Diflazon - instructions for use, dose, side effects, contraindications

Fluconazole is a representative of the class of triazole antifungal agents, it is a selective inhibitor of the synthesis of sterols in the fungal cell. The drug is active in mycoses caused by Candida spp. (C. albicans, C. tropicalis), Cryptococcus neoformans, Microsporum spp., Trichoptyton spp., Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum, are less effective against Aspergillus spp. and Penicillium marneffei and is ineffective against C. krusei, C. glabrata, Fussarium spp. and zygomycetes.

Pharmacokinetics:

After intravenous administration fluconazole well penetrates into tissues and body fluids.

Distribution

The concentration in the blood plasma is in direct proportion to the dose. The concentration of the active substance in breast milk, articular fluid, saliva, sputum and peritoneal fluid is similar to that in blood plasma. In the fluid, epidermis and stratum corneum (selective accumulation), concentrations exceeding serum levels are achieved. It penetrates well into the cerebrospinal fluid, with fungal meningitis the concentration in the cerebrospinal fluid is about 85% of that in the blood plasma. About 90% of the equilibrium concentration of fluconazole in the blood plasma (Css) is reached by 4-5 days. The introduction of a "shock" dose (on the first day), which is 2 times greater than the usual daily dose, makes it possible to reach a concentration corresponding to 90% Css by the second day.The apparent volume of distribution (Vd) approximates the total fluid content in the body. The connection with blood plasma proteins is low -11-12%.

Metabolism and excretion

The half-life (T1 / 2) is 30 hours. It is an inhibitor of the CYP2C9 isoenzyme in the liver. It is excreted primarily by the kidneys (80% unchanged, 11% - in the form of metabolites). The clearance of fluconazole is proportional to the clearance of creatinine (CC). The pharmacokinetics of fluconazole significantly depends on the functional state of the kidneys, and there is an inverse relationship between T1 / 2 and KK. After hemodialysis, within 3 hours, the concentration of fluconazole in the blood plasma is reduced by 50%. Pharmacokinetics of fluconazole is similar for intravenous administration and oral administration, which makes it easy to switch from one application to another.

Indications:

Systemic candidiasis in patients with or without neutropenia, including disseminated candidiasis (including chronic candidiasis) and other forms of progressive candidal infection, such as peritoneal, endocardial and intratracheal, urinary tract infections. Fluconazole can be used in patients with malignant neoplasms, patients with diseases,predisposing to the development of candidal infection, receiving cytotoxic drugs, immunosuppressants, while in the intensive care unit.
Candidiasis of the mucous membranes: oropharyngeal, esophageal; non-invasive lung infections, candiduria, superficial and chronic atrophic candidiasis of the oral cavity (including HIV-infected patients and patients with immunodeficiency).
- Cryptococcosis, including cryptococcal meningitis, sepsis, fungal infections of other organs (lungs, skin). Fluconazole can be used to treat and prevent cryptococcal infection in patients with AIDS and other forms of immunodeficiency.
Fluconazole can be used for prophylaxis of candidiasis in patients before myelotransplantation and in patients with malignant neoplasms, predisposed to such infections as a result of cytostatic or radiotherapy.

Contraindications:

Hypersensitivity to fluconazole, azole compounds and other ingredients included in the preparation; congenital or identified prolongation of the QT interval on an electrocardiogram, simultaneous administration of drugs,prolonging interval QT (including antiarrhythmics of IA and III classes), pregnancy, the period of breastfeeding, the simultaneous use of fluconazole with cisapride, terfenadine (against the background of continuous administration of fluconazole at a dose of 400 mg / day and more), astemizole, pimozide and quinidine.

Carefully:alcoholism, achlorhydria and hypochlorhydria, children under 6 months of age (safety and efficacy not established), hepatic insufficiency, the appearance of rash on the background of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, simultaneous use of terfenadine and fluconazole in a dose less than 400 mg / day, potentially proaritmogenic states in patients with multiple risk factors (organic heart disease, electrolyte balance disorders, at the same time Noe use of drugs that cause arrhythmias).

Pregnancy and lactation:

In pregnancy, the use of Diflazon is not recommended. Possible use of fluconazole in life-threatening infections, when the potential benefit to the mother exceeds the possible risk to the fetus.If you need to use the drug Diflazon® during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Intravenously drip.

If it is not possible to use the drug Diflazon ® inside, it is recommended to use it as a solution for infusions. The rate of intravenous administration should not exceed 1200 mg / h (20 mg / min.). As soon as it becomes possible to administer the drug inward, the patient must be transferred to therapy with Diflazon® in an oral dosage form. The daily dose should not be changed. In some cases, a double daily dose is possible on the first day of therapy.

Adults:

Disease	Dosage 1 vial (100 ml) = 200 mg
Candidiasis of mucous membranes (with the exception of genital candidiasis)	50 - 100 mg once a day
Severe candidiasis of mucous membranes	100 - 200 mg once a day
Systemic candidiasis	400 mg on the first day, then on 200 - 400 mg once a day
Severe systemic candidiasis	up to 800 mg once a day
Prophylaxis of candidiasis	50 - 400 mg once a day
Cryptococcal meningitis	400 mg on the first day, then 200 - 400 mg once a day
Prevention of cryptococcal meningitis	200 mg once a day

Duration of treatment

The duration of therapy for systemic candidiasis depends on the clinical effect.Treatment should last at least 2 weeks after receiving negative blood cultures or the disappearance of clinical manifestations of the disease. Candidiasis of the mucous membranes. At the first episode of the disease, the treatment is continued for 7-14 days; 3 weeks in patients with immunodeficiency. In severe cases, 30 days of therapy is needed. Cryptococcal meningitis in AIDS patients should be treated within 6-8 weeks. For the prevention of candidiasis before myelotransplantation and / or before treatment with cytostatics or radiotherapy in patients with malignant neoplasm, Diflazon® should be administered within a few days before the expected development of neutropenia and continue treatment at least 7 more days after the neutrophil count exceeds 1000 / mm3. Children: In patients with normal renal function with creep okokkoze including cryptococcal meningitis, septicemia, fungal infections of other organs (lung, skin) administered 6-12 mg / kg body weight per day to laboratory confirm the absence of pathogens in cerebrospinal fluid. For the prevention of fungal infection and for the treatment of superficial mycoses, a dose of 3-6 mg / kg per day is used.Depending on the response to therapy, the daily dose can be increased to 12 mg / kg per day for at least 3 weeks. Children with esophageal candidiasis are prescribed 3 mg / kg / day once for at least 3 weeks and within 2 weeks after regression of symptoms; with candidiasis of the mucous membranes - 3 mg / kg / day once for at least 3 weeks. For children from 5 to 13 years, the maximum daily dose is 400 mg fluconazole. The dose for newborns under 2 weeks should be the same as in children of the elder age, but every 72 hours, and for infants at the age of 2-4 weeks - the same dose every 48 hours. In case of impaired renal function, Diflazon ® is used according to the following scheme:

Creatinine clearance	Interval / daily dose
more than 40 ml / min 21-40 ml / min 10-20 ml / min	24 hours (regular dosing regimen) 48 hours or 1/2 of the usual daily dose of 72 hours or 1/3 of the usual daily dose

Children with kidney failure need dose adjustment in accordance with the recommendations for adults.

After each hemodialysis session, once again, 50 mg is required (some authors recommend 100-200 mg). In patients on peritoneal dialysis (long-term outpatient dialysis), 150 mg of fluconazole is recommended per 2 liters of dialysate at intervals of 2 days.

In elderly patients in the absence of violations of kidney function should follow the usual dosage regimen.

It should be used with caution fluconazole patients with impaired liver function (see "Special instructions").

Side effects:

Classification of the incidence of adverse events (WHO): very often> 1/10, often> 1/100 to <1/10, infrequently from> 1/1000 to <1/100, rarely> 1/10000 to <1 / 1000, very rarely from <1/10000, including individual messages.

From the digestive system:

often: flatulence, nausea, vomiting, abdominal pain, diarrhea, increased activity of "liver" enzymes, decreased appetite, constipation;

infrequently: violations of the liver (jaundice, hyperbilirubinemia, increased activity of alkaline phosphatase, hepatitis, hepatocellular necrosis), incl. with lethal outcome;

From the nervous system:

often: feeling tired, headache, dizziness; infrequently: convulsions;

From the skin: often: skin rash; infrequently: alopecia;

rarely: face swelling, urticaria, skin itching, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome);

From the immune system:

rarely: anaphylaxis and angioedema;

From the hematopoiesis:

rarely: leukopenia, thrombocytopenia, neutropenia, agranulocytosis;

From the cardiovascular system:

infrequent: prolongation of the QT interval, arrhythmia of the "pirouette" type;

Other:

rarely: renal dysfunction, hypercholesterolemia, hypokalemia, hypertriglyceridemia.

Overdose:

The most frequent symptoms of overdose are nausea, vomiting, diarrhea and in more severe cases - convulsions, hallucinations.

Treatment: symptomatic. As fluconazole is excreted mainly by the kidneys, forced diuresis accelerates its excretion. Conduction of a three-hour hemodialysis reduces the concentration of fluconazole in the blood plasma by half.

Interaction:

The simultaneous use of terfenadine, cisapride, astemizole, pimozide and quinidine causes an increase in the concentration of these drugs in the blood plasma, which may lead to prolongation of the QT interval and heart rhythm disturbances ("torsade de pointes", pirouette-type arrhythmia) simultaneous use of these drugs is contraindicated.

In patients taking both warfarin, prolonged prothrombin time.

Fluconazole prolongs T 1/2 hypoglycemic agents for oral administration and sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide and tolbutamide). These drugs can be used in combination with fluconazole, but you should consider the likelihood of developing hypoglycemia.

It should be noted that with the simultaneous use of hydrochlorothiazide and fluconazole, the concentration of the latter in the blood plasma may increase.

Rifampicin accelerates the metabolism of fluconazole, therefore, it is necessary to carefully increase the dose of fluconazole with simultaneous application with rifampicin.

In patients after kidney transplantation fluconazole can increase the concentration of cyclosporine in the blood plasma, therefore, it should be monitored.

Fluconazole increases the concentration of theophylline, the concentration of the latter should be monitored.

Fluconazole may increase the concentration of indinavir or midazolam, which may increase the risk of developing psychomotor effects (more pronounced with fluconazole administered intravenously than IV), therefore, an adequate dose reduction of these drugs is necessary.

The simultaneous use of fluconazole and zidovudine may lead to an increase in the concentration of zidovudine in blood plasma, whose AUC is increased. Fluconazole in a dose of 50-200 mg does not significantly affect the effectiveness of oral combined contraceptives.

There are reports of drug interactions with fluconazole in combination with rifabutin, which leads to an increase in the concentration of the latter in blood plasma. Patients receiving concomitantly rifabutin and fluconazole, should be under the supervision of a doctor.

The simultaneous use of fluconazole and phenytoin can clinically significantly increase the concentration of phenytoin. If both drugs are necessary, the concentration should be monitored and the dose of phenytoin adjusted to the therapeutic concentration.

There are reports of drug interactions with fluconazole and tacrolimus, which leads to an increase in tacrolimus concentration in the blood plasma. There are reports of nephrotoxicity in patients receiving concomitantly tacrolimus and fluconazole. Patients simultaneously using tacrolimus and fluconazole, should be under the supervision of a doctor.

Special instructions:

Diflazon ® should be used with caution in patients with impaired renal function. The dose of Diflazon® should be adjusted in accordance with the creatinine clearance.

Caution is advised to use Diflazone® in patients with impaired hepatic function. During the therapy with fluconazole, the activity of the liver enzymes should be regularly monitored and the patient's condition monitored (the likelihood of developing toxic effects). When the activity of "liver" enzymes is increased, the positive effect of continuing therapy should exceed the risk of toxic effects on the liver. The hepatotoxic effect of fluconazole is usually reversible, the symptoms disappear after discontinuation of therapy.

When a rash occurs in a patient receiving therapy for a superficial fungal infection, against the backdrop of the use of Diflazon®, further therapy with this drug should be discontinued.

The drug Diflazon®, when administered at a dose of 400 mg per day daily, can significantly increase the concentration of terfenadine in blood plasma with simultaneous application. In patients who simultaneously use fluconazole and terfenadine, spontaneous cases of palpitation, tachycardia, dizziness and chest pain were noted, and the connection between the observed side effects against the background of simultaneous application of these drugs was not obvious. In view of the potential danger of such drug interaction, simultaneous use of terfenadine and fluconazole is not recommended.

It is necessary to control the prothrombin index while using the coumarinic anticoagulants simultaneously.

There is limited experience with fluconazole in children less than 6 months of age, so Diflazon ® should only be taken if necessary.

Treatment with Diflazon® should be continued until the onset of clinicohematological remission. Premature termination of treatment leads to relapse.

Special Information

100 ml of the infusion solution (1 bottle) contains 353.8 mg (15.38 mmol) of sodium. 1 ml of the solution for infusions contains 3.538 mg (0.1538) of sodium, which should be taken into account for patients who are on a diet with a controlled sodium content.

Effect on the ability to drive transp. cf. and fur:

in connection with the risk of side effects, care must be taken when driving vehicles and working with other technical devices that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Solution for infusion, 2 mg / ml.

Packaging:

For 100 ml of the drug is placed in a bottle of colorless glass (type I, Ph.Eur.) With a rubber stopper, crimped with an aluminum cap and a colored plastic protective cap. An internal production code of the preparation is applied to the aluminum cap. 1 bottle is placed in a pack of cardboard along with instructions for use.

Storage conditions:

At temperatures not higher than 30 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use the drug after the expiration date

Terms of leave from pharmacies:For hospitals

Registration number:П N013210 / 01

Date of registration:02.08.2007

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, dd, Novo mesto, AO Slovenia

Information update date: & nbsp19.10.2015

Illustrated instructions

Instructions

Diflazon® (Diflazon® )