Micafungin-teva

INSTRUCTION FOR MEDICAL USE OF MEDICINAL PRODUCT MICAFUNGIN-TEVA (MICAFUNGIN-TEVA)

Composition:

Active substance: micafungin;

1 vial contains micafungin 50 mg or 100 mg as micafungin sodium 50.86 mg or 101.73 mg;

Excipients: citric acid, sucrose, sodium hydroxide (if necessary).

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical characteristics: white to almost white powder.

Pharmacotherapeutic group. Antifungal agents for systemic use.

ATC code J02A X05.

Pharmacological properties.

Mechanism of action.

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 activity against Aspergillus spp.

Pharmacodynamics.

In animal models of candidiasis, a correlation was observed between micafungin effect, normalized by MIC (AUC/MIC), and efficacy defined as the ratio required to prevent progressive fungal growth. Ratios of ~2400 and ~1300 were required for C. albicans and C. glabrata, respectively. At the recommended therapeutic dose of micafungin, these ratios are achievable for wild-type Candida spp isolates.

Resistance mechanisms. As with all antimicrobial agents, cases of reduced susceptibility and resistance have been reported; cross-resistance with other echinocandins cannot be excluded. Reduced susceptibility to echinocandins has been associated with mutations in the Fks1 and Fks2 genes encoding the primary subunit of glucan synthase.

Breakpoints.

EUCAST Breakpoints
Candida species	Breakpoint MIC (mg/l)
	≤ S (susceptible)	> R (resistant)
Candida albicans	0.016	0.016
Candida glabrata	0.03	0.03
Candida parapsilosis	0.002	2
Candida tropicalis1	Insufficient data
Candida krusei1	Insufficient data
Candida guilliermondii1	Insufficient data
Other Candida spp.	Insufficient data
1MICs for C. tropicalis are 1–2 doubling dilutions higher than for C. albicans and C. glabrata. In clinical studies, successful outcomes for C. tropicalis were slightly lower than for C. albicans at both doses (100 and 150 mg/day). However, the difference was not significant, and it is unknown whether it translates into a relevant clinical difference. MICs for C. krusei are approximately 3 doubling dilutions higher than for C. albicans, and similarly, for C. guilliermondii, approximately 8 doubling dilutions higher. Moreover, these species were included only in a small number of cases in clinical trials. This means there is insufficient evidence to consider the wild-type populations of these pathogens susceptible to micafungin.

Clinical efficacy and safety.

Candidemia and invasive candidiasis. Micafungin (100 mg/day or 2 mg/kg/day) was as effective and better tolerated than liposomal amphotericin B (3 mg/kg) as first-line therapy for candidemia and invasive candidiasis in a randomized, double-blind, multinational comparative efficacy study.

Micafungin and liposomal amphotericin B were administered for a mean duration of 15 days (range from 4 to 42 days in adults, from 12 to 42 days in children).

Equivalence was demonstrated in adult patients, with similar results observed in pediatric subpopulations (including neonates and preterm infants). Efficacy data were consistent and independent of the Candida infecting species, primary site of infection, and neutropenic status. Micafungin demonstrated a smaller mean peak decline in estimated glomerular filtration rate during treatment (p<0.001) and a lower incidence of infusion-related reactions (p=0.001) compared to liposomal amphotericin B.

Overall treatment success according to protocol, invasive candidiasis study

	Micafungin		Liposomal amphotericin B		% difference [95 % CI]
	N	n (%)	N	n (%)
Adult patients
Overall treatment success	202	181 (89.6)	190	170 (89.5)	0.1[-5.9, 6.1]†
Overall treatment success by neutropenic status
Neutropenia at baseline	24	18 (75.0)	15	12 (80.0)	0.7[-5.3, 6.7]‡
No neutropenia at baseline	178	163 (91.6)	175	158 (90.3)
Children
Overall treatment success	48	35 (72.9)	50	38 (76.0)	-2.7[-17.3, 11.9]‡
Children aged < 2 years	26	21 (80.8)	31	24 (77.4)
Preterm children	10	7 (70.0)	9	6 (66.7)
Neonates (age from 0 days to < 4 weeks)	7	7 (100)	5	4 (80)
Children aged 2 to 15 years	22	14 (63.6)	19	14 (73.7)
Adults and children, overall treatment success by Candida species
Candida albicans	102	91 (89.2)	98	89 (90.8)
Non-albicans species: all	151	133 (88.1)	140	123 (87.9)
C. tropicalis	59	54 (91.5)	51	49 (96.1)
C. parapsilosis	48	41 (85.4)	44	35 (79.5)
C. glabrata	23	19 (82.6)	17	14 (82.4)
C. krusei	9	8 (88.9)	7	6 (85.7)

† Micafungin level minus liposomal amphotericin B level, two-sided 95% confidence interval of the difference in overall success rate based on a large sample with distribution approximating normal.

‡ Adjusted for neutropenic status; primary endpoint.

§ Pediatric population was not included in the efficacy comparison.

Clinical efficacy was also observed (< 5 patients) for the following Candida species: C. guilliermondii, C. famata, C. lusitaniae, C. utilis, C. inconspicua, and C. dubliniensis.

Esophageal candidiasis. In a randomized, double-blind study comparing micafungin and fluconazole as first-line treatment for esophageal candidiasis, 518 patients received at least one dose of the investigational drug. The mean duration of treatment was 14 days, with a mean daily dose of 150 mg for micafungin (N=260) and 200 mg for fluconazole (N=258). Endoscopic assessment of 0 (endoscopically healed) at the end of treatment was observed in 87.7% (228/260) and 88.0% (227/258) of patients in the micafungin and fluconazole groups, respectively (95% CI for difference: [-5.9%, 5.3%]). The lower limit of the 95% CI was above the predefined equivalence margin of -10%, demonstrating equivalence. The nature and frequency of adverse reactions were similar between treatment groups.

Prophylaxis. Micafungin was more effective than fluconazole in preventing invasive fungal infections in a high-risk population for developing systemic fungal infection (patients undergoing hematopoietic stem cell transplantation) in a randomized, double-blind, multicenter study. Treatment efficacy was defined as the absence of proven, probable, or suspected systemic fungal infection at the end of therapy and the absence of proven or suspected systemic fungal infection at the end of the study. Most patients (97%, N=882) had neutropenia at study initiation (< 200 neutrophils/µL). Neutropenia persisted for a mean of 13 days. Micafungin was administered at a fixed daily dose of 50 mg (1.0 mg/kg), and fluconazole at 400 mg (8 mg/kg). The mean duration of treatment was 19 days for micafungin and 18 days for fluconazole in adults (N=798), and 23 days for both groups in children (N=84).

The treatment efficacy rate was statistically significantly higher for micafungin than for fluconazole (1.6% vs. 2.4% breakthrough infections). Breakthrough Aspergillus infections occurred in 1 vs. 7 patients, and proven or probable breakthrough Candida infections occurred in 4 vs. 2 patients in the micafungin and fluconazole groups, respectively. Other breakthrough infections were caused by Fusarium (1 and 2 patients, respectively) and Zygomycetes (1 and 0 patients, respectively). The nature and frequency of adverse reactions were similar between treatment groups.

Pharmacokinetics.

Absorption. The pharmacokinetics of micafungin are linear over the daily dose range of 12.5 mg to 200 mg and 3 mg/kg to 8 mg/kg. There are no data on systemic accumulation of the drug following multiple doses; steady-state concentrations are achieved within 4–5 days.

Distribution. Following intravenous administration, micafungin exhibits a biexponential 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 over the concentration range of 10–100 µg/mL. The volume of distribution at steady state (Vss) is 18–19 liters.

Biotransformation. Micafungin circulates in systemic blood predominantly in unchanged form. It undergoes metabolism to form several metabolites, among which M-1 (catechol form), M-2 (methoxy derivative of M-1), and M-5 (formed by hydroxylation of the side chain) 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 micafungin is a substrate for CYP3A in vitro, CYP3A-mediated hydroxylation is not the primary metabolic pathway for micafungin in vivo.

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 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. These data indicate that micafungin is primarily eliminated via non-renal pathways. Metabolites M-1 and M-2 were detected only in trace amounts in plasma, while metabolite M-5, formed in greater amounts, accounted for 6.5% of the parent compound.

Special patient groups.

Children. In children, AUC is dose-proportional over the dose range of 0.5–4 mg/kg. Clearance is body weight-dependent. Mean body weight-adjusted clearance values in younger children (4 months – 5 years) were 1.35 times higher, and in children aged 6–11 years, 1.14 times higher than in adults. In older children (12–16 years), clearance values were similar to those in adult patients. Mean body weight-adjusted clearance 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 dose-dependent penetration of micafungin into the central nervous system (CNS), with a minimum AUC of 170 µg*h/L required to achieve 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 sufficient to achieve the target exposure for treatment of Candida-related CNS infections.

Elderly patients. Following a single 50 mg dose administered as a 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 score 7–9), (n=8), the pharmacokinetics of micafungin did not differ significantly from those in healthy volunteers (n=8). Therefore, dose adjustment is not necessary for patients with mild to moderate hepatic impairment. In a study of patients with severe hepatic impairment (Child–Pugh score 10–12), (n=8), lower plasma concentrations of micafungin and higher plasma concentrations of the hydroxylated metabolite (M-5) were observed compared to healthy volunteers (n=8). These data are insufficient to make dosing recommendations for patients with severe hepatic impairment.

Patients with renal impairment. Severe renal impairment (glomerular filtration rate < 30 mL/min) did not significantly affect 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.

Adults, elderly patients and children ≥ 16 years of age:

• treatment of invasive candidiasis;
• treatment of esophageal candidiasis in patients requiring intravenous therapy;
• prevention of Candida infections in patients undergoing allogeneic hematopoietic stem cell transplantation or in whom neutropenia (neutrophil count < 500 cells/µL) is anticipated for 10 or more days.

Children (including infants) < 16 years of age:

• treatment of invasive candidiasis;
• prevention of Candida infections in patients undergoing allogeneic hematopoietic stem cell transplantation or in whom neutropenia (neutrophil count < 500 cells/µL) is anticipated for 10 or more days.

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

Official/national guidelines on the appropriate use of antifungal agents should also be taken into consideration.

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 administered concomitantly with such medicinal products as mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole, and amphotericin B. Dose adjustment of micafungin is not required when used concomitantly with these medicinal products.

When micafungin was administered, AUC of itraconazole, sirolimus, and nifedipine increased slightly (by 22%, 21%, and 18%, respectively).

Patients receiving sirolimus, nifedipine, or itraconazole concomitantly with micafungin require monitoring for toxic effects of sirolimus, nifedipine, or itraconazole and dose reduction of sirolimus, nifedipine, or itraconazole if necessary (see section "Special precautions").

When micafungin and amphotericin B deoxycholate are used concomitantly, 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 under strict monitoring of amphotericin B deoxycholate toxicity (see section "Special precautions").

Special precautions for use

In rats, after treatment lasting 3 months or longer, foci of altered hepatocytes (FAH) and hepatocellular tumors were observed. The potential threshold for tumor formation in rats is approximately within the range of clinical exposure. The clinical significance of these findings is unknown. Careful monitoring of liver function is required during micafungin treatment. To minimize the risk of adaptive regeneration and considering the possible development of liver tumors, discontinuation of the medicinal product is recommended if significant or persistent elevations in ALT/AST levels are detected.

Micafungin treatment should be administered with careful consideration of the risk-benefit ratio, especially in patients with severe hepatic dysfunction or chronic liver diseases that represent preneoplastic conditions, such as marked liver fibrosis, cirrhosis, viral hepatitis, liver diseases in infants, or congenital enzymopathies, as well as when co-administering medicinal products with hepatotoxic and/or genotoxic effects.

Micafungin treatment may be associated with significant worsening of liver function (increased ALT, AST, or total bilirubin levels more than 3 times the upper limit of normal) in both healthy volunteers and patients. In isolated 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").

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

Skin reactions. Serious exfoliative 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 the condition progresses.

Hemolysis. 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 for deterioration in their condition, and the risk-benefit ratio should be reassessed before considering continuation of therapy.

Kidneys. Micafungin may cause renal complications, renal failure, and changes in laboratory parameters of renal function; therefore, careful monitoring of kidney function is required.

Interaction with other medicinal products. Concomitant administration of micafungin and amphotericin B deoxycholate is possible only when the 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 micafungin, monitoring for toxicity of sirolimus, nifedipine, or itraconazole is recommended, or dose reduction of sirolimus, nifedipine, or itraconazole should be considered if necessary (see section "Interaction with other medicinal products and other forms of interaction").

Children. The frequency of certain adverse reactions is higher in children compared to adults (see section "Adverse reactions").

Excipients. This medicinal product contains less than 1 mmol (23 mg) of sodium per vial, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. 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-Teva should not be used during pregnancy unless clearly needed.

Breastfeeding. It is unknown whether micafungin is excreted in human breast milk. Animal studies have shown that micafungin is excreted in breast milk.

The decision to continue/stop breastfeeding or to continue/stop treatment with Micafungin-Teva should be made taking into account the benefit to the mother and the risk to the infant.

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

Ability to affect reaction speed when driving or operating machinery.

Micafungin has no effect or has a negligible effect on the ability to drive or operate machinery. However, patients should be informed that dizziness has been reported during micafungin treatment (see section "Adverse reactions").

Dosage and Administration

The medicinal product Micafungin-Teva must be prescribed by a physician experienced in the management of fungal infections.

Specimens for fungal culture and other relevant laboratory tests (including histopathological examinations) to identify the causative organism should be performed prior to initiating therapy.

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

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

Table 1

Dosing regimen for adults, children ≥ 16 years of age, and elderly patients

Indications	Body weight > 40 kg	Body weight < 40 kg
Treatment of invasive candidiasis	100 mg/day*	2 mg/kg/day*
Treatment of candidal esophagitis	150 mg/day	3 mg/kg/day
Prophylaxis of Candida infection	50 mg/day	1 mg/kg/day

* In case of inadequate patient response to treatment, e.g., pathogen resistance 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.

Duration of treatment.

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.

Esophageal candidiasis. When treating esophageal candidiasis, micafungin 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 should be administered for at least one week after recovery of normal neutrophil counts.

Table 2

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

Indications	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

* In cases of inadequate patient response to treatment, e.g., in case of pathogen resistance 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.

Table 3

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

Indications	Doses
Treatment of invasive candidiasis	4–10 mg/kg/day*
Prophylaxis of candidiasis	2 mg/kg/day

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

Duration of treatment.

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 of Candida infection. 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.

Patients with hepatic impairment. Dose adjustment is not required for patients with mild or moderate hepatic impairment (see section "Pharmacological properties"). There is no data on the use of micafungin in patients with severe hepatic impairment; therefore, the drug is not recommended for use in this patient population (see sections "Pharmacokinetic properties" and "Special precautions for use").

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

Children. Safety and efficacy in children (including neonates) under 4 months of age receiving doses of 4 and 10 mg/kg for treatment of invasive candidiasis with CNS involvement have not been sufficiently established. Available data are described in sections "Pharmacological properties" and "Adverse reactions".

Method of administration.

For intravenous use only.

After dilution and reconstitution, 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. Micafungin-Teva must not be mixed or co-administered with other medicinal products except as specified below.

At room temperature and under aseptic conditions, Micafungin-Teva, powder for solution for infusion, should be reconstituted and diluted as follows:

1. Remove the polypropylene cap from the vial and disinfect the rubber stopper with alcohol.
2. Aseptically and slowly inject 5 mL of 0.9% sodium chloride solution (9 mg/mL) for injection or 5% glucose solution (50 mg/mL) for injection (drawn from a 100 mL vial/bag) down the inner wall of each vial. Foaming should be minimized during reconstitution. Reconstitute sufficient vials of Micafungin-Teva to obtain the required total dose (see Table 4).
3. Gently rotate the vial. DO NOT SHAKE! The powder should dissolve completely. The reconstituted concentrate should be used immediately. The vial is intended for single use only. Any unused concentrate must be discarded immediately.
4. Withdraw the entire reconstituted concentrate from each vial and transfer it into an infusion bag/vial containing the infusion solution from which the diluent was initially withdrawn. The diluted solution should be used immediately. 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 diluted as described above.
5. Gently invert the infusion bag/vial, but DO NOT SHAKE, to avoid foaming. The solution must not be used if it is cloudy or contains particulate matter.
6. The infusion bag/vial containing the diluted infusion solution should be placed in an opaque bag to protect from light.

Table 4

Preparation of infusion solution

Dose (mg)	Micafungin-Teva vial for administration (mg/vial)	Volume of sodium chloride (0.9%) or glucose (5%) solution added to the vial	Volume (concentration) of reconstituted powder	Standard infusion (added to 100 mL), concentration of ready-to-use solution
50	1 × 50	5 mL	approximately 5 mL (10 mg/mL)	0.5 mg/mL
100	1 × 100	5 mL	approximately 5 mL (20 mg/mL)	1 mg/mL
150	1 × 100 + 1 × 50	5 mL	approximately 10 mL	1.5 mg/mL
200	2 × 100	5 mL	approximately 10 mL	2 mg/mL

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

Children.

The medicinal product is used in pediatric practice.

Overdose.

In clinical studies, repeated daily doses up to 8 mg/kg (maximum cumulative dose – 896 mg) were administered to adult patients without 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 are no data regarding micafungin overdose. In the event of a possible overdose, general supportive measures should be taken and symptomatic treatment administered. Micafungin is highly protein-bound in the blood and is not removed by dialysis.

Adverse reactions.

Summary of safety profile. During clinical studies, adverse reactions to the medicinal product were observed in 32.2% of patients. The most frequently reported adverse reactions were nausea (2.8%), increased alkaline phosphatase (ALP) levels – 2.7%, phlebitis (2.5%, mainly in HIV-infected patients with peripheral catheters), vomiting (2.5%), and increased AST levels (2.3%).

In the table below, adverse reactions are listed by system organ classes according to the MedDRA classification. Within each group, adverse reactions are presented in order of decreasing severity.

System Organ Classes	Common (≥ 1/100, < 1/10)	Uncommon (≥ 1/1000, < 1/100)	Rare (≥ 1/10000, < 1/1000)	Frequency not known (cannot be estimated from available data)
Blood and lymphatic system disorders	leukopenia, neutropenia, anemia	pancytopenia, thrombocytopenia, eosinophilia, hypoalbuminemia	hemolytic anemia, hemolysis (see section "Special precautions")	disseminated intravascular coagulation
Immune system disorders		anaphylactic/anaphylactoid reaction (see section "Special precautions"), hypersensitivity		anaphylactic/anaphylactoid shock (see section "Special precautions")
Endocrine disorders		hyperhidrosis
Metabolism and nutrition disorders	hypokalemia, hypomagnesemia, hypocalcemia	hyponatremia, hyperkalemia, hypophosphatemia, anorexia
Psychiatric disorders		insomnia, anxiety, confusion
Nervous system disorders	headache	drowsiness, tremor, dizziness, dysgeusia
Cardiac disorders		tachycardia, palpitations, bradycardia
Vascular disorders	phlebitis	arterial hypotension, arterial hypertension, flushing		shock
Respiratory, thoracic and mediastinal disorders		dyspnea
Gastrointestinal disorders	nausea, vomiting, diarrhea, abdominal pain	dyspepsia, constipation
Hepatobiliary disorders	increased levels of ALP, AST, ALT, serum bilirubin (particularly hyperbilirubinemia), abnormal liver function tests	hepatic failure (see section "Special precautions"), increased gamma-glutamyl transferase levels, jaundice, cholestasis, hepatomegaly, hepatitis		hepatocellular injury, including fatal cases (see section "Special precautions")
Skin and subcutaneous tissue disorders	rash	urticaria, pruritus, erythema		toxic skin eruptions, Stevens-Johnson syndrome, toxic epidermal necrolysis (see section "Special precautions")
Renal and urinary disorders		increased serum creatinine and urea, exacerbation of renal impairment		renal dysfunction (see section "Special precautions"), acute renal failure
General disorders and administration site conditions	hyperthermia, chills	thrombosis at injection site, inflammation at injection site, injection site pain, peripheral edema
Investigations		increased serum lactate dehydrogenase levels

Description of selected adverse reactions

Possible symptoms resembling allergic reactions. In clinical trials, symptoms such as rash and chills have been reported. Most of these were mild to moderate in severity and did not require discontinuation of treatment. Serious reactions during micafungin therapy have been infrequently reported (e.g., anaphylactoid reaction 0.2%, 6/3028), occurring only in patients with serious underlying conditions (e.g., progressive AIDS, malignancies) who required concomitant administration of multiple medications.

Hepatic-related adverse reactions. The overall incidence of hepatic adverse reactions in patients treated with micafungin in clinical trials was 8.6% (260/3028). Most of these adverse reactions were mild or moderate in 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 liver function test abnormalities (1.5%). Only a few patients (1.1%; 0.4% – serious adverse reactions) discontinued treatment due to hepatic adverse reactions. Cases of severe hepatic dysfunction occurred infrequently (see section "Special precautions").

Injection site reactions. None of the injection site adverse reactions limited therapy.

Children.

The incidence of certain 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 ALP levels were observed twice as frequently as in older children (see section "Special precautions"). The most likely reason for these differences was the differing baseline conditions compared to adults or older children observed in clinical trials. At the time of the study, the proportion of children with neutropenia was several times higher than in adult patients (40.2% vs. 7.3%, respectively), as well as those with allogeneic HSCT (29.4% vs. 13.4%, respectively) and hematological malignancies (29.1% vs. 8.7%, respectively).

Blood and lymphatic system disorders: frequently – thrombocytopenia.

Cardiac disorders: frequently – tachycardia.

Vascular disorders: frequently – hypertension, hypotension.

Hepatobiliary disorders: frequently – hyperbilirubinemia, hepatomegaly.

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

Reporting suspected adverse reactions

It is very important to report suspected adverse reactions after marketing authorization of the medicinal product. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. The medicinal product does not require special storage conditions.

Reconstituted concentrate in the vial

Chemical and physical in-use stability has been demonstrated for 48 hours at 25 °C when diluted with 0.9% (9 mg/mL) sodium chloride solution or 5% (50 mg/mL) glucose solution.

Diluted infusion solution

Chemical and physical in-use stability has been demonstrated for 96 hours at 25 °C protected from light and when diluted with 0.9% (9 mg/mL) sodium chloride solution or 5% (50 mg/mL) glucose solution.

From a microbiological standpoint, the reconstituted concentrate and diluted solution should be used immediately. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user and should not exceed 24 hours at 2–8 °C, unless reconstitution has been carried out under controlled and validated aseptic conditions.

Keep out of the reach of children.

Incompatibilities.

The medicinal product should not be mixed with other medicinal products except as specified in the section "Dosage and administration".

Packaging. 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Actavis Italia S.p.A.

Manufacturer's address and place of business.

Via Pasteur 10, 20014 Nerviano (Milan province), Italy.