CANCIDAS 70mg powder for concentrate infusion solution medication leaflet

CANCIDAS 50 mg powder for concentrate for solution for infusion

CANCIDAS 70 mg powder for concentrate for solution for infusion

CANCIDAS 50 mg powder for concentrate for solution for infusion

Each vial contains 50 mg caspofungin (as acetate).

CANCIDAS 70 mg powder for concentrate for solution for infusion

Each vial contains 70 mg caspofungin (as acetate).

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

Before reconstitution, the powder is a white to off-white-compact, powder.

* Treatment of invasive candidiasis in adult or paediatric patients.

* Treatment of invasive aspergillosis in adult or paediatric patients who are refractory to orintolerant 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 of7 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.

Caspofungin should be initiated by a physician experienced in the management of invasive fungalinfections.

Adult patients

A single 70 mg loading dose should be administered on Day-1, followed by 50 mg daily thereafter. Inpatients weighing more than 80 kg, after the initial 70 mg loading dose, caspofungin 70 mg daily isrecommended (see section 5.2). No dosage adjustment is necessary based on gender or race (seesection 5.2).

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 bodysurface area (see Instructions for Use in Paediatric Patients, Mosteller1 Formula). For all indications, asingle 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 the50-mg/m2 daily dose is well tolerated but does not provide an adequate clinical response, the dailydose can be increased to 70 mg/m2 daily (not to exceed an actual daily dose of 70 mg).

1 Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22;317(17):1098 (letter)

The safety and efficacy of caspofungin have not been sufficiently studied in clinical trials involvingneonates and infants below 12 months of age. Caution is advised when treating this age group. Limiteddata suggest that caspofungin 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 empirical therapy should be based on the patient’s clinical response. Therapy should becontinued until up to 72 hours after resolution of neutropaenia (ANC≥500). Patients found to have afungal infection should be treated for a minimum of 14 days and treatment should continue for at least7 days after both neutropaenia and clinical symptoms are resolved.

Duration of treatment of invasive candidiasis should be based upon the patient’s clinical andmicrobiological response. After signs and symptoms of invasive candidiasis have improved andcultures 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 bebased upon the severity of the patient’s underlying disease, recovery from immunosuppression, andclinical response. In general, treatment should continue for at least 7 days after resolution ofsymptoms.

The safety information on treatment durations longer than 4 weeks is limited. However, available datasuggest that caspofungin continues to be well tolerated with longer courses of therapy (up to 162 daysin adult patients and up to 87 days in paediatric patients).

In elderly patients (65 years of age or more), the area under the curve (AUC) is increased byapproximately 30 %. However, no systematic dosage adjustment is required. There is limitedtreatment experience in patients 65 years of age and older (see section 5.2).

No dosage adjustment is necessary based on renal impairment (see section 5.2).

For adult patients with mild hepatic impairment (Child-Pugh score 5 to 6), no dosage adjustment isneeded. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), caspofungin35 mg daily is recommended based upon pharmacokinetic data. An initial 70 mg loading dose shouldbe administered on Day-1. There is no clinical experience in adult patients with severe hepaticimpairment (Child-Pugh score greater than 9) and in paediatric patients with any degree of hepaticimpairment (see section 4.4).

Co-administration with inducers of metabolic enzymes

Limited data suggest that an increase in the daily dose of caspofungin to 70 mg, following the 70 mgloading dose, should be considered when co-administering caspofungin in adult patients with certaininducers of metabolic enzymes (see section 4.5). When caspofungin is co-administered to paediatricpatients (12 months to 17 years of age) with these same inducers of metabolic enzymes (seesection 4.5), a caspofungin dose of 70-mg/m2 daily (not to exceed an actual daily dose of 70 mg)should be considered.

After reconstitution and dilution, the solution should be administered by slow intravenous infusionover approximately 1 hour. For reconstitution directions see section 6.6.

Both 70 mg and 50 mg vials are available.

Caspofungin should be given as a single daily infusion.

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

Anaphylaxis has been reported during administration of caspofungin. If this occurs, caspofunginshould be discontinued and appropriate treatment administered. Possibly histamine-mediated adversereactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth, or bronchospasmhave been reported and may require discontinuation and/or administration of appropriate treatment.

Limited data suggest that less common non-Candida yeasts and non-Aspergillus moulds are notcovered by caspofungin. The efficacy of caspofungin against these fungal pathogens has not beenestablished.

Concomitant use of caspofungin with cyclosporin has been evaluated in healthy adult volunteers andin adult patients. Some healthy adult volunteers who received two 3 mg/kg doses of cyclosporin withcaspofungin showed transient increases in alanine transaminase (ALT) and aspartate transaminase(AST) of less than or equal to 3-fold the upper limit of normal (ULN) that resolved withdiscontinuation of the treatment. In a retrospective study of 40 patients treated during marketed usewith caspofungin and cyclosporin for 1 to 290 days (median 17.5 days), no serious hepatic adversereactions were noted. These data suggest that caspofungin can be used in patients receivingcyclosporin when the potential benefit outweighs the potential risk. Close monitoring of liver enzymesshould be considered if caspofungin and cyclosporin are used concomitantly.

In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20 % and75 %, respectively. A reduction of the daily dose to 35 mg is recommended for adults with moderatehepatic impairment. There is no clinical experience in adults with severe hepatic impairment or inpaediatric patients with any degree of hepatic impairment. A higher exposure than in moderate hepaticimpairment is expected and caspofungin should be used with caution in these patients (see sections 4.2and 5.2).

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and adult andpaediatric patients treated with caspofungin. In some adult and paediatric patients with seriousunderlying conditions who were receiving multiple concomitant medications with caspofungin, casesof clinically significant hepatic dysfunction, hepatitis and hepatic failure have been reported; a causalrelationship to caspofungin has not been established. Patients who develop abnormal liver functiontests during caspofungin therapy should be monitored for evidence of worsening hepatic function andthe risk/benefit of continuing caspofungin therapy should be re-evaluated.

Cases of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reportedafter post-marketing use of caspofungin. Caution should apply in patients with history of allergic skinreaction (see section 4.8).

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially‘sodium-free’.

Studies in vitro show that caspofungin is not an inhibitor of any enzyme in the cytochrome P450(CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of othersubstances. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome

P450 enzymes. However, caspofungin has been shown to interact with other medicinal products inpharmacological and clinical studies (see below).

In two clinical studies performed in healthy adult subjects, cyclosporin A (one 4 mg/kg dose or two3 mg/kg doses 12 hours apart) increased the AUC of caspofungin by approximately 35 %. These AUCincreases are probably due to reduced uptake of caspofungin by the liver. Caspofungin did not increasethe plasma levels of cyclosporin. There were transient increases in liver ALT and AST of less than orequal to 3-fold the upper limit of normal (ULN) when caspofungin and cyclosporin wereco-administered, that resolved with discontinuation of the medicinal products. In a retrospective studyof 40 patients treated during marketed use with caspofungin and cyclosporin for 1 to 290 days (median17.5 days), no serious hepatic adverse reactions were noted (see section 4.4). Close monitoring of liverenzymes should be considered if the two medicinal products are used concomitantly.

Caspofungin reduced the trough concentration of tacrolimus by 26 % in healthy adult volunteers. Forpatients receiving both therapies, standard monitoring of tacrolimus blood concentrations andappropriate tacrolimus dosage adjustments are mandatory.

Clinical studies in healthy adult volunteers show that the pharmacokinetics of caspofungin are notaltered to a clinically relevant extent by itraconazole, amphotericin B, mycophenolate, nelfinavir, ortacrolimus. Caspofungin did not influence the pharmacokinetics of amphotericin B, itraconazole,rifampicin or mycophenolate mofetil. Although safety data are limited it appears that no specialprecautions are needed when amphotericin B, itraconazole, nelfinavir or mycophenolate mofetil areco-administered with caspofungin.

Rifampicin caused a 60 % increase in AUC and 170 % increase in trough concentration ofcaspofungin on the first day of co-administration when both medicinal products were initiated togetherin healthy adult volunteers. Caspofungin trough levels gradually decreased upon repeatedadministration. After two weeks’ administration rifampicin had limited effect on AUC, but troughlevels were 30 % lower than in adult subjects who received caspofungin alone. The mechanism ofinteraction 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 caspofunginwith the inducers efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin, or carbamazepine mayresult in a decrease in caspofungin AUC. When co-administering inducers of metabolic enzymes, anincrease in the daily dose of caspofungin to 70 mg, following the 70 mg loading dose, should beconsidered in adult patients (see section 4.2).

All adult drug-drug interaction studies described above were conducted at a 50 or 70 mg dailycaspofungin dose. The interaction of higher doses of caspofungin with other medicinal products hasnot been formally studied.

In paediatric patients, results from regression analyses of pharmacokinetic data suggest thatco-administration of dexamethasone with caspofungin may result in clinically meaningful reductionsin caspofungin trough concentrations. This finding may indicate that paediatric patients will havesimilar reductions with inducers as seen in adults. When caspofungin is co-administered to paediatricpatients (12 months to 17 years of age) with inducers of drug clearance, such as rifampicin, efavirenz,nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70-mg/m2 daily (notto exceed an actual daily dose of 70 mg) should be considered.

There are no or limited data from the use of caspofungin in pregnant women. Caspofungin should notbe used during pregnancy unless clearly necessary. Animal studies have shown developmental toxicity(see section 5.3). Caspofungin has been shown to cross the placental barrier in animal studies.

It is unknown whether caspofungin is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of caspofungin in milk. Women receivingcaspofungin should not breast-feed.

For caspofungin, there were no effects on fertility in studies conducted in male and female rats (seesection 5.3). There are no clinical data for caspofungin to assess its impact on fertility.

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

Hypersensitivity reactions (anaphylaxis and possibly histamine-mediated adverse reactions) have beenreported (see section 4.4).

Also reported in patients with invasive aspergillosis were pulmonary oedema, adult respiratory distresssyndrome (ARDS), and radiographic infiltrates.

Adult patients

In clinical studies, 1,865 adult individuals received single or multiple doses of caspofungin:564 febrile neutropaenic patients (empirical therapy study), 382 patients with invasive candidiasis,228 patients with invasive aspergillosis, 297 patients with localised Candida infections, and394 individuals enrolled in Phase I studies. In the empirical therapy study patients had receivedchemotherapy for malignancy or had undergone hematopoietic stem-cell transplantation (including39 allogeneic transplantations). In the studies involving patients with documented Candida infections,the majority of the patients with invasive Candida infections had serious underlying medicalconditions (e.g., haematologic or other malignancy, recent major surgery, HIV) requiring multipleconcomitant medications. Patients in the non-comparative Aspergillus study often had seriouspredisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, haematologicmalignancy, 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 caspofungin (total 1,780)were typically mild and rarely led to discontinuation.

The following adverse reactions were reported during clinical studies and/or post-marketing use:

System Organ Common Uncommon (≥1/1,000 to <1/100) Not known

Class (≥1/100 to (cannot be<1/10) estimatedfromavailabledata)

Blood and haemoglobin anaemia, thrombocytopaenia,lymphatic system decreased, coagulopathy, leukopaenia, eosinophildisorders haematocrit count increased, platelet count decreased,decreased, white platelet count increased, lymphocyte countblood cell count decreased, white blood cell countdecreased increased, neutrophil count decreased

Metabolism and hypokalemia fluid overload, hypomagnesaemia,nutrition disorders anorexia, electrolyte imbalance,hyperglycaemia, hypocalcaemia, metabolicacidosis

System Organ Common Uncommon (≥1/1,000 to <1/100) Not known

Class (≥1/100 to (cannot be<1/10) estimatedfromavailabledata)

Psychiatric anxiety, disorientation, insomniadisorders

Nervous system headache dizziness, dysgeusia, paraesthesia,disorders somnolence, tremor, hypoaesthesia

Eye disorders ocular icterus, vision blurred, eyelidoedema, lacrimation increased

Cardiac disorders palpitations, tachycardia, arrhythmia, atrialfibrillation, cardiac failure congestive

Vascular phlebitis thrombophlebitis, flushing, hot flush,disorders hypertension, hypotension

Respiratory, dyspnoea nasal congestion, pharyngolaryngeal pain,thoracic and tachypnoea, bronchospasm, cough,mediastinal dyspnoea paroxysmal nocturnal, hypoxia,disorders rales, wheezing

Gastrointestinal nausea, abdominal pain, abdominal pain upper, drydisorders diarrhoea, mouth, dyspepsia, stomach discomfort,vomiting abdominal distension, ascites, constipation,dysphagia, flatulence

Hepatobiliary elevated liver cholestasis, hepatomegaly,disorders values (alanine hyperbilirubinaemia, jaundice, hepaticaminotransferase, function abnormal, hepatotoxicity, liveraspartate disorder, gamma-glutamyltransferaseaminotransferase, increasedblood alkalinephosphatase,bilirubinconjugated,blood bilirubin)

Skin and rash, pruritus, erythema multiforme, rash macular, rash Toxicsubcutaneous erythema, maculo-papular, rash pruritic, urticaria, epidermaltissue disorders hyperhidrosis dermatitis allergic, pruritus generalised, necrolysis andrash erythematous, rash generalised, rash Stevens-morbilliform, skin lesion Johnsonsyndrome (seesection 4.4)

Musculoskeletal arthralgia back pain, pain in extremity, bone pain,and connective muscular weakness, myalgiatissue disorders

Renal and urinary renal failure, renal failure acutedisorders

System Organ Common Uncommon (≥1/1,000 to <1/100) Not known

Class (≥1/100 to (cannot be<1/10) estimatedfromavailabledata)

General disorders pyrexia, chills, pain, catheter site pain, fatigue, feelingand infusion-site cold, feeling hot, infusion site erythema,administration site pruritus infusion site induration, infusion site pain,conditions infusion site swelling, injection sitephlebitis, oedema peripheral, tenderness,chest discomfort, chest pain, face oedema,feeling of body temperature change,induration, infusion site extravasation,infusion site irritation, infusion sitephlebitis, infusion site rash, infusion siteurticaria, injection site erythema, injectionsite oedema, injection site pain, injectionsite swelling, malaise, oedema

Investigations blood potassium blood creatinine increased, red blood cellsdecreased, blood urine positive, protein total decreased,albumin protein urine present, prothrombin timedecreased prolonged, prothrombin time shortened,blood sodium decreased, blood sodiumincreased, blood calcium decreased, bloodcalcium increased, blood chloridedecreased, blood glucose increased, bloodmagnesium decreased, blood phosphorusdecreased, blood phosphorus increased,blood urea increased, activated partialthromboplastin time prolonged, bloodbicarbonate decreased, blood chlorideincreased, blood potassium increased,blood pressure increased, blood uric aciddecreased, blood urine present, breathsounds abnormal, carbon dioxidedecreased, immunosuppressant drug levelincreased, international normalised ratioincreased, urinary casts, white blood cellsurine positive, and pH urine increased.

Caspofungin has also been evaluated at 150 mg daily (for up to 51 days) in 100 adult patients (seesection 5.1). The study compared caspofungin at 50 mg daily (following a 70-mg loading dose on

Day 1) versus 150 mg daily in the treatment of invasive candidiasis. In this group of patients, thesafety of caspofungin at this higher dose appeared generally similar to patients receiving the 50-mgdaily dose of caspofungin. The proportion of patients with a serious drug-related adverse reaction or adrug-related adverse reaction leading to caspofungin discontinuation was comparable in the2 treatment groups.

Data from 5 clinical studies completed in 171 paediatric patients suggest that the overall incidence ofclinical adverse experiences (26.3 %; 95 % CI -19.9, 33.6) is not worse than reported for adults treatedwith caspofungin (43.1 %; 95 % CI -40.0, 46.2). However, paediatric patients probably have adifferent adverse event profile compared to adult patients. The most common drug-related clinicaladverse experiences reported in paediatric patients treated with caspofungin were pyrexia (11.7 %),rash (4.7 %) and headache (2.9 %).

The following adverse reactions were reported:

System Organ Class Very Common (≥1/100 to <1/10)common(≥1/10)

Blood and lymphatic system eosinophil count increaseddisorders

Nervous system disorders headache

Cardiac disorders tachycardia

Vascular disorders flushing, hypotension

Hepatobiliary disorders elevated liver enzyme levels (AST, ALT)

Skin and subcutaneous rash, pruritustissue disorders

General disorders and fever chills, catheter site painadministration siteconditions

Investigations decreased potassium, hypomagnesemia, increasedglucose, decreased phosphorus, and increasedphosphorus

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

Inadvertent administration of up to 400 mg of caspofungin in one day has been reported. Theseoccurrences did not result in clinically important adverse reactions. Caspofungin is not dialysable.

Pharmacotherapeutic group: antimycotics for systemic use, ATC Code: J02AX04

Caspofungin acetate is a semi-synthetic lipopeptide (echinocandin) compound synthesised from afermentation product of Glarea lozoyensis. Caspofungin acetate inhibits the synthesis ofbeta (1,3)-D-glucan, an essential component of the cell wall of many filamentous fungi and yeast.

Beta (1,3)-D-glucan is not present in mammalian cells.

Fungicidal activity with caspofungin has been demonstrated against Candida yeasts. Studies in vitroand in vivo demonstrate that exposure of Aspergillus to caspofungin results in lysis and death ofhyphal 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], Aspergillusterreus [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], Candidarugosa [N = 1], and Candida tropicalis [N = 258]), including isolates with multiple resistancetransport mutations and those with acquired or intrinsic resistance to fluconazole, amphotericin B, and5-flucytosine. Susceptibility testing was performed according to a modification of both the Clinicaland Laboratory Standards Institute (CLSI, formerly known as the National Committee for Clinical

Laboratory Standards [NCCLS]) method M38-A2 (for Aspergillus species) and method M27-A3 (for

Candida species).

Standardised techniques for susceptibility testing have been established for yeasts by EUCAST.

EUCAST breakpoints have not yet been established for caspofungin, due to significantinter-laboratory variation in MIC ranges for caspofungin. In lieu of breakpoints, Candida isolates thatare susceptible to anidulafungin as well as micafungin should be considered susceptible tocaspofungin. Similarly, C. parapsilosis isolates intermediate to anidulafungin and micafungin can beregarded intermediate to caspofungin.

Isolates of Candida with reduced susceptibility to caspofungin have been identified in a small numberof patients during treatment (MICs for caspofungin >2 mg/L (4- to 30-fold MIC increases) have beenreported using standardized MIC testing techniques approved by the CLSI). The mechanism ofresistance identified is FKS1 and/or FKS2 (for C. glabrata) gene mutations. These cases have beenassociated with poor clinical outcomes.

Development of in vitro resistance to caspofungin by Aspergillus species has been identified. Inlimited clinical experience, resistance to caspofungin in patients with invasive aspergillosis has beenobserved. The mechanism of resistance has not been established. The incidence of resistance tocaspofungin by various clinical isolates of Aspergillus is rare. Caspofungin resistance in Candida hasbeen observed but the incidence may differ by species or region.

Invasive Candidiasis in Adult Patients: Two hundred thirty-nine patients were enrolled in an initialstudy 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 Candidaendocarditis, osteomyelitis, or meningitis were excluded from this study. Caspofungin 50 mg oncedaily was administered following a 70 mg loading dose, while amphotericin B was administered at 0.6to 0.7 mg/kg/day to non-neutropaenic patients or 0.7 to 1.0 mg/kg/day to neutropaenic patients. Themean duration of intravenous therapy was 11.9 days, with a range of 1 to 28 days. A favourableresponse 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) ofresponse at the end of IV study therapy; favourable response rates for the treatment of invasivecandidiasis 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 ratesat 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 ratesin neutropaenic patients were 7/14 (50 %) in the caspofungin group and 4/10 (40 %) in theamphotericin B group. These limited data are supported by the outcome of the empirical therapystudy.

In a second study, patients with invasive candidiasis received daily doses of caspofungin at 50 mg/day(following a 70-mg loading dose on Day 1) or caspofungin at 150 mg/day (see section 4.8). In thisstudy, the caspofungin dose was administered over 2 hours (instead of the routine 1-houradministration). The study excluded patients with suspected Candida endocarditis, meningitis, orosteomyelitis. As this was a primary therapy study, patients who were refractory to prior antifungalagents 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 andreceived one or more doses of caspofungin study therapy were included in the efficacy analysis. Thefavourable overall response rates at the end of caspofungin therapy were similar in the 2 treatmentgroups: 72 % (73/102) and 78 % (74/95) for the caspofungin 50-mg and 150-mg treatment groups,respectively (difference 6.3 % [95 % CI -5.9, 18.4]).

Invasive Aspergillosis in Adult Patients: Sixty-nine adult patients (age 18-80) with invasiveaspergillosis were enrolled in an open-label, non-comparative study to evaluate the safety, tolerability,and efficacy of caspofungin. Patients had to be either refractory to (disease progression or failure toimprove with other antifungal therapies given for at least 7 days) (84 % of the enrolled patients) orintolerant of (16 % of enrolled patients) other standard antifungal therapies. Most patients hadunderlying conditions (haematologic malignancy [N = 24], allogeneic bone marrow transplant or stemcell transplant [N = 18], organ transplant [N = 8], solid tumour [N = 3], or other conditions [N = 10]).

Stringent definitions, modelled after the Mycoses Study Group Criteria, were used for diagnosis ofinvasive aspergillosis and for response to therapy (favourable response required clinically significantimprovement in radiographs as well as in signs and symptoms). The mean duration of therapy was33.7 days, with a range of 1 to 162 days. An independent expert panel determined that 41 % (26/63) ofpatients receiving at least one dose of caspofungin had a favourable response. For those patients whoreceived more than 7 days of therapy with caspofungin, 50 % (26/52) had a favourable response. Thefavourable response rates for patients who were either refractory to or intolerant of previous therapieswere 36 % (19/53) and 70 % (7/10), respectively. Although the doses of prior antifungal therapies in5 patients enrolled as refractory were lower than those often administered for invasive aspergillosis,the favourable response rate during therapy with caspofungin was similar in these patients to that seenin the remaining refractory patients (2/5 versus 17/48, respectively). The response rates amongpatients with pulmonary disease and extrapulmonary disease were 47 % (21/45) and 28 % (5/18),respectively. Among patients with extrapulmonary disease, 2 of 8 patients who also had definite,probable, or possible CNS involvement had a favourable response.

Empirical Therapy in Febrile, Neutropaenic Adult Patients: A total of 1,111 patients with persistentfever and neutropaenia were enrolled in a clinical study and treated with either caspofungin 50 mgonce daily following a 70 mg loading dose or liposomal amphotericin B 3.0 mg/kg/day. Eligiblepatients had received chemotherapy for malignancy or had undergone hematopoietic stem-celltransplantation, and presented with neutropaenia (<500 cells/mm3 for 96 hours) and fever (>38.0°C)not responding to ≥96 hours of parenteral antibacterial therapy. Patients were to be treated until up to72 hours after resolution of neutropaenia, with a maximum duration of 28 days. However, patientsfound to have a documented fungal infection could be treated longer. If the drug was well tolerated butthe patient’s fever persisted and clinical condition deteriorated after 5 days of therapy, the dosage ofstudy drug could be increased to 70 mg/day of caspofungin (13.3 % of patients treated) or to5.0 mg/kg/day of liposomal amphotericin B (14.3 % of patients treated). There were 1,095 patientsincluded in the primary Modified Intention-To-Treat (MITT) efficacy analysis of overall favourableresponse; caspofungin (33.9 %) was as effective as liposomal amphotericin B (33.7 %) [% difference0.2 (95.2 % CI -5.6, 6.0)]. An overall favourable response required meeting each of 5 criteria:(1) successful treatment of any baseline fungal infection (caspofungin 51.9 % [14/27], liposomalamphotericin B 25.9 % [7/27]), (2) no breakthrough fungal infections during administration of studydrug or within 7 days after completion of treatment (caspofungin 94.8 % [527/556], liposomalamphotericin B 95.5 % [515/539]), (3) survival for 7 days after completion of study therapy(caspofungin 92.6 % [515/556], liposomal amphotericin B 89.2 % [481/539]), (4) no discontinuationfrom the study drug because of drug-related toxicity or lack of efficacy (caspofungin 89.7 %[499/556], liposomal amphotericin B 85.5 % [461/539]), and (5) resolution of fever during the periodof neutropaenia (caspofungin 41.2 % [229/556], liposomal amphotericin B 41.4 % [223/539]).

Response rates to caspofungin and liposomal amphotericin B for baseline infections caused by

Aspergillus species were, respectively, 41.7 % (5/12) and 8.3 % (1/12), and by Candida species were66.7 % (8/12) and 41.7 % (5/12). Patients in the caspofungin group experienced breakthroughinfections due to the following uncommon yeasts and moulds: Trichosporon species (1), Fusariumspecies (1), Mucor species (1), and Rhizopus species (1).

The safety and efficacy of caspofungin was evaluated in paediatric patients 3 months to 17 years ofage in two prospective, multicentre clinical trials. The study design, diagnostic criteria, and criteria forefficacy 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 caspofungin (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 treatmentfashion (56 on caspofungin, 26 on liposomal amphotericin B) as empirical therapy in paediatricpatients 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 caspofungin and 32.2 % (8/25) forliposomal amphotericin B.

The second study was a prospective, open-label, non-comparative study estimating the safety andefficacy of caspofungin in paediatric patients (ages 6 months to 17 years) with invasive candidiasis,oesophageal candidiasis, and invasive aspergillosis (as salvage therapy). Forty-nine patients wereenrolled and received caspofungin 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 hadinvasive candidiasis, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. Thefavourable response rate, by indication, at the end of caspofungin therapy was as follows in the MITTanalysis: 81 % (30/37) in invasive candidiasis, 50 % (5/10) in invasive aspergillosis, and 100 % (1/1)in oesophageal candidiasis.

In a double-blind, randomized (2:1) comparator-controlled study safety, tolerability and efficacy ofcaspofungin (2 mg/kg/d intravenously, infused over 2 hours) vs amphotericin B deoxycholate(1 mg/kg/d) was evaluated in neonates and infants less than 3 months of age with (culture-confirmed)invasive candidiasis. Due to poor enrolment, the study was terminated early and only 51 patients wererandomized. The proportion of patients with fungal-free survival at 2 weeks post-therapy in thecaspofungin treatment group (71.0 %) was similar to that seen in the amphotericin B deoxycholatetreatment group (68.8 %). Based on this study, no posology recommendations for neonates and infantscan be made.

Caspofungin is extensively bound to albumin. The unbound fraction of caspofungin in plasma variesfrom 3.5 % in healthy volunteers to 7.6 % in patients with invasive candidiasis. Distribution plays theprominent role in caspofungin plasma pharmacokinetics and is the rate-controlling step in both thealpha- and beta-disposition phases. The distribution into tissues peaked at 1.5 to 2 days after dosingwhen 92 % of the dose was distributed into tissues. It is likely that only a small fraction of thecaspofungin taken up into tissues later returns to plasma as parent compound. Therefore, eliminationoccurs in the absence of a distribution equilibrium, and a true estimate of the volume of distribution ofcaspofungin is currently impossible to obtain.

Caspofungin undergoes spontaneous degradation to an open ring compound. Further metabolisminvolves peptide hydrolysis and N-acetylation. Two intermediate products, formed during thedegradation of caspofungin to this open ring compound, form covalent adducts to plasma proteinsresulting 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 CYP3A4metabolism of other medicinal products. Caspofungin is not a substrate for P-glycoprotein and is apoor substrate for cytochrome P450 enzymes.

The elimination of caspofungin from plasma is slow with a clearance of 10-12 ml/min. Plasmaconcentrations of caspofungin decline in a polyphasic manner following single 1-hour intravenousinfusions. A short alpha-phase occurs immediately post-infusion, followed by a beta-phase with a half-life of 9 to 11 hours. An additional gamma-phase also occurs with a half-life of 45 hours. Distribution,rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance.

Approximately 75 % of a radioactive dose was recovered during 27 days: 41 % in urine and 34 % infaeces. There is little excretion or biotransformation of caspofungin during the first 30 hours afteradministration. Excretion is slow and the terminal half-life of radioactivity was 12 to 15 days. A smallamount of caspofungin is excreted unchanged in urine (approximately 1.4 % of dose).

Caspofungin displays moderate non-linear pharmacokinetics with increased accumulation as the doseis increased, and a dose dependency in the time to reach steady state upon multiple-doseadministration.

Increased caspofungin exposure was seen in adult patients with renal impairment and mild liverimpairment, in female subjects, and in the elderly. Generally the increase was modest and not largeenough to warrant dosage adjustment. In adult patients with moderate liver impairment or in higherweight patients, a dosage adjustment may be necessary (see below).

Weight: Weight was found to influence caspofungin pharmacokinetics in the populationpharmacokinetic analysis in adult candidiasis patients. The plasma concentrations decrease withincreasing weight. The average exposure in an adult patient weighing 80 kg was predicted to be about23 % 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 isincreased about 20 and 75 %, respectively. There is no clinical experience in adult patients with severehepatic impairment and in paediatric patients with any degree of hepatic impairment. In amultiple-dose study, a dose reduction of the daily dose to 35 mg in adult patients with moderatehepatic impairment has been shown to provide an AUC similar to that obtained in adult subjects withnormal hepatic function receiving the standard regimen (see section 4.2).

Renal impairment: In a clinical study of single 70 mg doses, caspofungin pharmacokinetics weresimilar in adult volunteers with mild renal impairment (creatinine clearance 50 to 80 ml/min) andcontrol subjects. Moderate (creatinine clearance 31 to 49 ml/min), advanced (creatinine clearance 5 to30 ml/min), and end-stage (creatinine clearance <10 ml/min and dialysis dependent) renal impairmentmoderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to49 % for AUC). However, in adult patients with invasive candidiasis, oesophageal candidiasis, orinvasive aspergillosis who received multiple daily doses of caspofungin 50 mg, there was nosignificant effect of mild to advanced renal impairment on caspofungin concentrations. No dosageadjustment is necessary for patients with renal impairment. Caspofungin is not dialysable, thussupplementary 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 subjectscompared with young male subjects. In patients who were treated empirically or who had invasivecandidiasis, 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 thepharmacokinetics of caspofungin were seen among Caucasians, Blacks, Hispanics, and Mestizos.

In adolescents (ages 12 to 17 years) receiving caspofungin at 50 mg/m2 daily (maximum 70 mg daily),the caspofungin plasma AUC0-24 hr was generally comparable to that seen in adults receivingcaspofungin at 50 mg daily. All adolescents received doses >50 mg daily, and, in fact, 6 of 8 receivedthe maximum dose of 70 mg/day. The caspofungin plasma concentrations in these adolescents werereduced 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), thecaspofungin plasma AUC0-24 hr after multiple doses was comparable to that seen in adults receivingcaspofungin 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 AUC0-24 hr after multiple doses was comparable tothat seen in adults receiving caspofungin at 50 mg daily and to that in older children (2 to 11 years ofage) receiving the 50 mg/m2 daily dose.

Overall, the available pharmacokinetic, efficacy, and safety data are limited in patients 3 to 10 monthsof age. Pharmacokinetic data from one 10-month old child receiving the 50 mg/m2 daily doseindicated an AUC0-24 hr within the same range as that observed in older children and adults at the50 mg/m2 and the 50 mg dose, respectively, while in one 6-month old child receiving the 50 mg/m2dose, the AUC0-24 hr was somewhat higher.

In neonates and infants (<3 months) receiving caspofungin at 25 mg/m2 daily (corresponding meandaily 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 mgdaily. On Day 1, C1 hr was comparable and C24 hr modestly elevated (36 %) in these neonates andinfants relative to adults. However, variability was seen in both C1 hr (Day 4 geometric mean11.73 µg/ml, range 2.63 to 22.05 µg/ml) and C24 hr (Day 4 geometric mean 3.55 µg/ml, range 0.13 to7.17 µg/ml). AUC0-24 hr measurements were not performed in this study due to the sparse plasmasampling. Of note, the efficacy and safety of caspofungin have not been adequately studied inprospective clinical trials involving neonates and infants under 3 months of age.

Repeated dose toxicity studies in rats and monkeys using doses up to 7-8 mg/kg given intravenouslyshowed injection site reactions in rats and monkeys, signs of histamine release in rats, and evidence ofadverse effects directed at the liver in monkeys. Developmental toxicity studies in rats showed thatcaspofungin caused decreases in foetal body weights and an increase in the incidence of incompleteossification of vertebra, sternebra, and skull bone at doses of 5 mg/kg that were coupled to adversematernal effects such as signs of histamine release in pregnant rats. An increase in the incidence ofcervical ribs was also noted. Caspofungin was negative in in vitro assays for potential genotoxicity aswell as in the in vivo mouse bone marrow chromosomal test. No long-term studies in animals havebeen performed to evaluate the carcinogenic potential. For caspofungin, there were no effects onfertility in studies conducted in male and female rats up to 5 mg/kg/day.

Sucrose

Mannitol (E421)

Glacial acetic acid

Sodium hydroxide (to adjust the pH)

Do not mix with diluents containing glucose, as CANCIDAS is not stable in diluents containingglucose. In the absence of compatibility studies, this medicinal product must not be mixed with othermedicinal products.

2 years

Reconstituted concentrate: should be used immediately. Stability data have shown that the concentratefor solution for infusion can be stored for up to 24 hours when the vial is stored at 25°C or less andreconstituted with water for injection.

Diluted patient infusion solution: should be used immediately. Stability data have shown that theproduct can be used within 24 hours when stored at 25°C or less, or within 48 hours when theintravenous infusion bag (bottle) is stored refrigerated (2 to 8°C) and diluted with sodium chloridesolution 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 beused immediately. If not used immediately, in use storage times and conditions prior to use are theresponsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unlessreconstitution and dilution have taken place in controlled validated aseptic conditions.

Unopened vials: store in a refrigerator (2°C - 8°C).

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

CANCIDAS 50 mg powder for concentrate for solution for infusion10 ml Type I glass vial with a grey butyl stopper and a plastic cap with a red aluminium band.

CANCIDAS 70 mg powder for concentrate for solution for infusion10 ml Type I glass vial with a grey butyl stopper and a plastic cap with an orange aluminium band.

Supplied in packs of 1 vial.

Reconstitution of CANCIDAS

DO NOT USE ANY DILUENTS CONTAINING GLUCOSE, as CANCIDAS is not stable in diluentscontaining glucose. DO NOT MIX OR CO-INFUSE CANCIDAS WITH ANY OTHER

MEDICINES, as there are no data available on the compatibility of CANCIDAS with otherintravenous substances, additives, or medicinal products. Visually inspect the infusion solution forparticulate matter or discolouration.

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

CANCIDAS 50 mg powder for concentrate for solution for infusion

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 forinjection. The concentrations of the reconstituted vials will be 5.2 mg/ml.

The white to off-white compact lyophilised powder will dissolve completely. Mix gently until a clearsolution is obtained. Reconstituted solutions should be visually inspected for particulate matter ordiscolouration. This reconstituted solution may be stored for up to 24 hours at or below 25°C.

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 amountof reconstituted concentrate (as shown in the table below) to a 250 ml infusion bag or bottle. Reducedvolume 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.

PREPARATION OF THE SOLUTION FOR INFUSION IN ADULTS

DOSE* Volume of recon- Standard preparation Reduced volumestituted (reconstituted infusion

CANCIDAS for CANCIDAS added to (reconstitutedtransfer to 250 ml) final CANCIDAS added tointravenous bag or concentration 100 ml) finalbottle concentration50 mg 10 ml 0.20 mg/ml -50 mg at reduced10 ml - 0.47 mg/mlvolume35 mg for moderatehepatic impairment 7 ml 0.14 mg/ml -(from one 50 mg vial)35 mg for moderatehepatic impairment7 ml - 0.34 mg/ml(from one 50 mg vial) atreduced volume

* 10.5 ml should be used for reconstitution of all vials.

INSTRUCTIONS FOR USE IN PAEDIATRIC PATIENTS

Calculation of Body Surface Area (BSA) for paediatric dosing

Before preparation of infusion, calculate the body surface area (BSA) of the patient using thefollowing formula: (Mosteller Formula)

Preparation of the 70 mg/m2 infusion for paediatric patients >3 months of age (using a 50-mg vial)1. Determine the actual loading dose to be used in the paediatric patient by using the patient's BSA(as calculated above) and the following equation:

BSA (m2) X 70 mg/m2 = Loading Dose

The maximum loading dose on Day 1 should not exceed 70 mg regardless of the patient'scalculated dose.

2. Equilibrate the refrigerated vial of CANCIDAS to room temperature.3. Aseptically add 10.5 ml of water for injection.a This reconstituted solution may be stored for upto 24 hours at or below 25°C.b This will give a final caspofungin concentration in the vial of5.2 mg/ml.

4. Remove the volume of medicinal product equal to the calculated loading dose (Step 1) from thevial. Aseptically transfer this volume (ml)c of reconstituted CANCIDAS to an IV bag (or bottle)containing 250 ml of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection, or Lactated Ringers

Injection. Alternatively, the volume (ml)c of reconstituted CANCIDAS can be added to areduced volume of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection or Lactated Ringers

Injection, not to exceed a final concentration of 0.5 mg/ml. This infusion solution must be usedwithin 24 hours if stored at or below 25°C or within 48 hours if stored refrigerated at 2 to 8°C.

Preparation of the 50 mg/m2 infusion for paediatric patients >3 months of age (using a 50-mg vial)1. Determine the actual daily maintenance dose to be used in the paediatric patient by using thepatient's BSA (as calculated above) and the following equation:

BSA (m2) X 50 mg/m2 = Daily Maintenance Dose

The daily maintenance dose should not exceed 70 mg regardless of the patient's calculated dose.

2. Equilibrate the refrigerated vial of CANCIDAS to room temperature.3. Aseptically add 10.5 ml of water for injection.a This reconstituted solution may be stored for upto 24 hours at or below 25°C.b This will give a final caspofungin concentration in the vial of5.2 mg/ml.

4. Remove the volume of medicinal product equal to the calculated daily maintenance dose(Step 1) from the vial. Aseptically transfer this volume (ml)c of reconstituted CANCIDAS to an

IV bag (or bottle) containing 250 ml of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection,or Lactated Ringers Injection. Alternatively, the volume (ml)c of reconstituted CANCIDAS canbe added to a reduced volume of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection or

Lactated Ringers Injection, not to exceed a final concentration of 0.5 mg/ml. This infusionsolution must be used within 24 hours if stored at or below 25°C or within 48 hours if storedrefrigerated at 2 to 8°C.

Preparation notes:

a. The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained.

b. Visually inspect the reconstituted solution for particulate matter or discolouration duringreconstitution and prior to infusion. Do not use if the solution is cloudy or has precipitated.

c. CANCIDAS is formulated to provide the full labeled vial dose (50 mg) when 10 ml is withdrawnfrom the vial.

CANCIDAS 70 mg powder for concentrate for solution for infusion

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 forinjection. The concentrations of the reconstituted vials will be: 7.2 mg/ml.

The white to off-white compact lyophilised powder will dissolve completely. Mix gently until a clearsolution is obtained. Reconstituted solutions should be visually inspected for particulate matter ordiscolouration. This reconstituted solution may be stored for up to 24 hours at or below 25°C.

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 amountof reconstituted concentrate (as shown in the table below) to a 250 ml infusion bag or bottle. Reducedvolume 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.

PREPARATION OF THE SOLUTION FOR INFUSION IN ADULTS

DOSE* Volume of recon- Standard preparation Reduced volumestituted (reconstituted infusion

CANCIDAS for CANCIDAS added to (reconstitutedtransfer to 250 ml) final CANCIDAS added tointravenous bag or concentration 100 ml) finalbottle concentration70 mg 10 ml 0.28 mg/ml Not Recommended70 mg(from two 50 mg 14 ml 0.28 mg/ml Not Recommendedvials)**

DOSE* Volume of recon- Standard preparation Reduced volumestituted (reconstituted infusion

CANCIDAS for CANCIDAS added to (reconstitutedtransfer to 250 ml) final CANCIDAS added tointravenous bag or concentration 100 ml) finalbottle concentration35 mg for moderatehepatic impairment 5 ml 0.14 mg/ml 0.34 mg/ml(from one 70 mg vial)

* 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

Calculation of Body Surface Area (BSA) for paediatric dosing

Before preparation of infusion, calculate the body surface area (BSA) of the patient using thefollowing formula: (Mosteller Formula)

Preparation of the 70 mg/m2 infusion for paediatric patients >3 months of age (using a 70-mg vial)1. Determine the actual loading dose to be used in the paediatric patient by using the patient's BSA(as calculated above) and the following equation:

BSA (m2) X 70 mg/m2 = Loading Dose

The maximum loading dose on Day 1 should not exceed 70 mg regardless of the patient'scalculated dose.

2. Equilibrate the refrigerated vial of CANCIDAS to room temperature.3. Aseptically add 10.5 ml of water for injection.a This reconstituted solution may be stored for upto 24 hours at or below 25°C.b This will give a final caspofungin concentration in the vial of7.2 mg/ml.

4. Remove the volume of medicinal product equal to the calculated loading dose (Step 1) from thevial. Aseptically transfer this volume (ml)c of reconstituted CANCIDAS to an IV bag (or bottle)containing 250 ml of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection, or Lactated Ringers

Injection. Alternatively, the volume (ml)c of reconstituted CANCIDAS can be added to areduced volume of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection or Lactated Ringers

Injection, not to exceed a final concentration of 0.5 mg/ml. This infusion solution must be usedwithin 24 hours if stored at or below 25°C or within 48 hours if stored refrigerated at 2 to 8°C.

Preparation of the 50 mg/m2 infusion for paediatric patients >3 months of age (using a 70-mg vial)1. Determine the actual daily maintenance dose to be used in the paediatric patient by using thepatient's BSA (as calculated above) and the following equation:

BSA (m2) X 50 mg/m2 = Daily Maintenance Dose

The daily maintenance dose should not exceed 70 mg regardless of the patient's calculated dose.

2. Equilibrate the refrigerated vial of CANCIDAS to room temperature.3. Aseptically add 10.5 ml of water for injection.a This reconstituted solution may be stored for upto 24 hours at or below 25°C.b This will give a final caspofungin concentration in the vial of7.2 mg/ml.

4. Remove the volume of medicinal product equal to the calculated daily maintenance dose(Step 1) from the vial. Aseptically transfer this volume (ml)c of reconstituted CANCIDAS to an

IV bag (or bottle) containing 250 ml of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection,or Lactated Ringers Injection. Alternatively, the volume (ml)c of reconstituted CANCIDAS canbe added to a reduced volume of 0.9 %, 0.45 %, or 0.225 % Sodium Chloride Injection or

Lactated Ringers Injection, not to exceed a final concentration of 0.5 mg/ml. This infusionsolution must be used within 24 hours if stored at or below 25°C or within 48 hours if storedrefrigerated at 2 to 8°C.

Preparation notes:

a. The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained.

b. Visually inspect the reconstituted solution for particulate matter or discolouration duringreconstitution and prior to infusion. Do not use if the solution is cloudy or has precipitated.

c. CANCIDAS is formulated to provide the full labelled vial dose (70 mg) when 10 ml is withdrawnfrom the vial.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/01/196/001

EU/1/01/196/003

Date of first authorisation: 24 October 2001.

Date of latest renewal: 07 September 2011.

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

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