Cisapride: instructions for use of the drug, doctors' recommendations

Cisapride: side effects

Common: transient abdominal cramps, diarrhea. Not very common: rash, urticaria, itching, mild and transient headache or dizziness, dose-related frequent urination. Rarely: transient gynecomastia, galactorrhea, sometimes with concomitant hyperprolactinemia. In rare cases, seizures and extrapyramidal symptoms. Temporary liver dysfunction with or without cholestasis and bronchospasm may also occur. There have been cases of QT prolongation and/or severe, sometimes fatal ventricular arrhythmias such as torsade de pointes (TdP), ventricular tachycardia and ventricular fibrillation. In most cases, these adverse reactions occurred in patients concomitantly receiving other drugs, including CYP3A4 inhibitors and/or in patients with a history of heart disease or risk factors for cardiac arrhythmias. In case of overdose: abdominal cramps, frequent bowel movements, prolongation of the QT interval and ventricular arrhythmias, including torsades de pointes; Hospitalization, the use of activated carbon, clinical observation of the patient and ECG monitoring are recommended; Factors predisposing to QT prolongation should be recognized and appropriately treated.

Efavirenz

Efavirenz was generally well tolerated in clinical studies. In the subgroup of patients receiving efavirenz 600 mg once daily in combination with HIV protease inhibitors and/or NRTIs, the most common (in at least 5% of patients) adverse reactions of at least moderate severity were skin rash (11.6% ), dizziness (8.5%), nausea (8%), headache (5.7%) and fatigue (5.5%).

The most notable adverse events associated with efavirenz were skin rash and nervous system symptoms. Nervous system symptoms usually appeared soon after initiation of therapy and usually disappeared after the first 2-4 weeks of therapy. Severe skin reactions, such as Stevens-Johnson syndrome and erythema multiforme, have also been observed in patients taking efavirenz; mental disorders, including severe depression, death due to suicide and psychosis-like behavior, as well as seizures. When using Efavirenz concomitantly with food, the systemic exposure of efavirenz may increase, which may lead to an increase in the frequency of adverse reactions (see section "Special Instructions").

The safety profile of long-term therapy that included efavirenz was assessed in a controlled study in which patients received either efavirenz + zidovudine + lamivudine for 180 weeks, or efavirenz + indinavir for 102 weeks, or indinavir + zidovudine + lamivudine for 76 weeks. Long-term use of efavirenz in this study did not result in any new safety data.

Moderate to severe adverse reactions are listed below. for which a possible causal relationship has been established with the treatment regimen used (in the opinion of the investigator) and which were observed during clinical trials of efavirenz used at the recommended dose as part of combination ART.

Adverse events that were reported during the post-registration period of efavirenz use as part of combination therapy are highlighted in italics. The frequency of adverse events is given according to the following classification: very often (>1/10); often (>1/100, <1/10); uncommon (> 1/1000, <1/100); rare (> 1/10000, <1/1000); very rare (<1/10000).

Immune system disorders: uncommon - hypersensitivity.

Metabolic and nutritional disorders: often - hypertriglyceridemia*; infrequently - hypercholesterolemia*.

Mental disorders: often - pathological dreams, anxiety, depression, insomnia*; infrequently - tendency to affect, aggressiveness, confusion, mood with a tendency towards euphoria, hallucinations, mania, paranoid behavior, psychosis, suicide attempt, suicidal intentions; rarely - delirium", neurosis", death due to suicide"*.

Nervous system disorders: often - disorders of cerebellar coordination and balance, attention disorder (3.6%), dizziness (8.5%), headaches (5.7%), drowsiness (2%)*; infrequently - anxious agitation, amnesia, ataxia, impaired coordination of movements, convulsions, impaired thinking, tremor.

Violations of the organ of vision: infrequently - blurred visual perception.

Hearing and labyrinthine disorders: uncommon - tinnitus, vertigo.

Vascular disorders: infrequently - “flushes” of blood to the facial skin.

Gastrointestinal disorders: often - abdominal pain, diarrhea, nausea, vomiting; infrequently - pancreatitis.

Disorders of the liver and biliary tract: often - increased activity of aspartate aminotransferase (ACT)*, alanine aminotransferase (ALT)* and gamma-glutamyltransferase (GGT)*; infrequently - acute hepatitis; rarely - liver failure *.

Disorders of the skin and subcutaneous tissues: very often - skin rash (11.6%)*; often - itchy skin; infrequently - exudative erythema multiforme; Stevens-Johnson syndrome*; rarely - photoallergic dermatitis.

Disorders of the genital organs and breast: infrequently - gynecomastia.

General disorders: often - increased fatigue.

* - see below for more detailed description.

' - these adverse reactions were recorded during the post-registration observation period; The incidence of these reactions was determined using data obtained from 16 clinical studies (3969 patients).

"—These adverse reactions were observed during post-marketing surveillance, but were not reported as efavirenz-related events in patients receiving efavirenz in 16 clinical studies. According to the frequency classification, these adverse events were considered to be “rare” (based on the upper limit of the 95% confidence interval for 0 events per number of patients treated with efavirenz in the designated clinical trials (n = 3969)).

Description of selected adverse events

Skin rash. In clinical studies, skin rash was observed in 26% of patients receiving efavirenz 600 mg, compared with 17% of patients in control groups. In 18% of patients, skin rash was associated with taking efavirenz, while in 1.7% of patients the drug was discontinued due to the appearance of skin rash. The incidence of erythema multiforme and Stevens-Johnson syndrome was approximately 0.1%.

Skin rash occurred in 59 of 182 children (32%) treated with efavirenz in 3 clinical studies with an average duration of 123 weeks. In 6 children the rash was severe. Before initiating efavirenz therapy in children, appropriate antihistamine therapy may be recommended as prophylaxis. Mild to moderate maculopapular skin rash usually develops and appears within the first two weeks after initiation of efavirenz therapy. In most patients, the skin rash disappears when efavirenz therapy is continued for one month. Efavirenz may be restarted in patients who stop taking it due to skin rash. When resuming efavirenz therapy, it is also recommended to take appropriate H1-blockers and/or glucocorticosteroids.

There is limited experience with the use of efavirenz in patients who have discontinued treatment with other NNRTI antiretroviral drugs. The incidence of skin rash recurrence after switching from nevirapine to efavirenz therapy, mainly estimated from published retrospective data, ranged from 13% to 18%, and is comparable to the rate found in patients treated with efavirenz in clinical trials (see section "Special considerations"). instructions").

Mental symptoms. Serious psychiatric adverse events have been observed in some patients taking efavirenz. In controlled clinical trials, the incidence of selected serious adverse psychiatric events was as follows: major depression 1.6% in the group of patients taking combination ART with efavirenz and 0.6% in the control group of patients; suicidal intentions 0.6% and 0.3%; non-fatal suicide attempts 0.4% and 0%; aggressive behavior 0.4% and 0.3%; paranoid reactions 0.4% and 0.3%; manic reactions 0.1% and 0%, respectively.

Patients with a history of mental disorders are at increased risk for the development of these serious adverse mental events, with the incidence of each of the above phenomena ranging from 0.3% for manic reactions to 2.0% for severe depression and suicidal intent. Also in the post-registration period, reports of deaths due to suicide, delusional disorders and psychosis-like behavior were received.

Symptoms from the nervous system. The following adverse reactions were frequently observed in patients receiving efavirenz 600 mg in controlled clinical trials: dizziness, insomnia, drowsiness, attention disturbance, nightmares. Other adverse events were also observed. Moderate to severe nervous system symptoms were observed in 19% (severe in 2%) of patients, while in patients receiving control therapy this figure was 9% (severe in 1%). During clinical trials, 2% of patients taking efavirenz discontinued therapy due to the above symptoms.

Symptoms from the nervous system were usually observed within the first or second day after the start of therapy and in most cases disappeared within the first 2-4 weeks. In a study of uninfected volunteers, the representative nervous system symptom occurred on average 1 hour after dosing and lasted for an average of 3 hours. Nervous system symptoms occurred more frequently if efavirenz was taken with food. This may be due to an increase in efavirenz plasma concentrations under such conditions (see section “Pharmacokinetics”). To improve tolerability of the drug in relation to these symptoms during the first weeks of therapy, it is recommended to take the drug before bedtime. This regimen is also recommended for those patients who continue to experience these symptoms (see section “Dosage and Administration”). Reducing the dose or splitting the daily dose usually does not provide a beneficial effect.

Analysis of data on long-term use of the drug showed that after 24 weeks of therapy, the frequency of new-onset nervous system symptoms in patients taking efavirenz was generally similar to that in the control group.

Liver failure. During the post-marketing surveillance period, several cases of liver failure were reported, including cases without indications of liver disease in the anamnesis, as well as without other identified risk factors. These cases were characterized by lightning-fast progression; in some cases liver transplantation was required or the patient's death was reported.

Immune reconstitution syndrome. In HIV-infected patients with severe immunodeficiency, when starting combined ART, the risk of inflammatory reactions to inactive or residual opportunistic infections may increase (see section "Special Instructions").

Lipodystrophy and metabolic disorders: Combination ART is associated with redistribution of body fat (lipodystrophy) in HIV-infected patients, including depletion of peripheral and facial subcutaneous fat, its accumulation in the intraperitoneal space, internal organs, and the back of the neck (“buffalo hump”) and hypertrophy of the mammary glands.

Combined ART may cause metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia (see section "Special Instructions").

Osteonecrosis. Cases of osteonecrosis have been observed, mainly in patients with well-known risk factors, with long-term HIV infection, as well as in patients who have been taking combination ART for a long time. However, the frequency of this complication has not been established (see section "Special Instructions").

Laboratory indicators

“Liver” enzymes: an increase in the activity of AST and ALT more than 5 times the upper limit of normal (ULN) was observed in 3% of 1008 patients taking zfavirenz at a dose of 600 mg per day (5-8% with long-term ART with efavirenz). A similar increase was observed in control group patients (5% with long-term ART without efavirenz). An increase in GGT activity greater than 5 times the ULN was observed in 4% of all patients receiving 600 mg efavirenz and in 1.5-2% of control patients (7% in long-term ART with efavirenz and 3% in long-term ART without efavirenz ). An isolated increase in GGT activity in patients taking efavirenz may indicate enzyme induction. In a clinical trial of long-term ART, approximately 1% of patients in each study group discontinued therapy due to liver and biliary disorders.

Amylase: An asymptomatic increase in serum amylase activity, more than 1.5 times the ULN, was detected in 10% of patients taking efavirenz and in 6% of patients in control groups. The clinical significance of asymptomatic increases in serum amylase activity is unknown.

Lipids: An increase in total cholesterol (TC) concentrations of 10-20% was observed in uninfected volunteers taking efavirenz. In clinical studies of the use of various combination ART with efavirenz in patients who had not previously received ART, during 48 weeks of treatment, an increase in the concentration of total cholesterol by 21-31%, high-density lipoprotein cholesterol (HDL-C) by 23-34% and triglycerides by 23-3 was observed. 49%. The proportion of patients whose TC/HDL-C ratio was greater than 5 did not change. The magnitude of the change in lipid concentrations may be due to factors such as the duration of therapy and the use of other drugs in combination ART.

Cannabinoid Test Interaction: Efavirenz does not bind to cannabinoid receptors, but there have been reports of false-positive urine cannabinoid test results in uninfected volunteers and in HIV-infected patients taking efavirenz. It is recommended that a positive cannabinoid screening test result be confirmed using specific techniques such as gas chromatography or mass spectrometry.

Children and teenagers

The type and frequency of adverse events in children are generally comparable to those observed in adult patients, with the exception of skin rash, which is more common in children (46% of children) than in adults and more severe (severe skin rash was observed in 5.3 % children). To prevent rash, it may be advisable to prescribe appropriate H1-blockers to children before starting efavirenz therapy. Although nervous system symptoms are difficult to detect in young children, it is believed that such symptoms are less common in children and are usually mild. 3.5% of patients experienced symptoms of moderate severity from the nervous system, mainly dizziness. No children experienced severe symptoms or required discontinuation of therapy due to nervous system symptoms.

Other special patient groups

Liver enzyme activity in patients co-infected with hepatitis B or C
Among patients seropositive for hepatitis B and/or C, an increase in AST activity more than 5 times the ULN was observed in 13% of patients taking efavirenz and in 7% of patients from the control group, and an increase in ALT activity more than 5 times the ULN was observed in 20% and 7% of patients, respectively. Among patients with co-infection, 3% of patients taking efavirenz and 2% of patients in the control group discontinued therapy due to liver dysfunction (see section "Special Instructions").

Release form and shelf life

Cisapride is available in the form of tablets of 5 and 10 mg, packaged in an aluminum blister of 10 pieces, or in the form of 100 ml suspension bottles.

1 ml of oral suspension contains 1 mg of active substance. A measuring syringe is included with the suspension bottle.

Sold under trade names:

Tablets and a bottle of suspension should be stored in a protected place at a temperature not exceeding 25°C. Tablets are stored for 3 years, suspension – 2 years.

Interaction with other drugs

The combined use of cisopride with pilocarpine enhances its clinical effect.

Many antifungal drugs, as well as erythromycin analogues, increase plasma concentrations of cisopride and increase the risk of fatal arrhythmias, leading to sudden cardiac death.

Cisapride: Pharmacological action

The digestion process is regulated by the motor function of the gastrointestinal tract. Violation of peristalsis in any part of the gastrointestinal tract leads to a slowdown in the digestive process and the development of pathological conditions - GERD, constipation, gastroparesis.

The substance Cisapride (trade name Coordinax) belongs to the pharmacological group of prokinetics. It stimulates the motor activity of the stomach, lower esophageal sphincter (LES) and intestines. The active substance of the drug promotes the release of the neurotransmitter acetylcholine, while simultaneously increasing the sensitivity of the receptors of the contractile tissue of the gastrointestinal tract to it, thereby achieving a stimulating effect on the peristalsis of the digestive tract.

The pharmacological action of the drug Cisapride is aimed at regulating the motility of the gastrointestinal tract:

• activation of peristalsis;
• increased activity of the lower esophageal sphincter;
• acceleration of evacuation of contents from the stomach;
• increasing intestinal tone, promoting bowel movement.

When taken orally, cisapride quickly dissolves and is absorbed from the gastrointestinal tract, reaching maximum concentration after 1.5 hours. The clinical effect develops half an hour after taking the medicine.

Description of the drug Cisapride

Digestive problems - indications for the use of Cisapride

Cisapride is a serotonergic drug. It is available both in the form of tablets for oral administration and in the form of a suspension - a crystalline powder dissolved in water. Indicated for use in diagnosing a number of problems with the gastrointestinal tract:

• Gastric paresis, including if its appearance was caused by diabetic neuropathy
• Partial gastrectomy or vagotomy
• Dyspeptic manifestations
• Idiopathic constipation, including chronic
• Reflux
• Gastric atony
• A number of gastrointestinal problems in infants - regurgitation, regurgitation syndrome

Thanks to its composition, Cisapride affects the entire gastrointestinal tract, normalizes the activity of the upper gastric sphincter (prevents the release of food eaten back into the esophagus), improves intestinal motility (conductivity), and increases its tone.

The principle of action of the drug has not been thoroughly studied at the moment. There is an opinion that its beneficial properties are associated with stimulation of the formation of the substance acetylcholine in the cholinergic nerve.

Cisapride can also be used to prevent certain gastrointestinal problems, such as stasis and reflux.

special instructions

Patients with a high risk of arrhythmias or suspected development of arrhythmias before treatment with the drug 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 co-prescribing anticoagulants with the drug, 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 the bioavailability of the drug.

Instructions for use

The medicine has a low speed of action. Many drugs begin to work within 30–40 minutes after ingestion, and Cisapride only an hour and a half after administration. The dosage of the drug is determined by the attending physician, taking into account the age and characteristics of the development of the underlying pathology.

For adults, a one-time dose of the drug in the form of a suspension is 10 mg. If acute symptoms of the primary disease are present, the dosage is increased to 20 mg. For children under 6 years of age, a single dose of the medicine taken is 0.3 mg, and for children under 12 years of age – 2.5 mg.

It is recommended to take the drug before meals, about 15 minutes. Last use - no earlier than half an hour before going to bed.

Side effects

According to research results, the drug Cisapride is well tolerated by the body. In some cases, usually when the dosage is exceeded, the following clinical manifestations may occur:

• dry mouth mucous membranes;
• headache;
• dizziness;
• ventricular arrhythmia;
• anemia;
• allergic reaction to the skin: itching, rash;
• increased frequency of urination.

An overdose of the drug causes pain in the epigastric region, nausea and vomiting syndrome, diarrhea, and decreased blood pressure. In this case, immediate gastric lavage is required.

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Interaction with other drugs

The instructions for the drug Cisapride indicate its combination with the most common medications.

Simultaneous therapy with antifungal agents (Ketoconazole, Fluconazole, Miconazole, etc.), macrolide antibiotics (Erythromycin, Clarithromycin, etc.), HIV protease inhibitors (Ritonavir, Indinavir, etc.) helps to inhibit the activity of the CYP3A4 isoenzyme, which slows down metabolism of cisapride.

Simultaneous interaction of Cisapride with drugs that cause an increase in the QT interval (Amiodarone, Quinidine, Sotalol, Astemizole, etc.) increases the risk of ventricular arrhythmia.

Concomitant therapy with Cisapride and Amantadine often causes increased tremor. If you take Cisapride, Warfarin or Acenocoumarol, there is a slight change in the activity of the latter. Simultaneous use with a drug such as Diazepam helps to increase the rate of its absorption in the gastrointestinal tract and the development of a transient sedative effect.

Analogs of Cisapride - Peristil, Prepulsid, Coordinax.

Interaction

Simultaneous administration of this substance and Cyclosporine leads to an increase in plasma concentrations of both substances.

The combined use of Cisapride and diazepam can lead to an increase in the rate of absorption of the latter from the gastrointestinal tract and an increase in the sedative effect.

When combined with ketoconazole, fluconazole, itraconazole, miconazole and other antifungal azole derivatives ; with macrolide antibiotics , erythromycin , clarithromycin , troleandomycin ; HIV protease inhibitors , ritonavir , indinavir , nefadozone and other drugs that inhibit the activity of the CYP3A4 , slow down the metabolism of Cisapride. Its plasma concentration increases, and the risk of developing life-threatening disorders of the cardiovascular system increases.

Anticholinergics reduce the effectiveness of this medication.

The combined use of the drug with disopyramide may lead to the development of additive cardiotoxicity .

Cisapride drugs, when combined with amantadine , increase tremor .

The following substances also affect the cardiotoxicity of the substance: amiodarone, disopyramide, quinidine, amitriptyline, astemizole, chlorpromazine, pimozide, bepridil, sparfloxacin, insulin, loop diuretics, bretylium tosylate, procainamide, Sotalol, lithium carbonate, terfenadine, haloperidol, thiodazine, maprotiline, thiazide diuretics .

The combined use of the drug and ranitidine increases the absorption capacity of ranitidine, but reduces its AUC. The drug affects the effectiveness of warfarin and acenocoumarol.

When the drug is combined with digoxin , the concentration and effectiveness of the cardiac glycoside .

A case has been described in which diltiazem in combination with cisapride caused an increase in the QT interval and loss of consciousness.

It should be taken into account that the drug increases plasma concentrations of substances from sustained-release dosage forms.

Instructions for use of Cisapride

Cisapride is a drug taken orally, that is, by mouth. However, it has a relatively low speed of action. While most medications have a beneficial effect half an hour to an hour after entering the intestines, Cisapride begins to be absorbed only after 60-90 minutes.

The dosage regimen directly depends on the age of the patient. According to the instructions for use of the drug, the following regimen must be followed for different age groups:

1. Adults – 10 mg suspension at one time; for acute symptoms of digestive problems, the dose can be increased to 20 mg; take up to 4 times a day.
2. Children under 6 years of age - 0.3 mg at a time, no more than 3 times a day.
3. Children under 12 years of age – 2.5 mg at a time; the dose can be increased to 5 mg; take up to 2 times a day.

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It is necessary to strictly follow the schedule for taking Cisapride. The drug should be taken strictly before meals, no later than 15 minutes. Take the last dose before going to bed. For convenience, the medicine is produced in two types of tablets - weighing 5 and 10 mg (1 ml of crystalline powder is equivalent to 1 mg of medicine).

Particular caution should be exercised when using Cisapride to treat gastrointestinal problems and belching in infants. The drug can be given to them only when newborns reach the age of 3 months.

In the case of premature babies, it is recommended to reduce the dosage by half. The dosage of Cisapride for use by young children, thanks to its release in the form of tablets and suspensions, is very easy to carry out.

special instructions

Should not be used for diseases and conditions where increased gastrointestinal motility is undesirable, incl. for bleeding, obstruction and perforation of the gastrointestinal tract, immediately after surgery.

Should not be used in patients at risk of developing cardiac arrhythmias, including AV block II and III degrees, with heart disease, with uncorrected electrolyte disturbances (especially with hypokalemia and hypomagnesemia), with renal failure, with respiratory failure.

Use with caution and in reduced doses in patients with impaired liver and/or kidney function. Do not exceed recommended doses

Do not exceed recommended doses.

If diarrhea occurs during treatment, it is recommended to reduce the frequency of dosing.

In case of renal and liver failure, it is recommended to reduce the initial dose by 2 times.

Use with caution in premature infants over 3 months

Description of the drug INDAPRIL

In some patients with arterial hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be stopped. When resuming combination therapy, the components should be used in low doses or only one of them should be used. Such patients require regular monitoring of potassium levels and creatinine concentrations in the blood serum - 2 weeks after the start of therapy and every 2 months thereafter. Renal failure occurs more often in patients with severe chronic heart failure or underlying renal impairment, incl. with renal artery stenosis.

In the case of initial hyponatremia, there is a risk of sudden development of arterial hypotension, especially in patients with renal artery stenosis. Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased electrolyte levels in the blood plasma, for example, after diarrhea or vomiting. Such patients require regular monitoring of blood plasma electrolyte levels.

The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with the combination of any antihypertensive drug and a diuretic, regular monitoring of plasma potassium levels is necessary.

The simultaneous administration of perindopril and potassium-sparing diuretics, as well as potassium supplements, potassium-containing table salt substitutes and food additives is not recommended.

In patients with normal renal function and without concomitant risk factors, neutropenia rarely occurs. Perindopril should be used with extreme caution against the background of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as while taking immunosuppressants, allopurinol or procainamide, or a combination of these factors, especially in patients with initially impaired renal function . Some of these patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should report any signs of infectious diseases (eg, sore throat, fever) to their doctor.

When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may occur. This can happen at any time during treatment. If symptoms appear, the drug should be stopped immediately and the patient should be observed until signs of edema completely disappear. If the swelling affects only the face and lips, it usually goes away on its own, although antihistamines can be used as symptomatic therapy. Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, you should immediately begin appropriate therapy, for example, administer subcutaneous epinephrine (adrenaline) in dilution 1:

• 1000 (0.3-0.5 ml) and/or ensure airway patency.

A higher risk of developing angioedema has been reported in black patients.

Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group.

In patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

There are isolated reports of the development of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (bees, wasps). ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescription of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, anaphylactoid reaction can be avoided by temporary withdrawal.

In rare cases, life-threatening anaphylactoid reactions have developed in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (eg, AN69®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive agent of a different pharmacotherapeutic group.

In some pathological conditions, significant activation of the RAAS may be observed, especially with severe hypovolemia and a decrease in plasma electrolytes (due to a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, renal artery stenosis, chronic heart failure or cirrhosis of the liver with edema and ascites. The use of an ACE inhibitor causes a blockade of this system and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in the concentration of creatinine in the blood plasma, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy. Sometimes these conditions develop acutely and during other periods of therapy. In such cases, when resuming therapy, it is recommended to use the drug at a lower dose and then gradually increase it.

Before starting to take the drug, it is necessary to assess the functional activity of the kidneys and the potassium content in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of reduction in blood pressure, especially in the case of dehydration and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.

The risk of arterial hypotension exists in all patients, however, special care should be taken when using the drug in patients with coronary artery disease and cerebrovascular insufficiency. In such patients, treatment should be started with low doses.

Treatment with the combination of perindopril/indapamide in patients with diagnosed or suspected renal artery stenosis should begin with a low dose of the drug in a hospital setting, monitoring renal function and potassium levels in the blood plasma. Some patients may develop functional renal failure, which disappears when this combination is discontinued.

In persons with severe heart failure (NYHA functional class IV) and patients with type 1 diabetes mellitus (risk of spontaneous increase in potassium levels), treatment should begin with a low dose of the drug and under close medical supervision.

During the first month of therapy with ACE inhibitors, plasma glucose concentrations should be carefully monitored in patients with diabetes mellitus and treated with oral hypoglycemic agents or insulin.

Perindopril, like other ACE inhibitors, apparently has a less pronounced antihypertensive effect in patients of the Black race compared to representatives of other races. This difference may be due to the fact that black patients with arterial hypertension are more likely to have low renin activity.

Carrying out general anesthesia while using ACE inhibitors can lead to a significant decrease in blood pressure, especially when using general anesthesia agents that have a hypotensive effect. It is recommended, if possible, to stop taking long-acting ACE inhibitors, incl. perindopril, the day before surgery. It is necessary to warn the anesthesiologist that the patient is taking ACE inhibitors.

If jaundice appears or a significant increase in the activity of liver enzymes while taking ACE inhibitors, you should stop taking the drug and consult a doctor.

Hyperkalemia may develop during treatment with ACE inhibitors, incl. and perindopril. Hyperkalemia can cause serious, sometimes fatal, abnormal heart rhythms. Risk factors for hyperkalemia are renal failure, deterioration of renal function, age over 70 years, diabetes mellitus, certain concomitant conditions (dehydration, acute decompensation of heart failure, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride ), as well as a number of medicines. In such cases, treatment should be carried out with caution and regular monitoring of serum potassium levels.

Before starting treatment, it is necessary to determine the content of sodium ions in the blood plasma. While taking the drug, this indicator should be regularly monitored. All diuretics can cause hyponatremia, which sometimes leads to serious complications. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ion levels is indicated for patients with liver cirrhosis and elderly patients.

Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. Hypokalemia (less than 3.4 mmol/L) should be avoided in the following high-risk patients:

• elderly patients, malnourished patients (both those receiving and not receiving concomitant drug therapy), patients with liver cirrhosis (with edema and ascites), coronary artery disease, heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of developing arrhythmias.

Patients with a prolonged QT interval, either congenital or drug-induced, are also at increased risk.

Hypokalemia, like bradycardia, contributes to the development of severe heart rhythm disturbances, especially polymorphic ventricular tachycardia of the “pirouette” type, which can be fatal. In all the cases described above, more regular monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion content should be carried out within the first week from the start of therapy. If hypokalemia is detected, appropriate treatment should be prescribed.

Thiazide and thiazide-like diuretics may reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in plasma calcium concentrations. Severe hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Before studying the function of the parathyroid glands, you should stop taking diuretics.

It is necessary to monitor blood glucose concentrations in patients with diabetes mellitus, especially in the presence of hypokalemia.

When the concentration of uric acid in the blood plasma increases during therapy, the frequency of gout attacks may increase.

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine concentration in adults below 25 mg/l or 220 µmol/l).

At the beginning of diuretic treatment, patients may experience a temporary decrease in GFR and an increase in plasma urea and creatinine concentrations due to hypovolemia and hyponatremia. This transient functional renal failure is not dangerous for patients with initially normal renal function, but its severity may increase in patients with renal failure.

Indapamide may give a positive reaction during doping control.

Impact on the ability to drive vehicles and machinery

The action of indapamide and perindopril, either individually or in combination, does not lead to impaired psychomotor reactions. However, some people may develop different individual reactions in response to lowering blood pressure, especially at the beginning of treatment or when other antihypertensive drugs are added to the therapy. In this case, the ability to drive a car or operate other machinery may be reduced.

Cisapride price, where to buy

It is almost impossible to buy Cisapride in Russia. Registration of the substance ended in 2001.

Education: Graduated from Rivne State Basic Medical College with a degree in Pharmacy. Graduated from Vinnitsa State Medical University named after. M.I. Pirogov and internship at his base.

Work experience: From 2003 to 2013 – worked as a pharmacist and manager of a pharmacy kiosk. She was awarded diplomas and decorations for many years of conscientious work. Articles on medical topics were published in local publications (newspapers) and on various Internet portals.



Side effects

Side effects that occur after taking Cisapride may manifest themselves as follows:

• in the form of discomfort in the intestinal area accompanied by spasms;
• attacks of vomiting and nausea;
• development of hepatitis;
• pharyngitis;
• xerostomia;
• swelling;
• myalgia;
• leukopenia;
• skin itching and allergic rashes;
• aplastic anemia;
• pancytopenia or development of granulocytopenia;
• increased urge to urinate;
• dizziness and headaches;
• migraine;
• tremors and convulsions;
• state of drowsiness;
• development of extrapyramidal disorders;
• arrhythmia or tachycardia and other complications of the cardiovascular system.

Overdose

Exceeding the recommended dosage of Cisapride is fraught with the development of catalepsy and the occurrence of seizures. The patient may experience diarrhea, tremor, difficulty breathing in frequency and depth (dyspnea) and drooping of the upper eyelid (ptosis). A drop in blood pressure is possible.

Carrying out therapeutic measures comes down to gastric lavage and the prescription of sorbent preparations, for example, activated carbon. It is necessary to monitor the normalization of heart rate and maintain vital functions.

Drug interactions

Drug interactions between Cisapride and some medications when combined can be characterized as follows:

• Cyclosporine - plasma concentrations of both drugs increase;
• Diazepam – enhances its sedative effect as the rate of absorption increases;
• Ketoconazole and other similar antifungal drugs, macrolide antibiotics, HIV protease inhibitors, drugs that inhibit the activity of the CYP3A4 enzyme, significantly slow down the metabolism of Cisapride, which in turn leads to an increase in its concentration in the blood plasma, thereby increasing the risk of developing conditions from the cardiovascular system, which can pose a serious threat to the patient’s life.
• Anticholinergic drugs reduce the effectiveness of Cisapride.
• Disopyramide – additive cardiotoxicity develops.
• Amantodine – increases the degree of tremor.
• The manifestation of cardiotoxicity can be facilitated by the combination of Cisapride with Amiodarone, thiazide and loop diuretics, Quinidine, Maprotiline, Amitriptyline, Thiodazine, Astemizole, Haloperidol, Chlorpromazine, Terfenadine, Pimozide, lithium carbonate, Bepridil, Sotalol, Sparfloxacin, Procainamide, Insulin , Bretylium tosylate.
• Digoxin – its effectiveness decreases.
• There are warnings about combining Diltiazem with Cisapride, which may cause loss of consciousness.

Additional instructions

Increasing the dose of the drug is highly undesirable.

If severe diarrhea develops during treatment, the dose of the drug is reduced.

Therapeutic measures with the use of Cisapride in relation to infants from 3 months of age require extreme caution

Cisapride: Side effects and overdose

The following effects may occur after taking cisapride:

• migraine, drowsiness, dizziness;
• convulsions, trembling of limbs, swelling;
• heart rhythm disturbances, tachycardia, arrhythmia;
• nausea, dry mouth, vomiting, hepatitis, increased concentration of liver enzymes in the blood;
• blood disorders: leukopenia, thrombocytopenia, granulocytopenia, pancytopenia, aplastic anemia;
• allergic reactions.

• drooping upper eyelid;
• trembling of the limbs and torso;
• dyspnea;
• movement disorders: catalepsy, catatonia;
• decrease in blood pressure;
• convulsions.

In case of overdose, the patient, first of all, needs to rinse the stomach and take adsorbents. Further, treatment is required aimed at maintaining all vital functions and restoring heart function.

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.

Indications for use of Cisapride

Cisapride is indicated for use in patients with impaired motility of the gastrointestinal tract. Used in the following conditions:

1. GERD (reflux esophagitis) is a condition associated with insufficiency of the lower esophageal sphincter, caused by the reflux of gastric contents into the esophagus.
2. Gastroparesis (impaired gastric motility) of any etiology.
3. Chronic constipation.
4. Intestinal obstruction caused by impaired intestinal motility.
5. Functional dyspepsia caused by impaired motility of the stomach and duodenum.
6. Hypokinesia (insufficiency) of the gallbladder.
7. Regurgitation in infants.

Cisapride can be used to stimulate intestinal motility as a preparation for diagnostic X-ray contrast studies of the digestive tract.

Directions for use and dosage

The course of treatment is determined by the attending gastroenterologist. The dosage is calculated individually, depending on the age and body weight of the patient:

1. Adults – from 5 to 40 mg per day, divided into 2 to 4 doses.
2. Children weighing from 25 to 50 kg - from 5 to 20 mg up to 4 doses per day.
3. Children up to 25 kg – 0.2 mg per kg of weight up to 4 times a day.

For constipation and intestinal obstruction, cisapride is taken after meals. For diseases of the upper gastrointestinal tract, the medicine should be taken 15 minutes before meals.

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 increases, and 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 reactions in liver tissue, with the participation of the cytochrome P450 enzyme. As a result, an inactive metabolite, norcisapride, is formed. The substance is excreted in feces and urine, about 10% of the drug leaves the gastrointestinal tract unchanged.

Instructions for use

pharmachologic effect

Gastrointestinal motility stimulator. 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.

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.

Application and dosage

Orally, adults – 5-10 mg 2-4 times a day, 15 minutes before meals and before bedtime; if necessary, the single dose can be increased to 20 mg. Children aged 2 months to 1 year – 0.15-0.3 mg/kg 2-3 times a day; 1-5 years – 2.5 mg 2-3 times a day; 6-12 years – 5 mg 2-3 times a day; over 12 years old – 5-10 mg 3 times a day. Children under 12 years of age - in the form of a suspension.

For chronic renal failure, the daily dose is reduced by 2 times.

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.

Interaction

When taken simultaneously with benzodiazepines, barbiturates, paracetamol, H2-histamine receptor blockers, anticoagulants, as well as ethanol, their absorption increases and the corresponding effects increase.

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.

Itraconzol

- Effect on cardiac activity: in a study on healthy volunteers, intravenous itraconazole was noted to be a transient, asymptomatic decrease in left ventricular ejection fraction, which returned to normal before the next infusion of the drug. The clinical significance of these data for oral dosage forms is unknown.

Itraconazole has a negative inotropic effect. Cases of chronic heart failure associated with itraconazole have been reported. At a daily dose of 400 mg of itraconazole, an increased incidence of heart failure was observed; at lower daily doses such a pattern was not revealed. The risk of chronic heart failure is presumably proportional to the daily dose. Itraconazole should not be taken by patients with chronic heart failure or a history of this symptom complex, unless the possible benefit significantly outweighs the potential risk. When individually assessing the balance of benefit and risk, factors such as the severity of the indications, dosage regimen and individual risk factors for heart failure (coronary heart disease, valvular disease, obstructive pulmonary disease, renal failure and other diseases accompanied by edema) should be taken into account. Such patients should be informed about the signs and symptoms of chronic heart failure and monitored for their occurrence during the course of treatment. If such signs appear, you should stop taking Itraconazole.

Life-threatening cardiac arrhythmias and/or sudden death have been reported in patients receiving methadone concomitantly.

Calcium channel blockers may have a negative inotropic effect, which may be additive to the effect of itraconazole. In addition, itraconazole may inhibit the metabolism of calcium channel blockers. Therefore, caution should be exercised when using itraconazole and calcium channel blockers concomitantly due to an increased risk of congestive heart failure.

- Drug interactions: Concomitant use of certain drugs with itraconazole may result in changes in the effectiveness of itraconazole and/or concomitant drugs, life-threatening adverse reactions and/or sudden death. Drugs that should not be taken concomitantly with itraconazole, are not recommended for concomitant use, and/or are recommended for concomitant use with itraconazole with caution are listed in the Interactions with Other Drugs section.

- Cross-hypersensitivity: Data regarding the presence of cross-hypersensitivity between itraconazole and other antifungals with an azole structure (from the azole group) are limited. If hypersensitivity to other azoles is present, itraconazole should be prescribed with caution.

- Interchangeability: The interchangeable use of itraconazole capsules and itraconazole oral solution is not recommended due to the fact that exposure to itraconazole is higher when used in oral solution form than in capsule form, even when taking the same doses of itraconazole.

- Reduced acidity of gastric juice: with reduced acidity of gastric juice, the absorption of itraconazole from capsules is impaired. Patients with reduced gastric acid levels due to medical conditions (eg, patients with achlorhydria) or due to medications (eg, gastric secretion suppressants) are advised to take itraconazole capsules at the same time as acidic drinks (such as non-diet cola). The antifungal activity of the drug should be monitored and the dose of itraconazole should be increased if necessary.

- Effect on liver function: in very rare cases, severe toxic liver damage has developed with the use of itraconazole, including several cases of acute liver failure with a fatal outcome. In most cases, this occurred in patients who already had liver disease, in patients with other severe diseases for whom the drug was prescribed for the treatment of systemic diseases, as well as in patients receiving other drugs that have hepagotoxic effects. However, some patients had no comorbidities or obvious risk factors for liver damage. Several such cases occurred in the first month of therapy, and some in the first week of treatment. In this regard, it is recommended to regularly monitor liver function in patients receiving itraconazole therapy. If symptoms suggestive of hepatitis occur, namely anorexia, nausea, vomiting, weakness, abdominal pain and dark urine, treatment should be stopped immediately and liver function testing should be performed. Patients with elevated liver enzymes, active liver disease, or history of liver toxicity due to other medications should not be treated with Itraconazole unless the expected benefit justifies the risk of liver damage. It is recommended to monitor the level of laboratory parameters of liver function in patients with pre-existing liver dysfunction or in patients who have experienced hepatotoxicity from other drugs. Itraconazole is predominantly metabolized in the liver. Since the total half-life of itraconazole is slightly increased in patients with impaired liver function, it is recommended to monitor itraconazole plasma concentrations and adjust the dose of the drug if necessary.

- Impaired renal function: Data on the use of the drug in patients with impaired renal function are limited; in some patients with impaired renal function, exposure to itraconazole may be reduced. Therefore, such patients should be prescribed the drug with caution. It is recommended to monitor plasma concentrations of itraconazole and, if necessary, adjust the dose of the drug.

- Immunocompromised patients: The bioavailability of oral itraconazole may be reduced in some immunocompromised patients, such as neutropenic patients, patients with AIDS, or those undergoing organ transplantation. Therefore, the dose should be adjusted depending on the clinical picture in this group of patients.

— Patients with systemic fungal infections that pose a threat to life: due to the pharmacokinetic characteristics (see subsection “Pharmacokinetics”) of the drug Itraconazole in capsule form, its use is not recommended for the initiation of treatment of systemic mycoses that pose a threat to the life of patients.

— Patients with AIDS: The attending physician should evaluate the need for maintenance therapy in HIV-infected patients with AIDS who are at risk of relapse and who have previously been treated for systemic fungal infections.

- Use in pediatric practice: since there is insufficient clinical data on the use of Itraconazole in children, it is recommended to prescribe the drug to children only if the possible benefits of treatment outweigh the potential risks.

- Women of childbearing potential taking Itraconazole should use highly effective methods of contraception throughout the course of treatment until the first menstrual period after its completion.

- Neuropathy: Treatment should be discontinued if peripheral neuropathy occurs, which may be associated with taking Itraconazole capsules.

- Cross-resistance: In systemic candidiasis suspected to be caused by fluconazole-resistant strains of Candida, sensitivity to itraconazole cannot be assumed, therefore, it is recommended to test sensitivity before starting itraconazole therapy.

- Elderly patients: Data on the use of Itraconazole in elderly patients are limited. It is recommended to prescribe the drug only if the possible benefits of treatment outweigh the potential risks. In general, when selecting a dose for elderly patients, it is recommended to pay attention to the frequency of decreased liver, kidney, cardiovascular function and concomitant diseases or other drug therapy.

- Hearing loss: Temporary or permanent hearing loss has been reported in patients taking itraconazole. In some cases, hearing loss occurred during concomitant use with quinidine (see section “Contraindications”). Hearing usually recovers after finishing itraconazole therapy, but in some patients hearing loss is permanent.

- Fertility: Reproductive toxicity of itraconazole has been observed in animal studies.
- Cystic fibrosis: in patients with cystic fibrosis, variability in plasma itraconazole concentrations was observed when itraconazole oral solution was administered at a dose of 2.5 mg/kg twice daily. As a result, the therapeutic equilibrium concentration of itraconazole in blood plasma may not be achieved. Steady-state concentrations >250 ng/mL were achieved in approximately 50% of patients over 16 years of age and were not achieved in any patients under 16 years of age. If there is no response to therapy with Itraconazole capsules, switching to alternative therapy should be considered.

Analogues and cost

Cisapride and its direct analogues - Coordinax, Propulsid, Peristil - do not have a license in the Russian Federation at the moment. The drug was withdrawn from sale in 2001 due to its numerous side effects, so it is impossible to buy cisapride in Russia, and its price is unknown.

According to some patients, cisapride was prescribed by their attending physician for gastrointestinal disorders, but they were unable to evaluate the clinical effect of the drug due to its unavailability in pharmacies.

To stimulate gastrointestinal motility, other prokinetic drugs can be used:

• Domperidone, Motilium, Passazhix;
• Trimebutin, Trimedat;
• Metoclopramide, Perinorm, Cerucal.

In gastroenterological practice, doperidone (Motilium, Passazhix) is more often used; unlike cisapride, the drug does not pass through the blood-brain barrier and has virtually no side effects on the body.

Cisapride contraindications

There are many contraindications, so you should study the instructions carefully!

As a very strong drug, Cisapride has a number of contraindications for use. It is completely prohibited for use simultaneously with drugs that inhibit the CYP3A4 isoenzyme. You should also avoid the drug if you are taking azole-based medications, which are often included in antifungal inhibitors.

In addition, Cisapride is not recommended for people diagnosed with gastric arrhythmia. It is not completely prohibited, but those who suffer from chronic insufficiency of the respiratory tract and lungs, kidneys and liver, and cardiovascular system should be careful when taking the medicine. The last point is especially important for people who are at high risk of developing 3rd degree AV block (heart rhythm disturbance).

Cisapride is dangerous if it enters the human blood or plasma directly.

For this reason, it should be taken with caution by patients in the following cases:

• Having recently undergone abdominal surgery.
• Suffering from frequent bleeding in the gastrointestinal tract.
• Pregnant and breastfeeding mothers.
• For obstructive problems of the gastrointestinal tract.
• For perforation diseases of the digestive system.

Read: Metformin: side effects, mechanism of action and possible side effects

You should be especially careful when taking Cisapride during pregnancy and breastfeeding. Although the medicine is not completely prohibited even during lactation, experts advise women in the third trimester of pregnancy to completely abandon the drug. Since Cisapride is also found in small quantities in breast milk, which can affect the baby’s appetite, it is better to replace it with safer analogue drugs.

For some diseases, for example, renal failure, it is not necessary to completely abandon Cisapride - it is enough to reduce the dose by half (5 mg for an adult).

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.

Drug interactions

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.

Fluconazole, 50 mg, capsules, 7 pcs.

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 1 time per day and cisapride at a dose of 20 mg 4 times a day leads to a marked increase in the plasma concentration of cisapride and an increase in the QT interval on the ECG. The simultaneous use of cisapride and fluconazole is contraindicated.

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 (see section “Contraindications”). Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be carried out under close monitoring.

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 adequate in vitro or in vivo studies have not been conducted, concomitant use of fluconazole and pimozide may result in inhibition of the metabolism of pimozide. 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 adequate in vitro or in vivo studies have not been conducted, concomitant use of fluconazole and quinidine may also result in 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. The development of ventricular tachysystolic arrhythmia of the “pirouette” type (torsade de pointes) is possible 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 use has been associated with prolongation of the OT interval. Caution should be exercised when using fluconazole and amiodarone simultaneously. especially when taking a high dose of fluconazole (800 mg).

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 leads to an increase in fluconazole plasma concentrations by 40%. 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 in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism in systemic C. albicans infection. A. fumigatus. The clinical significance of these results is unclear.

Anticoagulants: like other antifungal agents (azole derivatives), fluconazole, when used simultaneously with warfarin, increases prothrombin time (by 12%), and therefore bleeding may develop (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 patients with a kidney transplant, 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 cyclosporine concentrations were observed in bone marrow recipients. 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 increased bilirubin and creatinine concentrations.

Fentanyl: There has been a report of one death possibly related to the concomitant use of fentanyl and 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: When fluconazole is used concomitantly with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or the CYP2D6 isoenzyme (such as fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. If concomitant therapy with these drugs is necessary, patients should be monitored for 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.

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 increase 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 administration of 200 mg of fluconazole, the AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively, and with 300 mg of fluconazole once weekly administration, the AUCs of ethinyl estradiol and norethindrone increased 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 (M1) 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 can be used with appropriate dose adjustment of sirolimus depending on the effect/concentration.

Sulfonylureas: Fluconazole, when used concomitantly, results in 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.

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 an adverse reaction from the central nervous system (CNS) 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 CYP2C9, CYP2C19 and CYP3A4 isoenzymes): simultaneous use of voriconazole (400 mg twice daily on the first day, then 200 mg twice daily 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; interactions with drugs as a result of a single dose of fluconazole are not known.

Doctors should note that interactions with other drugs have not been specifically studied, but are possible.