Pfizer Healthcare Ireland

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 contains 0.77 mg/ml anidulafungin.

Excipients: Fructose 102.5 mg per vial

For a full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to off-white lyophilised solid.

The reconstituted solution has a pH of 3.5 to 5.5.

Treatment of invasive candidiasis in adult non-neutropenic patients.

ECALTA has been studied primarily in patients with candidaemia and only in a limited number of patients with deep tissue Candida infections or with abscess-forming disease (see section 4.4 and section 5.1).

Treatment with ECALTA should be initiated by a physician experienced in the management of invasive fungal infections. Specimens for fungal culture should be obtained prior to therapy. Therapy may be initiated before culture results are known and can be adjusted accordingly once they are available.

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.

ECALTA should be reconstituted with water for injections to a concentration of 3.33 mg/ml and subsequently diluted to a concentration of 0.77 mg/ml before use according to the instructions given in section 6.6.

It is recommended that ECALTA be administered at a rate of infusion that does not exceed 1.1 mg/minute (equivalent to 1.4 ml/minute when reconstituted and diluted per instructions). Infusion associated reactions are infrequent when the rate of anidulafungin infusion does not exceed 1.1 mg/minute.

ECALTA should not be administered as a bolus injection.

Renal and hepatic impairment

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

Duration of treatment

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

Other special populations

No dosing adjustments are required for adult patients based on gender, weight, ethnicity, HIV positivity, or geriatric status (see section 5.2).

Children and adolescents

ECALTA is not recommended for use in children below 18 due to insufficient data on safety and efficacy (see section 5.2).

Hypersensitivity to the active substance, or to any of the excipients.

Hypersensitivity to other medicinal products of the echinocandin class.

The efficacy of ECALTA in neutropenic patients with candidaemia and in patients with deep tissue Candida infections or intra-abdominal abscess and peritonitis has not been established.

Clinical efficacy has been evaluated primarily in non-neutropenic patients with C. albicans infections and in a smaller number of patients infected with non-albicans, mainly C. glabrata, C. parapsilosis and C. tropicalis. Patients with candida endocarditis, osteomyelitis or meningitis and known C.krusei infection have not been studied.

Hepatic effects

Increased levels of hepatic enzymes have been seen in healthy subjects and patients treated with anidulafungin. In some patients with serious underlying medical conditions who were receiving multiple concomitant medicines along with anidulafungin, clinically significant hepatic abnormalities have occurred. Cases of significant hepatic dysfunction, hepatitis, and hepatic failure were uncommon in clinical trials. Patients with increased hepatic enzymes during anidulafungin therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing anidulafungin therapy.

Infusion-related reactions

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

Fructose content

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 isoenzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A). Of note, in vitro studies do not fully exclude possible in vivo interactions.

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

There are no data regarding the use of anidulafungin in pregnant women. Slight developmental effects have been observed in rabbits administered anidulafungin during pregnancy, in the presence of maternal toxicity (see section 5.3). The potential risk for humans is unknown. Therefore anidulafungin is not recommended in pregnancy.

Animal studies have shown excretion of anidulafungin in breast milk. It is not known whether anidulafungin is excreted in human breast milk. A decision on whether to continue/discontinue breast-feeding or therapy with anidulafungin should be made taking into account the benefit of breast-feeding to the child and the benefit of anidulafungin to the mother.

No studies on the effects on the ability to drive and use machines have been performed.

Nine hundred and twenty-nine (929) subjects received single or multiple doses of intravenous anidulafungin in clinical trials: 672 in Phase 2/3 trials (287 patients with candidaemia/invasive candidiasis, 355 patients with oral/oesophageal candidiasis, 30 patients with invasive aspergillosis), and 257 in Phase I studies.

Three studies (one comparative vs fluconazole, two non-comparative) assessed the efficacy of anidulafungin in patients with candidaemia and a limited number of patients with deep tissue Candida infections. A total of 204 patients received the recommended daily dose of 100 mg; the mean duration of intravenous treatment in these patients was 13.5 days (range, 1 to 38 days). One hundred and nineteen patients received 14 days of anidulafungin. Adverse reactions were typically mild to moderate and seldom led to discontinuation.

Infusion-related adverse reactions have been reported with anidulafungin; in the pivotal ICC study, these included flushing/hot flush (2.3%), pruritus (2.3%), rash (1.5%), and urticaria (0.8%). Other treatment-related adverse reactions that occurred in 1% of patients in the pivotal study included hypokalaemia (3.1%), diarrhoea (3.1%), ALT increased (2.3%), hepatic enzyme increased (1.5%), blood alkaline phosphatase increased (1.5%), and blood bilirubin increased (1.5%).

The following table includes, the drug-related adverse reactions (MedDRA terms) from the 100 mg ICC database (N = 204),with frequency corresponding to Common (1/100 to <1/10) or Uncommon (1/1,000 to <1/100) and from spontaneous reports with frequency Not Known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

^ Frequency cannot be estimated from the available data

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

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

ECALTA is not dialysable.

General properties

Pharmacotherapeutic group: Other antimycotics for systemic use, ATC code: JO2AX06

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

Anidulafungin selectively inhibits 1,3-β-D glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3-β-D-glucan, an essential component of the fungal cell wall. Anidulafungin has shown fungicidal activity against Candida species and activity 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, and C. tropicalis. Susceptibility breakpoints for 1,3- β-D-glucan synthesis inhibitors have not been established. For the clinical relevance of these findings see below under clinical studies.

Minimum inhibitory concentration (MIC) determinations were performed according to the Clinical and Laboratory Standards Institute methods M27. There have been reports of Candida isolates with reduced susceptibility to echinocandins including anidulafungin but the clinical significance of this observation is unknown.

Activity in vivo

Parenterally administered anidulafungin was effective against Candida spp. in immunocompetent and immunocompromised mouse and rabbit models. Anidulafungin treatment prolonged survival and also reduced the organ burden of Candida spp., when determined at intervals from 24 to 96 hours after the last treatment.

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

Information from clinical studies

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 candidaemia and 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 either anidulafungin (200 mg intravenous loading dose followed by 100 mg intravenous daily) or fluconazole (800 mg intravenous loading dose followed by 400 mg intravenous daily), and were stratified by APACHE II score (20 and >20) and the presence or absence of neutropenia. Treatment was administered for at least 14 and not more than 42 days. Patients in both study arms were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they were able to tolerate oral medication and were afebrile for at least 24 hours, and that the most recent blood cultures were negative for Candida species.

Patients who received at least one dose of study medication 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 populations at the end of intravenous therapy, anidulafungin was compared to fluconazole in a pre-specified two-step statistical comparison (non-inferiority followed by superiority). A successful global response required clinical improvement and microbiological eradication. Patients were followed for six weeks beyond the end of all therapy.

Two hundred and fifty-six patients, ranging from 16 to 91 years in age, were randomised to treatment and 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 the last 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 1.

^a Calculated as anidulafungin minus fluconazole

^bWith or without concurrent candidaemia

^c Intra-abdominal

^d 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 2:

General pharmacokinetic characteristics

The pharmacokinetics of anidulafungin have been characterised in healthy subjects, special populations 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 the daily maintenance dose).

Distribution

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 have clinically relevant effects on the metabolism of drugs metabolised by cytochrome P450 isoenzymes.

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

Elimination

The clearance of anidulafungin is about 1 l/h. Anidulafungin has a predominant elimination half-life of approximately 24 hours that characterizes the majority of the plasma concentration-time profile, and a terminal 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 healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the faeces over 9 days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dose was excreted in the urine, indicating negligible renal clearance. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and faeces 8 weeks post-dose.

Linearity

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

Special populations

Patients with fungal infections

The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects based on population pharmacokinetic analyses. With the 200/100 mg daily dose regimen at an infusion rate of 1.1 mg/min, the steady state C_max and trough concentrations (C_min) could reach approximately 7 and 3 mg/l, respectively, with an average steady state AUC of approximately 110 mgh/l.

Weight

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

Gender

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

Elderly

The population pharmacokinetic analysis showed that median clearance differed slightly between the elderly 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.

Ethnicity

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

HIV positivity

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

Hepatic insufficiency

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

Renal insufficiency

Anidulafungin has negligible renal clearance (<1%). In a clinical study of subjects with mild, moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin pharmacokinetics were similar to those observed in subjects with normal renal function. Anidulafungin is not dialysable and may be administered without regard to the timing of hemodialysis.

Paediatric

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

In 3 month studies, evidence of liver toxicity, including elevated enzymes and morphologic alterations, was observed in both rats and monkeys at doses 4- to 6-fold higher than the anticipated clinical therapeutic exposure. In vitro and in vivo genotoxicity studies with anidulafungin provided no evidence of genotoxic potential. Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of anidulafungin.

Administration of anidulafungin to rats did not indicate any effects on reproduction, including male and 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) and between 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 dose tested. Developmental effects observed in rabbits (slightly reduced foetal weights) occurred only at the highest 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 in uninfected neonatal rats after five daily doses (brain to plasma ratio of approximately 0.7). In multiple dose studies in rabbits with disseminated candidiasis and in mice with CNS candida infection, anidulafungin has been shown to reduce fungal burden in the brain.

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

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 those mentioned in section 6.6.

3 years

Reconstituted solution:

The reconsituted solution may be stored up to 25°C for up to 24 hours.

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at 25°C.

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

Infusion solution:

The infusion solution may be stored at 25°C for 48 hours or stored frozen for at least 72 hours.

Chemical and physical in-use stability of the infusion solution has been demonstrated for 48 hours at 25°C.

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

.

Store this medicinal product in a refrigerator (2°C – 8°C). Excursions for 96 hours up to 25°C are permitted, and the powder can be returned to refrigerated storage.

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

ECALTA will be available as a box containing 1 vial of 100 mg powder.

ECALTA must be reconstituted with water for injections and subsequently diluted with ONLY 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion. The compatibility of reconstituted ECALTA with intravenous substances, additives, or medicines other than 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion has not been established.

Reconstitution

Aseptically reconstitute each vial with 30 ml water for injections to provide a concentration of 3.33 mg/ml. The reconstitution time can be up to 5 minutes. After subsequent dilution, the solution is to be discarded if particulate matter or discoloration is identified.

The reconstituted solution may be stored at up to 25°C for 24 hours.

Dilution and infusion

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 for infusion obtaining an anidulafungin concentration of 0.77 mg/ml. The table below provides the volumes required for each dose.

Dilution requirements for ECALTA administration

^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/minute (equivalent to 1.4 ml/minute when reconstituted and diluted per instructions).

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

For single use only. Waste materials should be disposed of in accordance with local requirements.

Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom.

EU/1/07/416/002

20 September 2007

August 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.ema.europa.eu/.