1. Name Of The Medicinal Product
CANCIDAS®* 50 mg powder for concentrate for solution for infusion
CANCIDAS®* 70 mg powder for concentrate for solution for infusion
* Intensive monitoring is requested only when used for the recently-licensed indication extension to paediatric patients.
2. Qualitative And Quantitative Composition
CANCIDAS 50 mg powder for concentrate for solution for infusion: Each vial contains 50 mg caspofungin (as acetate).
Each 50 mg vial contains 35.7 mg of sucrose.
CANCIDAS 70 mg powder for concentrate for solution for infusion: Each vial contains 70 mg caspofungin (as acetate).
Each 70 mg vial contains 50.0 mg of sucrose.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for concentrate for solution for infusion.
White to off
4. Clinical Particulars
4.1 Therapeutic Indications
• Treatment of invasive candidiasis in adult or paediatric patients.
• Treatment of invasive aspergillosis in adult or paediatric patients who are refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B and/or itraconazole. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.
• Empirical therapy for presumed fungal infections (such as Candida or Aspergillus) in febrile, neutropaenic adult or paediatric patients.
4.2 Posology And Method Of Administration
CANCIDAS should be initiated by a physician experienced in the management of invasive fungal infections.
After reconstitution and dilution, the solution should be administered by slow intravenous infusion over approximately 1 hour. Do not mix or co-infuse CANCIDAS with other medicines, as there are no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medicinal products. DO NOT USE DILUENTS CONTAINING GLUCOSE, as CANCIDAS is not stable in diluents containing glucose. For reconstitution directions see section 6.6.
Both 70 mg and 50 mg vials are available.
CANCIDAS should be given as a single daily infusion.
Dosage in adult patients
A single 70 mg loading dose should be administered on Day-1, followed by 50 mg daily thereafter. In patients weighing more than 80 kg, after the initial 70 mg loading dose, CANCIDAS 70 mg daily is recommended (see section 5.2). No dosage adjustment is necessary based on gender or race (see section 5.2).
Dosage in paediatric patients (12 months to 17 years)
In paediatric patients (12 months to 17 years of age), dosing should be based on the patient's body surface area (see Instructions for Use in Paediatric Patients, Mosteller[1] Formula). For all indications, a single 70 mg/m2 loading dose (not to exceed an actual dose of 70 mg) should be administered on Day 1, followed by 50 mg/m2 daily thereafter (not to exceed an actual dose of 70 mg daily). If the 50-mg/m2 daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg).
The efficacy and safety of CANCIDAS have not been sufficiently studied in clinical trials involving neonates and infants below 12 months of age. Caution is advised when treating this age group. Limited data suggest that CANCIDAS at 25 mg/m2 daily in neonates and infants (less than 3 months of age) and 50 mg/m2 daily in young children (3 to 11 months of age) can be considered (see section 5.2).
Duration of treatment
Duration of empirical therapy should be based on the patient's clinical response. Therapy should be continued until up to 72 hours after resolution of neutropaenia (ANC
Duration of treatment of invasive candidiasis should be based upon the patient's clinical and microbiological response. After signs and symptoms of invasive candidiasis have improved and cultures have become negative, a switch to oral antifungal therapy may be considered. In general, antifungal therapy should continue for at least 14 days after the last positive culture.
Duration of treatment of invasive aspergillosis is determined on a case by case basis and should be based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. In general, treatment should continue for at least 7 days after resolution of symptoms.
Dosage in elderly patients
In elderly patients (65 years of age or more), the area under the curve (AUC) is increased by approximately 30 %. However, no systematic dosage adjustment is required. There is limited treatment experience in patients 65 years of age and older.
Dosage in patients with renal impairment
No dosage adjustment is necessary based on renal impairment (see section 5.2).
Dosage in patients with hepatic insufficiency
For adult patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), no dosage adjustment is needed. For adult patients with moderate hepatic insufficiency (Child
Co-administration with inducers of metabolic enzymes
Limited data suggest that an increase in the daily dose of CANCIDAS to 70 mg, following the 70 mg loading dose, should be considered when co-administering CANCIDAS in adult patients with certain inducers of metabolic enzymes (see section 4.5). When CANCIDAS is co-administered to paediatric patients (12 months to 17 years of age) with these same inducers of metabolic enzymes (see section 4.5), a CANCIDAS dose of 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg) should be considered.
[1]Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22;317(17):1098 (letter)
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Limited data suggest that less common non-Candida yeasts and non-Aspergillus moulds are not covered by caspofungin. The efficacy of caspofungin against these fungal pathogens has not been established.
Concomitant use of CANCIDAS with ciclosporin has been evaluated in healthy adult volunteers and in adult patients. Some healthy adult volunteers who received two 3 mg/kg doses of ciclosporin with caspofungin showed transient increases in alanine transaminase (ALT) and aspartate transaminase (AST) of less than or equal to 3
In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20 and 75 %, respectively. A reduction of the daily dose to 35 mg is recommended for adults with moderate hepatic impairment. There is no clinical experience in adults with severe hepatic insufficiency or in paediatric patients with any degree of hepatic insufficiency. A higher exposure than in moderate hepatic insufficiency is expected and CANCIDAS should be used with caution in these patients (see sections 4.2 and 5.2).
The safety information on treatment durations longer than 4 weeks is limited.
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance or sucrase-isomaltase insufficiency should not take this medicinal product.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other substances. Caspofungin is not a substrate for P
In two clinical studies performed in healthy adult subjects, ciclosporin A (one 4 mg/kg dose or two 3 mg/kg doses 12 hours apart) increased the AUC of caspofungin by approximately 35 %. These AUC increases are probably due to reduced uptake of caspofungin by the liver. CANCIDAS did not increase the plasma levels of ciclosporin. There were transient increases in liver ALT and AST of less than or equal to 3
CANCIDAS reduced the trough concentration of tacrolimus by 26 % in healthy adult volunteers. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are mandatory.
Clinical studies in healthy adult volunteers show that the pharmacokinetics of CANCIDAS are not altered to a clinically relevant extent by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. Caspofungin did not influence the pharmacokinetics of amphotericin B, itraconazole, rifampicin or mycophenolate mofetil. Although safety data are limited it appears that no special precautions are needed when amphotericin B, itraconazole, nelfinavir or mycophenolate mofetil are co
Rifampicin caused a 60 % increase in AUC and 170 % increase in trough concentration of caspofungin on the first day of co-administration when both medicinal products were initiated together in healthy adult volunteers. Caspofungin trough levels gradually decreased upon repeated administration. After two weeks' administration rifampicin had limited effect on AUC, but trough levels were 30 % lower than in adult subjects who received caspofungin alone. The mechanism of interaction could possibly be due to an initial inhibition and subsequent induction of transport proteins. A similar effect could be expected for other medicinal products that induce metabolic enzymes. Limited data from population pharmacokinetics studies indicate that concomitant use of CANCIDAS with the inducers efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin, or carbamazepine may result in a decrease in caspofungin AUC. When co-administering inducers of metabolic enzymes, an increase in the daily dose of CANCIDAS to 70 mg, following the 70 mg loading dose, should be considered in adult patients (see section 4.2).
All adult drug
In paediatric patients, results from regression analyses of pharmacokinetic data suggest that co2 daily (not to exceed an actual daily dose of 70 mg) should be considered.
4.6 Pregnancy And Lactation
For CANCIDAS, no clinical data on exposed pregnancies are available. Caspofungin should not be used during pregnancy unless clearly necessary. There are no adequate data from the use of caspofungin in pregnant women. Developmental studies in animals have shown adverse effects (see section 5.3). Caspofungin has been shown to cross the placental barrier in animal studies. The potential risk to the human foetus is unknown.
Caspofungin is excreted in milk of lactating animals. It is not known whether it is excreted in human milk. Women receiving caspofungin should not breast-feed.
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.
4.8 Undesirable Effects
Adult Patients
In clinical studies, 1,865 adult individuals received single or multiple doses of CANCIDAS: 564 febrile neutropaenic patients (empirical therapy study), 382 patients with invasive candidiasis, 228 patients with invasive aspergillosis, 297 patients with localised Candida infections, and 394 individuals enrolled in Phase I studies. In the empirical therapy study patients had received chemotherapy for malignancy or had undergone haematopoietic stem-cell transplantation (including 39 allogeneic transplantations). In the studies involving patients with documented Candida infections, the majority of the patients with invasive Candida infections had serious underlying medical conditions (e.g., haematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the non-comparative Aspergillus study often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, haematologic malignancy, solid tumours or organ transplants) requiring multiple concomitant medications.
Phlebitis was a commonly reported local injection-site adverse reaction in all patient populations. Other local reactions included erythema, pain/tenderness, itching, discharge, and a burning sensation.
Reported clinical and laboratory abnormalities among all adults treated with CANCIDAS (total 1,780) were typically mild and rarely led to discontinuation.
The following adverse reactions were reported:
[Very common (
Blood and lymphatic system disorders:
Common:haemoglobin decreased, haematocrit decreased, white blood cell count decreased
Uncommon: anaemia, thrombocytopaenia, coagulopathy, leukopaenia, eosinophil count increased, platelet count decreased, platelet count increased, lymphocyte count decreased, white blood cell count increased, neutrophil count decreased
Metabolism and nutrition disorders:
Common : hypokalemia
Uncommon : fluid overload, hypomagnesaemia, anorexia, electrolyte imbalance, hyperglycaemia, hypocalcaemia, metabolic acidosis
Psychiatric disorders
Uncommon : anxiety, disorientation, insomnia
Nervous system disorders:
Common: headache
Uncommon : dizziness, dysgeusia, paraesthesia, somnolence, tremor, hypoaesthesia
Eye disorders:
Uncommon : ocular icterus, vision blurred, eyelid oedema, lacrimation increased
Cardiac disorders:
Uncommon : palpitations, tachycardia, arrhythmia, atrial fibrillation, cardiac failure congestive
Vascular disorders:
Common: phlebitis
Uncommon: thrombophlebitis, flushing, hot flush, hypertension, hypotension
Respiratory, thoracic and mediastinal disorders:
Common: dyspnoea
Uncommon : nasal congestion, pharyngolaryngeal pain, tachypnoea, bronchospasm, cough, dyspnoea paroxysmal nocturnal, hypoxia, rales, wheezing
Gastrointestinal disorders:
Common: nausea, diarrhoea, vomiting
Uncommon:abdominal pain, abdominal pain upper, dry mouth, dyspepsia, stomach discomfort, abdominal distension, ascites, constipation, dysphagia, flatulence
Hepatobiliary disorders:
Common : elevated liver values (alanine aminotransferase, aspartate aminotranserase, blood alkaline phosphatase, bilirubin conjugated, blood bilirubin)
Unommon : cholestasis, hepatomegaly, hyperbilirubinaemia, jaundice, hepatic function abnormal, hepatotoxicity, liver disorder
Skin and subcutaneous tissue disorders:
Common:rash, pruritus, erythema, hyperhidrosis
Uncommon: erythema multiforme, rash macular, rash maculo-papular, rash pruritic, urticaria, dermatitis allergic, pruritus generalised, rash erythematous, rash generalised, rash morbilliform, skin lesion
Musculoskeletal and connective tissue disorders
Common : arthralgia
Uncommon : back pain, pain in extremity, bone pain, muscular weakness, myalgia
Renal and urinary disorders
Uncommon : renal failure, renal failure acute
General disorders and administration site conditions:
Common: pyrexia, chills, infusion-site pruritus
Uncommon: pain, catheter site pain, fatigue, feeling cold, feeling hot, infusion site erythema, infusion site induration, infusion site pain, infusion site swelling, injection site phlebitis, oedema peripheral, tenderness, chest discomfort, chest pain, face oedema, feeling of body temperature change, induration, infusion site extravasation, infusion site irritation, infusion site phlebitis, infusion site rash, infusion site urticaria, injection site erythema, injection site oedema, injection site pain, injection site swelling, malaise, oedema
Investigations:
Common: blood potassium decreased, blood albumin decreased
Uncommon:blood creatinine increased, red blood cells urine positive, protein total decreased, protein urine present, prothrombin time prolonged, prothrombin time shortened, blood sodium decreased, blood sodium increased, blood calcium decreased, blood calcium increased, blood chloride decreased, blood glucose increased, blood magnesium decreased, blood phosphorus decreased, blood phosphorus increased, blood urea increased, gamma-glutamyltransferase increased, activated partial thromboplastin time prolonged, blood bicarbonate decreased, blood chloride increased, blood potassium increased, blood pressure increased, blood uric acid decreased, blood urine present, breath sounds abnormal, carbon dioxide decreased, immunosuppressant drug level increased, international normalised ratio increased, urinary casts, white blood cells urine positive, and pH urine increased.
Possible histamine
Also reported in patients with invasive aspergillosis were pulmonary oedema, adult respiratory distress syndrome (ARDS), and radiographic infiltrates.
CANCIDAS has also been evaluated at 150 mg daily (for up to 51 days) in 100 adult patients (see section 5.1). The study compared CANCIDAS at 50 mg daily (following a 70
Paediatric Patients
In clinical studies, 171 paediatric patients received single or multiple doses of CANCIDAS: 104 febrile, neutropenic patients; 56 patients with invasive candidiasis; 1 patient with esophageal candidiasis; and 10 patients with invasive aspergillosis. The overall safety profile of CANCIDAS in paediatric patients is generally comparable to that in adult patients.
The following adverse reactions were reported:
[Very common (
Blood and lymphatic system disorders:
Common : eosinophil count increased
Nervous system disorders :
Common: headache
Cardiac disorders :
Common: tachycardia
Vascular disorders :
Common: flushing, hypotension
Hepatobiliary disorders :
Common: elevated liver enzyme levels (AST, ALT)
Skin and subcutaneous tissue disorders :
Common: rash, pruritus
General disorders and administration site conditions :
Very Common: fever
Common: chills, catheter site pain
Investigations :
Common: decreased potassium, hypomagnesaemia, increased glucose, decreased phosphorus, and increased phosphorus
As in adult patients, similar histamine-mediated symptoms have also been reported in paediatric patients.
Post-Marketing experience:
The following post-marketing adverse events have been reported:
Hepatobiliary disorders:
Hepatic dysfunction
General disorders and administration site conditions:
Swelling and peripheral oedema
Investigations:
Hypercalcaemia
4.9 Overdose
Inadvertent administration of up to 400 mg of caspofungin in one day has been reported. These occurrences did not result in clinically important adverse experiences. Caspofungin is not dialysable.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: antimycotics for systemic use, ATC Code: J02AX04
Caspofungin acetate is a semiGlarea lozoyensis. Caspofungin acetate inhibits the synthesis of beta (1,3)
Fungicidal activity with caspofungin has been demonstrated against Candida yeasts. Studies in vitro and in vivo demonstrate that exposure of Aspergillus to caspofungin results in lysis and death of hyphal apical tips and branch points where cell growth and division occur.
Caspofungin has in vitro activity against Aspergillus species (Aspergillus fumigatus [N = 75], Aspergillus flavus [N = 111], Aspergillus niger[N = 31], Aspergillus nidulans [N = 8], Aspergillus terreus [N = 52], and Aspergillus candidus [N = 3]). Caspofungin also has in vitro activity against Candida species (Candida albicans [N = 1,032], Candida dubliniensis [N = 100], Candida glabrata [N = 151], Candida guilliermondii [N = 67], Candida kefyr [N = 62], Candida krusei [N = 147], Candida lipolytica [N = 20], Candida lusitaniae [N = 80], Candida parapsilosis [N = 215], Candida rugosa [N = 1], and Candida tropicalis [N = 258]), including isolates with multiple resistance transport mutations and those with acquired or intrinsic resistance to fluconazole, amphotericin B, and 5-flucytosine. Susceptibility testing was performed according to a modification of both the Clinical and Laboratory Standards Institute (CLSI, formerly known as the National Committee for Clinical Laboratory Standards [NCCLS]) method M38Aspergillus species) and method M27Candida species). Mutants of Candida with reduced susceptibility to caspofungin have been identified in some patients during treatment. However, standardised techniques for susceptibility testing for antifungal agents, including beta (1,3)in vitro resistance to caspofungin by Aspergillus species has not been identified. In limited clinical experience, resistance to caspofungin in patients with invasive aspergillosis has not been observed. The incidence of resistance to caspofungin by various clinical isolates of Candida and Aspergillus is unknown.
Invasive Candidiasis in Adult Patients: Two hundred thirty-nine patients were enrolled in an initial study to compare caspofungin and amphotericin B for the treatment of invasive candidiasis. Twenty-four patients had neutropaenia. The most frequent diagnoses were bloodstream infections (candidaemia) (77 %, n=186) and Candida peritonitis (8 %, n=19); patients with Candida endocarditis, osteomyelitis, or meningitis were excluded from this study. Caspofungin 50 mg once daily was administered following a 70 mg loading dose, while amphotericin B was administered at 0.6 to 0.7 mg/kg/day to non-neutropaenic patients or 0.7 to 1.0 mg/kg/day to neutropaenic patients. The mean duration of intravenous therapy was 11.9 days, with a range of 1 to 28 days. A favourable response required both symptom resolution and microbiological clearance of the Candida infection. Two hundred twenty-four patients were included in the primary efficacy analysis (MITT analysis) of response at the end of IV study therapy; favourable response rates for the treatment of invasive candidiasis were comparable for caspofungin (73 % [80/109]) and amphotericin B (62 % [71/115]) [% difference 12.7 (95.6 % CI -0.7, 26.0)]. Among patients with candidaemia, favourable response rates at the end of IV study therapy were comparable for caspofungin (72 % [66/92]) and amphotericin B (63 % [59/94]) in the primary efficacy analysis (MITT analysis) [% difference 10.0 (95.0 % CI -4.5, 24.5)]. Data in patients with non-blood sites of infection were more limited. Favourable response rates in neutropaenic patients were 7/14 (50 %) in the caspofungin group and 4/10 (40 %) in the amphotericin B group. These limited data are supported by the outcome of the empirical therapy study.
In a second study, patients with invasive candidiasis received daily doses of caspofungin at 50 mg/day (following a 70Candida endocarditis, meningitis, or osteomyelitis. As this was a primary therapy study, patients who were refractory to prior antifungal agents were also excluded. The number of neutropenic patients enrolled in this study was also limited (8.0 %). Efficacy was a secondary endpoint in this study. Patients who met the entry criteria and received one or more doses of caspofungin study therapy were included in the efficacy analysis. The favorable overall response rates at the end of caspofungin therapy were similar in the 2 treatment groups: 72 % (73/102) and 78 % (74/95) for the caspofungin 50
Invasive Aspergillosis in Adult Patients: Sixty-nine adult patients (age 18-80) with invasive aspergillosis were enrolled in an open
Empirical Therapy in Febrile, Neutropaenic Adult Patients: A total of 1,111 patients with persistent fever and neutropaenia were enrolled in a clinical study and treated with either caspofungin 50 mg once daily following a 70 mg loading dose or liposomal amphotericin B 3.0 mg/kg/day. Eligible patients had received chemotherapy for malignancy or had undergone hematopoietic stem-cell transplantation, and presented with neutropaenia (<500 cells/mm3 for 96 hours) and fever (>38.0°C) not responding to Aspergillus species were, respectively, 41.7 % (5/12) and 8.3 % (1/12), and by Candida species were 66.7 % (8/12) and 41.7 % (5/12). Patients in the caspofungin group experienced breakthrough infections due to the following uncommon yeasts and moulds: Trichosporon species (1), Fusarium species (1), Mucor species (1), and Rhizopus species (1).
Paediatric Patients
The safety and efficacy of CANCIDAS was evaluated in paediatric patients 3 months to 17 years of age in two prospective, multicenter clinical trials. The study design, diagnostic criteria, and criteria for efficacy assessment were similar to the corresponding studies in adult patients (see section 5.1).
The first study, which enrolled 82 patients between 2 to 17 years of age, was a randomized, double-blind study comparing CANCIDAS (50 mg/m2 IV once daily following a 70 mg/m2 loading dose on Day 1 [not to exceed 70 mg daily]) to liposomal amphotericin B (3 mg/kg IV daily) in a 2:1 treatment fashion (56 on caspofungin, 26 on liposomal amphotericin B) as empirical therapy in paediatric patients with persistent fever and neutropenia. The overall success rates in the MITT analysis results, adjusted by risk strata, were as follows: 46.6 % (26/56) for CANCIDAS and 32.2 % (8/25) for liposomal amphotericin B.
The second study was a prospective, open-label, non-comparative study estimating the safety and efficacy of caspofungin in paediatric patients (ages 6 months to 17 years) with invasive candidiasis, esophageal candidiasis, and invasive aspergillosis (as salvage therapy). Forty-nine patients were enrolled and received CANCIDAS at 50 mg/m2 IV once daily following a 70 mg/m2 loading dose on Day 1 (not to exceed 70 mg daily), of whom 48 were included in the MITT analysis. Of these, 37 had invasive candidiasis, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. The favorable response rate, by indication, at the end of caspofungin therapy was as follows in the MITT analysis: 81 % (30/37) in invasive candidiasis, 50 % (5/10) in invasive aspergillosis, and 100 % (1/1) in esophageal candidiasis.
5.2 Pharmacokinetic Properties
Distribution
Caspofungin is extensively bound to albumin. The unbound fraction of caspofungin in plasma varies from 3.5 % in healthy volunteers to 7.6 % in patients with invasive candidiasis. Distribution plays the prominent role in caspofungin plasma pharmacokinetics and is the rate-controlling step in both the alpha
Metabolism
Caspofungin undergoes spontaneous degradation to an open ring compound. Further metabolism involves peptide hydrolysis and N-acetylation. Two intermediate products, formed during the degradation of caspofungin to this open ring compound, form covalent adducts to plasma proteins resulting in a low-level, irreversible binding to plasma proteins.
In vitro studies show that caspofungin is not an inhibitor of cytochrome P450 enzymes 1A2, 2A6, 2C9, 2C19, 2D6 or 3A4. In clinical studies, caspofungin did not induce or inhibit the CYP3A4 metabolism of other medicinal products. Caspofungin is not a substrate for P
Elimination and excretion
The elimination of caspofungin from plasma is slow with a clearance of 10-12 ml/min. Plasma concentrations of caspofungin decline in a polyphasic manner following single 1
Approximately 75 % of a radioactive dose was recovered during 27 days: 41 % in urine and 34 % in faeces. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration. Excretion is slow and the terminal half-life of radioactivity was 12 to 15 days. A small amount of caspofungin is excreted unchanged in urine (approximately 1.4 % of dose).
Caspofungin displays moderate non-linear pharmacokinetics with increased accumulation as the dose is increased, and a dose dependency in the time to reach steady state upon multiple
Special populations
Increased caspofungin exposure was seen in adult patients with renal impairment and mild liver impairment, in female subjects, and in the elderly. Generally the increase was modest and not large enough to warrant dosage adjustment. In adult patients with moderate liver impairment or in higher weight patients, a dosage adjustment may be necessary (see below).
Weight: Weight was found to influence caspofungin pharmacokinetics in the population pharmacokinetic analysis in adult candidiasis patients. The plasma concentrations decrease with increasing weight. The average exposure in an adult patient weighing 80 kg was predicted to be about 23 % lower than in an adult patient weighing 60 kg (see section 4.2).
Hepatic impairment: In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20 and 75 %, respectively. There is no clinical experience in adult patients with severe hepatic insufficiency and in paediatric patients with any degree of hepatic insufficiency. In a multiple
Renal impairment: In a clinical study of single 70 mg doses, caspofungin pharmacokinetics were similar in adult volunteers with mild renal insufficiency (creatinine clearance 50 to 80 ml/min) and control subjects. Moderate (creatinine clearance 31 to 49 ml/min), advanced (creatinine clearance 5 to 30 ml/min), and end-stage (creatinine clearance <10 ml/min and dialysis dependent) renal insufficiency moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49 % for AUC). However, in adult patients with invasive candidiasis, oesophageal candidiasis, or invasive aspergillosis who received multiple daily doses of CANCIDAS 50 mg, there was no significant effect of mild to advanced renal impairment on caspofungin concentrations. No dosage adjustment is necessary for patients with renal insufficiency. Caspofungin is not dialysable, thus supplementary dosing is not required following haemodialysis.
Gender: Caspofungin plasma concentrations were on average 17-38 % higher in women than in men.
Elderly: A modest increase in AUC (28 %) and C24h (32 %) was observed in elderly male subjects compared with young male subjects. In patients who were treated empirically or who had invasive candidiasis, a similar modest effect of age was seen in older patients relative to younger patients.
Race: Patient pharmacokinetic data indicated that no clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, Hispanics, and Mestizos.
Paediatric Patients:
In adolescents (ages 12 to 17 years) receiving caspofungin at 50 mg/m2 daily (maximum 70 mg daily), the caspofungin plasma AUC0-24hr was generally comparable to that seen in adults receiving caspofungin at 50 mg daily. All adolescents received doses>50 mg daily, and, in fact, 6 of 8 received the maximum dose of 70 mg/day. The caspofungin plasma concentrations in these adolescents were reduced relative to adults receiving 70 mg daily, the dose most often administered to adolescents.
In children (ages 2 to 11 years) receiving caspofungin at 50 mg/m2 daily (maximum 70 mg daily), the caspofungin plasma AUC0-24hr after multiple doses was comparable to that seen in adults receiving caspofungin at 50 mg/day.
In young children and toddlers (ages 12 to 23 months) receiving caspofungin at 50 mg/m2 daily (maximum 70 mg daily), the caspofungin plasma AUC0-24hr after multiple doses was comparable to that seen in adults receiving caspofungin at 50 mg daily and to that in older children (2 to 11 years of age) receiving the 50 mg/m2 daily dose.
Overall, the available pharmacokinetic, efficacy, and safety data are limited in patients 3 to 10 months of age. Pharmacokinetic data from one 10-month old child receiving the 50 mg/m2 daily dose indicated an AUC0-24hr within the same range as that observed in older children and adults at the 50 mg/m2 and the 50 mg dose, respectively, while in one 6-month old child receiving the 50 mg/m2 dose, the AUC0-24hr was somewhat higher.
In neonates and infants (<3 months) receiving caspofungin at 25 mg/m2 daily (corresponding mean daily dose of 2.1 mg/kg), caspofungin peak concentration (C1 hr) and caspofungin trough concentration (C24 hr) after multiple doses were comparable to that seen in adults receiving caspofungin at 50 mg daily. On Day 1, C1 hr was comparable and C24 hr modestly elevated (36 %) in these neonates and infants relative to adults. However, variability was seen in both C1 hr (Day 4 geometric mean 11.73 µg/ml, range 2.63 to 22.05 µg/ml) and C24 hr (Day 4 geometric mean 3.55 µg/ml, range 0.13 to 7.17 µg/ml). AUC0-24hr measurements were not performed in this study due to the sparse plasma sampling. Of note, the efficacy and safety of CANCIDAS have not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age.
5.3 Preclinical Safety Data
Repeated dose toxicity studies in rats and monkeys using doses up to 7-8 mg/kg given intravenously showed injection site reactions in rats and monkeys, signs of histamine release in rats, and evidence of adverse effects directed at the liver in monkeys. Developmental toxicity studies in rats showed that caspofungin caused decreases in foetal body weights and an increase in the incidence of incomplete ossification of vertebra, sternebra, and skull bone at doses of 5 mg/kg that were coupled to adverse maternal effects such as signs of histamine release in pregnant rats. An increase in the incidence of cervical ribs was also noted. Caspofungin was negative in in vitro assays for potential genotoxicity as well as in the in vivo mouse bone marrow chromosomal test. No long
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sucrose
Mannitol
Glacial acetic acid
Sodium hydroxide (to adjust the pH)
6.2 Incompatibilities
Do not mix with diluents containing glucose, as CANCIDAS is not stable in diluents containing glucose. Do not mix or co
6.3 Shelf Life
2 years
Reconstituted concentrate: should be used immediately. Stability data have shown that the concentrate for solution for infusion can be stored for up to 24 hours when the vial is stored at 25°C or less and reconstituted with water for injections.
Dilute patient infusion solution: should be used immediately. Stability data have shown that the product can be used within 24 hours when stored at 25°C or less, or within 48 hours when the intravenous infusion bag (bottle) is stored refrigerated (2 to 8°C) and diluted with sodium chloride solution 9 mg/ml (0.9 %), 4.5 mg/ml (0.45 %), or 2.25 mg/ml (0.225 %) for infusion, or lactated Ringer's solution.
CANCIDAS contains no preservatives. From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution and dilution have taken place in controlled validated aseptic conditions.
6.4 Special Precautions For Storage
Unopened vials: store in a refrigerator (2°C to 8°C).
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
CANCIDAS 50 mg powder for concentrate for solution for infusion: 10 ml Type I glass vials with a grey butyl stopper and a plastic cap with a red aluminium band for single use only.
CANCIDAS 70 mg powder for concentrate for solution for infusion: 10 ml Type I glass vials with a grey butyl stopper and a plastic cap with a yellow/orange aluminium band for single use only.
Supplied in packs of 1 vial.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
Reconstitution of CANCIDAS
DO NOT USE ANY DILUENTS CONTAINING GLUCOSE, as CANCIDAS is not stable in diluents containing glucose. DO NOT MIX OR CO
INSTRUCTIONS FOR USE IN ADULT PATIENTS
Step 1 Reconstitution of conventional vials
To reconstitute the powder, bring the vial to room temperature and aseptically add 10.5 ml of water for injections. The concentrations of the reconstituted vials will be 5.2 mg/ml (50 mg vial) or 7.2 mg/ml (70 mg vial).
The white to off
Step 2 Addition of Reconstituted CANCIDAS to patient infusion solution
Diluents for the final solution for infusion are: sodium chloride solution for injection, or lactated Ringer's solution. The solution for infusion is prepared by aseptically adding the appropriate amount of reconstituted concentrate (as shown in the table below) to a 250 ml infusion bag or bottle. Reduced volume infusions in 100 ml may be used, when medically necessary, for 50 mg or 35 mg daily doses. Do not use if the solution is cloudy or has precipitated. This infusion solution must be used within 24 hours if stored at or below 25°C, or within 48 hours if stored refrigerated at 2 to 8°C. Chemical and physical in-use stability of the diluted solution in sterile lactated Ringer's solution and sodium chloride solution 9 mg/ml (0.9 %), 4.5 mg/ml (0.45 %), and 2.25 mg/ml (0.225 %) for infusion has been demonstrated for 24 hours at 25°C and for 48 hours at 2 to 8°C. From a microbiological point of view, the solution must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.
PREPARATION OF THE SOLUTION FOR INFUSION IN ADULTS
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* 10.5 ml should be used for reconstitution of all vials.
**If 70 mg vial is not available, the 70 mg dose can be prepared from two 50 mg vials
INSTRUCTIONS FOR USE IN PAEDIATRIC PATIENTS
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