Cisapride

Cisapride
International name of the medicinal substance:
Cisapride The list of drugs containing the active substance Cisapride is given after the description.
Pharmacological action:
Stimulator of gastrointestinal motility.
The mechanism of action is associated with stimulation of serotonin (5-HT4) receptors, increased release of acetylcholine from the endings of the cholinergic nerves of the mesenteric plexuses in the intestine and increased sensitivity of m-cholinergic receptors of intestinal smooth muscles to it. Increases the tone of the sphincter of the lower esophagus, preventing the reflux of stomach contents into the esophagus. Accelerates gastric and duodenal emptying, the movement of food through the small and large intestines, and reduces the threshold of antral stimulation. The clinical effect develops 30-60 minutes after oral administration. Pharmacokinetics:
Well absorbed. Bioavailability - about 40%. Cmax - 1-2 hours T1/2 - 7-10 hours Communication with plasma proteins - 98%. Distribution volume - 180 l. Plasma clearance - 100 ml/min. T1/2 - 6-12 hours with oral administration and up to 20 hours with intravenous administration. Metabolized by oxidative N-dealkylation in the liver with the participation of cytochrome P450 and aromatic hydroxylation. It is excreted approximately equally by the kidneys and bile, mainly in the form of metabolites, a small part (10%) is unchanged. Passes into breast milk (insignificant amounts). Pharmacokinetic parameters, incl. Css, do not depend on the duration of use.

Indications:
Gastric paresis (spontaneous, caused by diabetic neuropathy, vagotomy or partial gastrectomy), dyspepsia, chronic idiopathic constipation, reflux esophagitis, regurgitation and vomiting in infants, prevention of aspiration syndrome, functional intestinal obstruction, X-ray contrast examination of the gastrointestinal tract (to accelerate peristalsis) .
Contraindications:
Hypersensitivity, gastrointestinal bleeding, mechanical intestinal obstruction, intestinal or gastric perforation, prolongation of the QT interval (congenital long QT syndrome or its presence in the family history), severe bradycardia, premature infants (within the first 3 months after birth), pregnancy (especially the third trimester), lactation period. With caution.
Cardiovascular disease, history of heart rhythm disturbances, decreased concentrations of K+ and Mg2+ in plasma, taking drugs that prolong the QT interval. Side effects:
From the digestive system: dry mouth, dyspeptic disorders, spasm of smooth muscles of the gastrointestinal tract, impaired liver function (increased activity of “liver” enzymes in the blood - AST, ALT, LDH).
From the nervous system: headache, dizziness, in some cases - convulsions, extrapyramidal disorders. From the cardiovascular system: prolongation of the QT interval, ventricular arrhythmias. From the hematopoietic organs: thrombocytopenia, leukopenia, granulocytopenia, aplastic anemia, pancytopenia. Allergic reactions: skin itching, rash, urticaria, bronchospasm. Other: myalgia, frequent urination (when using high doses). Overdose. Symptoms: abdominal pain, vomiting, diarrhea, ptosis, tremor, dyspnea, catalepsy, catatonia, decreased blood pressure, generalized convulsions. Treatment: gastric lavage, activated charcoal, symptomatic therapy aimed at normalizing heart rate and maintaining vital functions. Interaction:
When taken simultaneously with benzodiazepines, barbiturates, paracetamol, H2-histamine receptor blockers, anticoagulants, as well as ethanol, their absorption is increased and the corresponding effects are enhanced.
Under the influence of cisapride, the absorption of drugs from the stomach decreases. Antagonists of cisapride are anticholinergic drugs. Anticholinesterase drugs and m-cholinergic stimulants enhance the effect. Cimetidine accelerates absorption. Inhibitors of the CYP3A4 isoenzyme of the cytochrome P450 system (ketoconazole, itraconazole, erythromycin, miconazole, clarithromycin, fluconazole, troleandomycin) increase the concentration of cisapride in plasma and increase the risk of side effects. Drugs that prolong the QT interval increase the likelihood of developing arrhythmias. Special instructions:
Patients with a high risk of arrhythmias or suspected of their development before treatment require a thorough examination, including an ECG, determination of the concentration of electrolytes (K+ and Mg2+) in the blood serum, and a study of renal function.
When prescribing anticoagulants together, it is recommended to monitor blood clotting time and adjust their dose. If diarrhea occurs during treatment, it is recommended to reduce the frequency of administration. In case of renal and liver failure, it is recommended to reduce the initial dose by 2 times. Simultaneous consumption of grapefruit juice increases bioavailability. Preparations containing the active ingredient Cisapride:
Coordinax, Peristil, Sizapro, Cisap, Cisapid

The information provided in this section is intended for medical and pharmaceutical professionals and should not be used for self-medication. The information is provided for informational purposes only and cannot be considered official.

Safocid

Single or repeated use of fluconazole at a dose of 50 mg does not affect the metabolism of phenazone (Antipyrin) when used simultaneously.

Concomitant use of fluconazole with the following drugs is contraindicated:

Cisapride: with the simultaneous use of fluconazole and cisapride, adverse reactions from the heart are possible, including ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes). The use of fluconazole at a dose of 200 mg once a day and cisapride at a dose of 20 mg 4 times a day leads to a marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. The simultaneous use of cisapride and fluconazole is contraindicated.

Astemizole: simultaneous use of fluconazole with astemizole or other drugs metabolized by the cytochrome P450 system may be accompanied by an increase in serum concentrations of these drugs. Elevated concentrations of astemizole in blood plasma can lead to prolongation of the QT interval and, in some cases, to the development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes). The simultaneous use of astemizole and fluconazole is contraindicated.

Pimozide: although no relevant in vitro

or
in vivo,
concomitant use of fluconazole and pimozide may lead to inhibition of pimozide metabolism. In turn, an increase in plasma concentrations of pimozide can lead to a prolongation of the QT interval and, in some cases, to the development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes). The simultaneous use of pimozide and fluconazole is contraindicated.

Quinidine: Although no relevant in vitro

or
in vivo,
concomitant use of fluconazole and quinidine may also lead to inhibition of quinidine metabolism. The use of quinidine is associated with prolongation of the QT interval and, in some cases, with the development of ventricular tachysystolic arrhythmia of the “torsade de pointes” type. The simultaneous use of quinidine and fluconazole is contraindicated.

Erythromycin: Concomitant use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (QT prolongation, torsade de pointes) and consequently sudden cardiac death. The simultaneous use of fluconazole and erythromycin is contraindicated.

The following medications are not recommended:

Halofantrine: Fluconazole may increase plasma concentrations of halofantrine due to inhibition of CYP3A4. It is possible to develop ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes) when used simultaneously with fluconazole, as well as with other azole antifungal drugs, so their combined use is not recommended.

Caution should be exercised when used simultaneously with fluconazole:

Amiodarone: Amiodarone has been associated with QT prolongation. Caution should be exercised when using fluconazole and amiodarone concomitantly, especially when taking a high dose of fluconazole (800 mg).

Terfenadine: When azole antifungals are used concomitantly with terfenadine, serious arrhythmias may occur as a result of prolongation of the QT interval. When using fluconazole at a dose of 200 mg/day, an increase in the QT interval has not been established; however, the use of fluconazole at doses of 400 mg/day and above causes a significant increase in the concentration of terfenadine in the blood plasma. Concomitant use of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be carried out under close monitoring (see section "Precautions").

Caution and possible dosage adjustments should be used when the following drugs are used concomitantly with fluconazole:

Drugs that affect fluconazole:

Hydrochlorothiazide: Repeated use of hydrochlorothiazide concomitantly with fluconazole results in a 40% reduction in plasma concentrations. An effect of this magnitude does not require a change in the fluconazole dosage regimen in patients receiving concomitant diuretics, but the physician should take this into account.

Rifampicin: Concomitant use of fluconazole and rifampicin results in a 25% decrease in AUC and a 20% decrease in fluconazole half-life. In patients concomitantly taking rifampicin, the advisability of increasing the dose of fluconazole must be considered.

Drugs affected by fluconazole:

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is also an inhibitor of the CYP2C19 isoenzyme. In addition, in addition to the effects listed below, there is a risk of increased plasma concentrations of other drugs metabolized by the isoenzymes CYP2C9, CYP2C19 and CYP3A4 when used simultaneously with fluconazole. In this regard, caution should be exercised when using these drugs simultaneously, and if such combinations are necessary, patients should be under close medical supervision.

It should be taken into account that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to the long half-life.

Alfentanil: There is a decrease in clearance and volume of distribution, and an increase in the half-life of alfentanil. This may be due to inhibition of the CYP3A4 isoenzyme by fluconazole. Alfentanil dosage adjustment may be required.

Amitriptyline, nortriptyline: increased effect. Concentrations of 5-nortriptyline and/or S-amitriptyline can be measured at the start of combination therapy with fluconazole and one week after initiation. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.

Amphotericin B: In studies in mice (including immunosuppressed mice), the following results were observed: a small additive antifungal effect against systemic C. albicans infection,

lack of interaction in intracranial infection caused by
Cryptococcus neoformans
and antagonism in systemic infection caused by
A. fumigatus.
The clinical significance of these results is unclear.

Anticoagulants: like other antifungal agents (azole derivatives), fluconazole, when used simultaneously with warfarin, increases the possible development of bleeding (hematomas, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin and indanedione anticoagulants and fluconazole, it is necessary to constantly monitor prothrombin time during therapy and for 8 days after simultaneous use. The feasibility of adjusting the dose of these anticoagulants should also be assessed.

Azithromycin: with simultaneous oral use of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg, no pronounced pharmacokinetic interaction has been established between both drugs.

Benzodiazepines (short-acting): After oral administration of midazolam, fluconazole significantly increases midazolam concentrations and psychomotor effects, and this effect is more pronounced after fluconazole is administered orally than when fluconazole is administered intravenously. If concomitant therapy with benzodiazepines is necessary, patients taking fluconazole should be monitored to assess the appropriateness of an appropriate reduction in the benzodiazepine dose.

With the simultaneous use of a single dose of triazolam, fluconazole increases the AUC of triazolam by approximately 50%, Cmax by 20-32% and half-life by 25-50% due to inhibition of triazolam metabolism. Triazolam dose adjustment may be necessary.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and increases the serum concentration of carbamazepine by 30%. The risk of carbamazepine toxicity must be taken into account. The need for carbamazepine dose adjustment based on concentration/effect should be assessed.

Calcium channel blockers: Some calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole increases the systemic exposure of calcium channel antagonists. Monitoring for the development of side effects is recommended.

Nevirapine: Coadministration of fluconazole and nevirapine increased nevirapine exposure by approximately 100% compared with control data for nevirapine alone. Due to the risk of increased excretion of nevirapine during concomitant use of drugs, some precautions and careful monitoring of patients are necessary.

Cyclosporine: In kidney transplant patients, the use of fluconazole at a dose of 200 mg/day leads to a slow increase in cyclosporine concentrations. However, with repeated use of fluconazole at a dose of 100 mg/day, no changes in the concentration of cyclosporine in bone marrow recipients were observed. When using fluconazole and cyclosporine simultaneously, it is recommended to monitor the concentration of cyclosporine in the blood.

Cyclophosphamide: with simultaneous use of cyclophosphamide and fluconazole, an increase in serum concentrations of bilirubin and creatinine is observed. This combination is acceptable given the risk of increasing the concentration of bilirubin and creatinine.

Fentanyl: There has been a report of one death possibly related to concomitant use of fentanyl fluconazole. The disturbances are believed to be related to fentanyl intoxication. Fluconazole has been shown to significantly prolong the clearance time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl can lead to depression of respiratory function.

HMG-CoA reductase inhibitors: with simultaneous use of fluconazole with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin simvastatin) or the CYP2D6 isoenzyme (such as fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. If simultaneous therapy with these drugs is necessary, patients should be monitored to identify symptoms of myopathy and rhabdomyolysis. It is necessary to monitor the concentration of creatinine kinase. If there is a significant increase in creatinine kinase concentrations or if myopathy or rhabdomyolysis is diagnosed or suspected, therapy with HMG-CoA reductase inhibitors should be discontinued.

Ibrutinib: Moderate CYP3A4 inhibitors such as fluconazole increase ibrutinib plasma concentrations and may increase the risk of toxicity. If the use of drugs in combination cannot be avoided, reduce the dose of ibrutinib as indicated in the ibrutinib prescribing information and ensure close clinical monitoring.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which is responsible for most of the effects associated with angiotensin II receptor antagonism. Regular monitoring of blood pressure is necessary.

Methadone: Fluconazole may increase plasma concentrations of methadone. Methadone dose adjustment may be necessary.

Nonsteroidal anti-inflammatory drugs (NSAIDs): Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] increased by 15% and 82%, respectively, when fluconazole was administered simultaneously with racemic ibuprofen (400 mg).

With simultaneous use of fluconazole at a dose of 200 mg/day and celecoxib at a dose of 200 mg, the Cmax and AUC of celecoxib increase by 68% and 134%, respectively. In this combination, it is possible to reduce the dose of celecoxib by half.

Although there are no targeted studies, fluconazole may increase the systemic exposure of other NSAIDs metabolized by CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac). NSAID dose adjustment may be necessary.

When NSAIDs and fluconazole are used concomitantly, patients should be closely monitored medically to identify and monitor NSAID-related adverse events and toxicities.

Olaparib: Moderate CYP3A4 inhibitors, such as fluconazole, increase plasma concentrations of olaparib. Their simultaneous use is not recommended. If concomitant use cannot be avoided, reduce the dose of olaparib to 200 mg twice daily.

Oral contraceptives: with simultaneous use of a combined oral contraceptive with fluconazole at a dose of 50 mg, no significant effect on hormone levels has been established, while with daily use of 200 mg fluconazole, the AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively, and with use of 300 mg fluconazole once weekly increased the AUCs of ethinyl estradiol and norethindrone by 24% and 13%, respectively. Thus, repeated use of fluconazole at the indicated doses is unlikely to affect the effectiveness of the combined oral contraceptive.

Phenytoin: Concomitant use of fluconazole and phenytoin may be accompanied by a clinically significant increase in phenytoin concentrations. If concomitant use of both drugs is necessary, phenytoin concentrations should be monitored and the dose adjusted accordingly to ensure therapeutic serum concentrations.

Ivacaftor: When coadministered with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) stimulator, there was a 3-fold increase in ivacaftor exposure and a 1.9-fold increase in hydroxymethyl-ivacaftor (Ml) exposure. For patients concomitantly taking moderate CYP3A inhibitors such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.

Prednisone: there is a report of the development of acute adrenal insufficiency in a patient after liver transplantation when fluconazole was discontinued after a three-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the CYP3A4 isoenzyme, which led to increased metabolism of prednisone.

Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision when discontinuing fluconazole to evaluate the condition of the adrenal cortex.

Rifabutin: Concomitant use of fluconazole and rifabutin can lead to an increase in serum concentrations of the latter by up to 80%. Cases of uveitis have been described with the simultaneous use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly should be monitored closely.

Saquinavir: AUC increases by approximately 50%, Cmax by 55%, clearance of saquinavir decreases by approximately 50% due to inhibition of hepatic metabolism of the CYP3A4 isoenzyme and inhibition of P-glycoprotein. Dose adjustment of saquinavir may be necessary.

Sirolimus: increased plasma concentrations of sirolimus, presumably due to inhibition of sirolimus metabolism through inhibition of the CYP3A4 isoenzyme and P-glycoprotein. This combination may be used with appropriate sirolimus dose adjustments based on effect/concentration.

Sulfonylureas: Fluconazole, when used concomitantly, leads to an increase in the half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes mellitus can be prescribed the combined use of fluconazole and oral sulfonylureas, but the possibility of hypoglycemia should be taken into account, in addition, regular monitoring of blood glucose is necessary and, if necessary, dose adjustment of sulfonylureas.

Tacrolimus: simultaneous use of fluconazole and tacrolimus (orally) leads to an increase in serum concentrations of the latter by 5 times due to inhibition of the metabolism of tacrolimus occurring in the intestine through the CYP3A4 isoenzyme. No significant changes in the pharmacokinetics of the drugs were observed when tacrolimus was administered intravenously. Cases of nephrotoxicity have been described. Patients receiving oral tacrolimus and fluconazole concomitantly should be monitored closely. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood.

Theophylline: when used simultaneously with fluconazole at a dose of 200 mg for 14 days, the average rate of plasma clearance of theophylline is reduced by 18%. When prescribing fluconazole to patients taking high doses of theophylline or to patients at increased risk of theophylline toxicity, monitor for symptoms of theophylline overdose and, if necessary, adjust therapy accordingly.

Tofacitinib: The exposure of tofacitinib is increased when coadministered with drugs that are both moderate inhibitors of CYP3A4 and CYP2C19 (eg, fluconazole). Dose adjustment of tofacitinib may be necessary.

Tolvaptan: Tolvaptan exposure is significantly increased (AUC by 200%, Cmax by 80%) when tolvaptan, a CYP3A4 substrate, is coadministered with fluconazole, a moderate CYP3A4 inhibitor. At the same time, there is a risk of a significant increase in the incidence of adverse events, in particular, such as increased diuresis, dehydration and acute renal failure. If these drugs are used concomitantly, the dose of tolvaptan should be reduced and the patient's condition should be closely monitored.

Vinca alkaloids: Although focused studies are lacking, it is suggested that fluconazole may increase plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine) and thus lead to neurotoxicity, which may be due to inhibition of CYP3A4.

Vitamin A: There has been a report of one case of central nervous system (CNS) adverse reactions in the form of pseudotumor cerebri with the simultaneous use of all-trans retinoic acid and fluconazole, which disappeared after discontinuation of fluconazole. The use of this combination is possible, but one should remember the possibility of adverse reactions from the central nervous system.

Zidovudine: when used simultaneously with fluconazole, an increase in the Cmax and AUC of zidovudine is observed by 84% and 74%, respectively. This effect is probably due to a decrease in the metabolism of the latter to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg/day for 15 days in patients with AIDS and ARC (AIDS-related complex), a significant increase in the AUC of zidovudine (20%) was found. Patients receiving this combination should be monitored for side effects of zidovudine.

Voriconazole (inhibitor of the isoenzymes CYP2C9, CYP2C19 and CYP3A4) simultaneous use of voriconazole (400 mg 2 times a day on the first day, then 200 mg twice a day for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg per day for 4 days) in 8 healthy male subjects resulted in an increase in Cmax and AUC of voriconazole by 57% and 79%, respectively. It has been shown that this effect persists when the dose is reduced and/or the frequency of administration of any of the drugs is reduced. Concomitant use of voriconazole and fluconazole is not recommended.

Studies of the interaction of oral forms of fluconazole when taken simultaneously with food, cimetidine, antacids, as well as after total body irradiation in preparation for bone marrow transplantation showed that these factors do not have a clinically significant effect on the absorption of fluconazole.

The listed interactions were established with repeated use of fluconazole; There are no known drug interactions resulting from a single dose of fluconazole. Doctors should note that interactions with other drugs have not been specifically studied, but are possible.

Azithromycin

Antacids: Antacids do not affect the bioavailability of azithromycin, but reduce the maximum blood concentration by 30%, so the drug should be taken at least one hour before or two hours after taking these drugs and food.

Cetirizine: Concomitant use of azithromycin with cetirizine (20 mg) for 5 days in healthy volunteers did not result in a pharmacokinetic interaction or a significant change in the QT interval.

Didanosine: (dideoxyinosine) simultaneous use of azithromycin (1200 mg/day) and didanosine (400 mg/day) in HIV-infected patients did not reveal changes in the pharmacokinetic indications of didanosine compared to the placebo group.

Digoxin and colchicine (P-gp substrates): Concomitant use of macrolide antibiotics, including azithromycin, with P-gp substrates, such as digoxin and colchicine, results in increased serum concentrations of the P-gp substrate. Thus, with the simultaneous use of azithromycin and digoxin, it is necessary to take into account the possibility of increasing the concentration of digoxin in the blood serum.

Zidovudine: Concomitant use of azithromycin (single dose of 1,000 mg and multiple doses of 1,200 mg or 600 mg) has little effect on the pharmacokinetics, including renal excretion, of zidovudine or its glucuronide metabolite. However, the use of azithromycin caused an increase in the concentration of phosphorylated zidovudine, a clinically active metabolite in peripheral blood mononuclear cells. The clinical significance of this fact is unclear. Azithromycin interacts weakly with isoenzymes of the cytochrome P450 system. Azithromycin has not been shown to participate in pharmacokinetic interactions similar to erythromycin and other macrolides. Azithromycin is not an inhibitor or inducer of cytochrome P450 isoenzymes.

Ergot alkaloids: Given the theoretical possibility of ergotism, the simultaneous use of azithromycin with ergot alkaloid derivatives is not recommended. Pharmacokinetic studies were conducted on the simultaneous use of azithromycin and drugs whose metabolism occurs with the participation of isoenzymes of the cytochrome P450 system.

Atorvastatin: Concomitant use of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not cause changes in atorvastatin plasma concentrations (based on an HMC-CoA reductase inhibition assay). However, in the post-marketing period, isolated case reports of rhabdomyolysis have been received in patients receiving concomitant azithromycin and statins.

Carbamazepine: Pharmacokinetic studies involving healthy volunteers did not reveal a significant effect on the plasma concentrations of carbamazepine and its active metabolite in patients receiving concomitant azithromycin.

Cimetidine: in pharmacokinetic studies of the effect of a single dose of cimetidine on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were detected when cimetidine was administered 2 hours before azithromycin.

Indirect anticoagulants (coumarin derivatives): In pharmacokinetic studies, azithromycin did not affect the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. Potentiation of the anticoagulant effect has been reported after simultaneous use of azithromycin and indirect anticoagulants (coumarin derivatives). Although a causal relationship has not been established, the need for frequent monitoring of prothrombin time should be considered when using azithromycin in patients receiving indirect oral anticoagulants (coumarin derivatives).

Cyclosporine: in a pharmacokinetic study involving healthy volunteers who took oral azithromycin (500 mg/day once) for 3 days, and then cyclosporine (10 mg/kg/day once), a significant increase in maximum plasma concentration (Cmax) was detected. ) and area under the concentration-time curve (AUC0-5) of cyclosporine. Caution is advised when using these drugs together. If simultaneous use of these drugs is necessary, it is necessary to monitor the concentration of cyclosporine in the blood plasma and adjust the dose accordingly.

Efavirenz: Concomitant use of azithromycin (600 mg/day as a single dose) and efavirenz (400 mg/day) daily for 7 days did not cause any clinically significant pharmacokinetic interaction.

Fluconazole: Concomitant use of azithromycin (1200 mg once) did not change the pharmacokinetics of fluconazole (800 mg once). The total exposure and half-life of azithromycin did not change with simultaneous use of fluconazole, however, a decrease in Cmax of azithromycin was observed (by 18%), which had no clinical significance.

Indinavir: simultaneous use of azithromycin (1200 mg once) did not cause a statistically significant effect on the pharmacokinetics of indinavir (800 mg three times a day for 5 days).

Methylprednisolone: ​​Azithromycin does not have a significant effect on the pharmacokinetics of methylprednisolone.

Nelfinavir: simultaneous use of azithromycin (1200 mg) and nelfinavir (750 mg 3 times a day) causes an increase in the steady-state concentrations of azithromycin in the blood serum. No clinically significant side effects were observed and no dose adjustment of azithromycin was required when used concomitantly with nelfinavir.

Rifabutin: Concomitant use of azithromycin and rifabutin does not affect the serum concentrations of either drug. Neutropenia has sometimes been observed with simultaneous use of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship between the use of the combination of azithromycin and rifabutin and neutropenia has not been established.

Sildenafil: When used in healthy volunteers, there is no evidence of the effect of azithromycin (500 mg/day daily for 3 days) on the AUC and Cmax of sildenafil or its main circulating metabolite.

Terfenadine: There was no evidence of interaction between azithromycin and terfenadine in pharmacokinetic studies.

There have been isolated cases reported where the possibility of such an interaction could not be completely excluded, but there was no concrete evidence that such an interaction occurred. It has been found that the simultaneous use of terfenadine and macrolides can cause arrhythmia and prolongation of the QT interval.

Theophylline: No interaction has been identified between azithromycin and theophylline.

Triazolam/midazolam: no significant changes in pharmacokinetic parameters were detected with simultaneous use of azithromycin with triazolam or midazolam in therapeutic doses.

Trimethoprim/sulfamethoxazole: Concomitant use of trimethoprim/sulfamethoxazole with azithromycin did not show a significant effect on Cmax, total exposure or renal excretion of trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those found in other studies.

Secnidazole

Disulfiram: when secnidazole is used together with disulfiram, psychotic reactions and a state of confusion are possible.

Oral anticoagulants (for example, warfarin): secnidazole enhances the effect of indirect anticoagulants (coumarin or indanedione derivatives) and increases the risk of bleeding by reducing the hepatic metabolism of anticoagulants.

Interaction with alcohol: combination with alcohol causes symptoms of the “Antabuse reaction” (abdominal cramps, nausea, vomiting, headache, “hot flashes”, tachycardia).

Side effects

After taking this substance, you may experience:

• spasms and discomfort in the intestines, diarrhea , liver failure, rumbling in the stomach, nausea, hepatitis , vomiting;
• allergic reactions, manifested in the form of skin rashes and itching;
• leukopenia , aplastic anemia , thrombocytopenia , granulocytopenia , pancytopenia ;
• tremor , dizziness, convulsions , drowsiness, headache, extrapyramidal disorders , migraine ;
• frequent urination;
• arrhythmia QT prolongation , tachycardia and fibrillation ;
• pharyngitis , myalgia , xerostomia , swelling.

Instructions for use FLUCONAZOLE

Fluconazole is used intravenously at a rate of no more than 10 ml/min once a day. When converting from intravenous administration to taking tablets and vice versa, there is no need to change the daily dose.

Fluconazole solution for infusion is compatible with the following solvents:

• 20% glucose solution, Ringer's solution, Hartmann's solution, potassium chloride solution in glucose, sodium bicarbonate solution 4.2%, aminofusin, isotonic sodium chloride solution.

For vaginal candidiasis and candidal balanitis, 100-200 mg/day is prescribed; often after a single administration of the drug recovery occurs. For other forms of mucosal candidiasis, 50-100 mg 1 time / day is recommended for 14-30 days.

For systemic candidiasis and cryptococcal infections, including meningitis, on the first day 400 mg, then 200-400 mg 1 time / day depending on the severity of the infection; the duration of therapy depends on clinical effectiveness; Usually the course of treatment for cryptococcal meningitis lasts 6-8 weeks.

To prevent relapse of cryptococcal meningitis in patients with AIDS, after completing the full course of primary therapy, the drug is prescribed to the patient in doses of at least 200 mg/day for a long period.

For skin mycoses, the recommended dose is 150-200 mg once a week or 50 mg 1 time / day, the duration of therapy is usually 2-4 weeks. However, athlete's foot may require treatment for up to 6 weeks. For onychomycosis, the recommended dose is 150-200 mg once a week; Treatment should be carried out until the affected nail is completely replaced with a healthy one.

Prevention of fungal infections in patients with malignant neoplasms - 100 mg every other day, while the patient is at high risk due to radiation or chemotherapy.

Elderly patients in the absence of renal dysfunction should adhere to the usual dosage regimen of the drug.

If renal function is impaired, the dose of fluconazole does not change after a single dose. When re-prescribing the drug to patients with impaired renal function, a loading dose of 50 mg to 400 mg should first be administered. If creatinine clearance (CC) is more than 50 ml/min, the usual dose of the drug is used (100% of the recommended dose). When CC is from 11 to 50 ml/min, a dose equal to 50% of the recommended dose is used. For patients regularly undergoing hemodialysis, one dose of the drug is administered after each hemodialysis session.

For children over one year of age with normal kidney function, fluconazole is administered daily 1 time/day at the rate of 1-3 mg/kg/day (for candidiasis of the mucous membranes) and 3-12 mg/kg/day (for systemic candidiasis or cryptococcosis), depending on the severity of the disease. For children with impaired renal function, the daily dose of the drug should be reduced (in the same proportion as for adults), in accordance with the severity of renal failure.

In newborns, fluconazole is eliminated slowly. In the first 2 weeks of life, the drug is prescribed in the same dose (in mg/kg) as for older children, but with an interval of 72 hours. For children aged 2-4 weeks, the same dose is administered with an interval of 48 hours.

Indications for use

The drug is prescribed:

• with spontaneous paresis ;
• to stimulate digestion during dyspepsia ;
• for gastric paresis caused by diabetic neuropathy , gastrectomy or vagotomy ;
• patients with gastroesophageal reflux or reflux esophagitis ;
• for chronic idiopathic constipation ;
• newborn children with regurgitation ;
• with functional pseudo-obstruction of the intestine;
• to prepare for X-ray contrast studies of the gastrointestinal tract to stimulate intestinal motility.

Cisapride

When used concomitantly with anticholinergics, the effects of cisapride are antagonized.

Antifungals, azole derivatives (including ketoconazole, itraconazole, fluconazole, miconazole), macrolide antibiotics (including erythromycin, clarithromycin, troleandomycin), HIV protease inhibitors (including indinavir, ritonavir), nefazodone inhibits the activity of the CYP3A4 isoenzyme, which leads to a slower rate of metabolism of cisapride. As a result, its concentration in the blood plasma increases and the risk of developing life-threatening cardiac arrhythmias, including ventricular arrhythmias, increases.

Drugs that increase the QT interval (including amiodarone, bretylium tosylate, disopyramide, procainamide, quinidine, sotalol, amitriptyline, lithium carbonate, astemizole, terfenadine, chlorpromazine, haloperidol, pimozide, thioridazine, bepridil, maprotiline, sparfloxacin, “loop” and thiazide diuretics, as well as insulin), with simultaneous use, increase the QT interval due to an additive effect on its value and the risk of developing ventricular dysfunction.

When used simultaneously with amantadine, cases of increased tremor have been described.

When used simultaneously with acenocoumarol and warfarin, minor changes in the effectiveness of acenocoumarol and warfarin were noted.

When used simultaneously with diazepam, the rate of absorption of diazepam from the gastrointestinal tract increases, and a sedative effect quickly develops, which is transient in nature.

When used simultaneously with digoxin, a slight decrease in the Cmax and AUC of digoxin in the blood plasma is possible.

When used simultaneously with disopyramide, the absorption and concentration of disopyramide in the blood plasma increases and there is a risk of additive cardiotoxicity.

When used simultaneously with diltiazem, a case of loss of consciousness has been described, which is associated with an increase in the QT interval. This is due to inhibition of the activity of the CYP3A4 isoenzyme under the influence of diltiazem, which leads to inhibition of the metabolism of cisapride, an increase in its concentration in the blood plasma and an increased risk of developing cardiotoxicity.

When used concomitantly, cisapride increases the rate of absorption of nifedipine from sustained-release dosage forms; with ranitidine - the absorption rate of ranitidine increases, but its AUC decreases slightly; with cyclosporine - the concentration of cyclosporine in the blood plasma increases and its bioavailability increases.

When used simultaneously with cimetidine, the Cmax of cisapride in the blood plasma increases, and the bioavailability of cimetidine slightly decreases.

Contraindications

The product is contraindicated:

• if allergic to the active substance;
• patients with bleeding in the stomach or intestines;
• with mechanical intestinal obstruction ;
• pregnant and lactating women;
• with perforation of the intestines or stomach;
• patients prone to gastric arrhythmias, prolongation of the QT ;
• premature babies up to 3 months.

Caution should be observed in case of liver and kidney diseases; it is recommended to adjust the dosage.

Pharmacodynamics and pharmacokinetics

The substance excites 5-HT4 serotonin receptors , thus stimulating the production of acetylcholine in the mesenteric nerve plexus and increasing the sensitivity of m-cholinergic receptors located in the smooth muscles of the intestine to this neurotransmitter. Food moves faster through the intestines, the tone of the esophageal sphincter enteral clearance decreases .

After taking the drug orally, it is quickly absorbed from the stomach, reaching its maximum concentration within an hour. The effect of the drug can also be noticed after an hour and a half. The biological availability of the substance is about 35-40%. With an increased pH value of gastric juice, the absorption capacity of the drug decreases.

Cisapride is 98% bound to plasma proteins. When administered orally, the half-life ranges from 6 to 12 hours, and when administered intravenously, up to 20 hours. The substance undergoes metabolism, dealkylation in liver tissue, with the participation of the cytochrome P450 . The result is the formation of an inactive metabolite , norcisapride . The substance is excreted in feces and urine, about 10% of the drug leaves the gastrointestinal tract unchanged.