DIFLAZON

Active material: Fluconazole
When ATH: J02AC01
CCF: Antifungal agent
ICD-10 codes (testimony): B35.0, B35.1, B35.2, B35.3, B35.4, B35.6, B36.0, B37.0, B37.1, B37.2, B37.3, B37.4, B37.6, B37.7, B37.8, B38, B39, B41, B42, B45, H19.2, Z29.8
When CSF: 08.01.01
Manufacturer: KRKA d.d. (Slovenia)

Pharmaceutical form, composition and packaging

◊ Capsules hard gelatin, №4, a cap is light blue and white body; contents of capsules – powder white or nearly white.

Excipients: lactose monohydrate, corn starch, colloidal silicon dioxide (anhydrous), sodium lauryl, magnesium stearate.

Ingredients of the capsule shell: housing – Titanium dioxide (E171), gelatin; cover – Titanium dioxide (E171), patented blue dye (E131), gelatin.

7 PC. – blisters (1) – packs cardboard.

◊ Capsules hard gelatin, №2, a blue cap and white body; contents of capsules – powder white or nearly white.

Excipients: lactose monohydrate, corn starch, colloidal silicon dioxide (anhydrous), sodium lauryl, magnesium stearate.

Ingredients of the capsule shell: housing – Titanium dioxide (E171), gelatin; cover – Titanium dioxide (E171), patented blue dye (E131), gelatin.

7 PC. – blisters (4) – packs cardboard.

◊ Capsules Solid, gelatin, №1, with lid and body is light blue; contents of capsules – powder white or nearly white.

Excipients: lactose monohydrate, corn starch, colloidal silicon dioxide (anhydrous), sodium lauryl, magnesium stearate.

Ingredients of the capsule shell: housing – Titanium dioxide (E171), gelatin, patented blue dye (E131); cover – Titanium dioxide (E171), gelatin, patented blue dye (E131).

1 PC. – blisters (1) – packs cardboard.
2 PC. – blisters (1) – packs cardboard.
4 PC. – blisters (1) – packs cardboard.

◊ Capsules hard gelatin, №0, with a cap of dark purple body and white; contents of capsules – powder white or nearly white.

Excipients: lactose monohydrate, corn starch, colloidal silicon dioxide (anhydrous), sodium lauryl, magnesium stearate.

Ingredients of the capsule shell: housing – Titanium dioxide (E171), gelatin; cover – Titanium dioxide (E171), gelatin, indigo dyes FD&C Blue (E132), azoruʙin (E122).

7 PC. – blisters (1) – packs cardboard.
10 PC. – blisters (2) – packs cardboard.

Pharmacological action

Antifungal agent. Fluconazole, representative of the class of triazole antifungal agents, It is a potent selective inhibitor of fungal enzyme 14-α-demethylase. The drug inhibits lanosterol to ergosterol transition – the main component of the cell membranes of fungi.

It is active against agents of opportunistic fungal infections, incl. caused by Candida spp.. (Candida albicans, Candida tropicalis), Cryptococcus neoformans, Microsporum spp., Trichophyton spp. Fluconazole is also shown activity in models of endemic mycoses, including infections, caused by Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum.

Pharmacokinetics

Absorption

After oral administration fluconazole is well absorbed. Bioavailability is 90%. After oral administration at a dose on an empty stomach 150 mg C_max is 90% the content of the plasma with / in a dose of drug in the 2.5-3.5 mg / l. Simultaneous food intake has no effect on absorption when administered. C_max achieved through 0.5-1.5 hours after administration of fluconazole. Plasma concentration is proportional to the dose.

Distribution

90% C_ss It is achieved by 4-5 day drug treatment (when receiving 1 time / day).

Bolus (1 day), in 2 times the average daily dose, achieves 90% Level C_ss to 2 Day. In Кажущийся_d It is approaching the total water content in the body. Protein binding – 11-12%.

Fluconazole penetrates well into all body fluids, including cerebrospinal fluid. Fluconazole concentration in saliva and sputum are similar to its level in plasma. Patients with fungal meningitis fluconazole levels in the cerebrospinal fluid are about 80% the levels in plasma.

In the stratum corneum, epidermis, derma and sweat liquid reaches high concentrations, which exceed serum.

Metabolism

Less 5% Fluconazole is metabolised in the “first pass” through the liver. Fluconazole metabolites in blood has been detected.

Deduction

Duration T_1/2 It allows the use of a single dose of the drug for the treatment of vaginal candidiasis and provides the drug 1 time / day for other indications. Fluconazole is derived mainly kidneys; about 80% of the administered dose excreted by the kidneys in unchanged form. The clearance of fluconazole is proportional to creatinine clearance.

Testimony

- Kryptokokkoz, including cryptococcal meningitis and other localizations of this infection (incl. lungs, skin), both in patients with a normal immune response, and in patients with various forms of immunosuppression (incl. AIDS patients, organ transplantation); drug can be used to prevent cryptococcal infection in AIDS patients;

- Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive Candida infections (incl. infection of the peritoneum, endokarda, eye, respiratory and urinary tract). Treatment can be performed in patients with malignant tumors, Patients in intensive care units, patients, receiving cytotoxic or immunosuppressive agents, and the presence of other factors, predisposing to candidiasis;

- Mucosal candidiasis, incl. oral cavity and pharynx (including atrophic oral candidiasis, associated with wearing dentures), esophagus, non-invasive bronchopulmonary candidiasis, kandidurija, skin candidosis; prevention of relapse of oropharyngeal candidiasis in patients with AIDS;

- Genital candidiasis: vaginal candidiasis (acute and chronic recurrent), prophylactic treatment to reduce the frequency of relapses vaginal candidiasis (3 or more episodes per year); kandidoznыj ʙalanit;

- Prevention of fungal infections in patients with malignant tumors, who are predisposed to such infections as a result of cytotoxic chemotherapy or radiotherapy;

- Fungal infections of the skin, including tinea pedis, body, groin, chromophytosis, onychomycosis and skin candidiasis;

- Deep endemic mycoses, coccidioidomycosis, Paracoccidioidomycosis, sporotrichosis and histoplasmosis in patients with normal immunity.

Dosage regimen

Adults at cryptococcal meningitis and cryptococcal infections at other sites administered on the first day 400 mg, and then continue treatment at a dose 200-400 mg 1 time / day. The duration of treatment of cryptococcal infections depends on the clinical effectiveness, confirmed by mycological examination; cryptococcal meningitis treatment is generally continued, at least, 6-8 weeks.

To prevention of relapse of cryptococcal meningitis in patients with AIDS after completing a full course of primary treatment therapy fluconazole 200 mg / day can continue for a very long period of time.

At kandidemii, disseminated candidiasis and other invasive Candida infections dose averages 400 mg on the first day, and then 200 mg / day. When insufficient clinical efficacy dose may be increased to 400 mg / day; at severe systemic candidiasis may increase the dose to 800 mg / day. The duration of therapy depends on the clinical effectiveness; should continue for at least 2 weeks after receipt of the negative blood culture or after the disappearance of symptoms.

At orofaringealьnom kandidoze the drug is prescribed an average of 50-100 mg 1 time / day; duration of therapy – 7-14 days. If necessary,, in patients with severe depression of immunity, treatment may be longer (3 of the week).

At atrophic oral candidiasis, associated with wearing dentures, the drug is prescribed in high doses 50 mg 1 times / day for 14 days in combination with local antiseptic agents for treatment of prosthesis.

At Others lokalizatsiyah candidiasis (for isklyucheniem genitalynogo candidiasis), such as esophagitis, non-invasive bronchopulmonary lesions, kandidurii, candidiasis of the skin and mucous membranes, effective dose averages 50-100 mg / day when the duration of treatment 14-30 days; at severe mucosal candidiasis – 100-200 mg / day.

To prevention of relapse of oropharyngeal candidiasis in patients with AIDS after completing a full course of primary therapy, fluconazole may be appointed by 150 mg 1 times / week.

At vaginal candidiasis fluconazole take a single oral dose 150 mg. To reduce the frequency of recurrent vaginal candidiasis preparation may be used in a dose of 150 mg 1 times / month. The duration of therapy is determined individually; it ranges from 4 to 12 Months. Some patients may require more frequent use of.

At ʙalanite, caused by Candida, Fluconazole prescribe a single dose 150 mg orally.

To preventions candidiasis The recommended dose of fluconazole 50-400 mg 1 times / day depending on the degree of risk of fungal infection. If you have a high risk of generalized infection, for example in patients with severe or long-anticipated persistent neutropenia, The recommended dose is 400 mg 1 time / day. Fluconazole administered a few days before the expected occurrence of neutropenia; after increasing the number of neutrophils more than 1000 / ml treatment was continued for 7 d.

At mycosis of the skin, including tinea pedis, smooth skin, groin and skin candidosis, The recommended dose is 150 mg 1 times / week. or 50 mg 1 time / day. Duration of therapy in conventional cases is 2-4 Sun., however athlete's foot may require longer therapy (to 6 Sun.).

At pityriasis versicolor The recommended dose is 300 mg 1 times / week. during 2 weeks; some patients required a third dose 300 mg / Sun., while in some cases it is sufficient a single dose of the drug in 300-400 mg. Alternative treatment is the use of the drug 50 mg 1 times / day for 2-4 Sun.

At onixomikoze The recommended dose is 150 mg 1 times / week. Treatment should be continued until infected nail replacement (sprouting uninfected nail). For the re-growth of the fingernails and feet normally required 3-6 months and 6-12 months, respectively.

At Deep endemic mycoses may be required drug dose 200-400 mg / day for up to 2 years. The duration of therapy is determined individually; it is 11-24 months with coccidioidomycosis, 2-17 months in paracoccidioidomycosis, 1-16 months in sporotrichosis and 3-17 months in histoplasmosis.

In children, as in the similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be administered in a daily dose of, greater than that of adults. Diflazon^® daily use 1 time / day.

At mucosal candidiasis The recommended dose of fluconazole 3 mg / kg / day. The first day can be assigned to the loading dose 6 mg / kg in order to more quickly achieve permanent equilibrium concentrations.

For the treatment of generalizovannogo candidiasis infections and kriptokokkovoy The recommended dose is 6-12 mg / kg / day, depending on the severity of the disease.

To prevention of fungal infections in immunocompromised children, in which the risk of infection associated with neutropenia, developing as a result of cytotoxic chemotherapy or radiotherapy, the drug is prescribed for 3-12 mg / kg / day, depending on the severity and duration of neutropenia induced by conservation. The maximum daily dose for children is – 12 mg / kg.

In children with impaired renal function the daily dose should be reduced (in the same proportion, in adults) in accordance with the severity of renal insufficiency.

In elderly patients in the absence of renal failure should follow the usual dose regimen of the drug.

Fluconazole is derived mainly from the urine in unchanged form. For a single admission of his change of dose is not required. If reappointment patients with impaired renal function enter “loading dose” from 50 mg 400 mg.

At CC>50 ml / min It applies average recommended dose; at KK from 11 to 50 ml / min applied dose, component 50% Recommended by, or recommended dose 1 once every 2 day. Patients, regular hemodialysis, One dose administered after each dialysis.

Side effect

From the digestive system: nausea, diarrhea, flatulence, vomiting, abdominal pain, change in taste; rarely – increase in liver enzymes and liver dysfunction (jaundice, giperʙiliruʙinemija, increased ALT, ACT and ALP, hepatitis, hepatocellular necrosis), incl. fatal.

CNS: headache, dizziness; rarely – convulsions.

From the hematopoietic system: rarely – agranulocytosis, neutropenia. In patients with severe fungal infections may occur hematological changes (leykopeniya and thrombocytopenia).

Cardio-vascular system: prolongation of QT interval on an electrocardiogram, flicker / ventricular flutter.

Allergic reactions: skin rash, erythema multiforme exudative (incl. Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), bronchial asthma (increasingly intolerant of acetylsalicylic acid), anaphylactoid reactions (incl. angioedema, swelling of the face, hives, itching).

Other: rarely – impairment of renal function, alopecia, hypercholesterolemia, hypertriglyceridemia, kaliopenia.

Contraindications

- Concomitant use of terfenadine (with the constant receiving fluconazole 400 mg / day or more), cisapride or astemizole and other drugs, prolong the QT interval and increase the risk of serious arrhythmias;

- Lactation;

- Children up to age 3 years (for a given dosage form);

- Hypersensitivity to fluconazole, other ingredients or other azole compounds.

FROM caution should be prescribed the drug for liver and / or kidney failure, the appearance of rash during treatment with fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, simultaneous reception of terfenadine and fluconazole less 400 mg / day, potentially proaritmogennoe states in patients with multiple risk factors (organic heart disease, electrolyte imbalance, concomitant use of drugs, arhythmogenic); patients with intolerance to acetylsalicylic acid, Pregnancy.

Pregnancy and lactation

Use of the drug Diflazon^® Pregnancy inappropriate, except for serious or life-threatening forms of fungal infections, if the expected benefit to the mother outweighs the potential risk to the fetus.

Fluconazole is found in the breast milk at the same concentration, as in plasma, Therefore, the appointment during lactation is not recommended.

Cautions

Treatment can be started in the absence of culture results or other laboratory tests, but if any corresponding correction recommended fungicide treatment.

As fluconazole is derived mainly kidneys, Caution should be exercised in patients with renal insufficiency. In the treatment of multiple doses of fluconazole, Dosing should take into account QA.

Caution must be exercised in the appointment of fluconazole in patients with impaired liver function. During treatment should regularly monitor the level of liver enzymes and conduct observation of the patient to identify possible toxic effects. At higher levels of liver enzymes physician must weigh the benefit, brought by ongoing therapy, and the risk of severe liver injury. Fluconazole hepatotoxicity is usually reversible; symptoms disappear after cessation of therapy.

AIDS patients are more prone to the development of severe skin reactions in the application of many drugs. Where, when patients with superficial fungal infection develops a rash, and it is regarded as definitely related to fluconazole, the drug should be discontinued. When the rash in patients with invasive / systemic fungal infections, they should be monitored closely and fluconazole to cancel the appearance of bullous erythema multiforme or changes.

It is necessary to monitor the prothrombin time in patients, concomitantly receiving fluconazole and coumarin anticoagulants. Treatment must be continued until clinical remission. Premature discontinuation of treatment leads to relapse.

Part of the capsules Diflazon^® 200 mg azo dye E122 may cause an allergic reaction, incl. bronhyalnuyu asthma. Allergic reactions are more common in patients with intolerance to acetylsalicylic acid.

Effects on ability to drive vehicles and management mechanisms

It is not known about the negative impact on the ability of driving and operating other machines.

Overdose

Symptoms: nausea, vomiting, diarrhea, in severe cases, seizures may occur, hallucinations, paranoidalynoe behavior.

Treatment: symptomatic, gastric lavage; tk. Fluconazole is excreted by the kidneys recommended diurez. Hemodialysis for 3 h decreases the plasma concentration 2 times.

Drug Interactions

A single dose of fluconazole in the treatment of vaginal candidiasis is not accompanied by significant interaction. Nonetheless, when applying multiple or higher dosages in conjunction with other drugs, the following drugs interact.

The interaction of fluconazole with terfenadine, astemizole and cisapride may lead to increased concentrations of these drugs in plasma, which in turn can cause QT prolongation and lead to serious disturbances of heart rhythm. Fluconazole inhibits the enzyme P450 system in the liver, decreasing, thus, terfenadine metabolism, cisapride and astemizole. Co-administration of fluconazole and these drugs are contraindicated.

The joint appointment of warfarin and fluconazole marked prolongation of prothrombin time. In this regard, prothrombin time must be monitored in patients, concomitantly receiving fluconazole and coumarin anticoagulants.

Fluconazole udlinyaet T_1/2 oral hypoglycemic drugs (sulfonylureas). Diabetic patients can simultaneously assign fluconazole and sulfonylureas, but it must take into account the potential risk of hypoglycemia.

It should be taken into account, that at the same time re-appointment of hydrochlorothiazide and fluconazole, fluconazole concentration in plasma increased.

Rifampicin accelerates metabolism of fluconazole. It is necessary to appropriately increase the dose of fluconazole when used simultaneously.

Patients, Kidney transplant, fluconazole may increase the plasma concentrations of cyclosporine. In this regard, we recommend monitoring the concentration of cyclosporine in patients, concomitantly receiving fluconazole and tacrolimus.

Fluconazole increases the concentration of theophylline in plasma. In this regard, it is recommended monitoring the concentration of theophylline in patients, concomitantly receiving fluconazole and theophylline.

Fluconazole may increase the plasma concentration of indinavir and midazolam. When concomitant administration of these drugs with fluconazole, their dosage should be reduced accordingly.

Clinical studies have shown, resulting in slow metabolism of zidovudine, may increase its concentration in the plasma, while the appointment with fluconazole. It is necessary to monitor patients, simultaneously receiving both drugs, as in this case, it may increase the frequency of side effects of zidovudine.

Fluconazole increases serum concentrations of phenytoin. When concomitant administration of phenytoin dose necessary to control and adjust their.

Fluconazole increases the effectiveness of rifabutin (while the application described cases of uveitis) and phenytoin to a clinically significant degree (the combined use requires monitoring of phenytoin plasma concentrations).

Fluconazole increases the concentration of tacrolimus and increases the risk of nephrotoxicity.

Conditions of supply of pharmacies

The drug is resolved to application as an agent Valium holidays.

Conditions and terms

The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 5 years.