Fluconazole + Azithromycin + Secnidazole - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Included in the formulation

Safocid

pills inwards

NIZHFARM, JSC Russia

АТХ:

J.01.R.A Combinations of antibacterial drugs

J.01.R.A.07 Azithromycin, fluconazole and secnidazole

Pharmacodynamics:

A combination kit containing an antifungal drug, an antibiotic and an antibacterial drug with antiprotozoal activity.

Fluconazole

Antifungal agent. The triazole derivative exhibits an antifungal effect by blocking the biosynthesis of the ergosterol of the fungal cell membrane. "Target" for the action of the drug is the enzyme 14-α-demethylase.

14-α-demethylase is part of a group of enzymes known collectively cytochrome P450. All enzymes of the cytochrome P450 group contain a hematinic iron-containing pigment. Fluconazole binds to the iron atom of the hematinic group and inactivates 14-α-demethylase, which leads to a disruption in the synthesis of ergosterol and the accumulation of lanosterol and other sterols. Their incorporation into the membrane instead of ergosterol significantly disrupts the structure and function of the fungal cell membrane.

The decrease in the synthesis of ergosterol, as well as the accumulation of 14α-methylsterols, destroys the densely packed acyl chains of the phospholipids of the fungal membranes.Destabilization of the fungal membrane leads to dysfunction of membrane enzymes, including those involved in the electron transport chain, and ultimately to cell death.

Used in systemic mycosis: candidosis, cryptococcosis, blastomycosis, histoplasmosis, coccidioidomycosis, as well as dermatomycosis. Relatively low toxic profile and a high degree of penetration into the cerebrospinal fluid make fluconazole a drug of choice in systemic candidiasis and cryptococcal meningitis. Due to complications associated with intrathecal administration of amphotericin B, fluconazole - The first-line drug in coccidioid meningitis. Although fluconazole and is active against the causative agents of blastomycosis, histoplasmosis, sporotrichosis, it is inferior in efficacy against pathogens of these infections to itraconazole. Fluconazole, being highly selective for cytochrome P450 fungi, practically does not inhibit these enzymes in the human body (in comparison with itraconazole, clotrimazole, econazole and ketoconazole to a lesser extent suppresses oxidative processes dependent on cytochrome P450 in human liver microsomes). Does not have anti-androgenic activity.

Azithromycin

Antibacterial agent with predominantly Gram-positive action spectrum, azalide, acts bacteriostatically. Linking to the 50S subunit of ribosomes, inhibits peptidranslokase at the stage of translation, suppresses protein synthesis, slows the growth and multiplication of bacteria, at high concentrations has a bactericidal effect. It is active against extracellular and intracellular pathogens.

Azithromycin susceptible microorganisms: aerobic Gram-positive microorganisms - Staphylococcus aureus (methicillin susceptible strains), Streptococcus pneumoniae (penicillin susceptible strains), Streptococcus pyogenes; aerobic gram-negative microorganisms - Haemophilus influenzae, Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis, Pasteurella multocida, Neisseria gonorrhoeae; anaerobic microorganisms - Clostridium perfringens, Fusobacterium spp., Prevotella spp., Porphyromonas spp .; other microorganisms - Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci, Mycoplasma pneumoniae, Mycoplasma hominis, Borrelia burgdorferi.

Microorganisms with acquired resistance to azithromycin: aerobic gram-positive microorganisms - Streptococcus pneumoniae (penicillin-resistant strains and strains with average sensitivity to penicillin).

Microorganisms with natural resistance: aerobic gram-positive microorganisms - Enterococcus faecalis, Staphylococcus aureus (methicillin-resistant strains), Staphylococcus epidermidis (methicillin-resistant strains); anaerobic microorganisms - Bacteroides fragilis.

Cases of cross-resistance between Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococcus), Enterococcus faecalis and Staphylococcus aureus, including Staphylococcus aureus (methicillin-resistant strains) to erythromycin, azithromycin, other macrolides and lincosamides are described.

Secnidazole

Antimicrobial bactericide is a synthetic derivative of nitroimidazole. It is active against obligate anaerobic bacteria (sporo- and non-spore forming), pathogens of some protozoal infections: Trichomonas spp., Giardia lamblia, Entamoeba histolytica. Not active against aerobic bacteria.

Many anaerobic bacteria and microaerophilic intracavitary parasites have a high negative redox potential. When exposed to microorganisms, the enzyme systems of these pathogens restore the nitro group of the drug (the nitro group of the secnidazole molecule - the electron acceptor). The reconstituted drug is inserted into the respiratory chain of protozoa and anaerobes, preventing the action of flavoproteins - carriers of electrons. As a result, respiratory processes are violated, which leads to cell death. In addition, in some species of anaerobes and protozoa in the reduction of the nitro group secnidazole promotes the formation of free radicals that damage DNA. Causes a violation of the spiral structure, rupture of nucleic acid strands and cell death. Causes sensitization to alcohol (tetur-like action).

Pharmacokinetics:

Fluconazole

Suction and distribution

Absorption is high, bioavailability is 90%. Simultaneous food intake does not affect the absorption of the drug taken internally. After oral administration of 150 mg, the maximum concentration is determined after 0.5-1.5 hours and is 90% of its plasma concentration when administered intravenously at the same dose.

The connection with plasma proteins is 11-12%. The concentration in the plasma is in direct proportion to the dose. Fluconazole well penetrates into all body fluids. The concentration of the active substance in breast milk, articular fluid, saliva, sputum and peritoneal fluid is similar to that in plasma. It penetrates well into the cerebrospinal fluid, with fungal meningitis, the concentration in the cerebrospinal fluid is about 85% of that in the plasma. In the fluid, epidermis and stratum corneum (selective accumulation), concentrations exceeding serum levels are achieved.The volume of distribution approximates the total water content in the body.

Metabolism and excretion

The half-life of fluconazole is about 30 hours. It is an inhibitor of the isoenzyme CYP2C9 in the liver. It is excreted mainly by the kidneys (80% - unchanged, 11% - in the form of metabolites). The clearance of fluconazole is proportional to the creatinine clearance.

Pharmacokinetics in special clinical cases

The pharmacokinetics of fluconazole significantly depend on the functional state of the kidneys, and there is an inverse relationship between the half-life and the clearance of creatinine. After hemodialysis for 3 hours the concentration of fluconazole in plasma is reduced by 50%.

Azithromycin

Suction and distribution

Azithromycin is rapidly absorbed from the digestive tract, which is due to its resistance to acidic environment and lipophilicity. Bioavailability after a single dose of 500 mg - 37% (the effect of the first passage through the liver). After oral administration of 500 mg, the maximum concentration is 0.4 mg / l and is observed after 2.5-2.9 hours.

In tissues and cells, the concentration is 10-50 times higher than in serum. The volume of distribution is 31.1 l / kg. Easily passes the histohematological barriers.It penetrates well into the respiratory tract, urino-genital organs and tissues, into the prostate gland, into the skin and soft tissues; accumulates in a medium with low pH, in lysosomes (which is especially important for the eradication of intracellular pathogens). It is also transported by phagocytes, polymorphonuclear leukocytes and macrophages (without significantly affecting their function). It penetrates the membranes of cells and creates high concentrations in them. The concentration in the foci of infection is significantly higher (by 24-34%) than in healthy tissues, and correlates with the severity of the inflammatory edema. In the focus of inflammation persists in effective concentrations within 5-7 days after taking the last dose. The connection with plasma proteins is 7-50% (inversely proportional to the concentration in the blood).

Metabolism and excretion

In the liver demethylated, the metabolites formed are inactive. Plasma clearance - 630 ml / min.

Excretion of azithromycin from the blood plasma takes place in 2 stages: the half-life is 14-20 hours in the interval from 8 to 24 hours after taking the drug and 41 hours in the interval from 24 to 72 hours. It is excreted with bile in unchanged form (50%) and kidneys (6%).

Pharmacokinetics in special clinical cases

Eating changes the pharmacokinetics: when taking azithromycin in tablets, the maximum concentration increases by 31%, while the AUC does not change.

In elderly men (65-85 years) pharmacokinetic parameters do not change, in women it increases (Cmax by 30-50%).

Secnidazole

Suction and distribution

Absorption is high, bioavailability is 80%. After a single oral dose of 2 g, the maximum concentration is detected after 4 hours.

Penetrates through the placental barrier, excreted in breast milk.

Metabolism and excretion

Metabolised in the liver.

It is excreted in the urine for 72 hours (16% of the dose).

Indications:

Combined infections of the genitourinary tract, transmitted sexually:

gonorrhea;
trichomoniasis;
chlamydia;
bacterial vaginosis;
fungal infections;
concomitant specific and nonspecific cystitis, urethritis, vulvovaginitis, cervicitis.

ICD-10

I.A50-A64.A54 Gonococcal infection

I.A50-A64.A56.0 Chlamydial infections of the lower parts of the genito-urinary tract

I.A50-A64.A56.1 Chlamydial infections of the pelvic organs and other urogenital organs

I.A50-A64.A59 Trichomoniasis

I.A70-A74.A74.9 Chlamydial infection, unspecified

I.B35-B49.B37.3 Candidiasis of the vulva and vagina (N77.1 *)

I.B35-B49.B37.4 Candidiasis of other urogenital localizations

I.B35-B49.B49 Mycosis, unspecified

XIV.N30-N39.N30 Cystitis

XIV.N30-N39.N34 Urethritis and urethral syndrome

XIV.N70-N77.N74.8 * Inflammatory diseases of female pelvic organs in other diseases classified elsewhere

XIV.N70-N77.N76 Other inflammatory diseases of the vagina and vulva

Contraindications:

Simultaneous reception of astemizole, erythromycin, pimozide, quinidine, cisapride, ergotamine, dihydroergotamine.
Simultaneous reception of other drugs that extend the QT interval.
Organic diseases of the central nervous system.
Severe hepatic insufficiency.
Renal failure with creatinine clearance less than 40 ml / min.
Diseases of the blood (including in the history).
Pregnancy, lactation.
Children under 18 years.
Hypersensitivity to fluconazole and other azole compounds.
Hypersensitivity to fluconazole (including other azole antifungal drugs in history), azithromycin (including macrolides), secnidazole (including other nitroimidazoles).
Hypersensitivity to other components of the tablets that make up the kit.

Carefully:With potentially proaritmogenic conditions in patients with multiple risk factors (organic heart disease,violation of the electrolyte balance); simultaneously with drugs that extend the QT interval (antiarrhythmice preparations of IA and III class), with arrhythmia (risk of ventricular arrhythmia and prolongation of the QT interval), with moderate violations of the liver and kidneys, with myasthenia; while taking with cisapride, rifabutin or other drugs that metabolizeusing the cytochrome P 450 system.

Pregnancy and lactation:The combination is contraindicated for use in pregnancy and lactation (breastfeeding).

Dosing and Administration:Inside once. Take all 4 tablets included in the blister at the same time, taking into account the food intake (since the absorption of azithromycin varies with simultaneous intake of food, it is better to take it an hour before meals or 2 hours after eating).

Side effects:

Fluconazole

Drug tolerance is usually very good.

From the side central and peripheral nervous system: headache, dizziness, convulsions, insomnia, drowsiness, tremor.

From the side digestive system: abdominal pain, diarrhea, flatulence, nausea, taste change, dyspepsia, vomiting,dryness of the oral mucosa, impaired liver function (jaundice, hyperbilirubinemia, increased concentrations of alkaline phosphatase, cholestasis, increased activity of "hepatic" enzymes, hepatitis, hepatocellular necrosis), including fatal.

Allergic reactions: skin rash, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), anaphylactic reactions (including angioedema, facial edema, hives, itching of the skin).

From the side hemopoiesis: leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

From the side of cardio-vascular system: increase in the duration of the QT interval, fibrillation / flutter of the ventricles, arrhythmia ventricular tachysystolic type of "pirouette" (torsade de pointes).

Other: renal dysfunction, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia, increased sweating, myalgia, asthenia, weakness, fever.

Azithromycin

From the side digestive system: flatulence, nausea, vomiting, constipation, abdominal pain, decreased appetite, gastritis, melena, cholestatic jaundice,increased activity "liver" enzymes, candidiasis of the oral mucosa, diarrhea, indigestion, changing the language of color, pseudomembranous colitis, pancreatitis, hepatitis, liver dysfunction, increase in the concentration of bilirubin, hepatic failure, hepatic necrosis (possibly fatal), fulminant hepatitis .

Allergic reactions: skin rash, pruritus, angioedema, urticaria, anaphylactic reaction, including edema (rarely fatal), erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the side reproductive system: vaginal candidiasis, vaginitis.

From the side urinary system: interstitial nephritis, acute renal failure, an increase in the concentration of urea and creatinine in the blood plasma.

From the side of cardio-vascular system: heart palpitations, chest pain, arrhythmia, decreased blood pressure, ventricular tachycardia, increased QT interval, bidirectional ventricular tachycardia.

From the side nervous system: dizziness, headache, vertigo, drowsiness, convulsions, paresthesia, hypoesthesia, insomnia,hyperactivity, aggressiveness, anxiety, anxiety, nervousness, fainting.

From the side hematopoiesis systems: lymphopenia, leukopenia, neutropenia, thrombocytopenia, hemolytic anemia, neutrophilia.

From the side sense organs: noise in the ears, reversible hearing loss down to deafness, a violation of the perception of taste and smell.

Other: asthenia, photosensitivity, conjunctivitis, impaired vision, eosinophilia, myasthenia gravis, arthralgia, peripheral edema, malaise, change in potassium concentration.

Secnidazole

Possible side effects noted when taking imidazole derivatives:

From the side digestive system: nausea, vomiting, abdominal pain, "metallic" taste in the mouth, glossitis, stomatitis.

From the side hematopoiesis system: leukopenia.

From the side central and peripheral nervous system: dizziness, impaired coordination of movements, ataxia, paresthesia, polyneuropathy.

Allergic reactions: hives.

Overdose:

Cases of overdose combination are not described. In case of overdose, immediately consult a doctor.

Fluconazole

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic; gastric lavage (if necessary), forced diuresis. Hemodialysis within 3 hours reduces the concentration of fluconazole in the blood plasma by approximately 50%.

Azithromycin

Symptoms: nausea, temporary loss of hearing, vomiting, diarrhea.

Treatment: symptomatic; reception of activated carbon, control of vital functions.

Secnidazole

In case of suspected overdose, supportive and symptomatic treatment should be performed; gastric lavage, reception of activated carbon.

Interaction:

Astemizole. Contraindicated simultaneous administration of fluconazole (in combination Fluconazole + azithromycin + secnidazole) and astemizole, extending the QT interval.

Bromocriptine. Azithromycin (in combination Fluconazole + azithromycin + secnidazole) slows down the excretion and increases the plasma concentration and toxicity of bromocriptine subjected to microsomal oxidation by inhibiting microsomal oxidation in hepatocytes.

Warfarin. With the combined use of fluconazole with warfarin increases prothrombin time (an average of 12%).

When co-prescribing warfarin and azithromycin (in usual doses), changes prothrombin time was not revealed, however, it should be taken into account that the interaction of macrolides and warfarin may enhance the anticoagulant effect. In this regard, it is recommended that the indicators prothrombin time in patients receiving a combination Fluconazole + azithromycin + secnidazole in combination with warfarin.

Glibenclamide. Fluconazole (in combination Fluconazole + azithromycin + secnidazole) increases the half-life of plasma glibenclamide in healthy people. The combined use of fluconazole (in combination Fluconazole + azithromycin + secnidazole) and glibenclamide in diabetic patients is allowed, but the doctor should keep in mind the possibility of developing hypoglycemia.

Glipizide. Fluconazole (in combination Fluconazole + azithromycin + secnidazole) increases the half-life of plasma glipizide in healthy people. The combined use of fluconazole (in combination Fluconazole + azithromycin + secnidazole) and glipizide in diabetic patients is allowed, but the doctor should keep in mind the possibility of developing hypoglycemia.

Dizopyramide. Azithromycin (in combination Fluconazole + azithromycin + secnidazole) slows down the excretion and increases the plasma concentration and toxicity of the disopyramide undergoing microsomal oxidation by inhibiting microsomal oxidation in hepatocytes.

Carbamazepine. Azithromycin (in combination Fluconazole + azithromycin + secnidazole) slows down excretion and increases plasma concentration and toxicity of carbamazepine subjected to microsomal oxidation, by inhibiting microsomal oxidation in hepatocytes.

Methylprednisolone. Azithromycin (in combination Fluconazole + azithromycin + secnidazole) slows down excretion and increases plasma concentration and toxicity of methylprednisolone.

Rifabutin. Caution should be exercised with simultaneous administration of fluconazole (as part of combination Fluconazole + azithromycin + secnidazole) with rifabutin metabolized by the cytochrome P450 system.

Theophylline. Azithromycin (in combination Fluconazole + azithromycin + secnidazole) slows down the excretion and increases the plasma concentration and toxicity of theophylline undergoing microsomal oxidation,by inhibiting microsomal oxidation in hepatocytes (patients who receive high theophylline doses or who are likely to develop theophylline intoxication should be monitored for the early detection of symptoms of theophylline overdose).

Terfenadine. Contraindicated simultaneous administration of fluconazole (in combination Fluconazole + azithromycin + secnidazole) and terfenadine, extending the QT interval.

Tolbutamide. Fluconazole (in combination Fluconazole + azithromycin + secnidazole) increases the half-life of plasma from tolbutamide in healthy people. The combined use of fluconazole (in combination Fluconazole + azithromycin + secnidazole) and tolbutamide in diabetic patients is allowed, but the doctor should keep in mind the possibility of developing hypoglycemia.

Felodipine. Azithromycin (in combination Fluconazole + azithromycin + secnidazole) slows down excretion and increases plasma concentration and toxicity of felodipine.

Chlorpropamide. Fluconazole (in combination Fluconazole + azithromycin + secnidazole) increases the half-life of plasma chloropropamid in healthy people.The combined use of fluconazole (in combination Fluconazole + azithromycin + secnidazole) and chlorpropamide in diabetic patients is allowed, but the doctor should keep in mind the possibility of developing hypoglycemia.

Cisapride. Caution should be exercised with simultaneous administration of fluconazole (as part of combination Fluconazole + azithromycin + secnidazole) with cisapride, a metabolized cytochrome P450 system.

Cycloserin. Azithromycin (in combination Fluconazole + azithromycin + secnidazole) slows down excretion and increases plasma concentration and toxicity of cycloserine.

Ethanol slows and reduces the absorption of azithromycin (in combination Fluconazole + azithromycin + secnidazole). With the joint use of secnidazole (in combination Fluconazole + azithromycin + secnidazole) with alcohol, a disulfiram-like reaction can develop (spasms in the abdomen, nausea, vomiting, headache, rush of blood to the face).

Special instructions:

With simultaneous use of antacids, a break of 2 hours should be observed before taking azithromycin.

In connection with the fact that with the joint use of secnidazole with alcohol, a disulfiram-like reaction can develop (spasms in the abdomen,nausea, vomiting, headache, rush of blood to the face), during the treatment should be avoided the use of ethanol.

Secnidazole can cause immobilization by treponem, which leads to false positive Nelson's test (reaction of immobilization of pale treponemes, RIBT).

Influence on the ability to drive vehicles, mechanisms.

The use of tablets, as a rule, does not affect the ability to drive a car and perform work that requires a high rate of mental and physical reactions, but it can lead to the development of dizziness and other side effects that may affect the above abilities.

Instructions

Fluconazole + Azithromycin + Secnidazole (Fluconazolum + Azithromycinum + Secnidazolum)