin can influence protein determination by the colorimetric method.

Clarithromycin Clarithromycin does not interact with oral contraceptives.

The use of the following drugs is strictly contraindicated due to the possible development of severe consequences of the interaction.

Cisapride, pimozide, astemizole, terfenadine. An increase in the level of cisapride, pimozide and terfenadine in the blood plasma was observed with their simultaneous use with clarithromycin, which can lead to a prolongation of the Q – T interval and the appearance of arrhythmias, including ventricular tachycardia, ventricular fibrillation and ventricular tachycardia of the pirouette type. Similar effects were noted with the combined use of astemizole and other macrolides.

Ergot alkaloids. The simultaneous use of clarithromycin and ergotamine or dihydroergotamine was associated with the appearance of signs of acute ergotism, which was characterized by vasospasm and ischemia of the limbs and other tissues, including the central nervous system.

The effect of other drugs on the pharmacokinetics of clarithromycin. Drugs that induce CYP 3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. Johns wort preparations) can induce the metabolism of clarithromycin. This can lead to subtherapeutic levels of clarithromycin and a decrease in its effectiveness. In addition, monitoring of plasma levels of the CYP 3A inducer may be required, which can be increased by inhibition of CYP 3A by clarithromycin. The simultaneous use of rifabutin and clarithromycin led to an increase in rifabutin levels and a decrease in plasma clarithromycin levels with a simultaneous increase in the risk of uveitis.

The effect of the following drugs on the concentration of clarithromycin in the blood is known or is expected, therefore, a dose change or the use of alternative therapy may be required.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin. Powerful cytochrome P450 enzyme inducers, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin, can accelerate the metabolism of clarithromycin, reducing its concentration in blood plasma, but increasing the concentration of 14-OH-clarithromycin, a microbiologically active metabolite.Since the microbiological activity of clarithromycin and 14-OH-clarithromycin is different in relation to different bacteria, the expected therapeutic effect may not be achieved with the simultaneous use of clarithromycin and inducers of cytochrome P450 enzymes.

Etravirine. The action of clarithromycin was attenuated by etravirine, but the concentration of the active metabolite of 14-OH-clarithromycin increased. Since 14-OH-clarithromycin has a reduced activity against MAC, the total activity against this pathogen can be changed. Therefore, the use of alternative drugs to clarithromycin should be considered for the treatment of MAC.

Fluconazole The equilibrium concentrations of the active metabolite of 14-OH-clarithromycin did not significantly change while using fluconazole. Changing the dose of clarithromycin is not required.

Ritonavir. The use of ritonavir and clarithromycin led to a significant suppression of the metabolism of clarithromycin