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

Active substanceMikafunginMikafungin

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Mikamin®

lyophilizate d / infusion

Astellas Farma Europe BV Netherlands

Mikafungin-native

lyophilizate d / infusion

NATIVA, LLC Russia

Dosage form: & nbsplyophilizate for solution for infusion

Composition:

Composition per one bottle:

Active substance: mikafungin (in the form of sodium mikafungina) 50 mg or 100 mg. Excipients: lactose monohydrate 200 mg; citric acid anhydrous q.s. to a pH of 5.0 to 7.0; sodium hydroxide q.s. to a pH of 5.0 to 7.0.

Description:

Lyophilized mass of white color.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A.X.05 Mikafungin

Pharmacodynamics:

Mechanism of action

Mikafungin uncompetently inhibits the synthesis of 1,3-β-D-glucan, an important component of the cell wall of fungi. 1,3-β-D-glucan is absent in mammalian cells. Mikafungin has fungicidal activity against fungi of the genus Candida spp.i significantly inhibits the active growth of hyphae Aspergillus spp.

Activity spectrum

Mikafungin in vitro is active in different types of Candida spp, in t.ch. Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, Candida kefyr, Candida parapsilosis, Candida guilliermondii, Candida lusitaniae, in relation to species sensitive to mikafungin of genus Aspergillus spp.: Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Aspergillus nidulans, Aspergillus versicolor, a also dimorphic fungi (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis). A drug in vitro not active against Cryptococcus spp., Pseudallescheria spp., Scedosporium spp., Fusarium spp., Trichosporon spp. and Zygomycetes spp. The likelihood of developing a secondary drug resistance is very low.

Kind of fungus of genus Candida	Minimum inhibitory concentration, mg / l (European data)
Candida albicans	[0,007 - 0,25]
Candida glabrata	[0,007-0,12]
Candida tropicalis	[0,007-0,12]
Candida krusei	[0,015-0,12]
Candida kefyr	[0,03-0,06]
Candida parapsilosis	[0,12-2]
Candida guilliermondii	[0,5]
Candida lusitaniae	[0,12-0,25]
Candida spp. (including C. famata,	[0,015-0,5]
FROM. dubliniensis, FROM. lipolytica, FROM. pelliculosa,
FROM. rugosa, FROM. stellatoidea and C.zeylanoides)

Pharmacokinetics:

The drug is administered intravenously. In the range of daily doses of 12.5-200 mg and 3-8 mg / kg mikafungin characterized by linear pharmacokinetics. There is no data on systemic cumulation of the drug upon repeated administration, the equilibrium concentration is established within 4-5 days from the moment of the beginning of application.

Distribution

After intravenous administration, the concentration of mikafungin is bi-exponentially reduced. Mikafungin quickly distributed in tissues. In the systemic circulation mikafungin actively binds to plasma proteins (> 99%), mainly with albumin. Binding with albumin remains stable in the concentration range of 10-100 μg / ml. The volume of distribution when an equilibrium concentration (Vss) is reached is 18-19 liters.

Metabolism

Mikafungin circulates in the systemic blood flow mainly unchanged. It was shown that mikafungin metabolized to form several compounds; of which M-1 (catechol form),M-2 (methoxy derivative of M-1) and M-5 (formed as a result of side chain hydroxylation) of mycaphungin derivatives are detected in small amounts in the systemic circulation. Metabolites have no significant effect on the effectiveness of mikafungin.

Although in vitro mikafungin can be metabolized by isoenzymes CYP3A, hydroxylation with isozymes CYP3A is not the main way of drug metabolism in vivo.

Elimination and excretion

The half-life of mikafungin (T₁/₂) is 10 to 17 hours, does not change in the dose range up to 8 mg / kg after a single and repeated administration of the drug. The total clearance in healthy volunteers and adult patients, both with single and repeated administrations, was 0.15-0.3 ml / min / kg and did not depend on the dose. 28 days after a single administration of 25 mg ¹⁴C-mikafungina to healthy volunteers, only 11.6% of the radioactive label was detected in urine, and 71.0% in feces, which indicates a predominantly non-spotted elimination of mycaphungin. Metabolites M-1 and M-2 were detected in plasma in trace concentrations, and the M-5 metabolite was 6.5% of the starting compound.

Pharmacokinetics in different patient groups

Children: In children, the area under the pharmacokinetic curve "concentration-time" (AUC) is proportional to the dose of the drug in the range of 0.5-4 mg / kg. Clearance depends on age: the average clearance in young children (2-11 years) is approximately 1.3 times higher than in older children (12-17 years) and adults. The average clearance in preterm infants (about 26 weeks) is approximately 5 times greater than in adults.

Elderly patients: With the infusion of 50 mg of mycaphungin for 1 h pharmacokinetic parameters in the elderly (66-78 years) did not differ significantly from those of the young (20-24 years).

Patients with impaired liver function: In a study involving 8 patients with impaired liver function of moderate severity (Child-Pugh index - 7-9), the pharmacokinetics of mikafungin slightly differed from pharmacokinetics in 8 healthy volunteers. In a study involving 8 patients with severe hepatic insufficiency (Child-Pugh index -10-12), a reduced concentration of plasma micsfungin and an elevated concentration in plasma of the metabolite hydroxide (M-5) were observed compared to the data obtained in 8 healthy volunteers .

Patients with renal dysfunction: Severe renal failure (glomerular filtration <30 mL / min) had no significant effect on pharmacokinetics of mikafungin.

Sex / race: Sex and race did not have a significant effect on the pharmacokinetic parameters of mycaphungin.

Indications:

1. Adults, incl. elderly and teenagers> 16 years old:

Treatment of invasive candidiasis;

Treatment of esophageal candidiasis in patients who require intravenous antifungal drugs;

Prophylaxis of candidiasis in patients after allogeneic transplantation of hematopoietic stem cells or patients in whom neutropenia is assumed (neutrophil count <500 / μl) for 10 days or more.

2. Children (including newborns) and adolescents <16 years of age:

Treatment of invasive candidiasis;

Prophylaxis of candidiasis in patients after allogeneic transplantation of hematopoietic stem cells or patients in whom neutropenia is assumed (neutrophil count <500 / μl) for 10 days or more.

Contraindications:

Hypersensitivity to the active substance, to other echinocandins or any of the auxiliary components or their intolerance (galactose intolerance, lactase deficiency, glucose-galactose malabsorption).

Carefully:

Severe liver dysfunction, chronic liver disease (liver fibrosis, liver cirrhosis, viral hepatitis, neonatal liver disease or congenital defects of enzymes), concomitant hepatotoxic and / or genotoxic therapy, childhood (especially up to 1 year), renal failure, simultaneous application with sirolimus, nifedipine, itraconazole and amphotericin B.

Pregnancy and lactation:

Clinical experience of the drug in pregnant women is not. In animal studies, the penetration of mikafungin through the placental barrier, as well as reproductive toxicity, was noted. Therefore, Mikamin® should be used during pregnancy, only after a thorough assessment of the risk / benefit ratio. It is not known whether the mikafungin in breast milk. The decision to continue / stop breastfeeding or continue / stop treatment with Mikamine® should be taken in consideration of the benefits of breastfeeding for the baby and the benefits of Mikamine® treatment for the mother.

In animal studies toxic effects on testicles were noted. Mikafungin can have a potential impact on the reproductive potential of men.

Dosing and Administration:

Mikamin® is for intravenous administration.

The dosage regimen of Mikamin® taking into account the indications, age and body weight of the patient is presented in Tables 1 and 2.

Table 1. Dosage regimen of Mikamin ® in adults, including. elderly and teenagers> 16 years:

Indication	Body weight> 40 kg	Body weight <40 kg
Treatment of invasive candidiasis	100 mg / day *	2 mg / kg / day *
Treatment of esophageal candidiasis	150 mg / day	3 mg / kg / day
Prophylaxis of candidiasis	50 mg / day	1 mg / kg / day

* In the absence of positive clinical dynamics or persistence of the causative agent, the dose may be increased to 200 mg / day for patients weighing> 40 kg or up to 4 mg / kg / day for patients weighing <40 kg.

Table 2. The dosage regimen of Mikamine® in children and adolescents <16 years:

Indication	Body weight> 40 kg	Body weight <40 kg
Treatment of invasive candidiasis	100 mg / day *	2 mg / kg / day *
Prophylaxis of candidiasis	50 mg / day	1 mg / kg / day

Treatment of invasive candidiasis by duration must be at least 14 days. Antifungal treatment should be continued for at least one week after receiving two consecutive negative blood test results and the disappearance of clinical signs of candidiasis.

For the treatment of esophageal candidiasis Mikamin® should be used for at least one week after the resolution of clinical signs.

For the prevention of candidiasis Mikamin® should be used for at least one week after restoring neutrophil concentrations. Experience in the preventive use of Mikamine® in children younger than 2 years is limited. The dosage regimen for certain categories of patients

With mild and moderate severity of violations of the liver, correction of the dosage regimen is not required. At present, there is insufficient data on the use of Mikamine® in patients with severe hepatic deficiency, so it is not recommended to use it in this category of patients. With renal failure, the dosing regimen does not change. Solution Mikamin ® for infusion is prepared at room temperature in accordance with the rules of asepsisin the following way:

1. The plastic cap must be removed from the bottle, and the stopper disinfected with alcohol.

2. 5 ml of 0.9% sodium chloride solution for infusion or 5% dextrose solution, taken from a 100 ml bottle / pack, should be slowly introduced into each vial of powder along the inner wall. When preparing the solution, minimize the amount of foam formed. It is necessary to use the number of vials of Mikamine® indicated in the table to obtain the dose of preparation necessary for infusion in mg (see below).

3. The bottle should be turned gently. DO NOT BURST. The powder must dissolve completely. Concentrate should be used immediately. The bottle is intended for single use. Dispose of unused solution.

4. The resulting concentrate is withdrawn from the vial and transferred to a vial / bag with the infusion solution from which it was originally taken (see clause 2). The prepared infusion solution should be used immediately. It remains stable for up to 96 hours at a temperature of 25 ° C under protection from light and preparation as described above.

5. The bottle / package for infusions should be carefully turned over, but NOT shaken to avoid foam formation. Do not use the solution if it is cloudy or contains sediment.

6. The vial / bag containing the prepared infusion solution should be placed in a closing opaque bag to protect it from light.

Table 3. Preparation of a solution for infusions

Dose (mg)	Vial of Mikamin® preparation, intended for use	Quantity of 0.9% sodium chloride solution or 5% dextrose solution added to vials	Scope reconstituted solution and concentration of active substance	The concentration of the finished solution (when using 100 ml of solvent)
50	1x50	5ml	about 5 ml (10 mg / ml)	0.5 mg / ml
100	1x100	5 ml	about 5 ml (20 mg / ml)	1.0 mg / ml
150	1 x 100 + 1 x 50	5 ml	approximately 10 ml	1.5 mg / ml
200	2x100	5 ml	approximately 10 ml	2.0 mg / ml

After dissolving and diluting the solution, it should be injected intravenously for about 1 hour. A faster infusion can increase the risk of histamine-mediated reactions.

Reconstituted solution in vial

Chemical and physical stability is maintained for up to 48 hours at 25 ° C if 0.9% sodium chloride solution or 5% dextrose solution is used as the solvent.

Ready-made solution for infusions

The chemical and physical stability is maintained up to 96 hours at 25 ° C, unless protection is provided by light, and as the solvent used 0.9% sodium chloride or 5% dextrose solution. Mikamin® does not contain preservatives. Prepared solutions should be used immediately. Normally, the storage time should not exceed 24 hours at a temperature of 2 to 8 ° C.

Side effects:

In the analysis of safety data, no clinically significant differences were found depending on sex or race.

Adverse reactions to different organs and systems with frequency indication are listed below: often from 1/100 to <1/10 infrequently from ≥ 1/1000 to <1/100 rarely from ≥ 1/10 to 1/1000, 000 , the frequency is unknown (the available data do not allow determining the frequency).

On the part of the blood and lymphatic system

Often: leukopenia, neutropenia, anemia.

Infrequently: pancytopenia, thrombocytopenia, eosinophilia, hypoalbuminemia.

Rarely: hemolytic anemia, hemolysis.

Frequency unknown: disseminated intravascular coagulation.

From the immune system

Infrequently: anaphylactic / anaphylactoid reactions, hypersensitivity reactions.

From the side of metabolism and nutrition

Often: hypokalemia, hypomagnesemia, hypocalcemia.

Infrequently: hyponatremia, hyperkalemia, hypophosphatemia, anorexia.

Disorders of the psyche

Infrequently: insomnia, anxiety, impaired consciousness.

From the nervous system

Often: headache.

Infrequently: drowsiness, tremor, dizziness, taste distortion, hyperhidrosis.

From the heart

Infrequently: tachycardia, palpitations, bradycardia.

From the side of the vessels

Often: phlebitis (mainly in HIV-infected patients with peripheral catheters).

Infrequently: arterial hypotension, arterial hypertension, hyperemia.

Frequency unknown: shock.

On the part of the respiratory system, the organs of the thorax and the mediastinum

Infrequently: dyspnea.

From the gastrointestinal tract

Often: nausea, vomiting, diarrhea, abdominal pain.

Infrequently: dyspepsia, constipation.

From the liver and biliary tract

Often: increased activity of alkaline phosphatase, alanine transaminase, aspartic transaminase, bilirubin in blood serum (including hyperbilirubinemia), changes in functional hepatic tests.

Infrequently: hepatic insufficiency, increased gamma activity glutamyltranspeptidase, jaundice, cholestasis, hepatomegaly, hepatitis.

Frequency unknown: hepatocellular lesions, incl. cases of death.

From the skin and subcutaneous tissue

Often: rash.

Infrequently: urticaria, itching, erythema.

Frequency unknown: toxic skin eruptions, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the side of the kidneys and urinary tract

Infrequently: increasing the concentration of creatinine, urea in the blood serum, progression of renal failure.

Frequency unknown: impaired renal function, acute renal failure.

General disorders and disorders at the site of administration

Often: hyperthermia, chills.

Infrequently: thrombus formation, pain at the injection site, inflammation in the infusion site, peripheral edema.

Laboratory and instrumental data

Infrequently: increase in lactate dehydrogenase activity in blood serum.

Pediatric Patients

The frequency of some of the undesirable reactions listed below in children was higher than in adults.In addition, in children under 1 year, twice as often as in older children, an increase in the activity of alanine transaminase, aspartic transaminase and alkaline phosphatase was detected.

On the part of the blood and lymphatic system

Often: thrombocytopenia.

From the heart

Often: tachycardia.

From the side of the vessels

Often: arterial hypertension, arterial hypotension.

From the liver and biliary tract

Often: hyperbilirubinemia, hepatomegaly.

From the side of the kidneys and urinary tract

Often: acute renal failure, increased urea concentration in blood serum.

Overdose:

There is no evidence of a misfungin overdose. In the event of a possible overdose, general supportive measures and symptomatic treatment should be used. Mikafungin is characterized by a high degree of binding to proteins and is not excreted in dialysis.

Interaction:

Mikafungin has a low potential for interactions with drugs that are metabolized with the participation of isoenzymes CYP3A.

Mikamin should not be mixed or administered to patients at the same time as other pharmaceutical products,except for 0.9% sodium chloride solution and 5% dextrose solution.

With the simultaneous use of mikafungin with drugs such as mycophenolate mofetil, ciclosporin, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole and amphotericin B, correction of the dosage regimen of micafungin is not required.

When using mikafungina AUC itraconazole, sirolimus and nifedipine slightly increased - by 22%, 21% and 18%, respectively. The combined use of mikafungin and amphotericin B in deoxycholate was associated with a 30% increase in the exposure of amphotericin B deoxycholate. Since this can be of clinical importance, this joint use should be resorted only if the benefit clearly exceeds the risk, with a careful control of the toxicity of amphotericin B deoxycholate.

Patients receiving sirolimus, nifedipine or itraconazole in combination with Mikamine®, monitoring is required to detect the toxic effects of sirolimus, nifedipine or itraconazole and, if necessary, reduce the dose of these drugs.

Special instructions:

With the introduction of mikafungina, anaphylactic / anaphylactoid reactions, including shock, are possible. If they occur, stop the infusion of mycaphungin and prescribe the necessary treatment.

When applying mikafungina may appear exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If the patient develops a rash, they should be carefully monitored and stop taking mikafungin in case of its progression.

In rare cases, patients treated with mikafungin observed hemolysis, including acute intravascular hemolysis, and hemolytic anemia.

When there are clinical or laboratory signs of hemolysis, careful monitoring of the patient's condition should be made and the risk / benefit ratio should be assessed.

When using mikafungina, renal function changes, including the development of renal failure, are noted, therefore, during monitoring, it is necessary to ensure careful monitoring of kidney function.

The use of mikafungin may be accompanied by a significant impairment of liver function (increased activity of alanine transaminase, aspartic transaminase or total bilirubin,more than 3 times the upper limit of the norm) both in healthy volunteers and in patients. In some cases, more severe liver dysfunction (hepatitis or liver failure with a fatal outcome) was noted. In patients under 2 years of age, the risk of hepatotoxicity is increased.

In rats, during the use of the drug for> 3 months, the appearance of local foci of altered hepatocytes and the formation of hepatocellular tumors were observed. The significance of this fact for the clinical use of the drug in patients is not established. In the process of treating mikafungin it is necessary to ensure careful monitoring of liver function. In order to minimize the risk of adaptive regeneration and, as a consequence, the possible subsequent formation of liver tumors, with a significant or persistent increase in the activity of alanine transaminase, aspartic transaminase, it is recommended to cancel the drug. Treatment with mikafungin should be done carefully weighing the risk-benefit relationship, especially in patients with severe impaired liver function or chronic liver disease, which are precancerous conditions such as severe liver fibrosis, cirrhosis,viral hepatitis, liver disease in newborns or congenital fermentopathies, as well as in the case of simultaneous use of drugs that have hepatotoxic and / or genotoxic effect.

The incidence of some adverse reactions was higher in children than in adult patients. In children under 1 year, an increase in the activity of alanine transaminase, aspartic transaminase and alkaline phosphatase was approximately twice as high as in children older than 1 year. The most likely cause of these differences was the different initial condition of children under 1 year of age in clinical trials, compared with older children

age and adult patients. At the time of enrollment, the proportion of patients with neutropenia, after allogeneic bone marrow transplantation, as well as with malignant hematologic formations among children (40.2%, 29.4% and 29.1%, respectively) was several times higher than among adults (respectively, 7.3%, 13.4% and 8.7%).

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

No studies have been conducted to evaluate the effect of micafungin on the ability to drive vehicles and work with mechanisms.However, there may be undesirable reactions that could adversely affect the ability to drive vehicles and work with machinery.

Form release / dosage:Liofilizate for the preparation of a solution for infusions of 50 mg and 100 mg.

Packaging:

For 52.5 mg (50 mg dosage) or 106.0 mg (100 mg dosage) of mycaphungin (in the form of sodium mikafungin) in a vial of colorless glass (type I) capped with a stopper, an aluminum / polypropylene cap and a shrink film.

One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

In the original packaging, in a dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-009005/09

Date of registration:10.11.2009

The owner of the registration certificate:Astellas Farma Europe BVAstellas Farma Europe BV Netherlands

Manufacturer: & nbsp

ASTELLAS PHARMA TECH, Co Ltd. Japan

Representation: & nbspASTELLAS PHARMA YUROP BV ASTELLAS PHARMA YUROP BV Netherlands

Information update date: & nbsp22.11.2015

Illustrated instructions

Instructions

Mikamin® (Mycamine®)