Active ingredients: Anidulafungin
ECALTA 100 mg powder for concentrate for solution for infusion
Indications Why is Ecalta used? What is it for?
ECALTA contains the active substance anidulafungin and is used in adults to treat a type of fungal infection of the blood or other internal organs called invasive candidiasis. The infection is caused by cells of a type of fungus (yeast) called Candida.
ECALTA belongs to a group of medicines called echinocandins. These medicines are used to treat severe fungal infections.
ECALTA prevents the normal development of fungal cell walls. In the presence of ECALTA, fungal cells have incomplete or defective cell walls and this makes them fragile or unable to grow.
Contraindications When Ecalta should not be used
Do not use ECALTA:
- if you are allergic to anidulafungin, other echinocandins (eg CANCIDAS) or any of the other ingredients of this medicine.
Precautions for use What you need to know before taking Ecalta
Talk to your doctor, pharmacist or nurse before using ECALTA. Your doctor may decide to monitor
- liver function more carefully if you develop liver problems during treatment.
- if you are given anesthetics during treatment with ECALTA.
Children
ECALTA should not be given to patients under 18 years of age.
Interactions Which drugs or foods can modify the effect of Ecalta
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Do not start taking any other medicines or stop using them without your doctor or pharmacist's approval.
Warnings It is important to know that:
Pregnancy and breastfeeding
The effect of ECALTA in pregnant women is not known. Therefore, the use of ECALTA is not recommended during pregnancy. Women of childbearing potential must use an adequate method of contraception. Contact your doctor immediately if you become pregnant while being treated with ECALTA.
The effect of ECALTA in breastfeeding women is not known. Ask your doctor or pharmacist for advice before using.
ECALTA while breastfeeding. Ask your doctor or pharmacist for advice before taking any medicine.
ECALTA contains fructose
This medicine contains fructose (a type of sugar). If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before using this medicine.
Dose, Method and Time of Administration How to use Ecalta: Posology
ECALTA will always be prepared and administered by a doctor or healthcare professional (you will find more information on the preparation method of this medicine at the end of the package leaflet in the section dedicated to doctors and healthcare professionals).
Treatment starts with 200 mg on the first day (loading dose). This will be followed by a daily dose of 100 mg (maintenance dose).
ECALTA must be given to you once a day by slow (drip) infusion into a vein. This will take at least 1.5 hours for the maintenance dose and 3 hours for the loading dose.
Your doctor will determine the duration of the treatment and the amount of ECALTA you will receive each day and will check your response to the treatment and your condition.
In general, treatment should continue for at least 14 days from the last day Candida was detected in the blood.
If you forget to use ECALTA
As this medicine will be given to you under close medical supervision, it is unlikely that a dose will be missed. However, tell your doctor or pharmacist if you think a dose has been missed.
You should not be given a double dose by your doctor.
If you stop taking ECALTA
If your doctor stops taking ECALTA there should be no effect.
Your doctor may prescribe another medicine following treatment with ECALTA to continue the treatment of the fungal infection or to prevent it from returning.
If the original symptoms of the infection recur, tell your doctor or other healthcare professional immediately.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Reconstitution
Each vial must be reconstituted under aseptic conditions with 30 ml of water for injections to obtain a concentration of 3.33 mg / ml. The reconstitution time can last up to 5 minutes. After a subsequent dilution, the solution must be discarded if the presence of particles or discolouration is identified.
The reconstituted solution can be stored up to 25 ° C for up to 24 hours before the next dilution.
Dilution and infusion
The contents of the reconstituted vial must be transferred under aseptic conditions into an intravenous bag (or bottle) containing sodium chloride for infusion 9 mg / ml (0.9%) or glucose for infusion 50 mg / ml (5%) in in order to obtain a concentration of anidulafungin equal to 0.77 mg / ml. The table below shows the volumes needed for each dose.
Dilution requirements for administration of ECALTA
A: Sodium chloride for infusion 9 mg / ml (0.9%) or glucose for infusion 50 mg / ml (5%)
B: The concentration of the solution for infusion is 0.77 mg / mL The infusion rate should not exceed 1.1 mg / min (equivalent to 1.4 mL / min when reconstituted and diluted as instructed).
Whenever the solution and container permit, parenteral medicinal products should be visually inspected prior to administration for the presence of particles or discolouration. If the presence of particles or a discoloration is identified, the solution must be discarded.
For single use only. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
Overdose What to do if you have taken too much Ecalta
If you are concerned that you may have been given more ECALTA than you should, tell your doctor or other healthcare professional immediately.
Side Effects What are the side effects of Ecalta
Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of these side effects will be observed by your doctor as he monitors your response and condition.
Life-threatening allergic reactions, including difficulty in breathing with wheezing or worsening of pre-existing rashes, have been reported rarely during administration of ECALTA.
Serious side effects - tell your doctor or other healthcare professional immediately if you experience any of the following:
- Convulsions (fits)
- Redness
- Skin rash, itching
- Hot flashes
- Urticaria
- Sudden contraction of the airway muscles which can cause wheezing or coughing
- Difficulty in breathing
Other side effects
Very common side effects (may affect more than 1 in 10 people) are:
- Low levels of potassium in the blood (hypokalaemia)
- Diarrhea
- Nausea
Common side effects (may affect up to 1 in 10 people) are:
- Convulsions (fits)
- Headache
- He retched
- Changes in liver function tests
- Skin rash, itching
- Changes in kidney function tests
- Alteration of the flow of bile from the gallbladder to the intestine (cholestasis)
- High blood sugar levels
- High blood pressure
- Low blood pressure
- Sudden contraction of the airway muscles which can cause wheezing or coughing
- Difficulty in breathing
Uncommon side effects (may affect up to 1 in 100 people) are:
- Coagulation disorders
- Redness
- Hot flashes
- Stomach ache
- Urticaria
- Pain at the injection site
Undesirable effects of unknown frequency (frequency cannot be estimated from the available data) are:
- Allergic reactions that are life-threatening
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system V. By reporting side effects you can help. to provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last day of that month.
Store in a refrigerator (2 ° C - 8 ° C).
The reconstituted solution can be stored up to 25 ° C for up to 24 hours. The solution for infusion can be stored at 25 ° C (room temperature) for up to 48 hours or stored frozen for at least 72 hours and should be given at 25 ° C (room temperature) within 48 hours.
Do not throw away any medicines via wastewater or household waste.
Other Information
What ECALTA contains
The active ingredient is anidulafungin. Each vial of powder contains 100 mg of anidulafungin
The other ingredients are: fructose, mannitol, polysorbate 80, tartaric acid, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment).
What ECALTA looks like and contents of the pack
ECALTA is available as a pack containing 1 vial of 100 mg powder for concentrate for solution for infusion.
The powder is white to off-white.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ECALTA 100 MG POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 100 mg of anidulafungin.
The reconstituted solution contains 3.33 mg / ml of anidulafungin and the diluted solution contains 0.77 mg / ml of anidulafungin.
Excipient with known effects: fructose 102.5 mg per vial.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
White to off-white solid lyophilisate.
The reconstituted solution has a pH of 3.5 to 5.5.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of invasive candidiasis in adult patients (see sections 4.4 and 5.1).
04.2 Posology and method of administration
ECALTA treatment should be initiated by a physician experienced in the treatment of invasive fungal infections. Samples of fungal cultures should be collected prior to initiation of therapy. Therapy can be initiated before culture test results are known and can be adapted accordingly when these results become available.
Dosage
A single 200 mg loading dose should be administered on the 1st day of treatment, followed by 100 mg per day 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.
Duration of the treatment
There is insufficient data to support the use of the 100 mg dose for a treatment period exceeding 35 days.
Patients with renal and hepatic impairment
No dosage adjustments are required in patients with mild, moderate or severe hepatic impairment. No dosage adjustments are required in patients with any degree of renal impairment, including patients undergoing dialysis. ECALTA can be administered regardless of when dialysis is performed (see section 5.2).
Other special patient populations
No dosage adjustments are required in adult patients based on gender, weight, ethnicity, HIV positivity or in elderly patients (see section 5.2).
Pediatric population
The safety and efficacy of ECALTA in children under 18 years of age have not been established. Currently available data are described in section 5.2 but it is not possible to deduce the recommended regimen.
Method of administration
For intravenous administration only.
ECALTA must be reconstituted with water for injections at a concentration of 3.33 mg / ml and subsequently diluted to a concentration of 0.77 mg / ml. For instructions on reconstitution of the medicinal product before administration, see section 6.6.
It is recommended that ECALTA be administered at an infusion rate that does not exceed 1.1 mg / min (equivalent to 1.4 ml / min when the powder is reconstituted and diluted as instructed). Infusion associated reactions are infrequent when the anidulafungin infusion rate does not exceed 1.1 mg / min (see section 4.4).
ECALTA must not be administered as a bolus.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypersensitivity to other medicines of the echinocandin class.
04.4 Special warnings and appropriate precautions for use
ECALTA has not been studied in patients with endocarditis, osteomyelitis or meningitis from Candida.
The efficacy of ECALTA has only been evaluated in a limited number of neutropenic patients (see section 5.1).
Hepatic effects
An increase in liver enzyme levels has been observed in healthy subjects and in patients treated with anidulafungin. Clinically significant liver changes have occurred in some patients with serious underlying medical conditions being treated with several concomitant medicinal products together with anidulafungin. Episodes of significant hepatic dysfunction, hepatitis and hepatic failure were uncommon in clinical studies. Patients with liver enzyme elevations during treatment with anidulafungin should be monitored for possible worsening of liver function and assess the risk-benefit balance of continuing anidulafungin therapy.
Anaphylactic reactions
Anaphylactic reactions, including shock, have been reported during the use of anidulafungin. If such reactions occur, administration of anidulafungin should be discontinued and appropriate therapies applied.
Infusion related reactions
Infusion-related adverse reactions, including rash, urticaria, flushing, pruritus, dyspnoea, bronchospasm and hypotension, have been reported during treatment with anidulafungin. Infusion-related adverse reactions are uncommon when the infusion rate does not exceed 1, 1 mg / min.
Worsening of infusion-related reactions following concomitant administration of anesthetics was observed in a non-clinical study (in rats) (see section 5.3). The clinical relevance of this effect is unknown. However, caution is required. when anidulafungin is administered together with anesthetic agents.
Fructose content
Patients with rare hereditary problems of fructose intolerance should not take this medicine.
04.5 Interactions 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). It is important to point out that the studies in vitro they do not completely rule out the possibility of interactions in vivo.
Interaction studies have been performed with anidulafungin and other medicinal products for which co-administration is likely. No dosage adjustment of these medicinal products or of anidulafungin is recommended when the latter is administered with cyclosporine, voriconazole, and tacrolimus and no dose adjustment of anidulafungin is recommended when given together with amphotericin B or rifampicin.
Pediatric population
Interaction studies have only been performed in adults.
04.6 Pregnancy and breastfeeding
Pregnancy
There are no adequate data from the use of anidulafungin in pregnant women.
Mild developmental effects were observed in rabbits treated with andidulafungin during pregnancy in the presence of maternal toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, the use of anidulafungin in pregnancy is not recommended.
Feeding time
Animal studies have shown that anidulafungin is excreted in breast milk. It is not known whether anidulafungin is excreted in human breast milk. A decision on whether to continue / discontinue breastfeeding or anidulafungin therapy must be made taking into account the benefit of breastfeeding for the child and the benefit of anidulafungin treatment for the mother.
Fertility
For anidulafungin, no effects on fertility were seen in studies conducted in male and female rats (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
Summary of the safety profile
Fifteen hundred and sixty-five subjects were treated with single or multiple doses of intravenous anidulafungin in clinical trials: 1308 patients in Phase 2/3 clinical trials (923 patients with invasive candidiasis / candidiasis, 355 patients with oral / oesophageal candidiasis, 30 patients with invasive aspergillosis) and 257 patients in Phase 1 studies.
The safety profile of anidulafungin is based on 840 patients with invasive candidemia / candidiasis treated with the recommended daily dose of 100 mg in 9 studies. Initially, in 3 studies (one comparative versus fluconazole, two non-comparatives) 204 patients were examined; the mean duration of intravenous treatment in these patients was 13.5 days (range 1 to 38 days) and 119 patients were treated with anidulafungin for ≥ 14 days. In 6 other studies (two comparative versus caspofungin and four non-comparatives), 636 patients were examined, including 53 neutropenic and 131 with deep tissue infection; the mean duration of intravenous treatment in neutropenic patients and patients with deep tissue infection in these studies was 10.0 (range 1 to 42) and 14.0 (range 1 to 42) days, respectively. Adverse reactions were generally mild to moderate in severity and rarely led to treatment discontinuation.
Infusion related adverse reactions have been reported during treatment with anidulafungin in clinical trials, as summarized in Table 1, such as: flushing, flushing, pruritus, rash and urticaria.
Tabulated adverse reactions
The table below includes all-cause adverse reactions (MedDRA terms) seen in 840 subjects treated with 100 mg anidulafungin with corresponding frequency very common (≥ 1/10), common (≥ 1/100 to
Table 1. Table of Adverse Reactions
* See section 4.4.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.
04.9 Overdose
As with any overdose, necessary general supportive measures should be used.
In case of overdose, the adverse reactions listed in section 4.8 may occur.
In clinical trials, a single 400 mg dose of anidulafungin was inadvertently administered as a loading dose. No adverse reactions were reported. No dose-limiting toxicity was observed in a study involving 10 healthy volunteers. administered a 260 mg loading dose, followed by 130 mg daily; 3 of 10 subjects reported a transient and asymptomatic elevation of transaminases (≤ 3 x Upper Normal Limit (ULN)).
ECALTA is not dialysable.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antifungals for systemic use, other antifungals for systemic use.
ATC code: JO2AX06.
Mechanism of action
Anidulafungin is a "semi-synthetic echinocandin, a lipopeptide synthesized from a fermentation product of"Aspergillus nidulans.
Anidulafungin selectively inhibits beta-D-glucan-synthase, an enzyme found in fungal but not mammalian cells. This involves an "inhibition of the formation of beta-D-glucan, an essential component of the fungal cell wall. Anidulafungin has demonstrated a" fungicidal activity against Candida spp. and an "activity against the areas of active cell growth of the hyphae Aspergillus fumigatus.
Activities in vitro
Anidulafungin showed an "activity in vitro towards C. albicans, C. glabrata, C. parapsilosis, C. krusei And C. tropicalis. For the clinical relevance of these data, see "Clinical efficacy and safety" Aspergillus fumigatus.
Isolates with mutations in the hot spot regions of the target gene have been associated with clinical failures or new onset fungal infections (breakthrough). Treatment with caspofungin is involved in most clinical cases. However, in animal experiments these mutations confer cross-resistance to all three echinocandins, so until further clinical experience is gained on anidulafungin these isolates are classified as resistant to echinocandins.
The activity in vitro of anidulafungin against the species of Candida it is not uniform. Specifically, for C. parapsilosis MICs (Minimum Inhibitory Concentrations) of anidulafungin are higher than those of other species of Candida. The "European Committee on Antimicrobial Susceptibility Testing (EUCAST) has defined a standardized technique for anidulafungin sensitivity test of species Candida as well as the respective interpretative breakpoints.
Table 2. EUCAST Breakpoints
1 C. parapsilosis has an inherent alteration in the target gene, which is the likely mechanism responsible for the higher MICs than other species of Candida. In clinical studies the outcome for anidulafungin with C. parapsilosis however, the use of echinocandins in candidemia was not statistically different from the other species C. parapsilosis it may not be considered a first choice therapy
2 EUCAST did not determine non-species-related breakpoints for Anidulafungin
Activities in vivo
Parenterally administered anidulafungin was effective against species of Candida in immunocompetent and immunocompromised mouse and rabbit models. Treatment with anidulafungin prolonged the survival rate and also reduced the burden of Candida spp. in the organ concerned, when determined at intervals between 24 and 96 hours from the last treatment.
Infections studied in laboratory animals included disseminated infection C. albicans in neutropenic rabbits, oesophageal / oropharyngeal infection in neutropenic rabbits with C. albicans resistant to fluconazole and disseminated infection neutropenic mice with infections C. glabrata resistant to fluconazole.
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, multicenter, Phase 3 clinical trial conducted in multiple countries in mainly non-neutropenic patients, with candidemia and in a limited number of patients with deep-seated infections. Candida localized to the tissues or associated with the formation of abscesses. Patients with endocarditis, osteomyelitis or meningitis from Candida, or those with infections from C. krusei, were specifically excluded from the study. Patients were randomized to receive anidulafungin (200 mg intravenous loading dose followed by 100 mg per day intravenously) or fluconazole (800 mg intravenous loading dose followed by 400 mg per day) and were stratified with the APACHE II scale (≤ 20 and> 20) and based on the presence or absence of neutropenia. Treatment was administered for at least 14 days and for no longer than 42 days. Patients in both treatment arms were allowed to switch to oral fluconazole after at least 10 days of intravenous therapy, provided they were able to tolerate the oral treatment and were afebrile for at least 24 hours and the more recent blood cultures were negative for Candida spp.
Patients who had received at least one dose of study drug and who had a positive culture for Candida spp. from a normally sterile site prior to study enrollment were included in the Modified Intent-To-Treat (MITT) population. In the primary efficacy analysis (overall response at end of intravenous therapy in MITT populations) anidulafungin was compared to fluconazole in a pre-defined two-stage statistical comparison (non-inferiority followed by superiority). A successful overall response required clinical improvement and microbiological eradication. Patients were followed up for six weeks beyond completion of all therapy.
Two hundred and fifty-six patients, aged 16 to 91 years, were randomized to treatment and received at least one dose of study drug. The most frequently isolated species at the baseline visit were C. albicans (63.8% anidulafungin, 59.3% fluconazole), followed by C. glabrata (15,7 %, 25,4 %), C. parapsilosis (10.2%, 13.6%) e C. tropicalis (11.8%, 9.3%) - with respectively 20, 13 and 15 strains of the last 3 species in the anidulafungin group. Most patients had an APACHE II score ≤ 20 and a very small number of patients were neutropenic.
The efficacy data, both global and related to the various subgroups, are shown below in Table 3.
a Calculated as anidulafungin minus fluconazole
b With or without concomitant candidemia
c Intra-abdominal
d Data presented for patients with a single pathogen at baseline
and 98.3% confidence intervals, for multiple comparisons made in subsequent times through post-hoc analysis.
Mortality rates in both anidulafungin and fluconazole treatment arms are shown below in Table 4:
Additional data in neutropenic patients
The efficacy of anidulafungin (200 mg intravenous loading dose followed by 100 mg per day intravenously) in adult neutropenic patients (defined with an absolute neutrophil count ≤ 500 cells / mm3, WBC ≤ 500 cells / mm3 or investigator classified as neutropenic at baseline) with microbiologically confirmed invasive candidiasis was evaluated in a "pooled analysis of 5 prospective studies (1 comparative versus caspofungin and 4 open, non-comparative). Patients were treated for at least 14 days. In clinically stable patients, switching to oral azole therapy was allowed after at least 5-10 days of anidulafungin treatment. A total of 46 patients were included in the analysis. Most patients had candidemia alone (84.8%; 39/46). The most frequently isolated pathogens 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). The overall success response rate at the end of intravenous treatment (primary endpoint) was 26/46 (56.5%) and at the end of all treatments 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 with an absolute neutrophil count ≤ 500 cells / mm3 at baseline) with invasive candidiasis was evaluated in a prospective, controlled, double-blind, randomized study.Eligible patients were treated with anidulafungin (200 mg intravenous loading dose followed by 100 mg per day intravenously) or caspofungin (70 mg intravenous loading dose followed by 50 mg per day intravenously. ) (2: 1 randomization). Patients were treated for at least 14 days.
In clinically stable patients, a switch to oral azole therapy was allowed after at least 10 days of study treatment. A total of 14 neutropenic patients with microbiologically confirmed invasive candidiasis (MITT population) (11 anidulafungin, caspofungin) were enrolled in the study. Most of the patients presented with candidemia alone. The pathogens most frequently isolated at baseline were C. tropicalis (4 anidulafungin, 0 caspofungin), C.. parapsilosis (2 anidulafungin, 1 caspofungin), C. krusei (2 anidulafungin, 1 caspofungin) C. ciferrii (2 anidulafungin, 0 caspofungin). The overall success rate at the end of intravenous treatment (primary endpoint) was 8/11 (72.7%) for anidulafungin and 3/3 (100%) for caspofungin (difference -27.3, 95% CI: -80.9, 40.3); the overall success response rate at the end of all treatments was 8/11 (72.7%) for anidulafungin and 3/100%) 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%) for caspofungin.
Patients with microbiologically confirmed invasive candidiasis (MITT population) and neutropenia were identified in a "pooled analysis of 4 similarly designed, open-label, non-comparative prospective studies. The efficacy of anidulafungin (200 mg loading dose for intravenous followed by 100 mg per day intravenously) was evaluated in 35 defined neutropenic adult patients with an absolute neutrophil count ≤ 500 cells / mm3 or in 22 patients with WBC ≤ 500 cells / mm3 or in 13 investigator-classified patients as neutropenic at baseline. Patients were treated for at least 14 days. In clinically stable patients, switching to oral azole therapy was allowed after at least 5-10 days of anidulafungin treatment. Most patients had candidemia alone (85.7%). The pathogens most frequently isolated at baseline were C. tropicalis (12 patients), C. albicans (7 patients), C. glabrata (7 patients), C. krusei (7 patients) e C. parapsilosis (6 patients). The overall successful response rate at the end of intravenous treatment (primary endpoint) was 18/35 (51.4%), and 16/35 (45.7%) at the end of all treatments. All cause mortality on day 28 was 10/35 (28.6%). The overall success response rate at the end of intravenous treatment and at the end of all treatments was 7/13 (53.8%) for both of the 13 patients classified by the investigator as neutropenic at baseline.
Additional data in patients with deep tissue infections
The efficacy of anidulafungin (200 mg intravenous loading dose followed by 100 mg per day intravenously) in adult patients with microbiologically confirmed deep tissue candidiasis was evaluated in a pooled analysis of 5 prospective studies from similar design (1 comparative and 4 open). Patients were treated for at least 14 days. In the 4 open-label studies, switching to oral azole therapy was allowed after at least 5-10 days of anidulafungin treatment. A total of 129 patients were included in the analysis. Twenty-one patients (16.3%) had concomitant candidemia. The mean APACHE II score was 14.9 (range 2-44). The most frequent sites of infection were the peritoneal cavity 54.3%, 70/129), the hepatobiliary tract (7.0%, 9/129), the pleural cavity (5.4%, 7/129) and the kidney (3.1%, 4 / 129) The pathogens most frequently isolated from deep tissue at baseline were C. albicans (64,3%; 83/129), C. glabrata (31,0%; 40/129), C. tropicalis (11.6%; 15/129) e C. krusei (5.4%; 7/129). Table 5 reports the overall success rate at the end of intravenous treatment (primary endpoint) and at the end of all treatments, as well as all-cause mortality up to the 6-week follow-up visit.
a Overall success response was defined as both clinical and microbiological success
b EOIVT, End of Intravenous Treatment; EOT, End of All Treatment
05.2 Pharmacokinetic properties
General characteristics of pharmacokinetics
The pharmacokinetics of anidulafungin have been characterized in healthy volunteers, in special populations and in patients. Low inter-subject variability was observed in systemic exposure (coefficient of variation? 25%) steady-state was achieved on the first day after a loading dose (twice the maintenance dose).
Distribution
The pharmacokinetics of anidulafungin are characterized by a rapid distribution half-life (0.5-1 hour) and a volume of distribution of 30-50 L, which is similar to the volume of total body fluid.
Anidulafungin is extensively bound (> 99%) to plasma proteins. No specific studies on tissue distribution of anidulafungin have been performed in humans. Therefore, no information is available on the penetration of anidulafungin into the cerebrospinal fluid (CSF) and / or through the blood-brain barrier.
Biotransformation
Hepatic metabolism of anidulafungin was not observed. Anidulafungin is not a clinically relevant substrate, inducer or inhibitor of cytochrome P450 isoenzymes. Anidulafungin is unlikely to have clinically relevant effects on the metabolism of drugs metabolised by cytochrome P450 isoenzymes.
Anidulafungin is transformed through slow chemical degradation at physiological temperatures and pH to an open-loop peptide devoid of antifungal activity. The half-life of degradation in vitro of anidulafungin in physiological conditions is about 24 hours. The open-loop product in vivoit is subsequently converted into peptide degradants and eliminated mainly through biliary excretion.
Elimination
The clearance of anidulafungin is approximately 1 l / h. Anidulafungin has a predominant elimination half-life of approximately 24 hours which characterizes most of the plasma concentration-time profile and a terminal half-life of 40-50 hours which characterizes the terminal elimination phase of the profile.
In a single dose clinical study, radiolabelled (14C) anidulafungin (≥ 88 mg) was administered to healthy volunteers. Approximately 30% of the administered radioactive dose was eliminated in the faeces over 9 days and less than 10% of the dose was recovered as unchanged drug. Less than 1% of the administered radioactive dose was excreted in the urine and this indicates negligible renal clearance. Concentrations of anidulafungin fell below the lower limits of quantification 6 days after administration. Negligible amounts of drug-derived radioactivity were revealed in blood, urine and faeces 8 weeks after administration.
Linearity
Anidulafungin exhibits linear pharmacokinetics across a wide range of single daily doses (15-130 mg).
Special patient populations
Patients with fungal infections
The anidulafungin pharmacokinetics in patients with fungal infections is similar to that observed in healthy subjects based on population pharmacokinetic analyzes. With the 200/100 mg daily dosing regimen at an infusion rate of 1.1 mg / min, Cmax at steady-state and trough concentrations (Cmin) reached 7 and 3 mg / l, respectively, with mean AUC at steady-state of about 110 mg • h / l.
Weight
Although weight was identified as a source of variability in clearance by the population pharmacokinetic analysis, weight has minimal clinical importance on the pharmacokinetics of anidulafungin.
Gender of belonging
Plasma concentrations of anidulafungin in male and female volunteers were similar. In studies performed in patients with multiple doses, drug clearance was slightly faster (approximately 22%) in men.
Senior citizens
The population pharmacokinetic analysis showed that the median clearance differed slightly between the elderly group (age ≥ 65 years, median CL = 1.07 l / h) and the non-elderly group (age
Race
The pharmacokinetics of anidulafungin were similar in Caucasian, Black, Asian and Hispanic subjects.
HIV positivity
Dosage adjustments are not required in HIV-positive patients, regardless of concomitant antiretroviral therapy.
Hepatic insufficiency
Anidulafungin is not metabolised by the liver. The pharmacokinetics of anidulafungin were examined in subjects with Child-Pugh grade A, B or C hepatic impairment. Anidulafungin concentrations were not increased in subjects with any degree of hepatic impairment.
Although a slight reduction in AUC was observed in patients with Child-Pugh grade C hepatic impairment, the reduction was within the range of population estimates observed for healthy subjects.
Kidney failure
Anidulafungin has negligible renal clearance (normal renal function. Anidulafungin is not dialysable and can be administered regardless of when dialysis is performed.
Pediatric patients
The pharmacokinetics of anidulafungin after at least 5 daily doses were examined in 24 immunocompromised pediatric (age 2-11 years) and adolescent (12-17 years) subjects with neutropenia. The steadystate was achieved on the first day after a loading dose (twice the maintenance dose) and the Cmax and AUCss at steady-state increased in a dose-proportional manner. Systemic exposure following administration of the 0.75 mg and 1.5 mg / kg / day maintenance dose in this population was comparable to that observed in adults after 50 and 100 mg / day administration, respectively. Both dosing regimens were well tolerated by these patients.
05.3 Preclinical safety data
In the 3-month studies, evidence of liver toxicity, including increased enzymes and morphological changes, was observed in both rats and monkeys treated with doses 4-6 times the anticipated clinical therapeutic exposure. Genotoxicity studies in vitro And in vivo with anidulafungin provided no evidence of a genotoxic potential. Long-term animal studies have not been performed to evaluate the carcinogenic potential of anidulafungin.
Administration of anidulafungin to rats showed no effects on reproduction, including fertility in males and females.
Anidulafungin crossed the placental barrier in rats and was detected in fetal plasma.
Embryo-fetal development studies were performed with doses between 0.2 and 2 times (rats) and between 1 and 4 times (rabbits) the proposed therapeutic maintenance dose of 100 mg / day. Anidulafungin did not produce any type of drug-related developmental toxicity in rats tested at the maximum dose. The developmental effects observed in rabbits (slightly reduced body weights) occurred only at the highest dose tested, a dose that also produced maternal toxicity.
Brain anidulafungin concentration was low (brain / plasma ratio approximately 0.2) in uninfected adult and neonatal rats after a single dose. However, brain concentrations increased in uninfected neonatal rats after 5 daily doses (brain / plasma ratio of approximately 0.7). In multiple dose studies in rabbits with disseminated candidiasis and in mice with CNS infection caused by Candida, anidulafungin reduced the fungal load in the brain.
Rats were treated with three doses of anidulafungin and anesthetized within one hour using a combination of ketamine and xylazine. Rats in the higher dose group reported infusion-related reactions that were aggravated by anesthesia. Some Rats in the intermediate dose group reported similar reactions, but only after administration of anesthesia.
No adverse reactions were reported in animals treated with the lower dose in the presence or absence of anesthesia and in the intermediate dose group in the absence of anesthesia, no infusion-related reactions occurred.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Fructose
Mannitol
Polysorbate 80
Tartaric acid
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
06.2 Incompatibility
This medicinal product must not be mixed with other products except those mentioned in section 6.6.
06.3 Period of validity
3 years.
Temperature excursions for 96 hours up to 25 ° C are allowed, and the powder can be returned to refrigerated storage conditions.
Reconstituted solution:
The reconstituted solution can be stored up to 25 ° C for up to 24 hours.
The chemical-physical stability of the reconstituted solution in use has been demonstrated for 24 hours at 25 ° C.
From a microbiological point of view, observing the optimal aseptic conditions, the reconstituted solution can be used up to 24 hours later if kept at 25 ° C.
Solution for infusion:
The solution for infusion can be stored at 25 ° C for 48 hours or stored frozen for at least 72 hours.
Physico-chemical stability of the infusion solution in use has been demonstrated for 48 hours at 25 ° C.
From a microbiological point of view, observing the optimal aseptic conditions, the infusion solution can be used for a period of 48 hours after preparation if stored at 25 ° C.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C).
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
30 ml Type I glass vial with an elastomeric stopper (butyl rubber with inert polymer coating on the surface in contact with the product and with lubricant on the upper surface to facilitate production) and aluminum seal with flip-off closure.
Pack of 1 vial.
06.6 Instructions for use and handling
No special instructions for disposal.
ECALTA must be reconstituted with water for injections and subsequently diluted with sodium chloride 9 mg / ml (0.9%) solution for injection with glucose 50 mg / ml (5%) for infusion ONLY. The compatibility of reconstituted ECALTA with intravenous substances, additives or medicinal products other than sodium chloride 9 mg / ml (0.9%) or glucose 50 mg / ml (5%) has not been established.
Reconstitution
Each vial must be reconstituted under aseptic conditions with 30 ml of water for injections to obtain a concentration of 3.33 mg / ml. The reconstitution time can last up to 5 minutes. After a subsequent dilution, the solution should be discarded if the presence of particles or discolouration is identified.
Dilution and infusion
The contents of the reconstituted vial must be transferred under aseptic conditions into an intravenous bag (or bottle) containing sodium chloride for infusion 9 mg / ml (0.9%) or glucose for infusion 50 mg / ml 5%) so that to obtain a concentration of anidulafungin equal to 0.77 mg / ml. The table below shows the volumes needed for each dose.
Dilution requirements for administration of ECALTA
A Sodium chloride for infusion 9 mg / ml (0.9%) or glucose for infusion 50 mg / ml (5%)
B The concentration of the solution for infusion is 0.77 mg / ml
The infusion rate should not exceed 1.1 mg / min (equivalent to 1.4 ml / min when reconstituted and diluted as instructed) (see sections 4.2, 4.4 and 4.8).
Whenever the solution and container permit, parenteral medicinal products should be visually inspected prior to administration for the presence of particles or discolouration. If the presence of particles or a discoloration is identified, the solution must be discarded.
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations
07.0 MARKETING AUTHORIZATION HOLDER
Pfizer Limited
Ramsgate Road, Sandwich
Kent, CT13 9NJ, United Kingdom.
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/07/416/002
038382026
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 20 September 2007
Date of most recent renewal: 23 August 2012
10.0 DATE OF REVISION OF THE TEXT
26 August 2014
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