Mikafungin-native - instructions for use, dose, side effects, contraindications

Active substanceMikafunginMikafungin

Similar drugsTo uncover

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:

Name of component Quantity, mg

	50 mg	100 mg
Active substance: *
Mikafungin sodium	52,6	106,0
(in terms of mikafungin)	(50,0)	(100,0)

* The bottle contains 3% excess of the claimed amount

Excipients:

Lactose monohydrate 210.0

Citric acid anhydrous to pH 5.0-7.0

Sodium hydroxide to pH 5.0-7.0.

Description:Lyophilized mass of white or almost 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. and significantly inhibits the active growth of hyphae of fungi of the genus Aspergillus spp.

Activity spectrum

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

Table 1.

Minimum inhibitory concentrations of mikafungin against fungi of the genus

Candida

Kinds of fungi Candida	Minimum inhibitory concentration, mg / l (European data)
Candida albicans	[0,007 - 0,25]
Candida gladrata	[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. (at Tom number of C.famata, FROM. dubliniensis. C. lipolytica, C. pelliculosa, C. rugosa, C. stellatoidea and FROM. zeylanoides)	[0,015-0,5]

Pharmacokinetics:

The drug Mikafungin-native is administered intravenously. In the range of daily doses of 12.5-200 mg and 3-8 mg / kg mikafungin characterized by linear pharmacokinetics. Data on systemic cumulation of mikafungin with repeated administration are absent, the equilibrium concentration is established within 4-5 days from the time 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 blood 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 the equilibrium concentration is reached (V_ss) is 18-19 liters.

Metabolism

Mikafungin circulates in the systemic blood flow mainly unchanged. Shown, that mikafungin metabolized to form several compounds; of them M-1 (catechol form), M-2 (methoxy derivative M-1) and M-5 (formed as a result of hydroxylation of the side chain), the mycafungin derivatives are determined 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 pathway of metabolism of mycaphungin in vivo.

Excretion

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

Pharmacokinetics in selected patient groups

Sex and race do not have a significant effect on the pharmacokinetic parameters of mycaphungin.

Children

In children, the area under the pharmacokinetic curve "concentration-time" (AUC) is proportional to the dose of mikafungin 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.

Older and older patients

With the infusion of 50 mg of mycaphungin for 1 hour, pharmacokinetic Parameters in elderly and older patients (66-78 years) do not differ significantly from those of young (20-24 years).

Patients with hepatic impairment

In patients with violations of liver function of moderate severity (7-9 points on the Child-Pugh scale) pharmacokinetics of mikafungin slightly differs from pharmacokinetics in healthy volunteers. In patients with severe hepatic insufficiency (10-12 points on the Child-Pugh scale), the concentration of micafungin in the blood plasma is decreased and the concentration of hydroxide in the metabolite (M-5) in the blood plasma is increased in comparison with the data obtained in healthy volunteers.

Patients with impaired renal function

Renal failure of severe degree (glomerular filtration <30 ml / min) does not significantly affect the pharmacokinetics of mycaphungin.

Indications:

1. Adults, including elderly and older patients, and adolescents 16 years of age or older:

- treatment of invasive candidiasis;

- treatment of esophageal candidiasis in patients who require intravenous antifungal medicines;

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

2.Children, including newborns, and adolescents under 16:

- treatment of invasive candidiasis;

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

Contraindications:

- Hypersensitivity to mikafungin, other echinocandins or any of the auxiliary components of the drug.

- Intolerance to galactose, insufficiency of lactase, glucose-galactose malabsorption.

Carefully:

Mikafungin should be administered with caution when used concomitantly with sirolimus, nifedipine, intraconazole, and amphotericin B.

The use of mikafungin may be accompanied by impaired liver function (increased concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (ACT) and total bilirubin, more than 3 times the upper limit of the norm) both in healthy volunteers and in patients. In some cases, there may be more severe liver dysfunction (hepatitis or liver failure with a fatal outcome).In patients under 2 years of age, the risk of developing hepatotoxicity is increased.

In pre-clinical studies in rats with the use of mikafungin for ≥ 3 months, local foci of altered hepatocytes and the formation of hepatic-cell tumors were observed. The significance of these observations for the clinical use of mikafungin in patients is not established. During the therapy with mikafungin it is necessary to ensure careful monitoring of liver function. In order to minimize the risk of adaptive regeneration and, as a consequence, possible subsequent formation of liver tumors, with a significant or persistent increase in ALT / AST concentrations, it is recommended that treatment with mikafungin be canceled. Treatment with mikafungin should be done carefully weighing the balance of risk and benefit, especially in the following groups of patients:

- Patients with severe hepatic insufficiency;

- Patients with chronic liver disease (pre-tumor conditions such as severe liver fibrosis, liver cirrhosis, viral hepatitis, neonatal liver disease or congenital fermentopathies);

- Patients who simultaneously take medicines that have hepatotoxic and / or genotoxic effects.

Pregnancy and lactation:

Clinical experience in the use of mikafungina in pregnant women is not.

Therefore, the drug Mikafungin-native 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 on continuation / discontinuation of breastfeeding or continuation / discontinuation of therapy with mikafungin should be taken, given the benefits of breastfeeding for the child and the benefits of mikafungin 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:

The drug Mikafungin-native is intended for intravenous administration.

The dosage regimen of the preparation Mikafungin-native taking into account the indications, age and body weight of the patient is presented in Tables 2 and 3.

Table 2.

The dosage regimen of the drug Mikafungin-native in adults, including patients older and older, and adolescents 16 years and older

Indication for use	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 pathogen, the dose of mikafungin can be increased to 200 mg / day for patients with a body weight> 40 kg or up to 4 mg / kg / day for patients with a body weight <40 kg.

Table 3.

The dosage regimen of the drug Mikafungin-native in children and adolescents under 16 years of age

Indication for use	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

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

Candidiasis of the esophagus. For treatment of esophageal candidiasis, the drug Mikafungin-native should be used for at least one week after the disappearance of clinical signs.

Prevention of candidiasis. The drug Mikafungin-native should be used for at least one week after the recovery of neutrophil count. Experience in the prophylactic use of mikafungin in children younger than 2 years is limited.

Use in selected patient groups

Patients with hepatic impairment

With hepatic insufficiency of mild and moderate severity, dose correction is not required. Currently, there is insufficient data on the use of mycaphungin in patients with severe hepatic insufficiency, so it is not recommended to use it in this category of patients.

Patients with impaired renal function

With renal failure, dose adjustment is not required.

Preparation of Mikafungin-native solution for intravenous infusion

A solution of the drug Mikafungin-native for infusion is prepared at room temperature with the observance of aseptic rules as follows:

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

2. 5 ml 0.9 % solution of sodium chloride for infusions or 5% of dextrose solution taken from a 100 ml vial / package should be slowly introduced into each vial with lyophilizate on the inner wall.

When preparing the solution, it is necessary to minimize the amount of foam formed. It is necessary to use the number of vials of Mikafungin-native preparation indicated in the table in order to obtain the dose of mikafungin necessary for infusion in mg (Table 4).

3. The bottle should be turned gently. DO NOT BREAK UP! The lyophilizate must dissolve completely. The reconstituted solution should be used immediately after preparation. The bottle is intended for single use. Dispose of unused solution.

4. The resulting reconstituted solution must be removed from the vial and transferred to a vial / bag with the infusion solution from which it was originally taken (see para. 2). The prepared infusion solution should be used immediately. It stays stable up to 96 hours at 25 ° C under protection from light and cooking as described above.

5. Vial / infusion bag should be carefully turned over.DO NOT BLIND to avoid the formation of foam. 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 4.

Preparation of a solution for infusions

Dose (mg)	The vial of the preparation Mikafungin-native, intended for use	The amount of 0.9% sodium chloride solution or 5% dextrose solution added to the vial	Scope reconstituted solution and concentration of active substance	Concentration of the prepared solution for infusions (when using 100 ml solvent)
50	1^x50	5 ml	Approximately 5 ml (10 mg / ml)	0.5 mg / ml
100	1^x100	5 ml	Approximately 5 ml (20 mg / ml)	1.0 mg / ml
150	1^x100 + 1^x50	5 ml	Approximately 10 ml	1.5 mg / ml
200	2^x100	5 ml	Approximately 10 ml	2.0 mg / ml

After the preparation of the solution, it should be administered intravenously for 1 hour. A faster infusion may increase the risk of developing histamine-mediated reactions.

Reconstituted solution in vial

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

Ready-made solution for infusions

Chemical and physical stability is maintained up to 96 hours at a temperature of 25 ° C if protection from light is provided, and 0.9% sodium chloride solution or 5% dextrose solution is used as the solvent. The drug Mikafungin-native does not contain preservatives. The prepared solution should be used immediately. Normally, the storage time should not exceed 24 hours at a temperature of +2 to +8 ° C.

Side effects:

Analysis of safety data in relation to gender or race showed no clinically significant differences.

The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems. The incidence of undesirable reactions is estimated as follows: "very often" occurring -> 10%, "often" -> 1% and < 10%, "infrequently" -> 0.1% and <1%, "rarely" -> 0.01% and <0.1%, "very rarely" - <0.01%, including individual messages, "frequency unknown".

Adults

Disorders from the blood and lymphatic system: often - Lakopenia, neutropenia, anemia; infrequently - pancytopenia, thrombocytopenia, eosinophilia, hypoalbuminemia; rarely - hemolytic anemia, hemolysis; frequency unknown - disseminated intravascular coagulation.

Immune system disorders: infrequently anaphylactic / anaphylactoid reactions, hypersensitivity reactions.

Disorders from the metabolism and nutrition: often - hypokalemia, hypomagnesemia, hypocalcemia; infrequently - hyponatremia, hyperkalemia, hypophosphatemia, anorexia.

Mental disturbance: infrequently - Insomnia, anxiety, impaired consciousness.

Disturbances from the nervous system: often - headache; infrequently - drowsiness, tremor, dizziness, perversion of taste, hyperhidrosis.

Disorders from the heart: infrequently - tachycardia, palpitations, bradycardia.

Violations from the vessels: often - phlebitis (mainly in HIV-infected patients with peripheral catheters); infrequently - arterial hypotension, arterial hypertension, hyperemia; frequency unknown - shock.

Disturbances from the respiratory system, of the chest and mediastinum: infrequently - shortness of breath.

Disorders from the gastrointestinal tract: often - nausea, vomiting, diarrhea, abdominal pain; infrequently - Dyspepsia, constipation.

Disorders from the liver and biliary tract: often - an increase in the concentrations of alkaline phosphatase, ACT, ALT, bilirubin in blood plasma (including hyperbilirubinemia), changes in functional hepatic tests; infrequently - hepatic insufficiency, increased concentrations of gamma glutamyltranspeptidase, jaundice, cholestasis, hepatomegaly, hepatitis; frequency unknown - hepatocellular lesions, in t. cases of lethal outcome.

Disorders from the kidneys and urinary tract: infrequently - increased concentrations of creatinine, urea in blood plasma, progression of renal failure; frequency unknown - impaired renal function, acute renal failure.

Disturbances from the skin and subcutaneous tissues: often - a rash; infrequently - urticaria, itching, erythema; frequency unknown - toxic skin eruptions, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

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 the concentration of lactate dehydrogenase in blood plasma.

Children

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 ALT concentrations, ACT and alkaline phosphatase.

Disturbances from the blood and lymphatic system: often - thrombocytopenia.

Disorders from the heart: often - tachycardia.

Violations from the vessels: often - arterial hypertension, arterial hypotension.

Disorders from the liver and biliary tract: often - hyperbilirubinemia, hepatomegaly.

Disorders from the kidneys and urinary tract: often - acute renal failure, increased urea concentration in blood plasma.

Overdose:

Data on the overdose of mikafungin are absent. 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 plasma proteins of the blood 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.

The drug Mikafungin-native can not be mixed or administered to patients simultaneously with other medicines, with the exception of 0.9% sodium chloride solution and 5 % solution of dextrose.

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

With simultaneous application of micafungin values AUC itraconazole, sirolimus and nifedipine slightly increase - by 22%, 21% and 18%, respectively.

The combined use of mikafungin and amphotericin B deoxyicholate causes 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 mikafungin, monitoring is required to detect the toxic effects of sirolimus, nifedipine or itraconazole and, if necessary, reduce the dose of these drugs.

Special instructions:

When using 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, it should be carefully monitored and stop taking the drug Mikafungin-native in case of its progression.

In rare cases, patients on the background of treatment with mikafungin can observe hemolysis, including acute intravascular hemolysis, and hemolytic anemia. When clinical or laboratory signs of hemolysis appear, careful monitoring of the patient's condition should be made and the risk-to-benefit ratio should be assessed.

When using mikafungina, renal dysfunction may be noted, including the development of renal failure, so during the treatment it is necessary to ensure careful monitoring of kidney function.

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

Studies to study the effect of mikafungin on the ability to drive vehicles and mechanisms were not conducted. Patients should be aware of the possible development of adverse reactions that may adversely affect the ability to drive vehicles and mechanisms.

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

Packaging:

For 50 mg or 100 mg of mikafungina in bottles with a capacity of 10 ml of colorless glass, hermetically sealed with rubber stoppers lyophilic, covered with caps aluminum-plastic.

On 1 bottle together with the instruction on application place in a pack a cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004466

Date of registration:19.09.2017

Expiration Date:19.09.2022

The owner of the registration certificate:NATIVA, LLC NATIVA, LLC Russia

Manufacturer: & nbsp

NATIVA, LLC Russia

Information update date: & nbsp05.10.2017

Illustrated instructions

Instructions

Mikafungin-native (Micafungin-nativ)