Mycamine® [Micafungin]

Brand Astellas

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Available since: 2019-09-19

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Clinical Pharmacology

Mycamine® - antifungal.

Pharmacodynamics

Micafungin noncompetitively inhibits the synthesis of 1,3-β-D-glucan, an important component of the fungal cell wall. 1,3-β-D-glucan is absent in mammalian cells. Micafungin has fungicidal activity against fungi of the genus.Candida spp. and has a pronounced fungistatic effect againstAspergillus spp.

Activity spectrum

Micafunginin vitro active against various types of mushroomsCandida spp., includingCandida albicans, Candida glabrata, Candida tropicalis, Candida krusei, Candida kefyr, Candida parapsilosis, Candida guilliermondii, Candida lusitaniae, andAspergillus spp., includingAspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Aspergillus nidulans, Aspergillus versicolor, as well as dimorphic fungi(Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis). A drugin vitroinactive againstCryptococcus spp., Pseudallescheria spp., Scedosporium spp., Fusarium spp., Trichosporon spp., Zygomycetes spp. The likelihood of developing secondary drug resistance is very low.

Pharmacokinetics

The drug is administered IV. In the range of daily doses of 12.5–200 mg and 3–8 mg / kg, micafungin is characterized by linear pharmacokinetics. There is no data on the systemic cumulation of the drug with repeated administration, C_ss set within 4–5 days from the start of use.

Distribution

After iv administration, the concentration of micafungin decreases biexponentially. Micafungin is rapidly distributed in tissues. In the systemic circulation, micafungin is actively bound to plasma proteins (> 99%), mainly albumin. Albumin binding remains stable in the concentration range 10–100 mcg / ml. V_ss - 18–19 l.

Metabolism

Micafungin circulates in the systemic circulation mainly unchanged. It has been shown that Micafungin is metabolized to form several compounds; of these, M1 (catechol form), M2 (methoxy derivative M1) and M5 (formed as a result of side chain hydroxylation), Micafungin derivatives are determined in small amounts in the systemic circulation. Metabolites do not have a significant impact on the effectiveness of Micafungin.

Despite the fact thatin vitro Micafungin can be metabolized by CYP3A isoenzymes, hydroxylation with the participation of CYP3A isoenzymes is not the main route of metabolism of the drugin vivo.

Elimination and excretion

T_1/2 - 10-17 hours, does not change in the dose range up to 8 mg / kg after single and repeated injections of the drug. The overall clearance in healthy volunteers and adult patients with both single and repeated injections was 0.15–0.3 ml / min / kg and was not dose dependent. 28 days after a single injection of 25 mg¹⁴C-mikafungin healthy volunteers 11.6% of the radioactive label was found in the urine and 71% in the feces, which indicates a predominantly non-renal elimination of micafungin. Metabolites M1 and M2 were detected in plasma in trace concentrations, and the metabolite M5 was 6.5% of the starting compound.

Pharmacokinetics in different groups of patients

Children. In children, AUC is proportional to the dose of the drug in the range of 0.5–4 mg / kg. Ground clearance depends on age: the average clearance values in younger children (2–11 years old) are about 1.3 times higher than in older children (12–17 years old) and adults. The average clearance in preterm infants (about 26 weeks) is about 5 times more than in adults.

Elderly patients. With the infusion of 50 mg of Micafungin for 1 hour, the pharmacokinetic parameters in the elderly (66–78 years) did not differ significantly from those in the young (20–24 years).

Patients with impaired liver function. In a study of 8 patients with moderately severe liver dysfunction (Child-Pugh index 7–9), the pharmacokinetics of Micafungin differed slightly from the pharmacokinetics in 8 healthy volunteers. A study of 8 patients with severe hepatic impairment (Child-Pugh index 10–12) showed a reduced plasma concentration of micafungin and an increased metabolite hydroxide concentration (M5) in plasma compared with data obtained from 8 healthy volunteers.

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Gender / Race. Gender and race did not significantly affect the pharmacokinetic parameters of Micafungin.

Indications

Adults, including Elderly, and teenagers ≥16 years:

treatment of invasive candidiasis;
treatment of esophageal candidiasis in patients who require intravenous anti-fungal medication;
prophylaxis of candidiasis in patients after allogeneic transplantation of hematopoietic stem cells or patients who are expected to have neutropenia (the number of neutrophils

Children, incl. newborns and teenagers

treatment of invasive candidiasis;
prophylaxis of candidiasis in patients after allogeneic transplantation of hematopoietic stem cells or patients who are expected to have neutropenia (the number of neutrophils

Composition

1 bottle contains:

Active substance: micafungin;

Excipients: lactose monohydrate; anhydrous citric acid; sodium hydroxide.

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Dosage and Administration

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

Table 1

The dosage regimen of Mycamine® in adults, incl. elderly and teenagers ≥16 years old

Indications	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
Candida Prevention	50 mg / day	1 mg / kg / day

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

table 2

Mycamine® dosing regimen in children and adolescents

Indications	Body weight> 40 kg	Body weight ≤40 kg
Treatment of invasive candidiasis	100 mg / day *	2 mg / kg / day *
Candida Prevention	50 mg / day	1 mg / kg / day

Treatment of invasive candidiasis the duration must be at least 14 days. Antifungal treatment should be continued for at least 1 week after receiving two consecutive negative blood test results and the disappearance of the clinical signs of candidiasis.

For the treatment of esophageal candidiasis Mycamine® should be used for at least 1 week after resolution of clinical signs.

For the prevention of candidiasis Mycamine® should be used for at least 1 week after neutrophil levels have been restored. The experience of prophylactic use of Mycamine® in children under 2 years of age is limited.

Adverse reactions

From the side of blood and lymphatic system: often - leukopenia, neutropenia, anemia; infrequently - pancytopenia, thrombocytopenia, eosinophilia, hypoalbuminemia; rarely - hemolytic anemia, hemolysis; frequency unknown - disseminated intravascular coagulation.

On the part of the immune system: infrequently - anaphylactic / anaphylactoid reactions, hypersensitivity reactions.

Metabolism and nutrition: often - hypokalemia, hypomagnesemia, hypocalcemia; infrequently - hyponatremia, hyperkalemia, hypophosphatemia, anorexia.

Mental Disorders: infrequently - insomnia, anxiety, impaired consciousness.

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

From the side of 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, organs of the chest and mediastinum: infrequently - shortness of breath.

From the digestive tract: often - nausea, vomiting, diarrhea, abdominal pain; infrequently - dyspepsia, constipation.

Liver and biliary tract: often - an increase in the activity of alkaline phosphatase phosphate, ALT, AST, serum bilirubin (including hyperbilirubinemia), changes in functional hepatic tests; infrequently - liver failure, increased GGTP activity, jaundice, cholestasis, hepatomegaly, hepatitis; frequency unknown - hepatocellular lesions, including cases of fatal outcome.

From the skin and subcutaneous tissue: often - a rash; infrequently - urticaria, pruritus, erythema; frequency is unknown - toxic skin rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the kidneys and urinary tract: infrequently - an increase in the concentration of creatinine, serum urea, 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 - blood clot formation, pain at the injection site, inflammation at the infusion site, peripheral edema.

Laboratory and instrumental data: infrequently - an increase in the activity of lactate dehydrogenase in the blood serum.

Pediatric patients

The incidence of some adverse reactions listed below in children was higher than in adults. In addition, in children under 1 year of age twice as often as in older children, an increase in the activity of ALT, AST, ALP was detected.

From the side of blood and lymphatic system: often - thrombocytopenia.

From the side of the heart: often - tachycardia.

From the side of the vessels: often - arterial hypertension, arterial hypotension.

Liver and biliary tract: often - hyperbilirubinemia, hepatomegaly.

From the kidneys and urinary tract: often - acute renal failure, increasing the concentration of urea in the blood serum.

Contraindications

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

Carefully: severe abnormal liver function; chronic liver diseases (liver fibrosis, cirrhosis, viral hepatitis, neonatal liver diseases, or congenital defects of enzymes); concomitant hepatotoxic and / or genotoxic therapy; children's age (especially up to 1 year); renal failure; simultaneous use with sirolimus, nifedipine, itraconazole and amphotericin B.

Drug interactions

Micafungin has a low potential for drug interactions that are metabolized by the CYP3A enzyme.

Mycamine® should not be mixed or administered to patients simultaneously with other pharmaceutical products, with the exception of 0.9% sodium chloride solution and 5% dextrose solution.

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

When using micafungin, the AUC of itraconazole, sirolimus, and nifedipine increased slightly, by 22, 21, and 18%, respectively. Patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine® need monitoring to identify the toxic effects of sirolimus, nifedipine or itraconazole and, if necessary, reduce the dose of these drugs.

Pregnancy and Lactation

There is no clinical experience with micafungin in pregnant women. Therefore, Mycamine® should be used during pregnancy only after a thorough assessment of the risk / benefit ratio.

It is not known whether micafungin passes into breast milk. The decision to continue / discontinue breastfeeding or to continue / discontinue Mycamine®’s treatment should be made taking into account the benefits of breastfeeding for the child and the benefits of Mycamine®’s treatment for the mother.

Special instructions

The use of Micafungin can be accompanied by a significant deterioration in liver function (an increase in the level of ALT, AST or total bilirubin, more than 3 times higher than VGN) in both healthy volunteers and patients. In some cases, more severe liver dysfunction was noted (hepatitis or liver failure with a fatal outcome). In patients under the age of 2 years, the risk of hepatotoxicity is increased.

In rats with 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 has not been established. In the process of treatment with micafungin, it is necessary to carefully monitor liver function.In order to minimize the risk of adaptive regeneration and, as a consequence, the possible subsequent formation of tumors in the liver, with a significant increase in the level of ALT / AST or prolonged persistence, it is recommended that the drug be removed.

Micafungin treatment should be carried out carefully weighing the balance between risk and benefit, especially in patients with severe liver dysfunction or chronic liver diseases, which are pretumorous conditions such as severe liver fibrosis, cirrhosis, viral hepatitis, liver disease in the newborn, or congenital fermentopathy, as well as in the case of simultaneous use of drugs that have a hepatotoxic and / or genotoxic effect.

Overdosage

No data on overdose of micafungin.

Treatment: in the event of a possible overdose, general supportive measures and symptomatic treatment should be used. Micafungin is characterized by a high degree of protein binding and is not eliminated during dialysis.