Safocid (Tablet kit) Instructions for Use

Marketing Authorization Holder

Nizhpharm JSC (Russia)

Manufactured By

Lyka Labs, Ltd. (India)

Labeled By

KHEMOFARM, LLC (Russia)

ATC Code

J01RA (Antimicrobial drugs in combination)

Active Substances

Azithromycin (Rec.INN registered by WHO)

Fluconazole (Rec.INN registered by WHO)

Secnidazole (Rec.INN registered by WHO)

Dosage Form

Safocid

Set of three types of tablets: 4 or 12 pcs. in a pack, incl.: 1 fluconazole 150 mg tablet in a blister; 1 film-coated azithromycin tablet 1000 mg in a blister; 2 film-coated secnidazole tablets 1000 mg in a blister

Dosage Form, Packaging, and Composition

Tablet kit of three types

Pink tablets, flat-cylindrical, with a bevel and a score; pink at the fracture (1 pc. in a blister).

Excipients: microcrystalline cellulose – 153 mg, calcium hydrogen phosphate – 14.5 mg, croscarmellose sodium – 5 mg, magnesium stearate – 4 mg, colloidal silicon dioxide – 1 mg, Ponceau 4R dye (E124) – 2.5 mg.

Film-coated pink tablets, capsule-shaped, biconvex, with a score; white or almost white core at the fracture (1 pc. in a blister).

Excipients: sodium lauryl sulfate – 12 mg, croscarmellose sodium – 37.24 mg, povidone K30 – 40 mg, magnesium stearate – 16 mg, colloidal silicon dioxide – 2 mg.

Shell composition hypromellose (hydroxypropyl methylcellulose) – 24.5 mg, diethyl phthalate – 3.8 mg, talc – 5.2 mg, titanium dioxide – 6 mg, macrogol 4000 – 4.2 mg, Ponceau 4R dye (E124) – 1.06 mg.

Film-coated white or almost white tablets, capsule-shaped, biconvex, with a score; white or almost white at the fracture (2 pcs. in a blister).

Excipients: corn starch – 95 mg, microcrystalline cellulose – 130 mg, colloidal silicon dioxide – 6 mg, sodium carboxymethyl starch – 20 mg, povidone (PVPK-30) – 2.5 mg, talc – 11.5 mg, magnesium stearate – 10 mg.

Shell composition hypromellose (hydroxypropyl methylcellulose) – 27.1 mg, diethyl phthalate – 4 mg, talc – 5.7 mg, titanium dioxide – 11.2 mg, macrogol 4000 – 4.6 mg.

4 pcs. – blisters (1) – cardboard packs.
4 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Combined drug with antiprotozoal, antifungal, and antibacterial action

Pharmacotherapeutic Group

Combined antimicrobial agent

Pharmacological Action

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

Fluconazole

Antifungal agent, has a highly specific action, inhibiting the activity of fungal enzymes dependent on cytochrome P450. It blocks the conversion of lanosterol in fungal cells to ergosterol; increases the permeability of the cell membrane, disrupts its growth and replication. Fluconazole, being highly selective for fungal cytochrome P450, practically does not inhibit these enzymes in the human body (compared to itraconazole, clotrimazole, econazole, and ketoconazole, it suppresses cytochrome P450-dependent oxidative processes in human liver microsomes to a lesser extent). Does not possess antiandrogenic activity.

Active against opportunistic mycoses, including those caused by Candida spp. (including generalized forms of candidiasis against the background of immunosuppression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp.; against endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including in immunosuppression).

Azithromycin

Broad-spectrum antibacterial agent, azalide, acts bacteriostatically. By binding to the 50S ribosomal subunit, it inhibits peptidyltransferase at the translation stage, suppresses protein synthesis, slows down the growth and reproduction of bacteria, and has a bactericidal effect at high concentrations. Active against extracellular and intracellular pathogens.

Microorganisms sensitive to azithromycin aerobic gram-positive microorganisms – Staphylococcus aureus (methicillin-sensitive strains), Streptococcus pneumoniae (penicillin-sensitive 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 intermediate 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 have been described.

Secnidazole

Antimicrobial bactericidal agent – a synthetic derivative of nitroimidazole. Active against obligate anaerobic bacteria (spore-forming and non-spore-forming), causative agents of some protozoal infections: Trichomonas spp., Giardia lamblia, Entamoeba histolytica. Not active against aerobic bacteria.

Interacts with the DNA of the microbial cell, causes disruption of the helical structure, strand breakage, suppression of nucleic acid synthesis and cell death. Causes sensitization to alcohol (disulfiram-like effect).

Pharmacokinetics

Fluconazole

Absorption and Distribution

Absorption is high, bioavailability is 90%. Concurrent food intake does not affect the absorption of the drug taken orally. After oral administration on an empty stomach of 150 mg, T_max is 0.5-1.5 h, C_max of fluconazole in plasma is 90% of its concentration in plasma after IV administration at the same dose.

Plasma protein binding is 11-12%. Plasma concentration is directly dependent on the dose. Fluconazole penetrates well into all biological fluids of the body. The concentration of the active substance in breast milk, synovial fluid, saliva, sputum, and peritoneal fluid is similar to that in plasma. It penetrates well into the cerebrospinal fluid; in fungal meningitis, the concentration in the cerebrospinal fluid is about 85% of that in plasma. In sweat fluid, epidermis, and stratum corneum (selective accumulation), concentrations exceeding serum levels are achieved. V_d approaches the total water content in the body.

Metabolism and Excretion

T_1/2 of fluconazole is about 30 h. It is an inhibitor of the CYP2C9 isoenzyme in the liver. Excreted mainly by the kidneys (80% unchanged, 11% as metabolites). Fluconazole clearance is proportional to creatinine clearance.

Pharmacokinetics in Special Clinical Cases

The pharmacokinetics of fluconazole significantly depend on the functional state of the kidneys, with an inverse relationship between T_1/2 and CrCl. After hemodialysis for 3 hours, the plasma concentration of fluconazole decreases by 50%.

Azithromycin

Absorption and Distribution

Azithromycin is rapidly absorbed from the gastrointestinal tract, which is due to its stability in an acidic environment and lipophilicity. Bioavailability after a single 500 mg dose is 37% (first-pass effect through the liver). After oral administration of 500 mg, C_max is 0.4 mg/l, T_max is 2.5-2.9 h.

Concentrations in tissues and cells are 10-50 times higher than in serum. V_d is 31.1 l/kg. Easily passes through histohematic barriers. Penetrates well into the respiratory tract, genitourinary organs and tissues, into the prostate gland, into the skin and soft tissues; accumulates in environments with low pH, in lysosomes (which is especially important for the eradication of intracellularly located pathogens). It is also transported by phagocytes, polymorphonuclear leukocytes and macrophages (without significantly affecting their function). Passes through cell membranes and creates high concentrations in them. The concentration at the site of infection is significantly higher (by 24-34%) than in healthy tissues and correlates with the severity of inflammatory edema. It remains at the site of inflammation in effective concentrations for 5-7 days after the last dose. Plasma protein binding is 7-50% (inversely proportional to blood concentration).

Metabolism and Excretion

It is demethylated in the liver; the resulting metabolites are inactive. Plasma clearance is 630 ml/min.

Elimination of azithromycin from blood plasma occurs in 2 stages: T_1/2 is 14-20 h in the interval from 8 to 24 h after taking the drug and 41 h in the interval from 24 to 72 h. Excreted in bile unchanged (50%) and by the kidneys (6%).

Pharmacokinetics in Special Clinical Cases

Food intake alters pharmacokinetics: when taking azithromycin in the tablet dosage form, C_max increases by 31%, while AUC does not change.

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

Secnidazole

Absorption and Distribution

Absorption is high, bioavailability is 80%. After a single oral dose of 2 g, T_max is 4 h.

Penetrates the placental barrier, excreted in breast milk.

Metabolism and Excretion

Metabolized in the liver.

Excreted in urine within 72 hours (16% of the dose).

Indications

Combined infections of the genitourinary tract, sexually transmitted

• Gonorrhea;
• Trichomoniasis;
• Chlamydia;
• Bacterial vaginosis;
• Fungal infections;
• Associated specific and nonspecific cystitis, urethritis, vulvovaginitis, cervicitis.

ICD codes

Dosage Regimen

Take all four tablets from the kit orally as a single, one-time dose.

This includes the one fluconazole 150 mg tablet, the one azithromycin 1000 mg tablet, and the two secnidazole 1000 mg tablets.

Administer the azithromycin tablet one hour before or two hours after a meal to ensure optimal absorption.

You may take the fluconazole and secnidazole tablets without regard to food.

Swallow the tablets whole with a full glass of water; do not crush or chew them.

This regimen is indicated for the treatment of specific combined genitourinary tract infections in adults.

Ensure the patient has no contraindications, such as severe renal or hepatic impairment, pregnancy, or hypersensitivity to the components, before administration.

Avoid concurrent consumption of alcohol during treatment and for at least 72 hours after the last dose due to the risk of a disulfiram-like reaction from secnidazole.

Observe a two-hour interval if the patient is taking antacids.

This is a single-dose therapy; no repeat dosing is required for this course of treatment.

Adverse Reactions

Fluconazole

Drug tolerance is usually very good.

From the central and peripheral nervous system headache, dizziness, seizures, insomnia, drowsiness, tremor.

From the digestive system abdominal pain, diarrhea, flatulence, nausea, taste change, dyspepsia, vomiting, dry oral mucosa, impaired liver function (jaundice, hyperbilirubinemia, increased alkaline phosphatase concentration, cholestasis, increased activity of “liver” enzymes, hepatitis, hepatocellular necrosis), including fatal outcome.

Allergic reactions skin rash, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylactic reactions (including angioedema, facial edema, urticaria, skin itching).

From the hematopoietic organs leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

From the cardiovascular system increased QT interval, ventricular fibrillation/flutter, torsade de pointes type ventricular tachyarrhythmia.

Other impaired renal function, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia, increased sweating, myalgia, asthenia, weakness, fever.

Azithromycin

From the digestive system: flatulence, nausea, vomiting, constipation, abdominal pain, decreased appetite, gastritis, melena, cholestatic jaundice, increased activity of “liver” transaminases, oral mucosa candidiasis, diarrhea, indigestion, tongue discoloration, pseudomembranous colitis, pancreatitis, hepatitis, liver dysfunction, increased bilirubin concentration, liver failure, liver necrosis (possibly fatal), fulminant hepatitis.

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

From the reproductive system: vaginal candidiasis, vaginitis.

From the urinary system: interstitial nephritis, acute renal failure, increased plasma urea and creatinine concentration.

From the cardiovascular system: palpitations, chest pain, arrhythmia, decreased blood pressure, ventricular tachycardia, increased QT interval, bidirectional ventricular tachycardia.

From the nervous system: dizziness, headache, vertigo, drowsiness, seizures, paresthesia, hypesthesia, insomnia, hyperactivity, aggressiveness, anxiety, nervousness, syncope.

From the hematopoietic system: lymphopenia, leukopenia, neutropenia, thrombocytopenia, hemolytic anemia, neutrophilia.

From the sensory organs: tinnitus, reversible hearing impairment up to deafness, impaired taste and smell perception.

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

Secnidazole

Possible side effects noted with the use of imidazole derivatives:

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

From the hematopoietic system: leukopenia.

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

Allergic reactions: urticaria.

Contraindications

• Concomitant use of astemizole, erythromycin, pimozide, quinidine, cisapride, ergotamine, dihydroergotamine;
• Concomitant use of other drugs that prolong the QT interval;
• Organic diseases of the central nervous system;
• Severe hepatic insufficiency;
• Renal failure with CrCl less than 40 ml/min;
• Blood diseases (including history);
• Pregnancy;
• Lactation period;
• Children under 18 years of age;
• Hypersensitivity to fluconazole and other azole compounds;
• Hypersensitivity to fluconazole (including to other azole antifungal drugs in history), azithromycin (including to macrolides), secnidazole (including to other nitroimidazoles);
• Hypersensitivity to other components of the tablets included in the kit.

With caution the drug should be used concomitantly with rifabutin or other drugs metabolized by the cytochrome P450 system; concomitantly with warfarin, digoxin, terfenadine; in potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance); concomitantly with drugs that prolong the QT interval (class IA and III antiarrhythmic drugs), in arrhythmia (risk of ventricular arrhythmias and QT interval prolongation), in moderate impairment of liver and kidney function, in myasthenia gravis.

Use in Pregnancy and Lactation

Safocid is contraindicated for use during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

The drug is contraindicated in severe hepatic insufficiency; in moderate impairment of liver function, the drug should be prescribed with caution

Use in Renal Impairment

The drug is contraindicated in severe renal insufficiency (CrCl less than 40 ml/min); in moderate impairment of renal function, the drug should be prescribed with caution

Pediatric Use

Contraindication: pediatric age under 18 years.

Special Precautions

When used concomitantly with antacids, a 2-hour break must be observed before taking azithromycin.

Since a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headache, facial flushing) may develop with the concomitant use of secnidazole and alcohol, it is necessary to avoid ethanol consumption during the treatment period.

Secnidazole may cause immobilization of treponemes, leading to a false-positive Nelson test (Treponema pallidum immobilization test, TPI test).

Effect on the ability to drive vehicles, machinery

The use of the Safocid tablet kit generally does not affect the ability to drive a car and perform work requiring high speed of mental and physical reactions; however, its use may cause dizziness and other side effects that could affect the aforementioned abilities.

Overdose

Cases of overdose with the Safocid tablet kit have not been described. In case of overdose, a doctor should be consulted immediately.

Fluconazole

Symptoms: hallucinations, paranoid behavior.

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

Azithromycin

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

Treatment: symptomatic; administration of activated charcoal, monitoring of vital functions.

Secnidazole

If an overdose is suspected, supportive and symptomatic treatment should be carried out; gastric lavage, administration of activated charcoal.

Drug Interactions

Fluconazole

Concomitant use of astemizole with fluconazole may reduce the clearance of astemizole and increase its plasma concentration, which can cause QT interval prolongation and the development of torsade de pointes ventricular arrhythmia.

Concomitant use of pimozide with fluconazole may inhibit the metabolism of pimozide. An increase in the plasma concentration of pimozide can cause QT interval prolongation and the development of torsade de pointes ventricular arrhythmia.

Concomitant use of quinidine with fluconazole may inhibit the metabolism of quinidine. The use of quinidine is associated with QT interval prolongation and rare cases of torsade de pointes ventricular arrhythmia.

Concomitant use of fluconazole and erythromycin may increase the risk of cardiotoxicity (QT interval prolongation, development of torsade de pointes ventricular arrhythmia), up to and including sudden cardiac arrest.

Cases of serious cardiac disorders, including paroxysms of ventricular tachycardia (torsade de pointes), have been reported with the concomitant use of cisapride and fluconazole. Concomitant administration of fluconazole (200 mg/day) and cisapride (20 mg 4 times/day) resulted in a significant increase in plasma cisapride concentration and an increase in QT interval duration.

Benzodiazepines (short-acting): Fluconazole increases the concentration of midazolam after its oral administration, which may lead to an increased risk of psychomotor effects. Fluconazole increases the AUC and T_1/2 of triazolam after its oral administration, which may result in an enhanced effect and increased duration of action of triazolam. When short-acting benzodiazepines and fluconazole are used concomitantly, a dose reduction of the benzodiazepines and careful monitoring of the patient’s condition may be required.

Rifampicin increases the metabolism of fluconazole, resulting in a decrease in the T_1/2 and plasma concentration of fluconazole by 20% and 25%, respectively. An increase in the dose of fluconazole may be required.

Fluconazole may increase the serum concentration of tacrolimus after its oral administration due to inhibition of tacrolimus metabolism in the intestine by the CYP3A4 isoenzyme. No significant changes in pharmacokinetic parameters were observed after intravenous administration of tacrolimus. An increase in tacrolimus concentration increases the risk of nephrotoxic effects. Monitoring of tacrolimus concentration and dose adjustment if necessary should be performed.

Fluconazole increases the C_max and AUC of zidovudine by 84% and 74%, respectively, due to a decrease in its clearance by approximately 45%. Therefore, an increased risk of zidovudine side effects is possible. Patients should be carefully monitored for the development of zidovudine-related adverse reactions.

Some azoles in combination with terfenadine have been associated with the occurrence of serious rhythm disturbances, including paroxysms of ventricular tachycardia (torsade de pointes), due to an increase in the QT interval on the ECG. Studies conducted with fluconazole have shown that at a daily dose of fluconazole 200 mg, no QT interval prolongation was observed. When fluconazole was used at a dose of 400 or 800 mg, a significant increase in terfenadine plasma concentration was observed. The use of fluconazole at a dose of 400 mg or more in combination with terfenadine is contraindicated. Patients should be carefully monitored when taking terfenadine and fluconazole at a dose of less than 400 mg/day concomitantly.

Hydrochlorothiazide increases the plasma concentration of fluconazole by 40% (clinical significance is unlikely).

Fluconazole increases the plasma concentration and T_1/2 of oral hypoglycemic drugs, sulfonylurea derivatives: chlorpropamide, glibenclamide, glipizide, and tolbutamide. Blood glucose concentration should be periodically monitored (risk of hypoglycemia) and, if necessary, the dose of oral hypoglycemic drugs should be adjusted.

An increase in prothrombin time was observed with the concomitant use of fluconazole during treatment with coumarin derivatives (warfarin). In patients concurrently receiving indirect anticoagulants, coumarin derivatives, careful monitoring of prothrombin time is required.

Concomitant use of fluconazole and rifabutin may lead to an increase in the plasma concentration of the latter; cases of uveitis have been described with concomitant use.

Fluconazole reduces the clearance of theophylline and increases its plasma concentration. Patients receiving high doses of theophylline or those who are likely to develop theophylline intoxication should be monitored for early detection of theophylline overdose symptoms.

Fluconazole clinically significantly increases the plasma concentration of phenytoin. When used concomitantly, monitoring of phenytoin plasma concentration and, if necessary, dose adjustment should be performed.

Fluconazole increases the AUC of cyclosporine. With the concomitant use of fluconazole (200 mg/day) and cyclosporine (2.7 mg/kg/day) in kidney transplant patients, the cyclosporine AUC value was increased by 1.8 times.

No significant changes in plasma concentrations of ethinyl estradiol and levonorgestrel were observed with the concomitant use of fluconazole 50 mg and oral contraceptives, but with the use of 200 mg fluconazole, an increase in the AUC of ethinyl estradiol by 40% and levonorgestrel by 24% was observed. Therefore, no effect of fluconazole on the efficacy of combined oral contraceptives is expected.

Azithromycin

Antacids (containing aluminum and magnesium), ethanol, and food slow down and reduce the absorption of azithromycin.

No changes in prothrombin time were detected with the combined prescription of warfarin and azithromycin (at usual doses); however, given that an enhancement of the anticoagulant effect is possible with the interaction of macrolides and warfarin, patients require careful monitoring of prothrombin time.

Azithromycin does not have a clinically significant effect on the blood concentration of carbamazepine, cimetidine, didanosine, efavirenz, fluconazole, indinavir, midazolam, theophylline, triazolam, trimethoprim/sulfamethoxazole, cetirizine, sildenafil, atorvastatin, rifabutin, and methylprednisolone when used concomitantly.

Caution should be exercised when co-prescribing terfenadine and azithromycin, as it has been established that the simultaneous intake of terfenadine and various types of antibiotics causes arrhythmia and QT interval prolongation. Based on this, the aforementioned complications cannot be ruled out with the combined use of terfenadine and azithromycin.

Ergotamine and dihydroergotamine: increased toxic effect (vasospasm, dysesthesia).

Macrolides slow down the elimination, increase the plasma concentration and toxicity of cycloserine, indirect anticoagulants, methylprednisolone, felodipine, as well as drugs undergoing microsomal oxidation (carbamazepine, terfenadine, cyclosporine, hexobarbital, ergot alkaloids, valproic acid, disopyramide, bromocriptine, phenytoin, oral hypoglycemic drugs), however, such interaction has not been noted with the use of azalides (including azithromycin).

Lincosamides weaken, and tetracycline and chloramphenicol enhance the effectiveness of azithromycin.

With the combined use of digoxin and azithromycin, it is necessary to monitor the concentration of digoxin in the blood, because many macrolides increase the absorption of digoxin in the intestine, thereby increasing its plasma concentration.

If it is necessary to use azithromycin concomitantly with cyclosporine, it is recommended to monitor the blood content of cyclosporine due to a significant increase in AUC.

When used concomitantly with zidovudine, Azithromycin does not affect the pharmacokinetic parameters of zidovudine in plasma or the renal excretion of zidovudine and its glucuronidated metabolite. However, the concentration of the active metabolite – phosphorylated zidovudine in monocytes increases. The clinical significance of this fact is unknown.

With concomitant use with nelfinavir, an increase in the plasma concentration of azithromycin is possible, which is not accompanied by a significant increase in adverse reactions and does not require adjustment of the drug doses.

Secnidazole

Enhances the effect of indirect anticoagulants. It is not recommended to combine with non-depolarizing muscle relaxants (vecuronium bromide). When taken concomitantly with lithium preparations, it increases its plasma concentration.

Enhances the hypoglycemic effect of insulin and oral hypoglycemic agents.

Similar to disulfiram, it causes ethanol intolerance.

Storage Conditions

The drug should be stored out of the reach of children, protected from light and moisture, at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.