Mikamin

General characteristics. Structure:

Active agent: микафунгин (in the form of a mikafungin of sodium) 50 mg or 100 mg.
Auxiliary, substances: lactoses monohydrate, citric acid anhydrous, sodium of hydras oxide.

Description
The lyophilized mass of white color.

Pharmacological properties:

Pharmacokinetics. The drug is administered in / century. In the range of daily doses of 12,5-200 mg and 3-8 mg/kg микафунгин it is characterized by linear pharmacokinetics. There are no data on system cumulation of drug at repeated introduction, CSS is established within 4–5 days since the beginning of use.

Distribution

Later in/in introductions concentration of a mikafungin bieksponentsialno decreases. Mikafungin is quickly distributed in fabrics. In a system blood-groove микафунгин actively contacts proteins of plasma (> 99%), mainly albumine. Linkng with albumine remains stable in the range of concentration of 10-100 mkg/ml. VSS — 18–19 l.

Metabolism

Mikafungin circulates in a system blood-groove preferential in not changed look. It was shown what микафунгин is metabolized with formation of several connections; from them M-1 (a katekholovy form), M-2 (metoksiproizvodny M-1) and M-5 (it is formed as a result of a hydroxylation of a side chain) derivatives of a mikafungin are defined in small amounts in a system blood-groove. Metabolites have no significant effect on efficiency of a mikafungin.

In spite of the fact that in vitro микафунгин can be metabolized by CYP3A isoenzymes, the hydroxylation with the participation of CYP3A is not the main way of metabolism of the drug in vivo.

Elimination and excretion

T1/2 is 10–17 h, also repeated administrations of drug do not change in the range of doses up to 8 mg/kg after single. The general clearance at healthy volunteers and adult patients both at single, and at repeated introductions made 0,15–0,3 ml/min. and did not depend on a dose. In 28 days after single introduction of 25 mg of a 14C-mikafungin to healthy volunteers of 11,6% of a radioactive label found out in urine and 71% — in excrements what demonstrates preferential not renal elimination of a mikafungin. Metabolites of M-1 and M-2 were found in plasma in trace concentration, and the metabolite of M-5 made 6,5% of initial connection.

Pharmacokinetics at various groups of patients

Children. At children of AUC it is proportional to a drug dose in the range of 0,5-4 mg/kg. The clearance depends on age: average sizes of clearance at children of younger age (2–11 years) are about 1,3 times higher, than at children of advanced age (12–17 years) and adults. Average clearance at premature newborns (about 26 weeks) approximately in 5 times more, than at adults.

Elderly patients. At infusional introduction of 50 mg of a mikafungin during 1 h pharmacokinetic parameters at elderly people (66–78 years) significantly did not differ from those at young people (20–24 years).

Patients with the broken function of a liver. In the research conducted with participation of 8 patients with a moderate abnormal liver function (Chayld-Pyyu index 7-9), the pharmacokinetics of a mikafungin slightly differed from pharmacokinetics at 8 healthy volunteers. At patients with a heavy liver failure the pharmacokinetics of a mikafungin was not studied.

Patients with renal dysfunction. A heavy renal failure (glomerular filtering <30 ml/min.) had no significant effect on pharmacokinetics of a mikafungin.

Floor/race. A floor and race had no significant effect on pharmacokinetic parameters of a mikafungin.

Indications to use:

1. Adult, including elderly and teenagers> 16 years:
- Treatment of invasive candidiasis;
- Treatment of candidiasis of a gullet at patients who need intravenous use of antifungal drugs;
- Prevention of candidiasis at patients after allogenic transplantation of the hemopoietic stem cells  or patients at whom the neutropenia (quantity of neutrophils <500/mkl) within 10 days and more is supposed.
2. Children (including newborns) and teenagers <16 years:
- Treatment of invasive candidiasis;
- Prevention of candidiasis at patients after allogenic transplantation of the hemopoietic stem cells  or patients at whom the neutropenia (quantity of neutrophils <500/mkl) within 10 days and more is supposed.

Route of administration and doses:

Mikamin is intended for intravenous administration.
The mode of dosing of Mikamin  taking into account testimonies, age and body weight of the patient is presented in tables 1 and 2.

Table 1. The mode of dosing of a mikamin at adults, including elderly and teenagers> 16 years:
Indication                                           Body weight> 40 kg                  Body weight <40 kg
Treatment of invasive candidiasis             of 100                         mg/day 2 mg/kg/day
Treatment of candidiasis of a gullet                 of 150                          mg/day 3 mg/kg/day
Prevention of candidiasis                        of 50                           mg/day 1 mg/kg/day
In the absence of positive clinical dynamics or a persistention of the activator the dose can be increased to 200 mg/day for patients by weight> 40 kg or to 4 mg/kg/day for patients is powerful <40 kg.

Table 2. The mode of dosing of Mikamin at children and teenagers <16 years:
Indication                                         Body weight> 40 kg                    Body weight <40 kg
Treatment of invasive candidiasis            of 100                            mg/day 2 mg/kg/day
Prevention of candidiasis                        of 50                               mg/day 1 mg/kg/day
 In the absence of positive clinical dynamics or a persistention of the activator the dose can be increased to 200 mg/day for patients by weight> 40 kg or to 4 mg/kg/day for patients is powerful <40 kg.

Treatment of invasive candidiasis on duration has to make not less than 14 days.
Antifungal treatment should be continued within, at least, one week after receiving two consecutive negative takes of a blood analysis and disappearance of clinical signs of candidiasis.

Mikamin it is necessary to apply to treatment of candidiasis of a gullet, at least, within one week after permission of clinical signs.

Mikamin it is necessary to apply to prevention of candidiasis, at least, within one week  after recovery of level of neutrophils. Experience of preventive use of Mikamin for children is younger than 2 years is limited.

The dosing mode at separate categories of patients
At an easy and moderate abnormal liver function of correction of the mode of a drug dosing it is not required. Now there are no data on Mikamin's use for patients with a heavy liver failure therefore  it is not recommended to use it at this category of patients. At  a renal failure the mode of dosing does not change.
Mikamin's solution for infusions is prepared at the room temperature with observance of rules
asepsises as follows:
1. The plastic cap needs to be removed from a bottle, and to disinfect a stopper alcohol.
2. 5 ml of 0,9% of solution of sodium chloride for infusions or 5% of solution of a dextrose which are selected from a bottle/package on 100 ml should be entered slowly into each bottle with powder on an internal wall. At preparation of solution to minimize amount of the formed foam. It is necessary to use  the quantity of bottles of a mikamin specified in the table to receive a drug dose, necessary for infusions, in mg (see below).
3. The bottle should be turned carefully. NOT to STIR UP. Powder has to be dissolved completely. The concentrate should be used immediately.  The bottle is intended for single use. Unused solution should be thrown out.
4. The received concentrate is taken away from a bottle and moved to a bottle/package of infusion  solution from which it   was originally taken (see item 2). The prepared solution for infusions should be used immediately. It remains stable to 96 h at  a temperature of 25 °C  on condition of protection against light and preparation according to the stated above description.
5. The bottle/package for infusions should be turned carefully, but not to shake up to avoid foaming. It is impossible to use solution if it muddy or contains a deposit.
6. The bottle/package containing the prepared solution for infusions should be placed in the closed opaque bag for protection against light.

Table 3. Preparation of solution for infusion

Dose   Bottle                    Number of 0,9% of solution         Volume                       Concentration
     Mikamin's (mg),              sodium chloride or 5%      of the recovered   ready solution
           intended  solution of a dextrose,             solution                   (when using
           for use     added to bottles    and concentration       of 100 ml of solvent)
                                                                                                                     active agent           
 50      1x50                         5                                                 ml about 5 ml 0,5 mg/ml
                                                                                             (10 mg/ml)
100     1x100                        5                                               ml about 5 ml 1,0 mg/ml   
                                                                                              (20 mg/ml)
150     1 x 100+1 x 50           5                                             ml about 10 ml 1,5 mg/ml
200     2x100                          5                                            ml about 10 ml 2,0 mg/ml

After preparation of solution it should be entered intravenously during 1 h. More bystry infusion can increase risk a histamine - the mediated reactions.

The recovered solution in a bottle
Chemical and physical stability remains to 48 h at 25 °C if as solvent 0,9% solution of sodium chloride or 5% dextrose solution are used.

Ready solution for infusions
Chemical and physical stability remains   till 96 o'clock at 25 °C if protection against light is provided, and as solvent 0,9% solution of sodium chloride or 5%  dextrose solution are used. Mikamin  does not contain preservatives. The prepared solutions should be used immediately. Normal storage time should not exceed 24 h at a temperature from 2 to 8 °C.

Features of use:

At introduction of a mikafungin anaphylactoid reactions, including shock are possible. At their emergence it is necessary to stop infusion of a mikafungin and to appoint necessary treatment, In rare instances at patients against the background of treatment mikafunginy were observed hemolysis, including an acute intravascular hemolysis, and hemolitic anemia. At emergence of clinical or laboratory signs  of hemolysis, it is necessary to provide careful monitoring of a condition of the patient and to estimate a ratio of risk and advantage of continuation of treatment.
When using a mikafungin change of function of kidneys, including development of a renal failure therefore during treatment it is necessary to provide careful monitoring of function of kidneys is noted.

Side effects:

In the analysis of data on safety depending on a floor or race clinically significant distinctions were not revealed.
Undesirable reactions on different bodies and systems with the indication of frequency are given below: often: from 1/100 to <1/10, infrequently: from> 1/1000 to <1/100, it is rare: from> 1/10 000 to 1/1000, frequency is unknown (the available data do not allow to determine frequency).

System of blood
Often: leukopenia, neutropenia, anemia.
Infrequently: pancytopenia, thrombocytopenia, eosinophilia, hypoalbuminemia.
Seldom: hemolitic anemia, hemolysis.

Immune system
Infrequently: anaphylactic/anaphylactoid reactions, hypersensitivity reactions.
Frequency is unknown: shock.

Disorders of metabolism and food
Often: hypopotassemia, hypomagnesiemia, hypocalcemia.
Infrequently: hyponatremia, hyperpotassemia, hypophosphatemia.

Mental disorders
Infrequently: sleeplessness, uneasiness, consciousness disturbance, anorexia.

Nervous system
Often: headache.
Infrequently: drowsiness, tremor, dizziness, food faddism, hyperhidrosis.
Cardiovascular system
Often: phlebitis (it is preferential at HIV-positive patients with peripheral catheters).
Infrequently: tachycardia, heartbeat, bradycardia, hypotension, hypertensia, blood "inflows".

Respiratory system
Infrequently: asthma.

Digestive tract
Often: nausea, vomiting, diarrhea, abdominal pain.
Infrequently: dyspepsia, locks.

Liver and biliary tract
Often: increase in level of an alkaline phosphatase of ACT, ALT, bilirubin in blood serum, change of functional hepatic tests.
Infrequently: liver failure, increase in the GGT level, jaundice, cholestasia, hepatomegalia, hepatitis.
Frequency is unknown: hepatocellular defeats, including cases of a lethal outcome.

Skin and hypodermic cellulose
Often: rash.
Infrequently: urticaria, itch, erythema.

Kidneys and uric ways
Infrequently: increase in level of creatinine, urea in blood serum, progressing of a renal failure.
Frequency is unknown: renal failure, acute renal failure.

The general frustration and reactions in an injection site
Often: hyperthermia, fever.
Infrequently: formation of blood clot, pain in the place of an injection, an inflammation in the place of infusion, pain in the place of an injection, peripheral hypostasis.

Data of laboratory researches
Infrequently: increase in the LDG level in blood serum.

Pediatric patients
Frequency of some undesirable reactions which are listed below at children was higher, than at adults. Besides, at children till 1 year twice more often than at children of advanced age, revealed increase in ALT, ACT and alkaline phosphatase.

System of blood
Often:  thrombocytopenia.
Cardiovascular system
Often:   tachycardia, hypertensia, gapotenziya.
Liver and biliary tract
Often:  hyperbilirubinemia, hepatomegalia.

Kidneys and uric ways
Often: an acute renal failure, increase in level of urea in blood serum.

Interaction with other medicines:

Mikafungin has the low potential of interactions with medicines which are metabolized with participation of isoenzymes of CYP3 A.
Mikamin patients cannot mix or enter along with other pharmaceutical products, except for 0,9% of solution of sodium chloride and 5% of solution of a dextrose.
At simultaneous use of a mikafungin with such drugs as mofetit, cyclosporine, такролимус, Prednisolonum, сиролимус, nifedipine, флуконазол, ритонавир, rifampicin, итраконазол, вориконазол and Amphotericinum In, correction of the mode of dosing of a mikafungin is not required.
When using a mikafungin of AUC of an itrakonazol, sirolimus and nifedipine slightly  increased  - by 22%, 21% and 18%, respectively. To the patients receiving сиролимус, nifedipine or итраконазол in a combination with Mikamin, is necessary monitoring for the purpose of identification of toxic action of a sirolimus, nifedipine or an itrakonazol and, if necessary, a dose decline of the specified drugs.

Contraindications:

Hypersensitivity to active agent or any of auxiliary components or their intolerance (intolerance of a galactose, insufficiency of lactase, glkzhozo-galaktozny malabsorption).

With care
Use of a mikafungin can be followed by considerable deterioration in function of a liver (increase in level of alanine transaminase (ALT), asparaginic transaminase (ACT) or the general bilirubin, more than by 3 times exceeding the upper bound of norm) both at healthy volunteers, and at patients. In some cases noted heavier dysfunction of a liver (hepatitis or a liver failure with a lethal outcome). At patients aged up to 2 years the risk of a hepatotoxic is increased. At rats at use of drug during> 3 months emergence of the local centers of the changed hepatocytes and formation pechenochno - cellular tumors was observed. The importance of this fact for a clinical use of drug at patients is not established. In the course of treatment mikafunginy it is necessary to provide careful monitoring of function of a liver. To minimize risk of adaptive regeneration and, as a result, possible subsequent formation of tumors of a liver, at substantial or persistent increase of level of ALT/nuclear heating plant drug withdrawal is recommended.
Treatment mikafunginy should be carried out, carefully weighing a ratio of risk and advantage, especially at patients with a heavy abnormal liver function or chronic diseases of a liver which represent pretumor states, such as the expressed liver fibrosis, cirrhosis, a viral hepatitis, liver diseases at newborns or inborn fermentopatiya, and also in case of simultaneous use of the drugs having hepatotoxic and/or genotoksichesky action.

Pregnancy and lactation
There is no clinical experience of use of drug for pregnant women. Therefore Mikamin  it is necessary to apply    during pregnancy, only after careful assessment of a ratio risk/advantage.
It is unknown  whether gets микафунгин into breast milk. The decision on continuation the termination of breastfeeding or about the continuation/termination of treatment by Mikamin should be accepted, considering advantage of breastfeeding for the child and advantage of treatment mikaminy for mother.

Overdose:

There are no data on overdose of a mikafungin. In case of possible overdose it is necessary to apply the general supporting measures and a symptomatic treatment. Mikafungin is characterized by high extent of linkng with proteins and not brought at dialysis.

Storage conditions:

In original packaging, in the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity: 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for infusions of 50 mg and 100 mg. On 2,625 g (a dosage of 50 mg) or 2,650 g (a dosage of 100 mg) of lyophilisate in a bottle from colourless glass (type I), the corked isobutylene - an isoprene stopper, a cap from aluminum/polypropylene and a packaging thermoshrinkable film. On 1 bottle together with the application instruction place in a cardboard pack.