ECALTA 100mg powder for concentrate infusion solution medication leaflet

ECALTA 100 mg powder for concentrate for solution for infusion

Each vial contains 100 mg anidulafungin.

The reconstituted solution contains 3.33 mg/mL anidulafungin and the diluted solution contains0.77 mg/mL anidulafungin.

Excipient with known effect: ECALTA contains 119 mg fructose in each vial.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to off-white solid.

The reconstituted solution has a pH of 3.5 to 5.5.

Treatment of invasive candidiasis in adults and paediatric patients aged 1 month to < 18 years (seesections 4.4 and 5.1).

Treatment with ECALTA should be initiated by a physician experienced in the management ofinvasive fungal infections.

Specimens for fungal culture should be obtained prior to therapy. Therapy may be initiated beforeculture results are known and can be adjusted accordingly once they are available.

Adult population (dosing and treatment duration)

A single 200 mg loading dose should be administered on Day 1, followed by 100 mg daily thereafter.

Duration of treatment should be based on the patient’s clinical response.

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

There are insufficient data to support the 100 mg dose for longer than 35 days of treatment.

No dosing adjustments are required for patients with mild, moderate, or severe hepatic impairment. Nodosing adjustments are required for patients with any degree of renal insufficiency, including those ondialysis. ECALTA can be given without regard to the timing of haemodialysis (see section 5.2).

No dosing adjustments are required for adult patients based on gender, weight, ethnicity, HIVpositivity, or elderly (see section 5.2).

Paediatric population (1 month to < 18 years) (dosing and treatment duration)

A single loading dose of 3.0 mg/kg (not to exceed 200 mg) should be administered on Day 1 followedby a daily maintenance dose of 1.5 mg/kg (not to exceed 100 mg) thereafter.

Duration of treatment should be based on the patient’s clinical response.

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

The safety and efficacy of ECALTA have not been established in neonates (< 1 month old) (seesection 4.4).

For intravenous use only.

ECALTA should be reconstituted with water for injection to a concentration of 3.33 mg/mL andsubsequently diluted to a concentration of 0.77 mg/mL for the final infusion solution. For a paediatricpatient, the volume of infusion solution required to deliver the dose will vary depending on the weightof the child. For instructions on reconstitution of the medicinal product before administration (seesection 6.6).

It is recommended that ECALTA be administered at a rate of infusion that does not exceed1.1 mg/min (equivalent to 1.4 mL/min when reconstituted and diluted per instructions). Infusionassociated reactions are infrequent when the rate of anidulafungin infusion does not exceed1.1 mg/min (see section 4.4).

ECALTA must not be administered as a bolus injection.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to other medicinal products of the echinocandin class.

ECALTA has not been studied in patients with Candida endocarditis, osteomyelitis or meningitis.

The efficacy of ECALTA has only been evaluated in a limited number of neutropenic patients (seesection 5.1).

Treatment with ECALTA in neonates (< 1 month old) is not recommended. Treating neonates requiresconsideration for coverage of disseminated candidiasis including central nervous system (CNS);nonclinical infection models indicate that higher doses of anidulafungin are needed to achieveadequate CNS penetration (see section 5.3), resulting in higher doses of polysorbate 80, a formulationexcipient. High doses of polysorbates have been associated with potentially life-threatening toxicitiesin neonates as reported in the literature.

There is no clinical data to support the efficacy and safety of higher doses of anidulafungin thanrecommended in 4.2.

Increased levels of hepatic enzymes have been seen in healthy subjects and patients treated withanidulafungin. In some patients with serious underlying medical conditions who were receivingmultiple concomitant medicines along with anidulafungin, clinically significant hepatic abnormalitieshave occurred. Cases of significant hepatic dysfunction, hepatitis, and hepatic failure were uncommonin clinical trials. Patients with increased hepatic enzymes during anidulafungin therapy should bemonitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuinganidulafungin therapy.

Anaphylactic reactions

Anaphylactic reactions, including shock, were reported with the use of anidulafungin. If thesereactions occur, anidulafungin should be discontinued and appropriate treatment administered.

Infusion-related adverse events have been reported with anidulafungin, including rash, urticaria,flushing, pruritus, dyspnoea, bronchospasm and hypotension. Infusion-related adverse events areinfrequent when the rate of anidulafungin infusion does not exceed 1.1 mg/min (see section 4.8).

Exacerbation of infusion-related reactions by co-administration of anaesthetics has been seen in anon-clinical (rat) study (see section 5.3). The clinical relevance of this is unknown. Nevertheless, careshould be taken when co-administering anidulafungin and anaesthetic agents.

Fructose content

ECALTA contains fructose.

Patients with hereditary fructose intolerance (HFI) should not be given this medicine unless strictlynecessary.

Babies and young children (below 2 years of age) may not yet be diagnosed with HFI. Medicines(containing fructose) given intravenously may be life-threatening and should not be administered inthis population unless there is an overwhelming clinical need and no alternatives are available.

A detailed history with regard to HFI symptoms has to be taken of each patient prior to being giventhis medicinal product.

ECALTA contains less than 1 mmol sodium (23 mg) per vial. Patients on low sodium diets can beinformed that this medicinal product is essentially ‘sodium-free’.

ECALTA may be diluted with sodium-containing solutions (see section 6.6) and this should beconsidered in relation to the total sodium from all sources that will be administered to the patient.

Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450isoenzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A). Of note, in vitro studies do not fully excludepossible in vivo interactions.

Drug interaction studies were performed with anidulafungin and other medicinal products likely to beco-administered. No dosage adjustment of either medicinal product is recommended whenanidulafungin is co-administered with ciclosporin, voriconazole or tacrolimus, and no dosageadjustment for anidulafungin is recommended when co-administered with amphotericin B orrifampicin.

Interaction studies have only been performed in adults.

There are no data from the use of anidulafungin in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

ECALTA is not recommended during pregnancy unless the benefit to the mother clearly outweighs thepotential risk to the foetus.

It is unknown whether anidulafungin is excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of anidulafungin in milk.

A risk to the suckling child cannot be excluded. A decision must be made whether to discontinuebreast-feeding or to discontinue/abstain from ECALTA therapy taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

For anidulafungin, there were no effects on fertility in studies conducted in male and female rats (seesection 5.3).

Not relevant.

Infusion-related adverse reactions have been reported with anidulafungin in clinical studies, includingrash, pruritus, dyspnoea, bronchospasm, hypotension (common events), flushing, hot flush, andurticaria (uncommon events), summarized in Table 1 (see section 4.4).

The following table includes, the all-causality adverse reactions (MedDRA terms) from 840 subjectsreceiving 100 mg anidulafungin with frequency corresponding to 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 from spontaneous reports with frequency not known (cannot be estimated from theavailable data). Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness.

Table 1. Table of Adverse Reactions

System Organ Very Common Uncommon Rare Very Not Known

Class Common ≥ 1/100 ≥ 1/1000 ≥ Rare≥ 1/10 to to 1/10,000 << 1/10 <1/100 to 1/10,000<1/1,000

Blood and Coagulopathy

Lymphatic System

Disorders

Immune System Anaphylacti

Disorders c shock,anaphylacticreaction*

Metabolism and Hypokalaemia Hyperglycaemia

Nutrition Disorders

Nervous System Convulsion,

Disorders headache

Vascular Disorders Hypotension, Flushing,hypertension hot flush

Respiratory, Bronchospasm,

Thoracic and Dyspnoea

Mediastinal

Disorders

Gastrointestinal Diarrhoea, Vomiting Abdominal

Disorders Nausea pain upper

Hepatobiliary Alanine Gamma-

Disorders aminotransferase glutamyltransincreased, feraseblood alkaline increasedphosphataseincreased,aspartateaminotransferaseincreased, bloodbilirubinincreased,cholestasis

Skin and Rash, Urticaria

Subcutaneous pruritus

Tissue Disorders

Renal and Urinary Blood creatinine

Disorders increased

General Disorders Infusion siteand Administration pain

Site Conditions

* See section 4.4.

The safety of anidulafungin was investigated in 68 paediatric patients (1 month to < 18 years) with

ICC in a prospective, open-label, non-comparative paediatric study (see section 5.1). The frequenciesof certain hepatobiliary adverse events, including alanine aminotransferase (ALT) increased andaspartate aminotransferase (AST) increased appeared at a higher frequency (7-10%) in these paediatricpatients than has been observed in adults (2%). Although chance or differences in underlying diseaseseverity may have contributed, it cannot be excluded that hepatobiliary adverse reactions occur morefrequently in paediatric patients compared to adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

As with any overdose, general supportive measures should be utilised as necessary. In case ofoverdose, adverse reactions may occur as mentioned in section 4.8.

During clinical trials, a single 400 mg dose of anidulafungin was inadvertently administered as aloading dose. No clinical adverse reactions were reported. No dose limiting toxicity was observed in astudy of 10 healthy subjects administered a loading dose of 260 mg followed by 130 mg daily; 3 of the10 subjects experienced transient, asymptomatic transaminase elevations ( 3 x Upper Limit of

Normal (ULN)).

During a paediatric clinical trial, one subject received two doses of anidulafungin that were 143% ofthe expected dose. No clinical adverse reactions were reported.

ECALTA is not dialysable.

Pharmacotherapeutic group: - Antimycotics for systemic use, other antimycotics for systemic use.

ATC code: JO2AX06

Anidulafungin is a semi-synthetic echinocandin, a lipopeptide synthesised from a fermentation productof Aspergillus nidulans.

Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme present in fungal, but notmammalian cells. This results in inhibition of the formation of 1,3--D-glucan, an essential componentof the fungal cell wall. Anidulafungin has shown fungicidal activity against Candida species andactivity against regions of active cell growth of the hyphae of Aspergillus fumigatus.

Activity in vitro

Anidulafungin exhibited in-vitro activity against C. albicans, C. glabrata, C. parapsilosis, C. kruseiand C. tropicalis. For the clinical relevance of these findings see “Clinical efficacy and safety.”

Isolates with mutations in the hot spot regions of the target gene have been associated with clinicalfailures or breakthrough infections. Most clinical cases involve caspofungin treatment. However, inanimal experiments these mutations confer cross resistance to all three echinocandins and thereforesuch isolates are classified as echinocandin resistant until further clinical experience are obtainedconcerning anidulafungin.

The in vitro activity of anidulafungin against Candida species is not uniform. Specifically, for

C. parapsilosis, the MICs of anidulafungin are higher than are those of other Candida species. Astandardized technique for testing the susceptibility of Candida species to anidulafungin as well as therespective interpretative breakpoints has been established by European Committee on Antimicrobial

Susceptibility Testing (EUCAST).

Table 2. EUCAST Breakpoints

Candida Species MIC breakpoint (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 evidence1 Non-species related breakpoints have been determined mainly on thebasis of PK/PD data and are independent of MIC distributions of specific

Candida species. They are for use only for organisms that do not havespecific breakpoints

Activity in vivo

Parenterally administered anidulafungin was effective against Candida species in immunocompetentand immunocompromised mouse and rabbit models. Anidulafungin treatment prolonged survival andalso reduced the organ burden of Candida species, when determined at intervals from 24 to 96 hoursafter the last treatment.

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

Candidaemia and other forms of Invasive Candidiasis

The safety and efficacy of anidulafungin were evaluated in a pivotal Phase 3, randomised,double-blind, multicentre, multinational study of primarily non-neutropenic patients with candidaemiaand a limited number of patients with deep tissue Candida infections or with abscess-forming disease.

Patients with Candida endocarditis, osteomyelitis or meningitis, or those with infection due to

C. krusei, were specifically excluded from the study. Patients were randomised to receive eitheranidulafungin (200 mg intravenous loading dose followed by 100 mg intravenous daily) orfluconazole (800 mg intravenous loading dose followed by 400 mg intravenous daily), and werestratified by APACHE II score (≤20 and >20) and the presence or absence of neutropenia. Treatmentwas administered for at least 14 and not more than 42 days. Patients in both study arms were permittedto switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they were ableto tolerate oral medicinal products and were afebrile for at least 24 hours, and that the most recentblood cultures were negative for Candida species.

Patients who received at least one dose of study medicinal products and who had a positive culture for

Candida species from a normally sterile site before study entry were included in the modified intent-to-treat (MITT) population. In the primary efficacy analysis, global response in the MITT populationsat the end of intravenous therapy, anidulafungin was compared to fluconazole in a pre-specifiedtwo-step statistical comparison (non-inferiority followed by superiority). A successful global responserequired clinical improvement and microbiological eradication. Patients were followed for six weeksbeyond the end of all therapy.

Two hundred and fifty-six patients, ranging from 16 to 91 years in age, were randomised to treatmentand received at least one dose of study medication. The most frequent species isolated at baseline were

C. albicans (63.8% anidulafungin, 59.3% fluconazole), followed by 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 thelast 3 species, respectively, in the anidulafungin group. The majority of patients had Apache II scores≤ 20 and very few were neutropenic.

Efficacy data, both overall and by various subgroups, are presented below in Table 3.

Table 3. Global success in the MITT population: primary and secondary endpoints

Anidulafungin Fluconazole Between groupdifference a(95% CI)

End of IV Therapy (1º endpoint) 96/127 (75.6%) 71/118 (60.2%) 15.42 (3.9, 27.0)

Candidaemia 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/IAc abscess 6/8 5/8

Other 2/3 3/7

C. albicansd 60/74 (81.1%) 38/61 (62.3%) -

Non-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%) -

Non-neutropenic (ANC, cells/mm3  94/124 (75.8%) 69/114 (60.5%) -500)

Neutropenic (ANC, cells/mm3 ≤ 500) 2/3 2/4 -

At Other Endpoints

End of All Therapy 94/127 (74.0%) 67/118 (56.8%) 17.24 (2.9, 31.6)e2 Week Follow-up 82/127 (64.6%) 58/118 (49.2%) 15.41 (0.4, 30.4)e6 Week Follow-up 71/127 (55.9%) 52/118 (44.1%) 11.84 (-3.4, 27.0)ea Calculated as anidulafungin minus fluconazoleb With or without concurrent candidaemiac Intra-abdominald Data presented for patients with a single baseline pathogen.e 98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time points.

Mortality rates in both the anidulafungin and fluconazole arms are presented below in Table 4:

Table 4. Mortality

Anidulafungin Fluconazole

Overall study mortality 29/127 (22.8%) 37/118 (31.4%)

Mortality during study therapy 10/127 (7.9%) 17/118 (14.4%)

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

Additional Data in Neutropenic Patients

The efficacy of anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenousdaily) in adult neutropenic patients (defined as absolute neutrophil count ≤ 500 cells/mm3, WBC≤ 500 cells/mm3 or classified by the investigator as neutropenic at baseline) with microbiologicallyconfirmed invasive candidiasis was assessed in an analysis of pooled data from 5 prospective studies(1 comparative versus caspofungin and 4 open-label, non-comparative). Patients were treated for atleast 14 days. In clinically stable patients, a switch to oral azole therapy was permitted after at least 5to 10 days of treatment with anidulafungin. A total of 46 patients were included in the analysis. Themajority of patients had candidaemia only (84.8%; 39/46). The most common pathogens isolated atbaseline 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). The successful global response rate at Endof Intravenous Treatment (primary endpoint) was 26/46 (56.5%) and End of All Treatment was 24/46(52.2%). All-cause mortality up to the end of the study (6 Week Follow-up Visit) was 21/46 (45.7%).

The efficacy of anidulafungin in adult neutropenic patients (defined as absolute neutrophil count≤ 500 cells/mm3 at baseline) with invasive candidiasis was assessed in a prospective, double-blind,randomized, controlled trial. Eligible patients received either anidulafungin (200 mg intravenousloading dose followed by 100 mg intravenous daily) or caspofungin (70 mg intravenous loading dosefollowed by 50 mg intravenous daily) (2:1 randomization). Patients were treated for at least 14 days.

In clinically stable patients, a switch to oral azole therapy was permitted after at least 10 days of studytreatment. A total of 14 neutropenic patients with microbiologically confirmed invasive candidiasis(MITT population) were enrolled in the study (11 anidulafungin; 3 caspofungin). The majority ofpatients had candidaemia 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). The successfulglobal response rate at the End of Intravenous Treatment (primary endpoint) was 8/11 (72.7%) foranidulafungin and 3/3 (100.0%) for caspofungin (difference -27.3, 95% CI -80.9, 40.3); the successfulglobal response rate at the End of All Treatment was 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 up to the 6 Week

Follow-Up visit for anidulafungin (MITT population) was 4/11 (36.4%) and 2/3 (66.7%) forcaspofungin.

Patients with microbiologically confirmed invasive candidiasis (MITT population) and neutropeniawere identified in an analysis of pooled data from 4 similarly designed prospective, open-label,non-comparative studies. The efficacy of anidulafungin (200 mg intravenous loading dose followed by100 mg intravenous daily) was assessed in 35 adult neutropenic patients defined as absolute neutrophilcount ≤ 500 cells/mm3 or WBC ≤ 500 cells/mm3 in 22 patients or classified by the investigator asneutropenic at baseline in 13 patients. All patients were treated for at least 14 days. In clinically stablepatients, a switch to oral azole therapy was permitted after at least 5 to 10 days of treatment withanidulafungin. The majority of patients had candidaemia only (85.7%). The most common pathogensisolated at baseline were C. tropicalis (12 patients), C. albicans (7 patients), C. glabrata (7 patients),

C. krusei (7 patients), and C. parapsilosis (6 patients). The successful global response rate at the Endof Intravenous Treatment (primary endpoint) was 18/35 (51.4%) and 16/35 (45.7%) at the End of All

Treatment. All-cause mortality by Day 28 was 10/35 (28.6%). The successful global response rate at

End of Intravenous Treatment and End of All Treatment were both 7/13 (53.8%) in the 13 patientswith neutropenia assessed by investigators at baseline.

Additional Data in Patients with Deep Tissue Infections

The efficacy of anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenousdaily) in adult patients with microbiologically confirmed deep tissue candidiasis was assessed in ananalysis of pooled data from 5 prospective studies (1 comparative and 4 open-label). Patients weretreated for at least 14 days. In the 4 open-label studies, a switch to oral azole therapy was permittedafter at least 5 to 10 days of treatment with anidulafungin. A total of 129 patients were included in theanalysis. Twenty one (16.3%) had concomitant candidaemia. The mean APACHE II score was 14.9(range, 2 - 44). The most common sites of infection included the peritoneal cavity (54.3%; 70 of 129),hepatobiliary tract (7.0%; 9 of 129), pleural cavity (5.4%; 7 of 129) and kidney (3.1%; 4 of 129). Themost common pathogens isolated from a deep tissue site at baseline were C. albicans (64.3%; 83 of129), C. glabrata (31.0%; 40 of 129), C. tropicalis (11.6%; 15 of 129), and C. krusei (5.4%; 7 of129). The successful global response rate at the end of intravenous treatment (primary endpoint) andend of all treatment and all-cause mortality up to the 6 week follow-up visit is shown in Table 5.

Table 5. Rate of Successful Global Responsea and All-Cause Mortality in Patients with Deep

Tissue Candidiasis - Pooled Analysis

MITT Populationn/N (%)

Global Response of Success at EOIVTb

Overall 102/129 (79.1)

Peritoneal cavity 51/70 (72.9)

Hepatobiliary tract 7/9 (77.8)

Pleural cavity 6/7 (85.7)

Kidney 3/4 (75.0)

Global Response of Success at EOTb 94/129 (72.9)

All-Cause Mortality 40/129 (31.0)a A successful global response was defined as both clinical and microbiologic successb EOIVT, End of Intravenous Treatment; EOT, End of All Treatment

A prospective, open-label, non-comparative, multi-national study assessed the safety and efficacy ofanidulafungin in 68 paediatric patients aged 1 month to < 18 years with invasive candidiasis includingcandidaemia (ICC). Patients were stratified by age (1 month to < 2 years, 2 to < 5 years, and 5 to< 18 years) and received once daily intravenous anidulafungin (3.0 mg/kg loading dose on Day 1, and1.5 mg/kg daily maintenance dose thereafter) for up to 35 days followed by an optional switch to oralfluconazole (6-12 mg/kg/day, maximum 800 mg/day). Patients were followed at 2 and 6 weeks after

EOT.

Among 68 patients who received anidulafungin, 64 had microbiologically confirmed Candidainfection and were evaluated for efficacy in the modified intent-to-treat (MITT) population. Overall,61 patients (92.2%) had Candida isolated from blood only. The most commonly isolated pathogenswere Candida albicans (25 [39.1%] patients), followed by Candida parapsilosis (17 [26.6%] patients),and Candida tropicalis (9 [14.1%] patients). A successful global response was defined as having botha clinical response of success (cure or improvement) and a microbiological response of success(eradication or presumed eradication). The overall rates of successful global response in the MITTpopulation are presented in Table 6.

Table 6. Summary of Successful Global Response by Age Group, MITT Population

Successful Global Response, n (%)

Timepoint Global 1 month to < 2 years 2 to < 5 years 5 to < 18 years Overall

Response (N=16) (N=18) (N=30) (N=64)n (n/N, %) n (n/N, %) n (n/N, %) n (n/N, %)

EOIVT Success 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)

EOT Success 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 FU Success 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 FU Success 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 Clopper-Pearson method;

EOIVT = End of Intravenous Treatment; EOT = End of All Treatment; FU = follow-up; MITT =modified intent-to-treat; N = number of subjects in the population; n = number of subjects withresponses

The pharmacokinetics of anidulafungin have been characterised in healthy subjects, specialpopulations and patients. A low intersubject variability in systemic exposure (coefficient of variation~25%) was observed. The steady state was achieved on the first day after a loading dose (twice thedaily maintenance dose).

The pharmacokinetics of anidulafungin are characterised by a rapid distribution half-life (0.5-1 hour)and a volume of distribution, 30-50 l, which is similar to total body fluid volume. Anidulafungin isextensively bound (>99%) to human plasma proteins. No specific tissue distribution studies ofanidulafungin have been done in humans. Therefore, no information is available about the penetrationof anidulafungin into the cerebrospinal fluid (CSF) and/or across the blood-brain barrier.

Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevantsubstrate, inducer, or inhibitor of cytochrome P450 isoenzymes. It is unlikely that anidulafungin willhave clinically relevant effects on the metabolism of drugs metabolised by cytochrome P450isoenzymes.

Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to aring-opened peptide that lacks antifungal activity. The in vitro degradation half-life of anidulafunginunder physiologic conditions is approximately 24 hours. In vivo, the ring-opened product issubsequently converted to peptidic degradants and eliminated mainly through biliary excretion.

The clearance of anidulafungin is about 1 l/h. Anidulafungin has a predominant elimination half-life ofapproximately 24 hours that characterizes the majority of the plasma concentration-time profile, and aterminal half-life of 40-50 hours that characterises the terminal elimination phase of the profile.

In a single-dose clinical study, radiolabeled (14C) anidulafungin (~88 mg) was administered to healthysubjects. Approximately 30% of the administered radioactive dose was eliminated in the faeces over9 days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dose wasexcreted in the urine, indicating negligible renal clearance. Anidulafungin concentrations fell belowthe lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivitywere recovered in blood, urine, and faeces 8 weeks post-dose.

Anidulafungin displays linear pharmacokinetics across a wide range of once daily doses (15-130 mg).

Patients with fungal infections

The pharmacokinetics of anidulafungin in patients with fungal infections are similar to thoseobserved in healthy subjects based on population pharmacokinetic analyses. With the 200/100 mgdaily dose regimen at an infusion rate of 1.1 mg/min, the steady state Cmax and troughconcentrations (Cmin) could reach approximately 7 and 3 mg/l, respectively, with an averagesteady state AUC of approximately 110 mgh/l.

Weight

Although weight was identified as a source of variability in clearance in the populationpharmacokinetic analysis, weight has little clinical relevance on the pharmacokinetics ofanidulafungin.

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

The population pharmacokinetic analysis showed that median clearance differed slightly between theelderly group (patients ≥ 65, median CL = 1.07 l/h) and the non-elderly group (patients < 65, median

CL = 1.22 l/h), however the range of clearance was similar.

Anidulafungin pharmacokinetics were similar among Caucasians, Blacks, Asians, and Hispanics.

HIV positivity

Dosage adjustments are not required based on HIV positivity, irrespective of concomitantanti-retroviral therapy.

Anidulafungin is not hepatically metabolised. Anidulafungin pharmacokinetics were examined insubjects with Child-Pugh class A, B or C hepatic insufficiency. Anidulafungin concentrations were notincreased in subjects with any degree of hepatic insufficiency. Although a slight decrease in AUC wasobserved in patients with Child-Pugh C hepatic insufficiency, the decrease was within the range ofpopulation estimates noted for healthy subjects.

Anidulafungin has negligible renal clearance (<1%). In a clinical study of subjects with mild,moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafunginpharmacokinetics were similar to those observed in subjects with normal renal function.

Anidulafungin is not dialysable and may be administered without regard to the timing ofhemodialysis.

The pharmacokinetics of anidulafungin after at least 5 daily doses were investigated in 24immunocompromised paediatric (2 to 11 years old) and adolescent (12 to 17 years old) patients withneutropenia. Steady state was achieved on the first day after a loading dose (twice the maintenancedose), and steady state Cmax and AUCss increase in a dose-proportional manner. Systemic exposurefollowing daily maintenance dose of 0.75 and 1.5 mg/kg/day in this population were comparable tothose observed in adults following 50 and 100 mg/day, respectively. Both regimens were well-tolerated by these patients.

The pharmacokinetics of anidulafungin was investigated in 66 paediatric patients (1 month to< 18 years) with ICC in a prospective, open-label, non-comparative paediatric study followingadministration of 3.0 mg/kg loading dose and 1.5 mg/kg/day maintenance dose (see section 5.1).

Based on population pharmacokinetic analysis of combined data from adult and paediatric patientswith ICC, the mean exposure parameters (AUC0-24,ss and Cmin,ss) at steady state in the overall paediatricpatients across age groups (1 month to < 2 years, 2 to < 5 years, and 5 to < 18 years) were comparableto those in adults receiving 200 mg loading dose and 100 mg/day maintenance dose. Body weightadjusted CL (L/h/kg) and volume of distribution at steady state (L/kg) were similar across the agegroups.

In 3 month studies, evidence of liver toxicity, including elevated enzymes and morphologicalterations, was observed in both rats and monkeys at doses 4- to 6-fold higher than the anticipatedclinical therapeutic exposure. In vitro and in vivo genotoxicity studies with anidulafungin provided noevidence of genotoxic potential. Long-term studies in animals have not been conducted to evaluate thecarcinogenic potential of anidulafungin.

Administration of anidulafungin to rats did not indicate any effects on reproduction, including maleand female fertility.

Anidulafungin crossed the placental barrier in rats and was detected in foetal plasma.

Embryo-foetal development studies were conducted with doses between 0.2- and 2-fold (rats) andbetween 1- and 4-fold (rabbits) the proposed therapeutic maintenance dose of 100 mg/day.

Anidulafungin did not produce any drug-related developmental toxicity in rats at the highest dosetested. Developmental effects observed in rabbits (slightly reduced foetal weights) occurred only at thehighest dose tested, a dose that also produced maternal toxicity.

The concentration of anidulafungin in the brain was low (brain to plasma ratio of approximately 0.2)in uninfected adult and neonatal rats after a single dose. However, brain concentrations increased inuninfected neonatal rats after five daily doses (brain to plasma ratio of approximately 0.7). In multipledose studies in rabbits with disseminated candidiasis and in mice with central nervous system (CNS)

Candida infection, anidulafungin has been shown to reduce fungal burden in the brain. Results ofpharmacokinetic-pharmacodynamic studies in rabbit models of disseminated candidiasis andhematogenous Candida meningoencephalitis indicated that higher doses of anidulafungin were neededto optimally treat infections of CNS tissues relative to non-CNS tissues (see section 4.4).

Rats were dosed with anidulafungin at three dose levels and anaesthetised within one hour using acombination of ketamine and xylazine. Rats in the high dose group experienced infusion-relatedreactions that were exacerbated by anaesthesia. Some rats in the mid dose group experienced similarreactions but only after administration of anaesthesia. There were no adverse reactions in the low-doseanimals in the presence or absence of anaesthesia, and no infusion-related reactions in the mid-dosegroup in the absence of anaesthesia.

Studies conducted in juvenile rats did not indicate a greater susceptibility to anidulafunginhepatotoxicity compared to adult animals.

6 PHARMACEUTICAL PARTICULARS

Fructose

Mannitol

Polysorbate 80

Tartaric acid

Sodium hydroxide (for pH-adjustment)

Hydrochloric acid (for pH-adjustment)

This medicinal product must not be mixed with other medicinal products or electrolytes except thosementioned in section 6.6.

3 years

Excursions for up to 96 hours at temperatures up to 25ºC are permitted, and the powder can bereturned to refrigerated storage.

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hoursat 25ºC.

From a microbiological point of view, following good aseptic practices, the reconstituted solution canbe utilized for up to 24 hours when stored at 25ºC.

Infusion solution

Do not freeze.

Chemical and physical in-use stability of the infusion solution has been demonstrated for 48 hours at25ºC.

From a microbiological point of view, following good aseptic practices, the infusion solution can beutilized for up to 48 hours from preparation when stored at 25ºC.

Store in a refrigerator (2°C - 8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

30 mL Type 1 glass vial with an elastomeric stopper (butyl rubber with an inert polymer coating onthe product contact surface and lubricant on the top surface for easier machinability, or alternativelybromobutyl rubber with a lubricant) and aluminium seal with flip-off cap.

Pack size of 1 vial.

There are no special requirements for disposal.

ECALTA must be reconstituted with water for injection and subsequently diluted with ONLY sodiumchloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose for infusion. Thecompatibility of reconstituted ECALTA with intravenous substances, additives, or medicines otherthan 9 mg/mL (0.9%) sodium chloride for infusion or 50 mg/mL (5%) glucose for infusion has notbeen established. The infusion solution must not be frozen.

Aseptically reconstitute each vial with 30 mL water for injection to provide a concentration of3.33 mg/mL. The reconstitution time can be up to 5 mins. After subsequent dilution, the solution is tobe discarded if particulate matter or discolouration is identified.

Dilution and infusion

Parenteral medicinal products should be inspected visually for particulate matter anddiscolouration prior to administration, whenever solution and container permit. If particulatematter or discolouration is identified, discard the solution.

Aseptically transfer the contents of the reconstituted vial(s) into an intravenous bag (or bottle)containing either 9 mg/mL (0.9%) sodium chloride for infusion or 50 mg/mL (5%) glucose forinfusion to obtain the appropriate ECALTA concentration. The table below provides the dilution to aconcentration of 0.77 mg/mL for the final infusion solution and infusion instructions for each dose.

Dilution requirements for ECALTA administration

Dose Number Total Infusion Total Rate of Minimumof vials of reconstituted volume A infusion infusion duration ofpowder volume volumeB infusion100 mg 1 30 mL 100 mL 130 mL 1.4 mL/ 90 minmin or84 mL/hour200 mg 2 60 mL 200 mL 260 mL 1.4 mL 180 min/min or84 mL/hour

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

B Infusion solution concentration is 0.77 mg/mL

The rate of infusion should not exceed 1.1 mg/min (equivalent to 1.4 mL/min or 84 mL/hour whenreconstituted and diluted per instructions) (see sections 4.2, pct. 4.4 and 4.8).

For paediatric patients aged 1 month to < 18 years, the volume of infusion solution required to deliverthe dose will vary depending on the weight of the patient. The reconstituted solution must be furtherdiluted to a concentration of 0.77 mg/mL for the final infusion solution. A programmable syringe orinfusion pump is recommended. The rate of infusion should not exceed 1.1 mg/minute (equivalentto 1.4 mL/minute or 84 mL/hour when reconstituted and diluted per instructions) (see sections4.2 and 4.4).

1. Calculate patient dose and reconstitute vial(s) required according to reconstitution instructionsto provide a concentration of 3.33 mg/mL (see sections 2 and 4.2)2. Calculate the volume (mL) of reconstituted anidulafungin required:

- Volume of anidulafungin (mL) = Dose of anidulafungin (mg)  3.33 mg/mL3. Calculate the total volume of dosing solution (mL) required to provide a final concentration of0.77 mg/mL:

- Total volume of dosing solution (mL) = Dose of anidulafungin (mg) ÷ 0.77 mg/mL4. Calculate the volume of diluent [5% Dextrose Injection, USP or 0.9% Sodium Chloride

Injection, USP (normal saline)] required to prepare the dosing solution:

- Volume of diluent (mL) = Total volume of dosing solution (mL) - Volume ofanidulafungin (mL)5. Aseptically transfer the required volumes (mL) of anidulafungin and 5% Dextrose Injection,

USP or 0.9% Sodium Chloride Injection, USP (normal saline) into an infusion syringe or IVinfusion bag needed for administration.

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

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/07/416/002

Date of first authorisation: 20 September 2007

Date of latest renewal: 28 August 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.