Expiration date: 09/2025

Structure and Composition: 

The capsules. 1 capsule contains Fluconazole 50, 100 or 150 mg

Excipients: lactose, corn starch, colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate

Capsule shell: titanium dioxide (E171), patent blue dye gelatin (E131 capsule 50 and 150 mg)

ink for marking of capsules: shellac glaze black iron oxide (E172), N-butyl alcohol, industrial methylated spirit 74 OP soy lecithin antifoam component DC 1510

in blister 7 pcs. In the paper cartons 1 or 4 blisters (dose capsules and 100 mg of 50) or in one piece blister. In the paper cartons 1 blister (for the 150 mg dose capsules)

Solution for intravenous administration. 1 ml contains Fluconazole 2 mg

Excipients: sodium chloride, water for injection

in bottles of 25, 50, 100 or 200 ml per 1 vial paper cartons.

Powder for suspension for oral (A suspension). 1 ml contains Fluconazole 10 or 40 mg

Excipients: anhydrous citric acid, sodium benzoate, xanthan gum, titanium dioxide (E 171), sucrose, colloidal anhydrous silica, sodium citrate dihydrate, orange flavoring (containing orange essential oil, maltodextrin and water)

Patients in plastic, complete with a dosing spoon in a stack of cardboard 1 bottle.

Description pharmaceutical form:

Capsules 50 mg: hard gelatine, number 4, with a turquoise cap and white body, with marks in the form of the logo «Pfizer» and «FLU-50" in black.

100 mg capsules: Hard gelatin, ? 2, with white and the housing cover, labeled as «Pfizer» logo and «FLU-100" black.

Capsules 150 mg: hard gelatine, number 1, with a turquoise cap and body, with marks in the form of «Pfizer» logo and «FLU-150" black.

Capsule contents: powder, white to pale yellow color.

A solution for intravenous administration: clear colorless solution.

Powder for suspension for oral administration: white or almost white powder, containing no visible contamination.

Characteristic:

Fluconazole, a triazole antifungal agent.

Pharmacokinetics:

It has a similar pharmacokinetic parameters in / in the introduction and ingestion. After oral administration, fluconazole is well absorbed, its level in plasma (total and bioavailability) over 90% of plasma levels of fluconazole at / in the introduction. Simultaneous food intake does not affect absorption of the drug when taken orally. Cmax plasma achieved through 0.5-1.5 h after administration of fluconazole fasting, and T1 / 2 is about 30 hours. The plasma concentration is proportional to dose. 90% CSS achieved a 4-5-th day drug treatment (when taking 1 per day).

Administering a loading dose (at day 1) at twice the normal daily dose, it makes it possible to achieve equilibrium concentration of 90% to the 2nd day. Vd is close to the total water content in the body. Protein binding - low (11-12%).

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

The stratum corneum, the epidermis-dermis and liquid sweat to achieve high concentrations which exceed the serum. Fluconazole is accumulated in the stratum corneum. When you receive a dose of 50 mg 1 time per day the concentration of fluconazole after 12 days was 73 mg / g and 7 days after cessation of treatment - only 5.8 g / g. When applied in a dose of 150 mg 1 time per week fluconazole concentration in the stratum corneum on the 7th day of 23.4 g / g, and 7 days after the second dose - 7.1 g / g.

Concentration of fluconazole in nails after 4 months of use in a dose of 150 mg 1 time per week was 4.05 g / g - in healthy and 1.8 ug / g - in the affected nails in 6 months after completion of therapy, fluconazole was still determined nails.

The drug is derived mainly kidneys approximately 80% of the dose found in the urine in unchanged form. Fluconazole clearance is proportional to creatinine clearance. Circulating metabolites were detected.

The long plasma half-life allows once to take fluconazole for vaginal candidiasis and 1 time per day or 1 time per week - in other indications.

By comparing the concentrations in saliva and plasma after a single dose of 100 mg fluconazole in the form of capsules and suspensions (rinsing, storing, in the mouth for 2 minutes and swallowing) found that Cmax fluconazole in saliva when taking a suspension was observed at 5 min after administration and at 182 times higher than that after taking the capsule (reached after 4 hours). After about 4 hours of fluconazole concentrations in saliva were similar. AUC (0-96) in the saliva was significantly higher when taking suspension than capsules. The rate of excretion of significant differences from saliva or plasma pharmacokinetic parameters were found when using the two formulations.

Pharmacokinetics in children

In children, the following pharmacokinetic parameters were obtained:

Age	Dose, mg/kg	T1/2, h	AUC, mcg·h/ml
11 days — 11 months	Once, intravenously, 3 mg/kg	23	110,1
9 months — 13 years	Once, intravenously, 2 mg/kg	25	94,7
9 months — 13 years	Once, intravenously, 8 mg/kg	19,5	362,5
5–15 years	Repeatedly, intravenously, 2 mg/kg	17,4*	67,4*
5–15 years	Repeatedly, intravenously, 4 mg/kg	15,2*	139,1*
5–15 years	Repeatedly, intravenously, 8 mg/kg	17,6*	196,7*
The average age of 7 years	Repeatedly, inside - 3 mg/kg	15,5	41,6

* The indicator marked on the last day

Premature babies (about 28 weeks of development) of fluconazole administered in / in a dose of 6 mg / kg every third day, before the introduction of a maximum of 5 days at a time, while the children remained in the intensive care unit. The average T1 / 2 was 74 hr (44-185 hr) Day 1, with a reduction on the 7th day - to an average of 53 hours (30-131 hours), and on the 13th day - an average of 47 hours (27-68 h).

AUC values ??were 271 pg * hr / ml (173-385 mg · hr / mL) in 1-day, then increased to 490 mcg / ml · h (292-734 mcg · hr / ml) at day 7 and fell to an average of 360 mcg · h / mL (167-566 mcg · h / mL) in 13-y day.

Vd was 1,183 ml / kg (1070-1470 ml / kg) at day 1, and then increased to an average of 1,184 ml / kg (510-2130 ml / kg) on ??day 7 and up to 1,328 ml / kg (1,040 -1680 ml / kg) - on the 13th day.

Pharmacokinetics in elderly patients

With a single application of fluconazole at a dose of 50 mg orally elderly patients aged 65 years and older, some of them at the same time taking diuretics, it is found that the Cmax in plasma achieved through 1.3 hours after administration and was 1.54 mcg / mL, mean values AUC - (76,4 ± 20,3) pg · h / mL, and the average T1 / 2 - 46.2 hours values ??of these pharmacokinetic parameters above, than in younger patients.. Simultaneous administration of diuretics did not cause pronounced changes in AUC and Cmax. Creatinine Cl (74 mL / min), the percentage of drug in the urine output in unchanged form (0-24 h, 22%) and fluconazole renal clearance (0.124 ml / min / kg) lower than in the elderly relative to young. Higher values ??of pharmacokinetic parameters in elderly patients receiving fluconazole is likely to be associated with reduced renal function characteristic of the elderly.

Description of the pharmacological actions:

It is a potent selective inhibitor of sterol synthesis in the fungal cell.

When administered intravenously and fluconazole exhibited activity in various models of fungal infections in animals. It demonstrates active medication for opportunistic fungal infections, including caused by Candida spp., including generalized candidiasis in immunocompromised animals Cryptococcus neoformans, including intracranial infection Microsporum spp. and Trychoptyton spp. Activity has also been established in models of fluconazole endemic mycosis in animals, including infections caused by Blastomyces dermatitides, Coccidioides immitis, including intracranial infection, Histoplasma capsulatum and in animals with normal and immunosuppressed.

There have been reports of superinfection caused by different strains of Candida albicans Candida, who often have a natural resistance to fluconazole (eg Candida krusei). In such cases, it may require alternative antifungal therapy.

Fluconazole has a high specificity for fungal enzymes, cytochrome P450-dependent. Therapy fluconazole at 50 mg / day for up to 28 days did not affect the plasma concentration of testosterone in males or the concentration of steroid in women of childbearing age. Fluconazole at a dose of 200-400 mg / day has no clinically significant effect on endogenous steroid levels and their response to ACTH stimulation in healthy male volunteers. Single or multiple administration of fluconazole 50 mg do not affect the metabolism of antipyrine in their simultaneous reception.

Indications:

• cryptococcosis, including cryptococcal meningitis and infections of other sites (eg pulmonary, skin), including: in patients with a normal immune response, and patients with AIDS, organ transplant recipients and patients with other forms of immunodeficiency maintenance therapy to prevent recurrences of cryptococcosis in patients with AIDS
  
• generalized candidiasis including candidemia, disseminated candidiasis and other forms of invasive Candida infections, such as infections of the peritoneum, endocardium, eyes, respiratory and urinary tract, including in patients with malignancy, in intensive care units and receiving cytotoxic or immunosuppressive agents, as well as in patients with other factors predisposing to the development of candidiasis
  
• candidiasis of the mucous membranes, including mucous membranes of the oral cavity and pharynx, esophagus, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic atrophic oral candidiasis (associated with wearing dentures), including: in patients with normal and suppressed immune function of prevention of relapse of oropharyngeal candidiasis in patients with AIDS
  
• Genital candidiasis acute or recurrent vaginal candidiasis prophylaxis to reduce the frequency of relapses of vaginal candidiasis (3 or more episodes per year), candidal balanitis
  
• prevention of fungal infections in patients with malignancy who are predisposed to such infections as a result of cytotoxic chemotherapy or radiation therapy
  
• fungal infections of the skin, including tinea pedis, body, groin, pityriasis versicolor, onychomycosis and skin candida infection
  
• deep endemic mycoses in patients with normal immunity, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis.
  

Contraindications:

• Hypersensitivity to fluconazole, other azole drug components or substances with a similar structure with fluconazole
  
• concomitant use of terfenadine during repeated use of fluconazole 400 mg / day or more (see. "Interaction" section)
  
• concurrent use of cisapride (see. "Interaction" section).
  

Carefully

• violation of liver function during treatment with fluconazole
  
• rash during treatment with fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections
  
• simultaneous administration of terfenadine and fluconazole less than 400 mg / day
  
• potentially pro-arrhythmic condition in patients with multiple risk factors (organic heart disease, electrolyte imbalance and promote the development of such violations concomitant therapy).
  

Application of pregnancy and breastfeeding:

There are no adequate and well-controlled studies in pregnant women have been conducted. There are cases of multiple congenital defects in newborns whose mothers for 3 months or more receiving fluconazole therapy with high dose (400-800 mg / day) over coccidioidomycosis. The relationship between these disorders and intake of fluconazole has not been established.

During pregnancy, the use of fluconazole should be avoided, except in cases of severe and potentially life-threatening fungal infections, the treatment when the expected benefits outweigh the potential risk to the fetus. Therefore, women of childbearing age must use contraception.

Fluconazole is found in breast milk in concentrations similar to plasma, so his appointment to women during lactation is not recommended.

Side effect:

Tolerability is usually very good.

The most commonly in clinical and post-marketing (*) Diflucan studies noted the following adverse reactions:

On the part of the central and peripheral nervous system: headache, dizziness *, * convulsions, * changes in taste.

On the part of the digestive tract: abdominal pain, diarrhea, flatulence, nausea, dyspepsia *, vomiting *.

Liver: hepatotoxicity, including rare cases with fatal outcome, increased levels of alkaline phosphatase, bilirubin, serum levels of ALT and AST, abnormal liver function *, * hepatitis, hepatocellular necrosis *, jaundice *.

Skin and subcutaneous tissue disorders: rash, alopecia *, exfoliative skin disorders *, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

From the hematopoietic system and lymphatic system *: leucopenia, including neutropenia and agranulocytosis, thrombocytopenia.

On the part of the immune system *: Anaphylaxis (including angioedema, face edema, urticaria, pruritus).

From the CCC *: increase in the QT interval on an electrocardiogram, flickering / ventricular fibrillation (see "Special Instructions" section.).

Metabolic / trophic disorders *: increased cholesterol and triglyceride levels in plasma, hypokalemia.

In some patients, particularly those suffering from serious illnesses, such as AIDS or cancer, the treatment Diflyukanom and similar drugs have been observed changes in blood counts, renal and hepatic function (see. Section "Special Instructions"), but the clinical significance of these changes and their relation with treatment installed.

Drug Interactions:

Anticoagulants. As with other anti-fungal agents - azole derivatives, fluconazole, while the use of warfarin, increases PV (12%), and therefore the development of possibly bleeding (hematoma, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, you need to constantly monitor the PV.

Azithromycin. When applied simultaneously inside fluconazole in a single dose of 800 mg of azithromycin in a single dose of 1200 mg expressed pharmacokinetic interaction between the two drugs is not established.

Benzodiazepines (short acting). After oral administration of midazolam, fluconazole significantly increases the concentration of midazolam and psychomotor effects and this effect is more pronounced after receiving fluconazole inside than when used intravenously. If necessary, concomitant therapy with benzodiazepines in patients taking fluconazole should be monitored with a view to a corresponding reduction in the dose of benzodiazepine.

Cisapride. With simultaneous use of fluconazole and cisapride may be adverse reactions of the heart, including flicker / ventricular fibrillation (torsade de pointes). Fluconazole 200 mg 1 time per day and cisapride 20 mg four times a day results in significant increase in plasma concentrations of cisapride and increase QT interval on the electrocardiogram. Simultaneous administration of cisapride and fluconazole is contraindicated.

Cyclosporin. In patients with kidney transplant fluconazole 200 mg / day results in a slow increase of the concentration of cyclosporine. However, when multiple dose Fluconazole, 100 mg / day of cyclosporine concentration changes in bone marrow transplant recipients was observed. With simultaneous use of fluconazole and cyclosporine is recommended to monitor the concentration of cyclosporine in the blood.

Hydrochlorothiazide. Repeated application concurrently with hydrochlorothiazide fluconazole Fluconazole increases the plasma concentration of 40%. The effect of this severity does not require changes in the fluconazole dose regimen in patients receiving concomitant diuretics, but a doctor should take this into account.

Oral contraceptives. With simultaneous use of combined oral contraceptive with fluconazole at 50 mg significant effect on hormone level is not set, whereas a daily intake of 200 mg fluconazole AUC ethinyl estradiol and levonorgestrel are increased by 40 and 24%, respectively, and upon receipt of 300mg fluconazole once a week - ethinyl estradiol and norethindrone AUC increased by 24 and 13%, respectively. Thus, the repeated use of fluconazole at these doses is unlikely to have an impact on the effectiveness of combined oral contraceptives.

Phenytoin. Concomitant use of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. If necessary, the simultaneous use of both drugs phenytoin concentrations should be monitored and to adjust the dose to provide a therapeutic concentration in serum.

Rifabutin. Concomitant use of fluconazole and rifabutin may increase serum concentrations of the latter. With simultaneous use of fluconazole and rifabutin uveitis cases are described. Patients simultaneously receiving rifabutin and fluconazole should be carefully observed.

Rifampicin. Simultaneous administration of fluconazole and rifampicin causes AUC decrease by 25% and the duration of T1 / 2 of 20% fluconazole. Patients taking concomitant rifampin, should take into account the feasibility of increasing the dose of fluconazole.

Sulfonylureas. Fluconazole, while reception results in increased T1 / 2 oral sulfonylureas (chlorpropamide, glibenclamide, tolbutamide and glipizide). Patients with diabetes can be assigned to the combined use of fluconazole and oral sulfonylureas, but it should take into account the possibility of hypoglycemia.

Tacrolimus. Concomitant use of fluconazole and tacrolimus increases the serum concentrations of the latter. Cases of nephrotoxicity. Patients simultaneously receiving tacrolimus and fluconazole should be carefully monitored.

Terfenadine. With simultaneous use of azole antifungals and terfenadine may cause serious arrhythmias by increasing the QT interval. When receiving Fluconazole, 200 mg / day increasing QT interval is not set, but the use of fluconazole in doses of 400 mg / day and above causes a significant increase in the plasma concentration of terfenadine. Simultaneous administration of fluconazole at doses of 400 mg / day or more with terfenadine is contraindicated (see. "Contraindications"). Treatment of fluconazole at doses less than 400 mg / day in combination with terfenadine should be carefully monitored.

Theophylline. While the use of fluconazole 200 mg for 14 days, the mean plasma clearance rate of theophylline is decreased by 18%. In the appointment of fluconazole patients receiving high doses of theophylline or patients with an increased risk of toxic action of theophylline should be monitored for the appearance of symptoms of theophylline overdose and adjust therapy accordingly, if necessary.

Zidovudine. In an application with fluconazole observed increasing concentrations of AZT, which is probably due to a decrease in metabolism of the latter to its main metabolite. Before and after treatment with Fluconazole, 200 mg / day for 15 days in patients with AIDS and ARC (complex, AIDS related), a significant increase in AUC set zidovudine (20%).

When applied in HIV-infected patients, zidovudine 200 mg every 8 hours for 7 days in combination with Fluconazole, 400 mg / day with or without an interval of 21 days between the two schemes set significant increase in AUC of zidovudine (74%) with the simultaneous use of fluconazole. Patients receiving this combination should be monitored in order to identify the side effects of zidovudine.

Concomitant use of fluconazole with astemizole or other drugs, the metabolism of which the cytochrome P450 system may be associated with an increase in serum concentrations of these agents. When concomitant administration of fluconazole, in the absence of reliable information, care must be taken. Patients should be carefully monitored.

Studies of interaction of oral formulations of fluconazole during its simultaneous administration with food, cimetidine, antacids, and after total body irradiation in preparation for bone marrow transplantation has shown that these factors do not have a clinically meaningful effect on the absorption of fluconazole.

These interactions are installed with repeated application of fluconazole interaction with drugs as a result of a single dose of fluconazole is not known.

Physicians should take into account the interaction with other drugs not specifically been studied, but it is possible.

Dosage and administration:

Capsules: inside, swallowing whole.

Solution for intravenous administration: in / in, as an infusion (not faster than 10 ml / min).

Suspension: inside.

Therapy can be started until culture results and other laboratory tests. However, anti-infectious therapy should be amended accordingly when the results of these studies will be known.

Fluconazole can be taken orally or administered intravenously by infusion at a rate of no more than 10 ml / min. Selecting the mode of administration depends on the clinical condition of the patient. When transferring the patient in / on oral medication or vice versa changes the daily dose is required. The solution for the on / in the fluconazole dissolved in 0.9% sodium chloride solution every 200 mg (100 ml vial) contained 15 mM Na + and Cl-. Therefore, patients who require limiting sodium intake or liquid, it is necessary to take into account the rate of fluid administration.

Diflucan daily dose depends on the nature and severity of the fungal infection. Vaginal candidiasis in most cases, effective single dose of the drug. For infections requiring repeated administration of the antifungal drug treatment should be continued until the disappearance of the clinical or laboratory signs of active fungal infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis for the prevention of recurrence of infection is usually necessary supportive therapy.

Use in Adults

1. For cryptococcal meningitis and cryptococcal infections at other sites in the 1 st day usually administered 400 mg, and then continue treatment at a dose of 200-400 mg 1 time per day. The duration of treatment of cryptococcal infections depends on the presence of clinical and mycological effect in cryptococcal meningitis treatment is usually continued for at least 6-8 weeks.

For the prevention of relapse of cryptococcal meninigita in patients with AIDS, after the completion of a full course of primary therapy, Diflyukanom therapy at a dose of 200 mg / day can be continued for a very long time.

2. When candidemia, disseminated candidiasis and other invasive Candida infections, the dose usually is 400 mg on day 1, followed by 200 mg / day. Depending on the clinical response, the dose may be increased to 400 mg / day. The duration of therapy depends on clinical efficacy.

3. For oropharyngeal candidiasis drug is usually administered 50-100 mg 1 time a day for 7-14 days. If necessary, patients with severe suppression of the immune function, treatment can continue for a longer time. In atrophic oral candidiasis associated with wearing dentures, the drug is usually administered in a dose of 50 mg 1 time per day for 14 days in combination with local antiseptic agents for treatment of prosthesis.

In other Candida infections of the mucous membranes (except genital candidiasis cm. Below), such as esophagitis, noninvasive bronchopulmonary infections candiduria candidiasis of the skin and mucous membranes, etc., the effective dose is usually 50-100 mg / day with treatment duration of 14-30 days.

For the prevention of relapse of oropharyngeal candidiasis in AIDS patients after completion of primary treatment of the full course of Diflucan can be assigned to 150 mg 1 time per week.

4. Vaginal candidiasis Diflucan appoint a single oral dose of 150 mg.

To reduce the frequency of relapses vaginal candidiasis drug can be used in a dose of 150 mg 1 time per month. The duration of therapy is determined individually, it varies from 4 to 12 months. Some patients may require more frequent use of the drug. The use of a single dose for children under 18 years and in patients older than 60 years old without a doctor's prescription is not recommended.

When balanitis caused of Candida, Diflucan is prescribed a single dose of 150 mg orally.

5. For the prevention of candidiasis Diflucan recommended dose is 50-400 mg 1 time per day, depending on the degree of risk of fungal infection. For patients with a high risk of generalized infection, such as severe or long-lasting neutropenia, the recommended dose is 400 mg 1 time per day. Diflucan is prescribed for a few days before the expected development of neutropenia and after the increase in the number of neutrophils over 1000 mm3, treatment was continued for 7 days.

6. In case of skin infections including tinea pedis, smooth skin, groin and candida infections the recommended dose is 150 mg 1 time per week or 50 mg 1 time per day. Duration of therapy is usually 2-4 weeks, but with athlete's foot may require a more prolonged treatment (up to 6 weeks).

In pityriasis versicolor the recommended dose is 300 mg 1 time per week for 2 weeks, some patients required a third dose of 300 mg / week, while for individual patients is enough single dose of 300-400 mg. An alternative regimen is the use of the drug at 50 mg 1 time a day for 2-4 weeks.

When tinea unguium (onychomycosis), the recommended dose is 150 mg 1 time per week. Treatment should be continued until the replacement of the infected nail (uninfected nail sprouting). For the re-growth of nails on the fingers of hands and feet usually require 3-6 and 6-12 months, respectively. However, the growth rate can vary widely from person to person and also depends on the age. After successful treatment of long-lasting chronic infections sometimes changing the form of nails observed.

7. In deep endemic mycoses may require use of the drug at a dose of 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 - with paracoccidioidomycosis 1-16 months - with sporotrichosis and 3-17 months - with histoplasmosis.

Use in children

As with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. For children, the daily dose should not exceed that for adults. Diflucan is used every day, 1 time per day.

When mucosal candidiasis recommended dose of Diflucan is 3 mg / kg / day. On the first day in order to more quickly achieve permanent CSS can be administered a loading dose of 6 mg / kg.

For the treatment of generalized candidiasis and cryptococcal infection recommended dose is 6-12 mg / kg / day, depending on the severity of the disease.

For the prevention of fungal infections in patients with immunocompromised, in whom the risk of infection associated with neutropenia, developing as a result of cytotoxic chemotherapy or radiation therapy, the drug is prescribed for 3-12 mg / kg / day, depending on the severity and duration of preservation-induced neutropenia ( see dosage for adults for children with kidney failure -. see dosage for patients with renal insufficiency)..

The use in children less than 4 weeks and

In infants Fluconazole is displayed slowly. In the first two weeks of life drug administered in the same dose (in mg / kg) as the older children, but with a 72 hour interval. Children aged 3 weeks and 4 are administered the same dose every 48 hr.

Use in the elderly

In the absence of signs of renal failure drug administered in the usual dose. Patients with renal insufficiency (Cl creatinine <50 ml / min), the drug dose is adjusted as described below.

Use in patients with renal insufficiency

Fluconazole is excreted mainly with urine in unchanged form. In single dose dose modification is required. In patients (including children) with impaired renal function after repeated use of the drug should initially enter a loading dose of 50 to 400 mg, followed by a daily dose (according to indication) is set as follows:

Creatinine clearance ml / min	The percentage of the recommended dose
>50	100%
<50 (without dialysis)	50%