Anidulafungin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANIDULAFUNGIN

Composition:

Active substance: anidulafungin;

1 vial contains anidulafungin 100 mg;

Excipients: fructose, mannitol (E 421), polysorbate 80, lactic acid,
hydrochloric acid, sodium hydroxide.

Pharmaceutical form. Powder for concentrate for solution for infusion.

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

Pharmacotherapeutic group. Antifungal agents for systemic use.
ATC code J02A X06.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Anidulafungin is a semisynthetic echinocandin, a lipopeptide derived from the fermentation products of Aspergillus nidulans. Anidulafungin selectively inhibits 1,3-β-D-glucan synthase—an essential enzyme in fungal cells that is absent in mammalian cells. This inhibition disrupts the formation of 1,3-β-D-glucan, a key structural component of the fungal cell wall. Anidulafungin exhibits fungicidal activity against various Candida species and demonstrates activity at sites of active hyphal growth of Aspergillus fumigatus.

In vitro activity.

Anidulafungin has shown in vitro activity against C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis. The clinical significance of these findings is described below (see "Clinical efficacy and safety"). Strains harboring mutations in the "hot spot" regions of the target gene have been associated with treatment failure or resistant infections. In most clinical cases, caspofungin has been used. However, animal model studies 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 varies among different Candida species. Specifically, the minimum inhibitory concentrations (MICs) of anidulafungin against C. parapsilosis are higher than those against other Candida species. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has established a standardized methodology for determining Candida species susceptibility to anidulafungin and has defined corresponding interpretive breakpoints.

Breakpoints established by EUCAST

Species of Candida	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 parapsilosis1	0.002	4
Other Candida species2	Insufficient data
1 A possible reason for the higher minimal inhibitory concentration (MIC) for C. parapsilosis compared to other Candida species is an inherent alteration in the gene encoding the antifungal target in this species. In clinical studies, the outcome of therapy with anidulafungin for C. parapsilosis did not differ statistically from therapy for other species; however, the use of echinocandins cannot be considered first-line therapy for candidemia due to C. parapsilosis. 2 EUCAST has not established species-independent breakpoints for anidulafungin.

In vivo activity.

Anidulafungin was effective against Candida species following parenteral administration, as demonstrated in models using immunocompetent and immunocompromised mice and rabbits. Administration of anidulafungin increased survival in animals and reduced organ burden of Candida species when assessed between 24 and 96 hours after the last dose.

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 primary neutropenia who had candidemia, as well as a limited number of patients with deep tissue candidiasis or abscess-forming disease. Patients with Candida 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 were stratified by APACHE II score (≤ 20 and > 20) and presence or absence of neutropenia. Treatment was administered for at least 14 days and no longer than 42 days. Patients in both study groups were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided they were able to tolerate oral medication, had been afebrile for at least 24 hours, and had negative blood cultures for Candida species on their most recent testing.

Patients who received at least one dose of the study drug and who had a baseline positive culture for Candida species from a normally sterile site were included in the modified intent-to-treat population (MITT population), which included all patients who received treatment. In the primary efficacy analysis, which evaluated 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 applying a non-inferiority approach, then a superiority approach). A successful complete response required both clinical improvement and microbiological eradication of the 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 study drug. 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, respectively, of the latter three species in the anidulafungin group. Most patients had an APACHE II score ≤ 20, and very few patients had neutropenia.

Efficacy data for the overall population and various subgroups are presented in Table 1.

Complete response in the MITT population: primary and secondary endpoints

Table 1

	Anidulafungin	Fluconazole	Between-group difference a (95% CI)
End of IV 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/visceral abscess	6/8	5/8
Other	2/3	3/7
C. albicans g	60/74 (81.1%)	38/61 (62.3%)	-
Non-C. albicans species g	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
Two-week follow-up	82/127 (64.6%)	58/118 (49.2%)	15.41 (0.4; 30.4)d
Six-week follow-up 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 2:

Mortality

Table 2

	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 due to Candida infection	2/127 (1.6%)	5/118 (4.2%)

Additional data in patients with neutropenia

The efficacy of anidulafungin (administered intravenously as a loading dose of 200 mg, followed by 100 mg once daily intravenously) in adult patients with neutropenia (defined by criteria: absolute neutrophil count ≤ 500 cells/mm³, white blood cells ≤ 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 versus caspofungin and four open-label non-comparative). Treatment for patients lasted 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). Complete response success at the end of intravenous therapy (primary endpoint) was observed in 26/46 (56.5%), and at the end of all therapy in 24/46 (52.2%). All-cause mortality at the end of the study (follow-up visit at week 6) 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 study. 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 lasted 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). Complete response success at the end of intravenous therapy (primary endpoint) was observed in 8/11 (72.7%) for anidulafungin and 3/3 (100.0%) for caspofungin (difference -27.3; 95% CI: -80.9, 40.3); complete response success at the end of all therapy was observed in 8/11 (72.7%) for anidulafungin and 3/3 (100.0%) for caspofungin (difference -27.3; 95% CI: -80.9, 40.3). All-cause mortality at the follow-up visit at week 6 was 4/11 (36.4%) for anidulafungin and 2/3 (66.7%) for caspofungin.

Patients with microbiologically confirmed invasive candidiasis were identified in a pooled analysis of data from four prospective open-label non-comparative studies with identical design. The efficacy of anidulafungin (administered intravenously as a loading dose of 200 mg, followed by 100 mg once daily intravenously) was evaluated in 35 adult patients with neutropenia, defined in 22 patients by criteria: absolute neutrophil count ≤ 500 cells/mm³ or white blood cells ≤ 500 cells/mm³, and 13 patients classified by the investigator as having neutropenia at baseline. Treatment for all patients lasted 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). Complete response success at the end of intravenous therapy (primary endpoint) was observed in 18/35 (51.4%), and at the end of all therapy in 16/35 (45.7%). All-cause mortality on day 28 was 10/35 (28.6%). Complete response success at the end of intravenous therapy and at the end of all therapy was observed with the same frequency of 7/13 (53.8%) in the 13 neutropenic patients classified by the investigator at baseline.

Additional data in patients with deep tissue infections

The efficacy of anidulafungin (administered intravenously as a loading dose of 200 mg, 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 lasted 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 concomitant candidemia. The mean APACHE II score was 14.9 (range: 2–44). The most common infection sites included intra-abdominal cavity (54.3%; 70 of 129), hepatobiliary tract (7.0%; 9 of 129), pleural space (5.4%; 7 of 129), and kidney (3.1%; 4 of 129). The most common pathogens isolated at baseline from deep tissue sites were C. albicans (64.3%; 83 of 129), C. glabrata (31.0%; 40 of 129), C. tropicalis (11.6%; 15 of 129), and C. krusei (5.4%; 7 of 129). Data on complete response success at the end of intravenous therapy (primary endpoint) and at the end of all therapy, as well as all-cause mortality at the follow-up visit at week 6, are presented in Table 3.

Table 3
Frequency of complete response success and all-cause mortality in patients with deep tissue candidiasis—pooled analysis

	Modified intention-to-treat (MITT) population, n/N (%)
Successful complete response at the end of intravenous therapy (EIVT)
Total	102/129 (79.1%)
Intra-abdominal	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 the end of total therapy (ETT)	94/129 (72.9%)
All-cause mortality	40/129 (31.0%)
a Successful complete response was defined as simultaneous clinical and microbiological success

Pharmacokinetics.

General pharmacokinetic properties.

The pharmacokinetics of anidulafungin have been described in healthy volunteers, special subgroups, and patients treated with anidulafungin. Low inter-subject variability in systemic exposure to the drug was observed (coefficient of variation was ~25%). Steady-state concentrations were achieved within the first day after administration of a 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 fluid 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, currently there is no information regarding penetration of anidulafungin into cerebrospinal fluid and/or across the blood-brain barrier.

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.

At physiological temperature and pH levels, 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 from the body via biliary excretion.

Elimination.

The clearance of anidulafungin is approximately 1 L/h. The major phase of the elimination half-life of anidulafungin is approximately 24 hours, corresponding to the majority of the "plasma concentration–time" profile, while the terminal phase of elimination 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 excreted 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. Six days after drug administration, anidulafungin concentrations declined below the lower limit of quantification. Eight weeks after administration, a small amount of radioactive compounds was detected in blood, urine, and feces.

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 and 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.

Pharmacokinetic changes due to body weight had minimal clinical significance.

Gender.

Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose studies involving patients, the clearance of the drug was slightly faster in men.

Elderly patients.

Population pharmacokinetic analysis showed that the mean clearance was slightly different in elderly patients (patients aged ≥65 years; median clearance 1.07 L/h) compared to younger patients (patients aged <65 years; median clearance 1.22 L/h); however, the range of clearance values in these groups was similar.

Ethnicity.

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

HIV-positive patients.

Dose adjustment of the drug is not required in HIV-positive patients without neutropenia, 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 levels obtained in healthy subjects.

Renal impairment.

Anidulafungin has minimal renal clearance (<1%). In a clinical study involving patients with mild, moderate, and severe renal impairment or end-stage renal disease (dialysis-dependent patients), the pharmacokinetics of anidulafungin in these patients 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.

Pediatrics.

The pharmacokinetics of anidulafungin after administration of at least five 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 parameters after administration of daily maintenance doses of 0.75 and 1.5 mg/kg/day in this population were comparable to those observed in adults receiving 50 and 100 mg/day, respectively. Both regimens were well tolerated by these patients.

Clinical characteristics.

Indications.

Invasive candidiasis in adult patients.

Contraindications.

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

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). It should be noted that *in* vitro studies do not completely exclude possible interactions under *in* vivo conditions.

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

Children.

Drug interaction studies have been conducted only in adults.

Special precautions for use.

The use of anidulafungin in patients with Candida 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 "Pharmacodynamics").

Hepatic effects.

Elevations in 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 diseases who were receiving multiple concomitant medications along with anidulafungin. Isolated cases of liver dysfunction, hepatitis, and hepatic failure have been reported. Patients who develop elevated liver enzymes during treatment with anidulafungin should be closely monitored for early 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. If such reactions occur, anidulafungin should be discontinued and appropriate treatment initiated.

Infusion-related reactions.

Infusion-related adverse reactions have been observed during anidulafungin administration, 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.

In preclinical studies, an increased incidence of infusion-related reactions was observed when anidulafungin was administered concomitantly with anesthetics. The clinical significance of this phenomenon is unknown. However, caution should be exercised when anidulafungin is used concomitantly with anesthetics.

Fructose content.

This medicinal product must not be used in patients with rare hereditary fructose intolerance.

Use during pregnancy or breastfeeding.

Anidulafungin should not be used during pregnancy.

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

Effects on ability to drive and use machines.

Specific studies on the effect of the drug on the ability to drive or operate machinery have not been conducted; however, the information provided in the section "Adverse reactions" should be considered.

Administration and Dosage

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

Invasive candidiasis in adult patients

Treatment should begin on day 1 with a single loading dose of 200 mg, 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 confirmation of fungal clearance.

Duration of treatment

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

Administration method Anidulafungin must be administered by intravenous infusion. The drug must not be administered as a bolus injection.

Anidulafungin must first 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. 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 must be reconstituted with Water for Injections and subsequently diluted ONLY with either 0.9% (9 mg/mL) Sodium Chloride Injection for Infusion or 5% (50 mg/mL) Glucose Injection for Infusion. Compatibility of the reconstituted Anidulafungin solution with other intravenous solutions and medicinal products administered by intravenous infusion, other than 9 mg/mL (0.9%) Sodium Chloride Injection for Infusion or 50 mg/mL (5%) Glucose Injection for Infusion, has not been studied.

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, do not use the solution.

Dilution and Infusion

Transfer the contents of the vial containing the reconstituted solution aseptically into an intravenous infusion container containing either 0.9% (9 mg/mL) Sodium Chloride Injection for Infusion or 5% (50 mg/mL) Glucose Injection for Infusion, to achieve a final anidulafungin concentration of 0.77 mg/mL. The table below provides the required volumes for each dose.

Dilution requirements for administration of Anidulafungin

Dose	Number of unit packs	Volume of reconstituting solution	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	90 minutes
200 mg	2	60 ml	200 ml	260 ml	1.4 ml/min	180 minutes

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 is 0.77 mg/mL.

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

Parenteral medicinal 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 should not be used.

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

Patients with renal or hepatic impairment.

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

Other special populations.

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

Children.

The safety and efficacy of anidulafungin in pediatric patients (under 18 years of age) have not been established. Current available data are described in the section "Pharmacokinetics," but dosage recommendations cannot be provided.

Overdose.

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

During clinical trials, one case of accidental administration of a 400 mg loading dose of anidulafung游戏副本 was reported. No clinical adverse effects were reported in this case. In a study involving 10 healthy volunteers who received a 260 mg loading dose of anidulafungin followed by 130 mg daily, no dose-limiting toxicity was observed. Asymptomatic elevations in transaminase levels (≤ 3 times the upper limit of normal) were observed in three out of ten patients, which resolved spontaneously. As with any case of overdose, general supportive measures should be employed as needed.

Anidulafungin is not dialyzable.

Adverse Reactions

A total of 1565 patients received anidulafungin intravenously, either as a single dose or multiple doses, in clinical studies: 1308 patients in phase 2/3 studies (923 patients with candidemia/invasive candidiasis, 355 patients with oropharyngeal/esophageal candidiasis, 30 patients with invasive aspergillosis) and 257 patients in a phase 1 study.

The safety profile of anidulafungin is based on data from 840 patients with candidemia/invasive candidiasis who received the medicinal product at the recommended dosage of 100 mg per day across 9 clinical trials. Initially, 204 patients were studied in three trials (one comparative trial versus fluconazole and two non-comparative trials); the mean duration of intravenous administration in these patients was 13.5 days (range: 1–38 days), and 119 patients received anidulafungin for ≥14 days. In six additional trials (two comparative versus caspofungin and four non-comparative), 636 patients were studied, including 53 patients with neutropenia and 131 patients with deep tissue infection; the mean duration of intravenous administration in patients with neutropenia and in those with deep tissue infection in these trials was 10.0 days (range: 1–42 days) and 14.0 days (range: 1–42 days), respectively. Adverse reactions were generally mild to moderate in severity and rarely led to drug discontinuation. Infusion-related adverse reactions observed during clinical trials with anidulafungin are listed below, including pathological flushing, hot flushes, pruritus, rash, and urticaria.

All adverse reactions (MedDRA) occurring in 840 individuals receiving anidulafungin at a dosage of 100 mg are listed below.

Classification of adverse reaction frequencies: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders.
Uncommon: coagulopathy.

Immune system disorders.
Frequency not known: anaphylactic shock, anaphylactic reaction (see section "Special precautions for use").

Metabolism and nutrition disorders.
Very common: hypokalemia; common: hyperglycemia.

Nervous system disorders.
Common: convulsion, headache.

Vascular disorders.
Common: arterial hypotension, arterial hypertension; uncommon: pathological flushing, hot flushes.

Respiratory, thoracic and mediastinal disorders.
Common: bronchospasm, dyspnea.

Gastrointestinal disorders.
Very common: diarrhea, nausea; common: vomiting; uncommon: upper abdominal pain.

Hepatobiliary disorders.
Common: increased alanine aminotransferase, increased alkaline phosphatase, increased aspartate aminotransferase, increased blood bilirubin, cholestasis; uncommon: increased gamma-glutamyl transferase.

Skin and subcutaneous tissue disorders.
Common: rash, pruritus; uncommon: urticaria.

Renal and urinary disorders.
Common: increased blood creatinine.

General disorders and administration site conditions.
Uncommon: pain at the site of drug administration.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 36 months.

Storage conditions.

Store in the original packaging in a refrigerator (2–8 °C).

Temperature excursions up to 25 °C are permitted for up to 96 hours. After exposure to higher temperatures, the vial may be returned to refrigerated storage.

Keep out of the reach of children.

Reconstituted solution.

The reconstituted solution may be stored at a temperature not exceeding 25 °C for up to 24 hours.

Infusion solution.

The prepared infusion solution may be stored at a temperature up to 25 °C for 48 hours or frozen for up to 72 hours.

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

Packaging.

1 vial of powder in a cardboard carton.

Prescription status. Prescription only.

Manufacturer.

LLC «PHARMIDEA», Latvia.

Manufacturer’s address and place of business.

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