Fromilid Uno coated pills prolonged 500mg N7
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Active ingredients
Clarithromycin
Release form
Pills
Composition
1 tablet contains: Clarithromycin 500 mg Supplementary substances: sodium alginate - 80 mg, sodium calcium alginate - 90 mg, lactose monohydrate - 225 mg, povidone - 30 mg, polysorbate 80 - 30 mg, silicon dioxide, colloidal anhydrous - 5 mg, magnesium stearate - 10 mg, talc - 30 mg. The composition of the shell: hypromellose - 14.45 mg, talc - 1.33 mg, dye quinoline yellow (E104) - 0.5 mg, titanium dioxide - 2.64 mg, propylene glycol - 1.08 mg.
Pharmacological effect
Clarithromycin is a semisynthetic macrolide antibiotic and has an antibacterial effect by interacting with the 50S ribosomal subunit and inhibiting the synthesis of protein bacteria that are sensitive to it. Clarithromycin showed high activity in vitro with respect to both standard laboratory strains of bacteria and those isolated from patients during clinical practice. It shows high activity against many aerobic and anaerobic gram-positive and gram-negative microorganisms. The minimum inhibitory concentrations (MPC) of clarithromycin for most pathogens are less than the IPC of erythromycin, on average, one log2 dilution. Clarithromycin in vitro is highly active against Legionella pneumophila, Mycoplasma pneumoniae. It has a bactericidal effect on Helicobacter pylori, this activity of clarithromycin is higher at neutral pH than when it is acidic. In addition, data in vitro and in vivo indicate that clarithromycin acts on clinically important mycobacteria. Enterobacteriaceae and Pseudomonas spp. as well as other non-fermenting lactose gram-negative bacteria, are not sensitive to clarithromycin. The activity of clarithromycin against most strains listed below microorganisms has been proven both in vitro and in clinical practice for the diseases listed in the “Indications” section. Aerobic Gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes. Aerobic Gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Ipus I, Io, I, Io, I, I, I, I, I, I, I, I, I, I, I, myrax, myrax. : Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR). Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC) - complex that includes: Mycobacterium neciumiumium, which has been found in the form of an extract, Mycobacterium, Mycobacterium avium complex (MAC) is a complex that includes: Mycobacterium clarithromycin activity. Most of the methicillin and oxacillin resistant staphylococci strains are also resistant to clarithromycin. Helicobacter pylori.The sensitivity of Helicobacter pylori to clarithromycin was studied on Helicobacter pylori isolates isolated from 104 patients before the start of therapy with the drug. In 4 patients, strains resistant to clarithromycin were isolated Helicobacter pylori, in 2 patients strains with moderate resistance, in the remaining 98 patients Helicobacter pylori isolates were sensitive to clarithromycin. Clarithromycin has an effect in vitro and for most strains of the following microorganisms ( however, the safety and efficacy of clarithromycin in clinical practice has not been confirmed by clinical studies, and the practical significance remains unclear): Aerobic gram-positive microorganisms: Str eptococool , Treponema pallidum. Campilobacteria: Campilobacter jejuni. The main metabolite of clarithromycin in humans is the microbiologically active metabolite 14-hydroxylarithromycin (14-OH-clarithromycin). The microbiological activity of the metabolite is the same as the original substances, or 2 times weaker for most microorganisms. An exception is Haemophilus influenzae, for which the efficiency of the metabolite is twice as high. The parent compound and its main metabolite have either an additive or a synergistic effect on Haemophilus influenzae in vitro and in vivo, depending on the bacterial strain.
Pharmacokinetics
Suction. The drug is rapidly absorbed in the digestive tract. Absolute bioavailability is about 50%. When receiving repeated doses of the drug, cumulation was practically not detected, and the nature of the metabolism in the human body did not change. Distribution, metabolism and elimination In vitro. Clarithromycin binds to plasma proteins at 70% in a concentration of from 0.45 to 4.5 μg / ml. At a concentration of 45 μg / ml, the binding decreases to 41%, probably as a result of saturation of the binding sites. This is observed only at concentrations that are many times higher than the therapeutic concentration. Healthy. In patients taking 500 mg of clarithromycin 1 time per day after meals, the Cmax of clarithromycin and 14-OH-clarithromycin in the blood plasma was 1.3 and 0.48 mcg / ml, respectively. T1 / 2 of clarithromycin and metabolite were 5.3 and 7.7 hours, respectively.When taking a single dose of clarithromycin in the dosage form - pills of prolonged action, film-coated, 1000 mg (2 × 500 mg), Cmax of clarithromycin and its hydroxylated metabolite in plasma were 2.4 and 0.67 μg / ml, respectively. T1 / 2 clarithromycin when taken in a dose of 1000 mg was 5.8 hours, while the same indicator for 14-OH-clarithromycin was 8.9 hours. Tmax with the ingestion of both 500 and 1000 mg of clarithromycin was approximately 6 hours. Cmax 14-OH clarithromycin did not increase in proportion to the oral dose of clarithromycin, while T1 / 2 of both clarithromycin and its hydroxylated metabolite tended to lengthen with increasing dose. Such non-linear pharmacokinetics of clarithromycin in combination with a decrease in the formation of 14-hydroxylated and N-demethylated products at high dosages indicates a non-linear metabolism of clarithromycin, which becomes more pronounced at high dosages. Approximately 40% of the ingested dose of clarithromycin is eliminated by the kidneys; intestine - about 30%. Patients. Clarithromycin and its metabolite (14-OH-clarithromycin) quickly penetrate the tissues and body fluids. There are limited data indicating that the concentration of clarithromycin in the cerebrospinal fluid when administered orally is insignificant (that is, only 1–2% of the concentration in the blood serum with normal permeability of the blood-brain barrier). The concentration in the tissues is usually several times higher than in the serum. Violation of the liver. In patients with moderate and severe liver dysfunction, but with preserved renal function, dose adjustment of clarithromycin is not required. Css in blood plasma and systemic clearance of clarithromycin do not differ in patients of this group and healthy patients. Css 14-OH-clarithromycin in patients with impaired liver function is lower than in healthy patients. Renal impairment. In case of impaired renal function, Cmax and Cmin clarithromycin in plasma, T1 / 2, AUC of clarithromycin and its metabolite increase (14-OH-clarithromycin). The elimination constant and kidney excretion decrease. The degree of change of these parameters depends on the degree of renal dysfunction. Elderly patients. Elderly patients had a higher concentration of clarithromycin and its metabolite (14-OH-clarithromycin), and excretion is slower than in a group of young people. However, after correction with regard to renal creatinine clearance, there were no differences in both groups.Thus, the main influence on the pharmacokinetic parameters of clarithromycin is rendered by renal function, not age.
Indications
Infectious and inflammatory diseases caused by microorganisms susceptible to the drug: - infections of the upper respiratory tract and upper respiratory tract (tonsillitis, pharyngitis, sinusitis, acute otitis media); - lower respiratory infections (bronchitis, community-acquired pneumonia); - infections of the skin and soft tissues (including folliculitis, erysipelas).
Contraindications
- chronic renal failure severe (CC <30 ml / min); - episodes of cholestatic jaundice and / or abnormal liver function that occurred while receiving clarithromycin (in history); - porphyria; - I trimester of pregnancy; - lactation (breastfeeding ); - age up to 18 years (efficacy and safety have not been established); - simultaneous use with astemizol, cisapride, pimozide, terfenadine, ergotamine and other ergot alkaloids, midazolam, alprazolam, triazolam; - lactose intolerance, lactase deficiency, glucose alaktoznaya malabsorption; - hypersensitivity to clarithromycin and other ingredients; - sensitivity to other antibiotics of the macrolide.
Precautionary measures
With care: moderate renal failure; moderate and severe liver failure; the simultaneous administration of clarithromycin with benzodiazepines, such as alprazolam, triazolam, midazolam for iv administration (see "Interaction"); concomitant use with drugs that are metabolized by the CYP3A isoenzyme, for example, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, inaccurator patterns, acacromines, tacrolimine, acupuncture, inaccuracyline; simultaneous use with drugs that induce CYP3A4 isoenzyme, such as rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort perforated (see. "Interaction"); simultaneous administration with CCBs that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem); simultaneous use with other ototoxic drugs, especially aminoglycosides; simultaneous reception with statins,CYP3A4 isoenzyme-independent metabolism (for example, fluvastatin); patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), as well as patients simultaneously taking antiarrhythmic drugs of class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol ); pregnancy.
Use during pregnancy and lactation
The safety of using clarithromycin during pregnancy and during breastfeeding has not been established. Use of clarithromycin during pregnancy (especially in the first trimester) is possible only when there is no alternative therapy, and the potential benefit to the mother outweighs the potential risk to the fetus. Clarithromycin is excreted in the breast milk. If necessary, the reception during the breastfeeding period should be discontinued.
Dosage and administration
The drug is taken orally during meals. Tablets should be swallowed whole, not breaking and not chewing. Adults are prescribed in a dose of 500 mg (1 tab.) 1 time / day. In severe infections: 1000 mg (2 tab.) 1 time / day. The treatment course is 5-14 days , for community-acquired pneumonia and sinusitis - 6-14 days. Elderly patients do not need to change the dose of clarithromycin, except in cases of marked impaired renal function. It should not be used Fromilide uno when CC <30 ml / min. Patients with hepatic insufficiency do not have dose adjustment required.
Side effects
On the part of the digestive system: often - dyspepsia, nausea, abdominal pain, increased activity of liver enzymes; infrequently - vomiting, diarrhea, stomatitis, glossitis, candidiasis of the oral mucosa, discoloration of the teeth and tongue, acute pancreatitis, hepatocellular and cholestatic hepatitis, cholestatic jaundice, pseudomembranous colitis, anorexia, constipation, dry oral mucosa, pneumogranous colitis, anorexia, constipation, dry mucous membrane gastritis; very rarely - cases of fatal liver failure were reported, mainly on the background of severe concomitant diseases and / or concomitant drug therapy. On the side of the skin and subcutaneous tissue: often - increased sweating; frequency is unknown - drug rash with eosinophilia and systemic symptoms, acne, erysipelas,Erythrasma. From the nervous system: often - headache; infrequently - paresthesias, drowsiness, anxiety, hallucinations, convulsions, psychosis, dizziness, confusion, fear, insomnia, nightmares, depersonalization, disorientation, tremor, depression; frequency is unknown - mania. For the sense organs: often - distortion or loss of taste sensations (dysgeusia); infrequently - noise, ringing in the ears, isolated cases of hearing loss (after drug withdrawal, hearing is restored), vertigo; very rarely - cases of changes in smell. From the cardiovascular system: infrequently - ventricular tachycardia, incl. such as pirouette, fluttering and ventricular fibrillation, prolongation of the QT interval on the ECG. From the hematopoietic system: rarely - thrombocytopenia (unusual bleeding, hemorrhage), leukopenia; frequency is unknown - agranulocytosis. From the musculoskeletal system: infrequently - myalgia, arthralgia; frequency is unknown - myopathy. From the urinary system: infrequently - interstitial nephritis; frequency is unknown - renal failure. Allergic reactions: infrequently - skin rash, pruritus, urticaria, skin flushing, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), anaphylactic reactions; frequency unknown - Scheinlein-Genoh purpura. Laboratory parameters: infrequently - increased creatinine concentration, hypoglycemia (including with simultaneous use of hypoglycemic drugs), increased alkaline phosphatase activity, increased bilirubin content; frequency is unknown - increase in INR, prolongation of prothrombin time. Other: secondary infections (development of resistance to microorganisms); infrequently - asthenia.
Overdose
Symptoms: ingestion of a large dose of clarithromycin can cause symptoms of disorders of the gastrointestinal tract. In one patient with bipolar disorder in the history after taking 8 g of clarithromycin, changes in mental state, paranoid behavior, hypokalemia and hypoxemia are described. . Hemodialysis and peritoneal dialysis do not have a significant effect on the concentration of clarithromycin in serum, which is typical of other drugs of the macrolide group.
Interaction with other drugs
The use of the following drugs simultaneously with clarithromycin is contraindicated in connection with the possibility of serious side effects Zisapride, pimozide, terfenadine and astemizole. With simultaneous administration of clarithromycin with cisapride, pimozide, terfenadine or astemizole, an increase in plasma concentrations of the latter was reported, which can lead to a prolongation of the QT interval on the ECG and the appearance of cardiac arrhythmias, including ventricular tachycardia (including ventricular tachycardia such as "p-ventricular tachycardia" ) and ventricular fibrillation (see "Contraindications"). Ergot alkaloids. Postmarketing studies show that with simultaneous use of clarithromycin with ergotamine or dihydroergotamine, the following effects associated with acute poisoning by drugs of the ergotamine group are possible: vascular spasm, ischemia of the limbs and other tissues, including the central nervous system. The simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see "Contraindications"). HMG-CoA reductase inhibitors (statins). Simultaneous use of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications") due to the fact that these statins are largely metabolized by the isoenzyme CYP3A4, and simultaneous use with clarithromycin increases their serum concentrations, which leads to an increased risk of myopathy, including rhabdomyolysis . Cases of rhabdomyolysis have been reported in patients taking clarithromycin at the same time as these drugs. In case of need of use of clarithromycin, lovastatin or simvastatin should be discontinued for the duration of therapy. Clarithromycin should be used with caution in the case of combination therapy with other statins. It is recommended to use statins, the metabolism of which does not depend on the CYP3A isoenzyme (for example fluvastatin). If necessary, the simultaneous reception is recommended to take the lowest dose of a statin. The development of signs and symptoms of myopathy should be monitored. The effect of other drugs on clarithromycin Drugs that are inducers of CYP3A isoenzyme (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort), can induce the metabolism of clarithromycin.This can lead to a subtherapeutic concentration of clarithromycin and, accordingly, to a decrease in its effectiveness. In addition, it is necessary to monitor the concentration of CYP3A isoenzyme inducer in the blood plasma, which may increase due to the inhibition of CYP3A isoenzyme by clarithromycin. With the simultaneous use of rifabutin and clarithromycin, there was an increase in the concentration of rifabutin and a decrease in the concentration of clarithromycin in the blood plasma with an increased risk of uveitis. The following drugs have a proven or suspected effect on the concentration of clarithromycin in the blood plasma, and if they are used simultaneously with clarithromycin, dose adjustment or transition may be necessary on alternative treatment: Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin. Strong inducers of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin, can accelerate the metabolism of clarithromycin and thus lower the concentration of clarithromycin in the blood plasma and weaken the therapeutic effect, and at the same time increase the plasma concentration of 14-HE-plasma-14-HE. metabolite, which is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs in relation to various bacteria, the therapeutic effect may be reduced with the simultaneous use of clarithromycin and inductors of the cytochrome P450 system. Etravirin. The concentration of clarithromycin in the blood plasma decreases with simultaneous use with etravirine, but the concentration in the blood plasma of the active metabolite 14-OH clarithromycin increases. Since 14-OH-clarithromycin has low activity against MAC infections, the overall activity against these pathogens may change, therefore alternative treatment should be considered for treatment of MAC. Fluconazole. Simultaneous administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg 2 times a day in 21 healthy volunteers resulted in an increase in the average minimum Css clarithromycin and AUC by 33 and 18%, respectively. At the same time, simultaneous administration did not significantly affect the average Css of the active metabolite of 14-OH-clarithromycin. Correction of the dose of clarithromycin in the case of simultaneous administration of fluconazole is not required. Ritonavir.A pharmacokinetic study showed that simultaneous administration of ritonavir at a dose of 200 mg every 8 hours and clarithromycin at a dose of 500 mg every 12 hours resulted in a marked suppression of the metabolism of clarithromycin. While taking ritonavir, Cmax of clarithromycin increased by 31%, Cmin increased by 182%, and AUC increased by 77%. A complete suppression of the formation of 14-OH clarithromycin was noted. Due to the wide therapeutic range of clarithromycin, reducing its dose in patients with normal renal function is not required. In patients with renal insufficiency, it is advisable to consider the following dose adjustment options: when creatinine Cl is 30–60 ml / min, the dose of clarithromycin should be reduced by 50%. Ritonavir should not be taken simultaneously with clarithromycin in doses exceeding 1 g / day. Effect of clarithromycin on other drugsAntiarrhythmic drugs (quinidine and disopyramide). The occurrence of ventricular tachycardia of the “pirouette” type is possible with simultaneous use of clarithromycin and quinidine or disopyramide. With simultaneous use of clarithromycin with these drugs, ECG monitoring should be carried out regularly to determine whether the QT interval is lengthened, and serum concentrations of these drugs should also be monitored. Disopyramide. With post-marketing use, cases of hypoglycemia have been reported with simultaneous administration of clarithromycin and disopyramide. It is necessary to control the concentration of glucose in the blood while applying clarithromycin and disopyramide. Hypoglycemic agents for oral / insulin. With simultaneous use of clarithromycin and hypoglycemic agents for oral administration (for example, sulfonylurea derivatives) and / or insulin, severe hypoglycemia may occur. Simultaneous use of clarithromycin with certain hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide, and rosiglitazone) can lead to inhibition of the isoenzyme CYP3A clarithromycin, as a result of which hypoglycemia may develop. Recommended by careful control of the concentration of glucose in krovi.Vzaimodeystviya due isoenzyme CYP3AOdnovremenny reception of clarithromycin, which is known to inhibit isoenzyme CYP3A, and drugs primarily metabolized isoenzyme CYP3A, may be associated with a reciprocal increase in their concentration, which can enhance or extend as therapeutic and side effects.Clarithromycin should be used with caution in patients receiving drugs that are substrates of CYP3A isoenzyme, especially if these drugs have a narrow therapeutic range (for example, carbamazepine) and / or drugs that are extensively metabolized by this isoenzyme. If necessary, should be carried out dose adjustment of the drug, taken simultaneously with clarithromycin. If possible, monitoring of serum concentrations of drugs primarily metabolized by the CYP3A isoenzyme should be carried out. Metabolism of the following types of cereals is carried out by the same CYP3A isoenzyme as the metabolism of clarithromycin: alprazolam, carbamazepine, cilostazol, cyclosporin, disopyramide, methylpredisolone, and Iymectyroidyyolyolyolyyolyyyyyyyyyyyyyyyyyyyyyyyyyyyyuyuu like like it, alprazolam, carbamazepine, cilostazol, cyclosporin, disopyramide, methylpredisolone, Iymectyroidyolyolyolyolyolyolyyyyyyyyyyyyyyushin for example, warfarin), atypical neuroletics (for example, quetiapine), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also, the following drugs are contraindicated for simultaneous use with clarithromycin: inhibitors of CYP3A isoenzyme: astemizol, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see "Contraindications"). The drugs that interact in a similar way through other isoenzymes within the framework of the cytochrome P450 system include phenytoin, theophylline, and valproic acid. Indirect anticoagulants. With simultaneous use of warfarin and clarithromycin, bleeding is possible, a pronounced increase in INR and lengthening of PT. In the case of simultaneous use with warfarin or other indirect anticoagulants, it is necessary to control INR and PV.Omeprazole. Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily). With simultaneous use of clarithromycin and omeprazole, plasma Css of omeprazole was increased (Cmax, AUC0-24 and T1 / 2 increased by 30, 89 and 34%, respectively). The average pH of the stomach within 24 hours was 5.2 (when taking omeprazole separately) and 5.7 (when taking omeprazole simultaneously with clarithromycin). Sildenafil, tadalafil and vardenafil. Each of these PDE inhibitors is metabolized, at least partially, with the participation of the CYP3A isoenzyme. At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin.The simultaneous use of clarithromycin with sildenafil, tadalafil or vardenafil can lead to an increase in the inhibitory effect on PDE. When using these drugs simultaneously with clarithromycin, consider reducing the dose of sildenafil, tadalafil and vardenafil. Theophylline, carbamazepine. With simultaneous use of clarithromycin and theophylline or carbamazepine may increase the concentration of these drugs in the systemic circulation. Tolterodin. The primary metabolism of tolterodine is via the CYP2D6 isoenzyme. However, in a part of a population lacking the CYP2D6 isoenzyme, metabolism occurs through the CYP3A isoenzyme. In this population, inhibition of CYP3A isoenzyme results in significantly higher serum tolterodine concentrations. In a population with a low metabolic rate through the CYP2D6 isoenzyme, it may be necessary to reduce the dose of tolterodine while simultaneously using inhibitors of the CYP3A isoenzyme, such as clarithromycin. Benzodiazepines (for example, alprazolam, midazolam, triazolam). With simultaneous use of midazolam and clarithromycin pills (500 mg 2 times a day), an increase in the AUC of midazolam was noted: 2.7 times after i / v administration of midazolam and 7 times after ingestion. Simultaneous use of clarithromycin with midazolam for oral administration is contraindicated. If midazolam is used in the dosage form along with clarithromycin, a solution for intravenous administration should be carefully monitored for possible correction of the dose of midazolam. The same precautions should be applied to other benzodiazepines that are metabolized by the CYP3A isoenzyme, including triazolam and alprazolam. For benzodiazepines, the elimination of which does not depend on CYP3A isoenzyme (temazepam, nitrazepam, lorazepam), clinically significant interactions with clarithromycin are unlikely. If you use clarithromycin and triazolam at the same time, you may have an effect on the central nervous system, such as drowsiness and confusion. In this regard, in the case of simultaneous use, it is recommended to monitor the symptoms of the CNS disorder. Interactions with other drugs Aminoglycosides. At the same time taking clarithromycin with other ototoxic drugs, especially aminoglycosides, care must be taken to monitor the functions of the vestibular and hearing aids, both during therapy and after its termination. Colchicine. Colchicine is a substrate of both the CYP3A isoenzyme and the P-glycoprotein transfer protein (Pgp).It is known that clarithromycin and other macrolides are inhibitors of the isoenzyme CYP3A and Pgp. With simultaneous use of clarithromycin and colchicine, inhibition of Pgp and / or CYP3A isoenzyme can lead to an increase in the action of colchicine. The development of the clinical symptoms of colchicine poisoning should be monitored. Post-marketing reports of cases of colchicine poisoning during its simultaneous use with clarithromycin have been registered, more often in elderly patients. Some of the cases described occurred with patients suffering from renal failure. Some cases have been reported to be fatal. The simultaneous use of clarithromycin and colchicine is contraindicated (see "Contraindications"). Digoxin. Digoxin is assumed to be a Pgp substrate. It is known that clarithromycin inhibits Pgp. With the simultaneous use of clarithromycin and digoxin, inhibition of Pgp by clarithromycin can lead to an increase in the action of digoxin. Simultaneous administration of digoxin and clarithromycin can also lead to an increase in the serum concentration of digoxin. Some patients had clinical symptoms of digoxin poisoning, including potentially lethal arrhythmias. While taking clarithromycin and digoxin, the concentration of digoxin in the serum should be carefully controlled. Zidovudin. The simultaneous administration of clarithromycin and zidovudine pills orally by adult HIV-infected patients can lead to a decrease in Css zidovudine in the blood plasma. Since clarithromycin affects the absorption of zidovudine when taken orally, interactions can be largely avoided by taking clarithromycin and zidovudine at 4-hour intervals. No such interaction was observed in HIV-infected children who took a children's suspension of clarithromycin with zidovudine or dideoxyinosine. Since clarithromycin may interfere with zidovudine absorption when administered simultaneously in adult patients, such an interaction is hardly possible with the use of clarithromycin IV. Phenytoin and valproic acid. There is evidence of the interaction of CYP3A isoenzyme inhibitors (including clarithromycin) with drugs that are not metabolized by the CYP3A isoenzyme (phenytoin and valproic acid).For these drugs with simultaneous use with clarithromycin, the determination of their serum concentrations is recommended, since there are reports of their increase. The two-way drug interaction is Atazanavir. Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of bidirectional interaction of these drugs. The simultaneous use of clarithromycin (500 mg 2 times a day) and atazanavir (400 mg 1 time a day) can lead to a twofold increase in the effects of clarithromycin and a decrease in the effects of 14-OH clarithromycin by 70% with an increase in AUC of atazanavir by 28%. Due to the wide therapeutic range of clarithromycin, a reduction in its dose in patients with normal renal function is not required. In patients with moderately severe renal failure (Cl creatinine 30–60 ml / min), the dose of clarithromycin should be reduced by 50%. In patients with Cl creatinine less than 30 ml / min, the dose of clarithromycin should be reduced by 75%, using the appropriate dosage form of clarithromycin. Clarithromycin in doses exceeding 1000 mg / day cannot be used simultaneously with protease inhibitors. BKK. At simultaneous use of clarithromycin and BPC, which are metabolized by CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem), caution should be exercised, since there is a risk of arterial hypotension. With simultaneous use may increase plasma concentrations of clarithromycin and BPC. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible while taking clarithromycin and verapamil. Itraconazole. Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bi-directional interaction of drugs. Clarithromycin may increase the plasma concentration of itraconazole, while itraconazole may increase the plasma concentration of clarithromycin. Patients who are simultaneously taking itraconazole and clarithromycin should be carefully examined for symptoms of increased or prolonged pharmacological effects of these drugs. Saquinavir. Clarithromycin and saquinavir are substrates and inhibitors of the CYP3A isoenzyme, which determines the bi-directional interaction of drugs.The simultaneous use of clarithromycin (500 mg 2 times a day) and saquinavir (in soft gelatin capsules, 1200 mg 3 times a day) in 12 healthy volunteers caused an increase in plasma AUC and Cmax by 177 and 187%, respectively, compared with saquinavir separately