Mikaliof rompharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MICALIOF ROMPHARM

Composition:

Active substance: micafungin (as micafungin sodium);

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

Excipients: lactose monohydrate; citric acid; sodium hydroxide.

Pharmaceutical form. Lyophilisate for preparation of a concentrate for solution for infusion.

Main physicochemical characteristics: white or almost white powder (50 mg strength);

white or almost white powder or compacted mass (100 mg strength).

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.

In vitro, micafungin is active 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., and zygomycetes.

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

Pharmacokinetics

Absorption. Micalioph Rompharm is an intravenous medicinal product.

Pharmacokinetics are linear within the daily dose range of 12.5 mg to 200 mg and from 3 mg/kg to 8 mg/kg. There are no data indicating systemic accumulation of the drug with multiple dosing; steady-state concentration is achieved within 4–5 days of initiation.

Distribution. After intravenous administration, micafungin plasma concentrations decline in a biphasic exponential manner. 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 over a concentration range of 10–100 mcg/mL. The volume of distribution at steady state (Vss) is 18–19 liters.

Metabolism. Micafungin circulates in the systemic circulation predominantly in unchanged form. It undergoes metabolism to form several compounds, among which M-1 (catechol derivative), M-2 (methoxy derivative of M-1), and M-5 (formed via side-chain hydroxylation) have been detected in systemic circulation. Exposure to these metabolites is low, and they do not contribute significantly to 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 after 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 amounts in plasma, while metabolite M-5, formed in greater quantity, 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, corrected for body weight, were 1.35 times higher in younger children (4 months to 5 years) and 1.14 times higher in children aged 6 to 11 years. In older children (12–16 years), clearance values were similar to those in adults. Mean clearance, corrected 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 mcg×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 is adequate in children under 4 months of age to achieve target exposure for the treatment of Candida-related CNS infections.

Elderly Patients. After a single 50 mg infusion, the pharmacokinetics of micafungin in elderly patients (66–78 years) were similar to those in younger subjects (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 <30 mL/min) had no significant effect on the pharmacokinetics of micafungin. Dose adjustment is not required for patients with renal impairment.

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

Clinical characteristics.

Indications.

For 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.

For 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 whether to use Mikafof Rompharm, the potential risk of liver tumors should be taken into account (see section "Special precautions"). Therefore, Mikafof Rompharm should be used only when other antifungal agents cannot be used.

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 interaction.

Micafungin has a low potential for interaction with medicinal products metabolized by CYP3A.

There is no evidence of changes in micafungin pharmacokinetics when co-administered with drugs such as mycophenolate, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole, and amphotericin B. Dose adjustment of micafungin is not required in such cases.

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

When micafungin is used concomitantly with amphotericin B deoxycholate, the exposure to amphotericin B deoxycholate increases by 30%. Since this may be clinically significant, concomitant administration 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 Mikafof Rompharm, 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 administration. In order to minimize the risk of adaptive regeneration, and considering the potential for hepatic tumor formation, discontinuation of the drug is recommended upon detection of significant, persistent elevation of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST).

Micafungin treatment should be administered with careful consideration of the risk-benefit ratio, particularly 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 function abnormalities (elevation of ALT, AST, or total bilirubin more than 3 times the upper limit of normal) in both healthy volunteers and patients. In individual cases, more severe liver dysfunction, hepatitis, or hepatic failure with fatal outcome have been observed. Infants under 1 year of age are more susceptible to liver injury (see section "Adverse reactions").

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

Severe skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. If skin rashes occur in patients, careful monitoring is required, 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 treatment should be closely monitored, and the benefit-risk ratio should be reassessed before continuing therapy.

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

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

In patients receiving sirolimus, nifedipine, or itraconazole concomitantly with Micalief Rompharm, 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 Micalief Rompharm in pregnant women. In animal studies, micafungin crossed the placental barrier and reproductive toxicity was observed. The potential risk for humans is unknown. Micalief Rompharm 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. A decision regarding continuation/discontinuation of breastfeeding or continuation/discontinuation of Micalief Rompharm therapy should be made, taking into account the benefit to the mother and the risk to the infant.

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

Ability to influence the ability to drive and use machines

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

Dosage and Administration

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

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

Specimens for fungal cultures and other relevant laboratory tests (including histopathological examinations) should be obtained prior to initiating therapy.

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

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

Table 1

Dosing regimen of Micafungin Rompharm for adults and children aged 16 years and older, and elderly patients

*In case of inadequate patient response to treatment, 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 Rompharm should be administered for at least one week after the resolution of clinical symptoms.

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

Table 2

Dosage regimen of Micafungin Rompharm for children aged ≥4 months and adolescents <16 years

*In case of inadequate patient response to treatment, for example, 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 exposure in children under 4 months of age receiving a dose of 4 mg/kg approaches the 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 central nervous system (CNS) infection is suspected, as micafungin penetration into the CNS (see section "Pharmacokinetics") is dose-dependent.

The safety and efficacy of the medicinal product in children (including neonates) under 4 months of age receiving doses from 4 to 10 mg/kg/day for the treatment of CNS-involved 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 be continued for at least one week after obtaining two consecutive negative blood culture results and after resolution of clinical signs and symptoms of candidiasis.

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

Gender/race

Dose adjustment based on patient gender or race is not required (see section "Pharmacokinetic properties").

Treatment of patients with hepatic impairment

No dose adjustment is necessary for patients with mild or moderate hepatic impairment (see section "Pharmacological properties").

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

Treatment of patients with renal impairment

No dose adjustment is necessary for patients with renal impairment (see section "Pharmacological properties").

Administration method

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

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

Micaliof Rompharm must not be mixed or co-administered with other medicinal products except those specified below. Micaliof Rompharm, lyophilisate for preparation of concentrate for solution for infusion, should be reconstituted and diluted at room temperature under aseptic conditions as follows:

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 injection solution or 5% glucose injection solution (drawn from a 100 mL vial/bag) into each vial along the inner wall. Minimize foaming during reconstitution. Reconstitute sufficient vials of Micaliof Rompharm 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; therefore, any unused concentrate should be immediately discarded.
4. Withdraw the entire reconstituted concentrate from each vial and transfer it into the infusion vial/bag containing the diluent from which it was originally drawn (see step 2). The diluted solution should be used immediately. Chemical and physical stability is maintained for up to 96 hours at 25°C when protected from light and 0.9% sodium chloride solution is used as diluent, or up to 48 hours at 25°C when protected from light and 5% glucose solution is used as diluent.
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 medicinal product is used in pediatric practice (see section "Indications").

Overdose.

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

There is no information available 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 has been evaluated in 3028 patients who received this drug during clinical studies: 2002 patients had Candida infection, including candidemia, invasive candidiasis, and esophageal candidiasis; 375 patients had invasive aspergillosis (predominantly refractory infection); and 651 patients received micafungin for prophylaxis of systemic fungal infection.

Patients receiving micafungin in clinical studies represent a population of severely ill patients with underlying conditions requiring concomitant use of multiple medications, including antineoplastic therapy, potent systemic immunosuppressants, and broad-spectrum antibiotics. These patients had numerous underlying diseases, 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 for fungal infections received micafungin prophylactically.

Overall, adverse reactions were reported 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 lines, vomiting (2.5%), and increased aspartate aminotransferase (2.3%). Analysis of safety data revealed no clinically significant differences based on patient sex or race.

In Table 4, adverse reactions are classified according to MedDRA and listed by system organ class in decreasing order of frequency.

Table 4

Possible allergic-type symptoms

During clinical trials, symptoms such as rash and chills were observed. Most symptoms were of mild to moderate severity and did not require discontinuation of treatment. Serious reactions during micafungin treatment were infrequent (e.g., anaphylactoid reaction in 0.2% or 6/3028 patients) and occurred only in patients with severe underlying conditions (e.g., patients with advanced AIDS, malignancies), 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 of these 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").

Pediatric 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, increased levels of ALT, AST, and alkaline phosphatase were observed twice as often as in older children (see section "Special precautions"). The most likely reason for these differences was the underlying conditions, which differed from those observed in clinical trials in adult and older pediatric patients. For example, neutropenia was observed several times more frequently in pediatric patients than in adults (40.2% and 7.3% in children and adults, respectively). This also applies to allogeneic hematopoietic stem cell transplantation (HSCT) (29.4% and 13.4%, respectively) and hematologic malignancies (29.1% and 8.7%, respectively).

Blood-related: Common — thrombocytopenia.

Cardiac: Common — tachycardia.

Vascular disorders: Common — arterial hypertension and hypotension.

Hepatobiliary system: Common — hyperbilirubinemia, hepatomegaly.

Renal and urinary system: Common — acute renal failure, increased blood urea levels.

Shelf life. 3 years.

Storage conditions.

Micafiol Rompharm 50 mg should be stored in the original packaging to protect from light at a temperature not exceeding 25 °C.

Micafiol Rompharm 100 mg should be stored at a temperature not exceeding 25 °C.

Reconstituted solution in vial.

Chemical and physical stability is maintained for up to 48 hours at a temperature not exceeding 25 °C, provided the solution is protected from light and 0.9% sodium chloride solution or 5% glucose solution is used as diluent.

Infusion solution after dilution.

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

Chemical and physical stability is maintained for up to 48 hours at 25 °C, provided the solution is protected from light and 5% glucose solution is used as diluent.

Micafiol Rompharm contains no preservatives. From a microbiological standpoint, the reconstituted and diluted solution should be used immediately unless reconstitution/dilution was performed under aseptic conditions. If the solution is not used immediately, responsibility for storage duration and conditions lies with the user.

Keep out of reach of children.

Incompatibility. Micafiol Rompharm must not be mixed or administered simultaneously with other medicinal products except those specified in the section "Dosage and administration".

Packaging. Lyophilisate for preparation of concentrate for infusion solution, 50 mg or 100 mg, 1 vial per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

K.T. Rompharm Company S.R.L.

Manufacturer's address and location of business activity.

Street Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania