Micafungin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MICAFUNGIN

Composition:

Active substance: micafungin (as micafungin sodium);

1 vial contains 50 mg or 100 mg of micafungin (as micafungin sodium);

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

Pharmaceutical form. Powder for concentrate for solution for infusion.

Main physicochemical characteristics: porous mass or powder, white to almost white in color.

Pharmacotherapeutic group. Antifungal agents for systemic use.

ATC code J02A X05.

Pharmacological properties.

Pharmacodynamics.

Micafungin non-competitively inhibits the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall. 1,3-β-D-glucan is absent in mammalian cells.

Micafungin exhibits fungicidal activity against Candida species and has pronounced fungistatic effects against Aspergillus spp.

Micafungin is active in vitro against various Candida spp., including Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, Candida kefyr, Candida parapsilosis, Candida guilliermondii, Candida lusitaniae, and against Aspergillus spp., including Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Aspergillus nidulans, Aspergillus versicolor, as well as dimorphic fungi (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis). The drug is not active in vitro against Cryptococcus spp., Pseudallescheria spp., Scedosporium spp., Fusarium spp., Trichosporon spp., or Zygomycetes.

The likelihood of developing secondary resistance to the drug is very low.

Pharmacokinetics.

Absorption. Micafungin is a medicinal product administered intravenously.

The pharmacokinetics are linear within the daily dose range of 12.5 mg to 200 mg and 3 mg/kg to 8 mg/kg. There are no data indicating systemic accumulation of the drug following multiple doses; steady-state concentration is achieved within 4–5 days after initiation of treatment.

Distribution. Following intravenous administration, micafungin exhibits a biphasic decline in plasma concentration. The drug rapidly distributes into tissues. In systemic circulation, micafungin is highly bound to plasma proteins (>99%), primarily to albumin. Binding to albumin is stable within the concentration range of 10–100 μg/mL. The volume of distribution at steady state (Vss) is 18–19 liters.

Metabolism. Micafungin circulates in systemic blood predominantly in unchanged form. It undergoes metabolism to form several compounds; metabolites M-1 (catechol derivative), M-2 (methoxy derivative of M-1), and M-5 (formed by hydroxylation in the side chain), derivatives of micafungin, have been detected in systemic circulation. Exposure to these metabolites is low, and they do not influence the overall efficacy of micafungin.

Although in vitro studies indicate that micafungin may be metabolized by CYP3A isoenzymes, CYP3A-mediated hydroxylation is not the primary metabolic pathway in vitro.

Elimination and excretion. The elimination half-life is approximately 10–17 hours and remains constant across the dose range up to 8 mg/kg after both single and multiple doses. Total clearance is 0.15–0.3 mL/min/kg in healthy volunteers and adult patients and is independent of dose following both single and multiple administrations. Twenty-eight days after a single intravenous dose of 14C-micafungin (25 mg) administered to healthy volunteers, 11.6% of the radioactive label was recovered in urine and 71.0% in feces. Metabolites M-1 and M-2 were detected only in trace concentrations in plasma, while metabolite M-5, formed in greater amounts, accounted for 6.5% of the parent compound.

Pharmacokinetics in specific patient populations

Pediatric patients. In children, the area under the plasma concentration-time curve (AUC) was dose-proportional within the dose range of 0.5–4 mg/kg. Clearance was body weight-dependent. Mean clearance values, adjusted for body weight, were 1.35 times higher in younger children (4 months–5 years) and 1.14 times higher in children aged 6–11 years. In older children (12–16 years), clearance values were similar to those in adult patients. Mean clearance, adjusted for body weight, in infants under 4 months of age was approximately 2.6 times higher than in older children (12–16 years) and 2.3 times higher than in adults. Pharmacokinetic/pharmacodynamic studies demonstrated that micafungin penetrates into the central nervous system (CNS), achieving a minimum AUC of 170 μg•h/L, which is sufficient for maximal eradication of fungal infection in CNS tissues. Population pharmacokinetic modeling indicates that a dose of 10 mg/kg in children under 4 months of age is adequate to achieve the target exposure for treatment of Candida-related CNS infections.

Elderly patients. After administration of a single 50 mg dose via one-hour infusion, the pharmacokinetics of micafungin in elderly patients (66–78 years) were similar to those in younger patients (20–24 years). Dose adjustment is not required for elderly patients.

Patients with hepatic impairment. In a study involving patients with moderate hepatic impairment (Child-Pugh classes 7–9), the pharmacokinetics of micafungin were slightly different from those in healthy volunteers. Therefore, dose adjustment is not necessary for patients with mild to moderate hepatic dysfunction. The pharmacokinetics of micafungin have not been studied in patients with severe hepatic impairment.

Patients with renal impairment. Severe renal impairment (glomerular filtration rate [GFR] <30 mL/min) did not significantly affect the pharmacokinetics of micafungin. Dose adjustment is not required for patients with renal impairment.

Sex/Race. Sex and race do not influence the pharmacokinetic parameters of micafungin.

Clinical characteristics.

Indications.

Adults and children aged 16 years and older:

treatment of invasive candidiasis;

treatment of esophageal candidiasis in patients requiring intravenous antifungal therapy;

prophylaxis of candidiasis in patients undergoing allogeneic hematopoietic stem cell transplantation or in whom neutropenia (neutrophil count < 500 cells per 1 µL) is anticipated for 10 or more days.

Children (including infants) under 16 years of age:

treatment of invasive candidiasis;

prophylaxis of Candida infection in patients undergoing allogeneic hematopoietic stem cell transplantation or in whom neutropenia (neutrophil count < 500 cells per 1 µL) is anticipated for 10 or more days.

When deciding on the use of micafungin, the potential risk of liver tumor development should be taken into account (see section "Special precautions"). Therefore, micafungin should be used only when other antifungal agents cannot be administered.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product, or to other echinocandins.

Interaction with other medicinal products and other forms of interactions.

Micafungin has a low potential for interactions with medicinal products metabolized via CYP3A.

There is no evidence of altered pharmacokinetics of micafungin when administered concomitantly with mycophenolate, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole, or amphotericin B. Dose adjustment of micafungin is not required in such cases.

When micafungin is administered, AUC of itraconazole, sirolimus, and nifedipine increased slightly (by 22%, 21%, and 18%, respectively). Patients receiving sirolimus, nifedipine, or itraconazole in combination with micafungin require monitoring for toxic effects of sirolimus, nifedipine, or itraconazole. If necessary, the dose of these medicinal products should be reduced.

Concomitant administration of micafungin and amphotericin B deoxycholate increases the exposure to amphotericin B deoxycholate by 30%. Since this may be clinically significant, concomitant use of these medicinal products should be prescribed only if the benefit clearly outweighs the risk and with careful monitoring of amphotericin B deoxycholate toxicity (see section "Special precautions").

In patients receiving sirolimus, nifedipine, or itraconazole concomitantly with micafungin, monitoring for toxicity of sirolimus, nifedipine, or itraconazole should be performed, and the dose of sirolimus, nifedipine, or itraconazole should be reduced if necessary (see section "Special precautions").

Special precautions for use

In animals treated for 3 months or longer, foci of altered hepatocytes (FAH) and hepatocellular tumors have been observed. The threshold for tumor formation in animals is approximately within the range of clinical exposure. The significance of this finding in human treatment cannot be excluded. Careful monitoring of liver function is required during micafungin use. To minimize the risk of adaptive regeneration and considering the potential for liver tumor formation, discontinuation of the drug is recommended if significant, persistent elevations in ALT/AST levels are detected.

Micafungin treatment should be administered only after careful consideration of the risk-benefit ratio, especially in patients with severe hepatic impairment or chronic liver diseases representing premalignant conditions, such as marked liver fibrosis, cirrhosis, viral hepatitis, neonatal liver disease, or inherited enzymopathies, as well as when concomitantly using medicinal products with hepatotoxic and/or genotoxic effects.

Micafungin therapy may be associated with significant liver dysfunction (elevation of ALT, AST, or total bilirubin more than 3 times the upper limit of normal) in both healthy volunteers and patients. In some cases, more severe liver dysfunction, hepatitis, or liver failure with fatal outcome have been reported. Infants under 1 year of age are more susceptible to liver injury (see section "Adverse reactions").

Anaphylactoid reactions, including shock, may occur during micafungin administration. If such reactions occur, micafungin infusion must be discontinued immediately and appropriate treatment initiated.

Severe skin reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis, have been reported. Patients who develop skin rashes should be closely monitored, and micafungin should be discontinued if symptoms progress.

Rare cases of hemolysis, including acute intravascular hemolysis and hemolytic anemia, have been observed in patients receiving micafungin. Patients who develop clinical or laboratory signs of hemolysis during micafungin therapy should be closely monitored, and the risk-benefit ratio should be reassessed before continuing treatment.

Micafungin may cause renal complications, renal failure, and abnormal renal function laboratory parameters; therefore, careful monitoring of renal function is required.

Concomitant use of micafungin and deoxycholate amphotericin B should only be considered when the expected benefit outweighs the risk and under strict monitoring of deoxycholate amphotericin B toxicity (see section "Interaction with other medicinal products and other forms of interaction").

In patients receiving sirolimus, nifedipine, or itraconazole concomitantly with micafungin, toxicity of sirolimus, nifedipine, or itraconazole should be monitored, and the dose of sirolimus, nifedipine, or itraconazole should be reduced if necessary (see section "Interaction with other medicinal products and other forms of interaction"). The frequency of certain adverse reactions is higher in children compared to adults (see section "Adverse effects").

Precautions related to excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

There are no data on the use of micafungin in pregnant women. In animal studies, micafungin crossed the placental barrier and reproductive toxicity was observed. The potential risk to humans is unknown. Micafungin should not be used during pregnancy unless clearly necessary.

It is unknown whether micafungin is excreted in human breast milk. Animal studies have shown that micafungin is excreted in milk. The decision to continue or discontinue breastfeeding or to continue or discontinue micafungin therapy should be made considering the benefit to the mother and the potential risk to the infant.

Testicular toxicity was observed in animal studies. Micafungin may affect male fertility in humans.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of the drug on the ability to drive or operate machinery have not been conducted; however, adverse reactions may affect this ability (see section "Adverse reactions").

Method of Administration and Dosage.

Official guidelines for the use of antifungal agents should be followed.

Micafungin must be prescribed by a physician experienced in the management of fungal infections.

Specimens for fungal culture testing and other relevant laboratory investigations (including histopathological) should be performed prior to initiating therapy.

Treatment may be initiated before laboratory results are available. However, antifungal therapy should be appropriately adjusted once results are obtained.

The dosing regimen of Micafungin depends on the patient's body weight (see Tables 1 and 2).

Table 1

Micafungin Dosing Regimen for Adults and Adolescents Aged 16 Years and Older, and Elderly Patients

*If the patient's response to treatment is inadequate, for example, in case of pathogen persistence or lack of positive clinical progress, the dose may be increased to 200 mg/day for patients with body weight > 40 kg or to 4 mg/kg/day for patients with body weight < 40 kg.

Treatment Duration

Invasive candidiasis. Treatment of candidiasis should be continued for at least 14 days. Antifungal therapy should be continued for at least one week after obtaining two consecutive negative blood culture results and after resolution of clinical symptoms of candidiasis.

Esophageal candidiasis. When treating esophageal candidiasis, micafungin should be administered for at least one week after resolution of clinical symptoms.

Prophylaxis of Candida infection. For prophylaxis of fungal infections caused by Candida species, micafungin should be administered for at least one week after recovery of normal neutrophil counts.

Table 2

Micafungin dosing regimen for children aged ≥4 months and adolescents <16 years

*In case of inadequate patient response to treatment, e.g. in case of pathogen persistence or lack of positive clinical dynamics, the dose may be increased to 200 mg/day for patients with body weight > 40 kg or to 4 mg/kg/day for patients with body weight < 40 kg.

Use in children (including newborns) under 4 months of age

*Micafungin administered at a dose of 4 mg/kg in children under 4 months of age approaches the drug exposure observed in adult patients receiving 100 mg/day for the treatment of invasive candidiasis. Higher doses (e.g., 10 mg/kg) should be used if CNS infection is suspected, as micafungin penetration into the CNS (see section "Pharmacokinetics") is dose-dependent.

The safety and efficacy of micafungin use in children (including neonates) under 4 months of age at doses ranging from 4 to 10 mg/kg/day for the treatment of CNS-involving invasive candidiasis have not been adequately studied in controlled clinical trials.

Treatment duration

Invasive candidiasis. Treatment of candidiasis should be continued for at least 14 days. Antifungal therapy should continue for at least one week after obtaining two consecutive negative blood culture results and after resolution of clinical signs and symptoms of candidiasis.

Prophylaxis against Candida infection. For prophylaxis of fungal infections caused by Candida species, micafungin should be administered for at least one week after recovery of normal neutrophil counts. Experience with micafungin treatment in patients under 2 years of age is limited.

Gender/Race

There is no need to adjust the dose based on patient gender or race (see section "Pharmacokinetic properties").

Treatment of patients with hepatic impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment (see section "Pharmacological properties").

There are currently no data on the use of micafungin in patients with severe hepatic impairment; therefore, the use of this medicinal product is not recommended in this patient population (see sections "Pharmacological properties" and "Special precautions for use").

Treatment of patients with renal impairment

Dose adjustment is not required in patients with renal impairment (see section "Pharmacological properties").

Method of administration

After reconstitution and dilution, the medicinal product must be administered intravenously by infusion over 1 hour. More rapid administration may lead to histamine-mediated allergic reactions.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Micafungin should not be mixed or co-administered with other medicinal products except those specified below. Micafungin, powder for solution for infusion, should be reconstituted and diluted at room temperature under aseptic conditions:

1. Remove the plastic cap from the vial and disinfect the stopper with alcohol.
2. Aseptically and slowly inject 5 mL of 0.9% sodium chloride solution for injection or 5% glucose solution for injection (drawn from a 100 mL vial/bag) down the inner wall of each vial. Efforts should be made to minimize foaming during reconstitution. Reconstitute sufficient vials of micafungin to obtain the required full dose (see Table 3).
3. Gently rotate the vial. Do not shake. The powder should dissolve completely. The reconstituted solution should be used immediately. The vial is intended for single use only. Any unused concentrate should be discarded immediately.
4. Withdraw the entire reconstituted concentrate from each vial and transfer it into the infusion vial/bag containing the diluent from which the 5 mL was initially withdrawn (see step 2). The diluted solution should be used immediately. The chemical and physical stability of the solution is maintained for up to 96 hours at 25°C, provided the solution is protected from light and dilution has been performed as described.
5. Gently invert the infusion vial/bag, but do not shake, to avoid foaming. Do not use the solution if it is cloudy or contains particulate matter.
6. The infusion vial/bag containing the diluted infusion solution should be placed in an opaque bag to protect from light.

Table 3

Preparation of infusion solution

After reconstitution and dilution, the solution should be administered by intravenous infusion over a period of 1 hour.

Children.

The drug is used in pediatric practice (see section "Indications").

Overdose.

In clinical studies, daily doses of up to 8 mg/kg (maximum total dose – 896 mg) were administered to adult patients, and there were no reports of dose-limiting toxicity. A single spontaneous case has been reported in which a newborn infant received a dose of 16 mg/kg/day. This high dose did not cause any adverse reactions.

There are no data on micafungin overdose. In the event of a suspected overdose, general supportive measures should be taken and symptomatic treatment administered. Micafungin is highly protein-bound and is not removed by dialysis.

Adverse reactions

The safety profile of micafungin was evaluated in 3028 patients who received this drug during clinical studies: 2002 patients had Candida infection, including candidemia, invasive candidiasis, and esophageal candidiasis; 375 had invasive aspergillosis (predominantly refractory infection); and 651 patients received micafungin for prophylaxis of systemic fungal infection.

Patients receiving micafungin in clinical trials represent a population of severely ill patients with underlying conditions requiring concomitant use of multiple medications, including anticancer therapy, potent systemic immunosuppressants, and broad-spectrum antibiotics. These patients had numerous comorbidities, such as hematologic malignancies and HIV infection, or were transplant recipients and/or treated in intensive care units. Patients undergoing hematopoietic stem cell transplantation and at high risk of fungal infections received micafungin prophylactically.

Overall, adverse reactions were observed in 32.2% of patients. The most frequently reported adverse reactions were nausea (2.8%), increased alkaline phosphatase (2.7%), phlebitis (2.5%), predominantly in HIV-infected patients with peripheral catheters, vomiting (2.5%), and increased aspartate aminotransferase (2.3%). There were no clinically significant differences in safety data when analyzed by patient sex or race.

In Table 4, adverse reactions are listed by MedDRA classification system and categorized by frequency in decreasing order of severity.

Table 4

Possible allergic-type symptoms

During clinical trials, symptoms such as rash and chills were observed. Most symptoms were of mild or moderate severity and did not require discontinuation of treatment. Serious reactions during micafungin therapy were infrequent (e.g., anaphylactoid reaction in 0.2% or 6/3028 patients) and occurred only in patients with serious underlying conditions (e.g., patients with advanced AIDS, malignancy) who required concomitant administration of multiple medications.

Hepatic function-related adverse reactions

During clinical trials, the overall incidence of adverse reactions related to liver function in patients treated with micafungin was 8.6% (260/3028). Most adverse reactions were of mild or moderate severity. The most common adverse reactions included increased levels of alkaline phosphatase (ALP) (2.7%), AST (2.3%), ALT (2.0%), blood bilirubin (1.6%), and abnormal liver function test results (1.5%). A small number of patients discontinued treatment due to adverse reactions (1.1%; 0.4% – serious adverse reactions). Cases of serious liver dysfunction were infrequent (see section "Special precautions").

Injection site reactions

None of the injection site adverse reactions required discontinuation of treatment.

Paediatric population

The frequency of some of the adverse reactions listed below was higher in children than in adults. In addition, in children under 1 year of age, increases in ALT, AST, and alkaline phosphatase levels occurred twice as often as in older children (see section "Special precautions"). The most likely reason for these differences was the underlying diseases, which differed from those observed in clinical trials in adult and older paediatric patients. For example, neutropenia was observed several times more frequently in paediatric patients than in adults (40.2% and 7.3% in children and adults, respectively). This also applies to allogeneic HSCT indicators (29.4% and 13.4%, respectively) and haematological malignancies (29.1% and 8.7%, respectively).

Blood and lymphatic system disorders: common – thrombocytopenia.

Cardiac disorders: common – tachycardia.

Vascular disorders: common – arterial hypertension and hypotension.

Hepatobiliary disorders: common – hyperbilirubinemia, hepatomegaly.

Renal and urinary disorders: common – acute renal failure, increased blood urea levels.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions in accordance with local requirements.

Shelf life. 24 months.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Reconstituted solution in vial.

Chemical and physical in-use stability has been demonstrated for up to 48 hours at a temperature not exceeding 25 °C when 0.9% sodium chloride solution or 5% glucose solution is used as diluent.

Infusion solution after dilution.

Chemical and physical in-use stability is maintained for up to 96 hours at 25 °C, provided the solution is protected from light and 0.9% sodium chloride solution or 5% glucose solution is used as diluent.

Micafungin does not contain preservatives. From a microbiological point of view, the solution should be used immediately. If not used immediately, the responsibility for storage duration and conditions lies with the user. Under normal circumstances, storage in a glass vial should not exceed 24 hours at 2–8 °C, unless the solution is prepared under strictly controlled and validated aseptic conditions.

Packaging. Powder for concentrate for solution for infusion, 50 mg or 100 mg, 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC «PHARMIDEA» / Limited Liability Company «PHARMIDEA».

Address of manufacturer and location of its business operations.

4 Rupnicu Str., Olaine, Olaine district, LV-2114, Latvia.