Anidulafungin rompharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANIDULAFUNGIN ROMPHARM (ANIDULAFUNGIN ROMPHARM)

Composition:

active substance: anidulafungin;

1 vial contains 100 mg of anidulafungin;

excipients: fructose, mannitol, polysorbate 80, tartaric acid, hydrochloric acid, sodium hydroxide.

Pharmaceutical form. Lyophilisate for concentrate for solution for infusion.

Main physico-chemical properties: white to almost white powder.

Pharmacotherapeutic group. Antifungal agents for systemic use.

ATC code J02AX06.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Anidulafungin is a semisynthetic echinocandin lipopeptide produced by fermentation of Aspergillus nidulans products. Anidulafungin selectively inhibits 1,3-β-D-glucan synthase, a fungal cell enzyme that is absent in mammalian cells. This results in disruption of 1,3-β-D-glucan formation, a key component of the fungal cell wall. Anidulafungin exhibits fungicidal activity against various Candida species and shows activity at sites of active hyphal growth of Aspergillus fumigatus.

In vitro activity

Anidulafungin has demonstrated in vitro activity against C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis. The clinical significance of these data is described below («Clinical Efficacy and Safety»). Strains with mutations in the "hot spot" regions of the target gene have been associated with treatment failure or classified as resistant infections. In most clinical cases, caspofungin has been used. However, animal experiments indicate that these mutations confer cross-resistance to all three echinocandins; therefore, such strains are classified as echinocandin-resistant until further clinical experience with anidulafungin becomes available.

In vitro activity of anidulafungin against different Candida species varies. Specifically, minimal inhibitory concentrations (MICs) of anidulafungin for C. parapsilosis are higher than those for other Candida species. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has established a standardized methodology for determining Candida species susceptibility to anidulafungin, as well as corresponding tentative breakpoints.

Table 1. Breakpoints established by EUCAST
Candida species	Breakpoint MIC (mg/l)
	≤S (susceptible)	>R (resistant)
Candida albicans	0.03	0.03
Candida glabrata	0.06	0.06
Candida tropicalis	0.06	0.06
Candida krusei	0.06	0.06
Candida parapsilosis	4	4
Other Candida spp.1	Insufficient evidence
1 The breakpoints not species-specific were primarily determined based on pharmacokinetic/pharmacodynamic data and are not dependent on the MIC distribution for specific Candida strains. These values should only be used for organisms lacking specific breakpoints.

Activity in vivo

Anidulafungin was effective against Candida species when administered parenterally, as demonstrated in immunocompetent and immunocompromised mouse and rabbit models. Treatment with anidulafungin increased survival in animals and reduced organ burden of Candida species at time points between 24 and 96 hours after the last dose.

Experimental infections included disseminated C. albicans infection in neutropenic rabbits, esophageal/oropharyngeal infection in neutropenic rabbits with fluconazole-resistant C. albicans, and disseminated infection in neutropenic mice with fluconazole-resistant C. glabrata.

Clinical efficacy and safety

Candidemia and other forms of invasive candidiasis

The safety and efficacy of anidulafungin were evaluated in a pivotal, randomized, double-blind, multinational, multicenter phase 3 study involving patients without pre-existing neutropenia who had candidemia, as well as a limited number of patients with deep tissue candidiasis or infection associated with abscess formation. Patients with candidal endocarditis, osteomyelitis, or meningitis, or those whose infection was caused by C. krusei, were specifically excluded from the study. Patients were randomized to receive either anidulafungin (intravenous loading dose of 200 mg followed by 100 mg intravenously once daily) or fluconazole (intravenous loading dose of 800 mg followed by 400 mg intravenously once daily), and stratified by APACHE II score (≤ 20 and > 20) and presence or absence of neutropenia. Treatment was administered for at least 14 days and up to 42 days.

Patients who received at least one dose of the investigational medicinal product and who had a positive culture for Candida species from a normally sterile site prior to study initiation were included in the modified intent-to-treat population (MITT population), which included all patients who received treatment. In the primary efficacy analysis, which assessed complete response in the MITT population at the end of intravenous therapy, anidulafungin was compared with fluconazole using a pre-specified two-stage statistical comparison (first non-inferiority, then superiority approach). A successful complete response required both clinical improvement and eradication of the microbial pathogen. Patients were followed for 6 weeks after completion of all therapy. A total of 256 patients aged 16 to 91 years were randomized and received at least one dose of the investigational medicinal product. The most common species isolated at baseline was C. albicans (63.8% in the anidulafungin group and 59.3% in the fluconazole group). Less common species included C. glabrata (15.7%, 25.4%), C. parapsilosis (10.2%, 13.6%), and C. tropicalis (11.8%, 9.3%), with 20, 13, and 15 isolates of the latter three species, respectively, in the anidulafungin group. Most patients had an APACHE II score ≤ 20, and only a small number had neutropenia.

Efficacy data, both overall and by subgroup, are presented in Table 2 below.

Table 2. Successful complete response in the MITT population: primary and secondary endpoints
	Anidulafungin	Fluconazole	Between-group difference a (95% CI)
End of intravenous therapy (endpoint 1)	96/127 (75.6%)	71/118 (60.2%)	15.42 (3.9; 27.0)
Candidemia only	88/116 (75.9%)	63/103 (61.2%)	14.7 (2.5; 26.9)
Other sterile sitesb	8/11 (72.7%)	8/15 (53.3%)	-
Peritoneal fluid / intra-abdominal abscess	6/8	5/8
Other	2/3	3/7
C. albicansd	60/74 (81.1%)	38/61 (62.3%)	-
Non–C. albicans speciesd	32/45 (71.1%)	27/45 (60.0%)	-
APACHE II score ≤20	82/101 (81.2%)	60/98 (61.2%)	-
APACHE II score >20	14/26 (53.8%)	11/20 (55.0%)	-
Without neutropenia (ANC [absolute neutrophil count], cells/mm3 >500)	94/124 (75.8%)	69/114 (60.5%)	-
With neutropenia (ANC, cells/mm3 ≤ 500)	2/3	2/4	-
In other endpoints
End of all therapy	94/127 (74.0%)	67/118 (56.8%)	17.24 (2.9; 31.6)d
2-week follow-up	82/127 (64.6%)	58/118 (49.2%)	15.41 (0.4; 30.4)d
6-week follow-up	71/127 (55.9%)	52/118 (44.1%)	11.84 (-3.4; 27.0)d

a. Calculation: anidulafungin minus fluconazole.

b. With or without concomitant candidemia.

c. Intraperitoneal.

d. Data are presented for patients with a single pathogen at baseline.

e. 98.3% confidence intervals, which were subsequently adjusted for multiple comparisons of secondary time points.

Mortality in both groups (anidulafungin and fluconazole) is presented below in Table 3.

Table 3. Mortality
	Anidulafungin	Fluconazole
Overall mortality in the study	29/127 (22.8%)	37/118 (31.4%)
Mortality during the study therapy	10/127 (7.9%)	17/118 (14.4%)
Mortality considered to be a consequence of Candida infection	2/127 (1.6%)	5/118 (4.2%)

Additional Data in Patients with Neutropenia

The efficacy of anidulafungin (administered intravenously as a 200 mg loading dose, followed by 100 mg once daily intravenously) in adult patients with neutropenia (defined by criteria: absolute neutrophil count ≤ 500 cells/mm³, leukocytes ≤ 500 cells/mm³, or the patient classified by the investigator as having neutropenia at baseline) and microbiologically confirmed invasive candidiasis was evaluated by analysis of pooled data from five prospective studies (one comparative study versus caspofungin and four open-label non-comparative studies). Treatment duration for patients was at least 14 days. For clinically stable patients, a switch to oral azole therapy was permitted after at least 5 to 10 days of anidulafungin therapy. A total of 46 patients were included in this analysis. Most patients had candidemia only (84.8%; 39/46). The most common pathogens isolated at baseline were C. tropicalis (34.8%; 16/46), C. krusei (19.6%; 9/46), C. parapsilosis (17.4%; 8/46), C. albicans (15.2%; 7/46), and C. glabrata (15.2%; 7/46). Successful complete response at the end of intravenous therapy (primary endpoint) occurred in 26/46 (56.5%) patients, and at the end of all therapy in 24/46 (52.2%) patients. All-cause mortality by the end of the study (at the 6-week follow-up visit) was 21/46 (45.7%).

The efficacy of anidulafungin in adult patients with neutropenia (defined as absolute neutrophil count ≤ 500 cells/mm³ at baseline) and invasive candidiasis was evaluated in a prospective, double-blind, randomized, controlled trial. Eligible patients received either anidulafungin (intravenous loading dose of 200 mg, followed by 100 mg once daily intravenously) or caspofungin (intravenous loading dose of 70 mg, followed by 50 mg once daily intravenously) (randomization ratio 2:1). Treatment duration for patients was at least 14 days. For clinically stable patients, a switch to oral azole therapy was permitted after at least 10 days of study drug therapy. Overall, 14 neutropenic patients with microbiologically confirmed invasive candidiasis (MITT population) were included in the study (11 in the anidulafungin group and 3 in the caspofungin group). Most patients had candidemia only. The most common pathogens isolated at baseline were C. tropicalis (4 anidulafungin, 0 caspofungin), C. parapsilosis (2 anidulafungin, 1 caspofungin), C. krusei (2 anidulafungin, 1 caspofungin), and C. ciferrii (2 anidulafungin, 0 caspofungin). Successful complete response at the end of intravenous therapy (primary endpoint) occurred in 8/11 (72.7%) patients in the anidulafungin group and 3/3 (100.0%) in the caspofungin group (difference –27.3; 95% CI –80.9; 40.3); successful complete response at the end of all therapy occurred in 8/11 (72.7%) in the anidulafungin group and 3/3 (100.0%) in the caspofungin group (difference –27.3; 95% CI –80.9; 40.3). All-cause mortality at the 6-week follow-up visit was 4/11 (36.4%) in the anidulafungin group (MITT population) and 2/3 (66.7%) in the caspofungin group.

Patients with microbiologically confirmed invasive candidiasis (MITT population) and neutropenia were identified in the pooled analysis of data from four prospective open-label non-comparative studies with identical design. The efficacy of anidulafungin (administered intravenously as a 200 mg loading dose, followed by 100 mg once daily intravenously) was evaluated in 35 adult patients with neutropenia, where neutropenia was defined in 22 patients as absolute neutrophil count ≤ 500 cells/mm³ or leukocytes ≤ 500 cells/mm³, and 13 patients were classified by the investigator as having neutropenia at baseline. Treatment duration for all patients was at least 14 days. For clinically stable patients, a switch to oral azole therapy was permitted after at least 5 to 10 days of anidulafungin therapy. Most patients had candidemia only (85.7%). The most common pathogens isolated at baseline were C. tropicalis (12 patients), C. albicans (7 patients), C. glabrata (7 patients), C. krusei (7 patients), and C. parapsilosis (6 patients). Successful complete response at the end of intravenous therapy (primary endpoint) occurred in 18/35 (51.4%) patients, and at the end of all therapy in 16/35 (45.7%) patients. All-cause mortality by day 28 was 10/35 (28.6%). Successful complete response at the end of intravenous therapy and at the end of all therapy occurred with equal frequency of 7/13 (53.8%) in the 13 patients with neutropenia who were classified by the investigator at baseline.

Additional Data in Patients with Deep Tissue Infections

The efficacy of anidulafungin (administered intravenously as a 200 mg loading dose, followed by 100 mg once daily intravenously) in adult patients with microbiologically confirmed deep tissue candidiasis was evaluated in a pooled analysis of data from five prospective studies (one comparative and four open-label). Treatment duration for patients was at least 14 days. In four open-label studies, a switch to oral azole therapy was permitted after at least 5 to 10 days of anidulafungin therapy. A total of 129 patients were included in this analysis. Twenty-one (16.3%) had concurrent candidemia. The mean APACHE II score was 14.9 (range: 2–44). The most common infection sites included the intra-abdominal cavity (54.3%; 70 out of 129), hepatobiliary tract (7.0%; 9 out of 129), pleural space (5.4%; 7 out of 129), and kidney (3.1%; 4 out of 129). The most common pathogens isolated at baseline from deep tissue sites were C. albicans (64.3%; 83 out of 129), C. glabrata (31.0%; 40 out of 129), C. tropicalis (11.6%; 15 out of 129), and C. krusei (5.4%; 7 out of 129). Data on successful complete response at the end of intravenous therapy (primary endpoint) and at the end of all therapy, as well as all-cause mortality at the 6-week follow-up visit, are presented in Table 5.

Table 4. Frequency of successful complete response and all-cause mortality in patients with deep tissue candidiasis—pooled analysis
	MITT population, n/N (%)
Successful complete response at EOTIVb
Total	102/129 (79.1)
Intra-abdominal cavity	51/70 (72.9)
Hepatobiliary tract	7/9 (77.8)
Pleural cavity	6/7 (85.7)
Kidney	3/4 (75.0)
Successful complete response at EOTb	94/129 (72.9)
All-cause mortality	40/129 (31.0)
a Successful complete response was defined as both clinical and microbiological success. b EOTIV — end of intravenous therapy; EOT — end of all therapy

Children

In a prospective, open-label, non-comparative, multinational study, the safety and efficacy of anidulafungin in 68 children aged 1 month to < 18 years with invasive candidiasis, including candidemia (ICC), were evaluated. Patients were stratified by age (1 month to < 2 years, 2 to < 5 years, and 5 to < 18 years) and received intravenous anidulafungin once daily (loading dose of 3.0 mg/kg on Day 1 and maintenance dose of 1.5 mg/kg/day thereafter) for 35 days, followed by optional transition to oral fluconazole (6–12 mg/kg/day, maximum 800 mg/day). Patients were followed up at 2 and 6 weeks after completion of all antifungal therapy (AFT).

Of the 68 patients who received anidulafungin, 64 had microbiologically confirmed Candida infection and were evaluable for efficacy in the modified intent-to-treat (MITT) population. Overall, Candida was isolated solely from blood in 61 patients (92.2%). The most frequently isolated pathogens were Candida albicans (25 [39.1%] patients), Candida parapsilosis (17 [26.6%] patients), and Candida tropicalis (9 [14.1%] patients). Complete successful response was defined as both clinical success response (resolution or improvement) and microbiological success response (eradication or presumed eradication). Overall complete successful response rates in the MITT population are presented in Table 5.

Table 5. Summary of complete successful response by age groups, MITT population
		Complete successful response, n (%)
Timepoint	Complete response	1 month to < 2 years (N = 16) n (n/N, %)	2 to < 5 years (N = 18) n (n/N, %)	5 to < 18 years (N = 30) n (n/N, %)	Total (N = 64) n (n/N, %)
End of IV therapy	Successful	11 (68.8)	14 (77.8)	20 (66.7)	45 (70.3)
	95% CI	(41.3, 89.0)	(52.4, 93.6)	(47.2, 82.7)	(57.6, 81.1)
End of therapy	Successful	11 (68.8)	14 (77.8)	21 (70.0)	46 (71.9)
	95% CI	(41.3, 89.0)	(52.4, 93.6)	(50.6, 85.3)	(59.2, 82.4)
2-week follow-up	Successful	11 (68.8)	13 (72.2)	22 (73.3)	46 (71.9)
	95% CI	(41.3, 89.0)	(46.5, 90.3)	(54.1, 87.7)	(59.2, 82.4)
6-week follow-up	Successful	11 (68.8)	12 (66.7)	20 (66.7)	43 (67.2)
	95% CI	(41.3, 89.0)	(41.0, 86.7)	(47.2, 82.7)	(54.3, 78.4)
95% CI — exact 95% confidence interval for binomial proportions using the Clopper-Pearson method; End of IV therapy — end of intravenous therapy; End of therapy — end of all therapy; Follow-up — follow-up period; MITT — modified intention-to-treat population; N — number of subjects in the population; n — number of subjects with response.

Pharmacokinetics

General pharmacokinetic properties

The pharmacokinetics of anidulafungin have been characterized in healthy volunteers, special subpopulations, and patients treated with anidulafungin. Low inter-subject variability in systemic drug exposure was observed (coefficient of variation approximately 25%). Steady-state concentrations were achieved on the first day after administration of the loading dose (double the maintenance dose).

Distribution

The pharmacokinetics of anidulafungin are characterized by a short half-life (0.5–1 hour) and a volume of distribution of 30–50 L, which is close to the total body water volume. Anidulafungin is highly bound (>99%) to human plasma proteins. Specific studies on the distribution of anidulafungin in human tissues have not been conducted. Therefore, information on the penetration of anidulafungin into cerebrospinal fluid (CSF) and/or across the blood-brain barrier is currently unavailable.

Biotransformation

Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 isoenzymes. It is unlikely that anidulafungin will exert a clinically significant effect on the metabolism of drugs metabolized by cytochrome P450 isoenzymes.

Under physiological temperature and pH conditions, anidulafungin undergoes slow chemical degradation to an open-ring peptide compound that lacks antifungal activity. The in vitro half-life of anidulafungin under physiological conditions is approximately 24 hours. In vivo, the open-ring compound is subsequently converted into peptide degradation products and is primarily eliminated via biliary excretion.

Elimination

The clearance of anidulafungin is approximately 1 L/h. The main elimination phase half-life of anidulafungin is approximately 24 hours, which corresponds to the majority of the plasma concentration–time profile, while the terminal elimination phase half-life is 40–50 hours, corresponding to the terminal elimination phase of this profile.

In a clinical study using a single dose, healthy subjects received radiolabeled (14C) anidulafungin (~88 mg). Approximately 30% of the administered radioactive dose was recovered in feces over more than 9 days, of which less than 10% was unchanged drug. Less than 1% of the administered radioactive dose was excreted in urine, indicating minimal renal clearance. Anidulafungin concentrations declined below the lower limit of quantification within 6 days after administration. A small amount of radioactive compounds was detected in blood, urine, and feces 8 weeks after administration.

Linearity

Anidulafungin exhibits linear pharmacokinetics over a wide dose range (15–130 mg) when administered once daily.

Special populations

Patients with fungal infections. The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy individuals, based on population pharmacokinetic analyses. When administered at a daily dose of 200/100 mg with an infusion rate of 1.1 mg/min, steady-state maximum (Cmax) and minimum (Cmin) concentrations may be approximately 7 and 3 mg/L, respectively, with a mean steady-state AUC of approximately 110 mg·h/L.

Body weight. Although body weight was identified as a source of clearance variability in population pharmacokinetic analysis, its clinical impact on anidulafungin pharmacokinetics is minor.

Gender. Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose studies, drug clearance was slightly faster in men (approximately 22%).

Elderly patients. Population pharmacokinetic analysis showed that median clearance differed slightly between elderly patients (age ≥ 65 years, mean CL = 1.07 L/h) and younger patients (age < 65 years, mean CL = 1.22 L/h), although the range of clearance values was similar.

Ethnicity. The pharmacokinetics of anidulafungin were similar in Caucasian, African American, Asian, and Hispanic populations.

HIV-positive patients. Dose adjustment of anidulafungin is not required for HIV-positive patients, regardless of concomitant antiretroviral therapy.

Hepatic impairment. Anidulafungin is not metabolized in the liver. The pharmacokinetics of anidulafungin were studied in patients with Child-Pugh classes A, B, and C hepatic impairment. Anidulafungin concentrations did not increase in patients with any degree of hepatic impairment. Although a slight decrease in AUC was observed in patients with Child-Pugh class C hepatic impairment, this reduction was within the range of AUC values observed in healthy subjects.

Renal impairment. Anidulafungin has minimal renal clearance (<1%). In a clinical study involving patients with mild, moderate, or severe renal impairment or end-stage renal disease (on dialysis), the pharmacokinetics of anidulafungin were similar to those observed in individuals with normal renal function. Anidulafungin is not dialyzable and can be administered irrespective of the timing of hemodialysis.

Pediatric population. The pharmacokinetics of anidulafungin after administration of at least 5 daily doses were evaluated in 24 immunocompromised pediatric (2–11 years) and adolescent (12–17 years) patients with neutropenia. Steady-state was achieved on the first day after the loading dose (twice the maintenance dose), and steady-state Cmax and AUCss increased proportionally with dose. Systemic exposure after daily maintenance doses of 0.75 and 1.5 mg/kg/day in this population was comparable to that observed in adults after administration of 50 and 100 mg/day, respectively. Both regimens were well tolerated in these patients.

The pharmacokinetics of anidulafungin were studied in 66 children (aged 1 month to <18 years) with invasive candidiasis (ICC) in a prospective, open-label, non-comparative pediatric study using a loading dose of 3.0 mg/kg and a maintenance dose of 1.5 mg/kg/day (see section "Pharmacodynamics"). Based on population pharmacokinetic analysis of combined data from adults and children with ICC, mean steady-state exposure values (AUC0–24,ss and Cmin,ss) across all pediatric age groups (1 month to <2 years, 2 to <5 years, and 5 to <18 years) were comparable to those in adults receiving a 200 mg loading dose and 100 mg/day maintenance dose. Body weight-adjusted clearance (L/h/kg) and volume of distribution at steady state (L/kg) were similar across age groups.

Clinical Characteristics

Indications. For the treatment of invasive candidiasis in adult patients and children aged 1 month to < 18 years (see sections "Dosage and Administration" and "Pharmacodynamics").

Contraindications

Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to other medicinal products of the echinocandin class.

Interaction with other medicinal products and other forms of interaction

Anidulafungin is not a clinically significant inducer or inhibitor of cytochrome P450 isoenzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A). However, in vitro studies do not completely exclude the possibility of interactions under in vivo conditions.

Interaction studies have been conducted with other medicinal products that may be co-administered with anidulafungin. When anidulafungin is administered concomitantly with cyclosporine, voriconazole, or tacrolimus, dose adjustment of any of these medicinal products is not recommended; when the drug is administered concomitantly with amphotericin B or rifampicin, there is no need for dose adjustment of anidulafungin.

Children. Interaction studies have been conducted only in adults.

Special precautions for use

The use of the medicinal product Anidulafungin Rompharm in patients with candidal endocarditis, osteomyelitis, or meningitis has not been studied.

The efficacy of the drug has been evaluated only in a limited number of neutropenic patients (see section "Pharmacological properties").

Children

Use of Anidulafungin Rompharm in neonates (age < 1 month) is not recommended. For treatment of neonates, the spectrum of activity against disseminated candidiasis, including the central nervous system (CNS), should be considered. Preclinical infection models indicate that higher doses of anidulafungin are required for adequate penetration into the CNS, which means the patient would receive higher doses of polysorbate 80, an excipient. High doses of polysorbates have been associated with potentially life-threatening toxicity in neonates.

There are no clinical data confirming the efficacy and safety of higher doses of anidulafungin than those recommended in the section "Dosage and administration".

Hepatic effects

Elevated liver enzyme levels have been observed in healthy volunteers and patients treated with anidulafungin. Clinically significant hepatic disorders have been observed in some patients with serious underlying conditions who were receiving multiple concomitant medications along with anidulafungin. Isolated cases of liver dysfunction, hepatitis, or hepatic failure have been reported. Patients who develop elevated liver enzymes during treatment with anidulafungin should be monitored closely for early detection of signs of worsening liver function and for assessment of the risk/benefit of continuing anidulafungin therapy.

Anaphylactic reactions

Anaphylactic reactions, including shock, have been reported during anidulafungin administration. In the event such reactions occur, anidulafungin should be discontinued and appropriate treatment initiated.

Infusion-related reactions

Adverse reactions related to intravenous infusion of anidulafungin have been reported, including rash, urticaria, pathological flushing, pruritus, dyspnea, bronchospasm, and hypotension. Infusion-related adverse reactions are uncommon when the infusion rate does not exceed 1.1 mg/min (see section "Adverse reactions").

Exacerbation of infusion-related reactions with concomitant administration of anesthetics was observed in a preclinical study (in rats). The clinical significance of this finding is unknown. However, caution should be exercised when anidulafungin is administered concomitantly with anesthetics.

Fructose content

The medicinal product Anidulafungin Rompharm contains fructose.

This medicinal product should not be administered to patients with hereditary fructose intolerance (HFI), unless there is an acute clinical need.

HFI may be undiagnosed in infants and young children (under 2 years of age). Intravenous medicinal products containing fructose may be life-threatening and should not be administered to this patient population unless there is an urgent clinical need or no alternative. A careful patient history regarding symptoms of HFI should be obtained before administering this medicinal product.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e., essentially "sodium-free". This information may be provided to patients following a low-sodium diet.

Anidulafungin Rompharm can be diluted with solutions containing sodium (see below "Preparation for administration"), and this should be taken into account when calculating the total sodium intake from all sources for the patient.

Use during pregnancy or breastfeeding

Anidulafungin Rompharm should not be used during pregnancy.

It is unknown whether anidulafungin passes into human breast milk. The decision whether to continue/stop breastfeeding or to continue/stop therapy with anidulafungin should be made taking into account the benefits of breastfeeding for the child and the benefits of anidulafungin therapy for the mother.

Ability to affect reaction speed when driving or operating machinery. No specific studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted; however, the information provided in the section "Adverse reactions" should be taken into account.

Method of Administration and Dosage

Treatment with Anidulafungin Rompharm should be initiated by a physician experienced in the management of invasive fungal infections. Specimens for fungal culture should be obtained prior to starting therapy. Treatment may be initiated before the results of these specimens are available, and therapy may be adjusted accordingly once results are obtained.

Adult Patients (Dosage and Duration of Treatment)

Treatment is initiated with a single loading dose of 200 mg on Day 1, followed by 100 mg of the drug administered daily.

The duration of treatment depends on the patient's clinical response to therapy. In general, antifungal therapy should be continued for at least 14 days after laboratory results confirm the absence of fungi.

There is insufficient data on the use of the drug for longer than 35 days at a dosage of 100 mg.

Pediatric Patients (Aged 1 Month to < 18 Years) (Dosage and Duration of Treatment)

A single loading dose of 3.0 mg/kg (not exceeding 200 mg) should be administered on Day 1, followed by a daily maintenance dose of 1.5 mg/kg (not exceeding 100 mg).

The duration of treatment should be based on the patient's clinical response.

In general, antifungal therapy should last at least 14 days after the last positive fungal culture result.

Method of Administration. Anidulafungin Rompharm is administered intravenously by infusion. Anidulafungin Rompharm must not be administered as a bolus injection.

Anidulafungin Rompharm must be reconstituted with water for injections to a concentration of 3.33 mg/mL and then diluted to a concentration of 0.77 mg/mL to obtain the final infusion solution. For pediatric patients, the volume of infusion solution required to administer the dose will vary depending on the child's body weight. Instructions for reconstitution of the medicinal product prior to administration are described in the section "Preparation of the Medicinal Product for Administration."

Preparation of the Medicinal Product for Administration. Anidulafungin Rompharm must be reconstituted with water for injections and then diluted ONLY with 9 mg/mL (0.9%) sodium chloride solution for infusion or 50 mg/mL (5%) glucose solution for infusion. The compatibility of the reconstituted Anidulafungin Rompharm solution with other intravenous solutions and medicinal products administered by intravenous infusion, other than 9 mg/mL (0.9%) sodium chloride solution for infusion or 50 mg/mL (5%) glucose solution for infusion, has not been studied. The infusion solution must not be frozen.

Reconstitution

Reconstitute the contents of each vial aseptically with 30 mL of water for injections to achieve a concentration of 3.33 mg/mL. Reconstitution may take up to 5 minutes. If visible particles or discoloration are observed in the solution after further dilution, the solution must not be used.

Dilution and Infusion

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or discoloration is observed, the solution must not be used.

Adult Patients

Transfer the contents of the vial containing the reconstituted solution aseptically into an intravenous infusion container containing either 9 mg/mL (0.9%) sodium chloride solution or 50 mg/mL (5%) glucose solution for infusion, to obtain the appropriate concentration of Anidulafungin Rompharm. The table below provides dilution instructions to achieve a final infusion solution concentration of 0.77 mg/mL and infusion instructions for each dose.

Dilution Requirements for Administration of Anidulafungin Rompharm

| Dose (mg) | Volume of Reconstituted Solution (mL) | Volume of Diluent (mL) | Total Volume of Infusion Solution (mL) | Infusion Duration (hours) | |-----------|----------------------------------------|------------------------|----------------------------------------|----------------------------| | 100 | 30 | 270 | 300 | 1–2 | | 200 | 60 | 540 | 600 | 2–4 |

Note: The infusion must be administered over 1 to 4 hours, depending on the dose. The diluted solution should be used immediately. If immediate use is not possible, the diluted solution is stable for up to 24 hours at 2–8°C and must be brought to room temperature before administration.

Dose	Number of packs	Volume of reconstitution solvent	Volume of infusion solutionA	Total volume of ready-to-use infusionB	Infusion rate	Minimum duration of infusion
100 mg	1	30 mL	100 mL	130 mL	1.4 mL/min, or 84 mL/h	90 min.
200 mg	2	60 mL	200 mL	260 mL	1.4 mL/min, or 84 mL/h	180 min.

A or 9 mg/mL (0.9%) sodium chloride for infusion, or 50 mg/mL (5%) glucose for infusion.

B Concentration of the infusion solution: 0.77 mg/mL.

The recommended infusion rate is not more than 1.1 mg/min, equivalent to 1.4 mL/min or 84 mL/hour, for the reconstituted and diluted solution according to the instructions. Cases of infusion-related reactions to anidulafungin occur rarely if the infusion rate does not exceed 1.1 mg/min.

Children

For children aged 1 month to < 18 years, the volume of infusion solution required for dose administration will vary depending on the patient's body weight. The reconstituted solution must be further diluted to a concentration of 0.77 mg/mL to obtain the final infusion solution. A programmable syringe pump or infusion pump is recommended. The infusion rate must not exceed 1.1 mg/min (equivalent to 1.4 mL/min or 84 mL/hour after reconstitution and dilution according to the instructions) (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

1. Calculate the dose for the patient and reconstitute the required content of vial(s) according to the reconstitution instructions to achieve a concentration of 3.33 mg/mL (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").
2. Calculate the required volume (mL) of reconstituted anidulafungin:
   • volume of anidulafungin (mL) = anidulafungin dose (mg) ÷ 3.33 mg/mL.
3. Calculate the total volume of infusion solution (mL) required to achieve the final concentration of 0.77 mg/mL:
   • total volume of infusion solution (mL) = anidulafungin dose (mg) ÷ 0.77 mg/mL.
4. Calculate the volume of diluent [5% dextrose for injection, USP or 0.9% sodium chloride for injection, USP (normal saline)] required to prepare the infusion solution:
   • volume of diluent (mL) = total volume of infusion solution (mL) – volume of anidulafungin (mL).
5. Aseptically transfer the required volumes (mL) of anidulafungin and 5% dextrose for injection, USP or 0.9% sodium chloride for injection, USP (normal saline) into an infusion syringe or intravenous infusion bag as needed for administration.

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

Patients with renal or hepatic impairment.

Dose adjustment is not required for patients with mild, moderate, or severe hepatic impairment, or for patients with any degree of renal impairment, including those undergoing dialysis. Anidulafungin Rompharm may be administered irrespective of the timing of hemodialysis.

Other special populations.

Dose adjustment based on gender, body weight, ethnicity, HIV infection status, or for elderly patients is not required in adult patients.

Children.

The safety and efficacy of Anidulafungin Rompharm have not been established in neonates (age < 1 month).

Overdose

As in any case of overdose, general supportive measures should be applied if necessary.

In case of overdose, adverse reactions described in section "Adverse Reactions" may occur.

During clinical trials, one case of accidental administration of a loading dose of 400 mg anidulafungin was reported. No clinical adverse effects were reported. In a study involving 10 healthy volunteers who received a 260 mg loading dose of anidulafungin followed by 130 mg anidulafungin daily, no dose-limiting toxicity was observed. Asymptomatic elevations in transaminase levels (≤ 3 times the upper limit of normal) were observed in 3 out of 10 subjects and resolved spontaneously.

During a pediatric clinical trial, one subject received two doses of anidulafungin, amounting to 143% of the expected dose. No clinical adverse reactions were reported.

Anidulafungin is not dialyzable.

Adverse Reactions

During clinical trials with anidulafungin, infusion-related adverse reactions were reported, including rash, pruritus, dyspnea, bronchospasm, and arterial hypotension (common events), as well as flushing and urticaria (uncommon events) (see section "Special Instructions").

The table below lists adverse reactions reported regardless of causality (MedDRA terms [Medical Dictionary for Regulatory Activities]) from data on 840 subjects who received 100 mg of anidulafungin.

Adverse reaction frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data). Within each frequency group, adverse effects are listed in order of decreasing severity.

Table 7. Adverse Reactions

Body systems	Very common	Common	Uncommon	Frequency unknown
Blood and lymphatic system disorders			Coagulopathy
Immune system disorders				Anaphylactic shock, anaphylactic reaction*
Metabolism and nutrition disorders	Hypokalemia	Hypoglycemia
Nervous system disorders		Convulsions, headache
Vascular disorders		Arterial hypotension, arterial hypertension	Pathological flushing, hot flashes
Respiratory, thoracic and mediastinal disorders		Bronchospasm, dyspnea
Gastrointestinal disorders	Diarrhea, nausea	Vomiting	Upper abdominal pain
Hepatobiliary disorders		Increased blood alanine aminotransferase, increased blood alkaline phosphatase, increased blood aspartate aminotransferase, increased blood bilirubin, cholestasis	Increased gamma-glutamyltransferase levels
Skin and subcutaneous tissue disorders		Rash, pruritus	Urticaria
Renal and urinary disorders		Increased blood creatinine
General disorders and administration site conditions			Pain at the injection site

* See section "Special precautions for use".

Children

The safety of anidulafungin use in children has been evaluated in 68 pediatric patients (aged 1 month to < 18 years) with invasive candidiasis in a prospective, open-label, non-comparative pediatric study (see section "Pharmacodynamics"). Certain hepatobiliary adverse reactions, including increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, were observed more frequently in children (7–10%) than in adults (2%). Although this may be attributable to the severity of the underlying disease, it cannot be excluded that hepatobiliary adverse reactions occur more frequently in children compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 36 months.

Reconstituted solution. Chemical and physical in-use stability of the reconstituted solution using Water for Injections has been demonstrated for 24 hours at 25 °C. The reconstituted solution should be used immediately.

Reconstituted and diluted solution. Chemical and physical in-use stability of the infusion solution (reconstituted and diluted) has been demonstrated for 48 hours at 25 °C when the reconstituted solution was diluted in 9 mg/mL (0.9%) sodium chloride for infusion or 50 mg/mL (5%) glucose. The infusion solution (reconstituted and diluted) should be used immediately.

Anidulafungin Rompharm does not contain preservatives. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, the responsibility for storage duration and conditions prior to use lies with the user.

Storage conditions. Store in a refrigerator (2–8 °C).

Incompatibilities. Anidulafungin Rompharm must not be mixed with other medicinal products or solutions except those specified in the section "Dosage and administration".

Packaging. 100 mg in a vial, 1 vial in a cardboard carton.

Prescription status. Prescription only.

Manufacturer. K.T. ROMPHARM COMPANY S.R.L.

Manufacturer's address and location of operations.

Strada Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Building Rompharm 1 and Rompharm 2.