1. Name Of The Medicinal Product
ECALTA ®
2. Qualitative And Quantitative Composition
Each vial contains 100 mg anidulafungin.
The reconstituted solution contains 3.33 mg/ml anidulafungin and the diluted solution contains 0.36 mg/ml anidulafungin.
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For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder and solvent for concentrate for solution for infusion.
Powder: White to off-white lyophilised solid.
Solvent: Clear colourless solution.
The reconstituted solution has a pH of 4.0 to 6.0.
4. Clinical Particulars
4.1 Therapeutic Indications
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).
4.2 Posology And Method Of Administration
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 the solvent to a concentration of 3.33 mg/ml and subsequently diluted to a concentration of 0.36 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 3.0 ml/minute). 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).
4.3 Contraindications
Hypersensitivity to the active substance, or to any of the excipients.
Hypersensitivity to other medicinal products of the echinocandin class.
4.4 Special Warnings And Precautions For Use
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. Isolated cases of significant hepatic dysfunction, hepatitis, or hepatic failure have been reported. 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.
Alcohol content
This medicinal product contains 24 vol% ethanol (alcohol); this is equivalent to 6 g ethanol in the 100 mg maintenance dose (administered over a 1.5-hour period), and 12 g ethanol in the 200 mg loading dose (administered over a 3-hour period). Ethanol could be harmful for those suffering from alcoholism. This should be taken into account in pregnant or breast-feeding women, children, and in high-risk groups such as those with liver disease or epilepsy.
The amount of alcohol in this medicinal product may alter the effects of other medicines.
The amount of alcohol in this medicinal product may impair the ability to drive or use machines.
Fructose content
Patients with rare hereditary problems of fructose intolerance should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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.
4.6 Pregnancy And Lactation
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.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
The amount of alcohol in this medicinal product may impair the ability to drive or use machines.
4.8 Undesirable Effects
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
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
The following table includes, the drug-related adverse reactions (MedDRA terms) from the 100 mg ICC database (N = 204) with frequencies corresponding to Common (
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^ Frequency cannot be estimated from the available data
4.9 Overdose
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 (
ECALTA is not dialysable.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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 (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
Efficacy data, both overall and by various subgroups, are presented below in Table 1.
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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:
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5.2 Pharmacokinetic Properties
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
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 is extensively bound (>99%) to human plasma proteins. No specific tissue distribution studies of anidulafungin have been done in humans. Therefore, no information is available about the penetration of anidulafungin into the cerebrospinal fluid (CSF) 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 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 Cmax and trough concentrations (Cmin) could reach approximately 7 and 3 mg/l, respectively, with an average steady state AUC of approximately 110 mg
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
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 Cmax and AUCss 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.
5.3 Preclinical Safety Data
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
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.
Crossing of the blood-brain barrier by anidulafungin was limited in healthy rats; however, in rabbits with disseminated candidiasis, anidulafungin has been shown to cross the blood-brain barrier and 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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Powder:
Fructose
Mannitol
Polysorbate 80
Tartaric acid
Sodium hydroxide (for pH-adjustment)
Hydrochloric acid (for pH-adjustment)
Solvent:
Ethanol anhydrous
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products or electrolytes except those mentioned in section 6.6.
6.3 Shelf Life
Powder and solvent: 3 years
Reconstituted solution:
The reconstituted solution should be further diluted within an hour. Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 3 hours at 25ºC and for 2 hours at 5°C.
Infusion solution:
Chemical and physical in-use stability of the infusion solution has been demonstrated for 24 hours at 25ºC.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
6.4 Special Precautions For Storage
Powder and solvent:
Do not store above 25ºC.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
Powder:
30 ml Type 1 glass vial with an elastomeric stopper and aluminium seal with flip
Solvent:
30 ml of 20 % (w/w) ethanol anhydrous in water for injections in a Type 1 glass vial with an elastomeric stopper and aluminium seal with flip
ECALTA will be available as a box containing 1 vial of 100 mg powder and 1 vial of 30 ml solvent.
6.6 Special Precautions For Disposal And Other Handling
ECALTA must be reconstituted with the solvent (20% (w/w) ethanol anhydrous in 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 the solvent (20% (w/w) ethanol anhydrous in water for injections) to provide a concentration of 3.33 mg/ml. The reconstitution time can be up to 5 minutes. The reconstituted solution should be clear and free from visible particulates. After subsequent dilution, the solution is to be discarded if particulate matter or discoloration is identified.
The reconstituted solution must be further diluted within an hour and administered within 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 0.36 mg/ml. The table below provides the volumes required for each dose.
Dilution requirements for ECALTA administration
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A Either 9 mg/ml (0.9%) sodium chloride for infusion or 50 mg/ml (5%) glucose for infusion.
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.
7. Marketing Authorisation Holder
Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom.
8. Marketing Authorisation Number(S)
EU/1/07/416/001
9. Date Of First Authorisation/Renewal Of The Authorisation
20th September 2007
10. Date Of Revision Of The Text
1st September 2010
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.ema.europa.eu/.
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