MYCAMINE 100mg powder infusion solution medication leaflet

Mycamine 50 mg powder for concentrate for solution for infusion

Mycamine 100 mg powder for concentrate for solution for infusion

Mycamine 50 mg

Each vial contains 50 mg micafungin (as sodium).

After reconstitution each ml contains 10 mg micafungin (as sodium).

Mycamine 100 mg

Each vial contains 100 mg micafungin (as sodium).

After reconstitution each ml contains 20 mg micafungin (as sodium).

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion

White compact powder

Mycamine is indicated for:

Adults, adolescents ≥ 16 years of age and elderly:

- Treatment of invasive candidiasis.

- Treatment of oesophageal candidiasis in patients for whom intravenous therapy is appropriate.

- Prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem celltransplantation or patients who are expected to have neutropenia (absolute neutrophilcount < 500 cells/µl) for 10 or more days.

Children (including neonates) and adolescents < 16 years of age:

- Treatment of invasive candidiasis.

- Prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem celltransplantation or patients who are expected to have neutropenia (absolute neutrophilcount < 500 cells/µl) for 10 or more days.

The decision to use Mycamine should take into account a potential risk for the development of livertumours (see section 4.4). Mycamine should therefore only be used if other antifungals are notappropriate.

Consideration should be given to official/national guidance on the appropriate use of antifungal agents.

Treatment with Mycamine should be initiated by a physician experienced in the management of fungalinfections.

Specimens for fungal culture and other relevant laboratory studies (including histopathology) shouldbe obtained prior to therapy to isolate and identify causative organism(s). Therapy may be institutedbefore the results of the cultures and other laboratory studies are known. However, once these resultsbecome available, antifungal therapy should be adjusted accordingly.

The dose regimen of micafungin depends on the body weight of the patient as given in the followingtables:

Use in adults, adolescents ≥ 16 years of age and elderly

Indication

Body weight > 40 kg Body weight ≤ 40 kg

Treatment of invasive candidiasis 100 mg/day* 2 mg/kg/day*

Treatment of oesophageal candidiasis 150 mg/day 3 mg/kg/day

Prophylaxis of Candida infection 50 mg/day 1 mg/kg/day

*If the patient’s response is inadequate, e.g. persistence of cultures or if clinical condition does not improve, thedose may be increased to 200 mg/day in patients weighing > 40 kg or 4 mg/kg/day in patients ≤ 40 kg.

Invasive candidiasis: The treatment duration of Candida infection should be a minimum of 14 days.

The antifungal treatment should continue for at least one week after two sequential negative bloodcultures have been obtained and after resolution of clinical signs and symptoms of infection.

Oesophageal candidiasis: Micafungin should be administered for at least one week after resolution ofclinical signs and symptoms.

Prophylaxis of Candida infections: Micafungin should be administered for at least one week afterneutrophil recovery.

Use in children ≥ 4 months of age up to adolescents < 16 years of age

Indication

Body weight > 40 kg Body weight ≤ 40 kg

Treatment of invasive candidiasis 100 mg/day* 2 mg/kg/day*

Prophylaxis of Candida infection 50 mg/day 1 mg/kg/day

*If the patient’s response is inadequate, e.g. persistence of cultures or if clinical condition does not improve, thedose may be increased to 200 mg/day in patients weighing > 40 kg or 4 mg/kg/day in patients weighing ≤ 40 kg.

Use in children (including neonates) < 4 months of age

Indication

Treatment of invasive candidiasis 4 -10 mg/kg/day*

Prophylaxis of Candida infection 2 mg/kg/day

*Micafungin dosed at 4 mg/kg in children less than 4 months approximates drug exposures achieved in adultsreceiving 100 mg/day for the treatment of invasive candidiasis. If central nervous system (CNS) infection issuspected, a higher dosage (e.g. 10 mg/kg) should be used due to the dose-dependent penetration of micafungininto the CNS (see section 5.2).

Invasive candidiasis: The treatment duration of Candida infection should be a minimum of 14 days.

The antifungal treatment should continue for at least one week after two sequential negative bloodcultures have been obtained and after resolution of clinical signs and symptoms of infection.

Prophylaxis of Candida infections: Micafungin should be administered for at least one week afterneutrophil recovery. Experience with Mycamine in patients less than 2 years of age is limited.

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (see section5.2). There are currently insufficient data available for the use of micafungin in patients with severehepatic impairment and its use is not recommended in these patients (see sections 4.4 and 5.2).

No dose adjustment is necessary in patients with renal impairment (see section 5.2).

The safety and efficacy in children (including neonates) less than 4 months of age of doses of 4 and10 mg/kg for the treatment of invasive candidiasis with CNS involvement has not been adequatelyestablished. Currently available data are described in section 4.8, 5.1, pct. 5.2.

For intravenous use.

After reconstitution and dilution, the solution should be administered by intravenous infusion overapproximately 1 hour. More rapid infusions may result in more frequent histamine mediated reactions.

For reconstitution instructions see section 6.6.

Hypersensitivity to the active substance, to other echinocandins or to any of the excipients listed insection 6.1.

The development of foci of altered hepatocytes (FAH) and hepatocellular tumours after atreatment period of 3 months or longer were observed in rats. The assumed threshold fortumour development in rats is approximately in the range of clinical exposure. The clinicalrelevance of this finding is not known. Liver function should be carefully monitored duringmicafungin treatment. To minimise the risk of adaptive regeneration and potentiallysubsequent liver tumour formation, early discontinuation in the presence of significant andpersistent elevation of ALT/AST is recommended. Micafungin treatment should be conductedon a careful risk/benefit basis, particularly in patients having severe liver functionimpairment or chronic liver diseases known to represent preneoplastic conditions, such asadvanced liver fibrosis, cirrhosis, viral hepatitis, neonatal liver disease or congenital enzymedefects, or receiving a concomitant therapy including hepatotoxic and/or genotoxicproperties.

Micafungin treatment was associated with significant impairment of liver function (increase of ALT,

AST or total bilirubin > 3 times ULN) in both healthy volunteers and patients. In some patients moresevere hepatic dysfunction, hepatitis, or hepatic failure including fatal cases have been reported.

Paediatric patients < 1 year of age might be more prone to liver injury (see section 4.8).

Anaphylactic reactions

During administration of micafungin, anaphylactic/anaphylactoid reactions, including shock, mayoccur. If these reactions occur, micafungin infusion should be discontinued and appropriate treatmentadministered.

Exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysishave been reported. If patients develop a rash they should be monitored closely and micafungindiscontinued if lesions progress.

Haemolysis

Rare cases of haemolysis, including acute intravascular haemolysis or haemolytic anaemia, have beenreported in patients treated with micafungin. Patients who develop clinical or laboratory evidence ofhaemolysis during micafungin therapy should be monitored closely for evidence of worsening of theseconditions and evaluated for the risk/benefit of continuing micafungin therapy.

Renal effects

Micafungin may cause kidney problems, renal failure, and abnormal renal function test. Patientsshould be closely monitored for worsening of renal function.

Co-administration of micafungin and amphotericin B desoxycholate should only be used when thebenefits clearly outweigh the risks, with close monitoring of amphotericin B desoxycholate toxicities(see section 4.5).

Patients receiving sirolimus, nifedipine or itraconazole in combination with micafungin should bemonitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine oritraconazole dosage should be reduced if necessary (see section 4.5).

The incidence of some adverse reactions was higher in paediatric patients than in adult patients (seesection 4.8).

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

Micafungin has a low potential for interactions with medicines metabolised via CYP3A mediatedpathways.

Drug interaction studies in healthy human subjects were conducted to evaluate the potential forinteraction between micafungin and mycophenolate mofetil, ciclosporin, tacrolimus, prednisolone,sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole and amphotericin

B. In these studies, no evidence of altered pharmacokinetics of micafungin was observed. Nomicafungin dose adjustments are necessary when these medicines are administered concomitantly.

Exposure (AUC) of itraconazole, sirolimus and nifedipine was slightly increased in the presence ofmicafungin (22%, 21% and 18% respectively).

Co-administration of micafungin and amphotericin B desoxycholate was associated with a 30%increase in amphotericin B desoxycholate exposure. Since this may be of clinical significance this co-administration should only be used when the benefits clearly outweigh the risks, with close monitoringof amphotericin B desoxycholate toxicities (see section 4.4).

Patients receiving sirolimus, nifedipine or itraconazole in combination with micafungin should bemonitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine oritraconazole dosage should be reduced if necessary (see section 4.4).

There are no data from the use of micafungin in pregnant women. In animal studies micafungincrossed the placental barrier and reproductive toxicity was seen (see section 5.3). The potential risk forhumans is unknown.

Mycamine should not be used during pregnancy unless clearly necessary.

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

Testicular toxicity was observed in animal studies (see section 5.3). Micafungin may have the potentialto affect male fertility in humans.

Micafungin has no or negligible influence on the ability to drive or use machines. However, patientsshould be informed that dizziness has been reported during treatment with micafungin (see section4.8).

Based on clinical trial experience, overall 32.2% of the patients experienced adverse drug reactions.

The most frequently reported adverse reactions were nausea (2.8%), blood alkaline phosphataseincreased (2.7%), phlebitis (2.5%, primarily in HIV infected patients with peripheral lines), vomiting(2.5%), and aspartate aminotransferase increased (2.3%).

In the following table adverse reactions are listed by system organ class and MedDRA preferred term.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Common Uncommon Rare Not known

Class ≥ 1/100 to < 1/10 ≥ 1/1,000 to < 1/100 ≥ 1/10,000 to (frequency< 1/1,000 cannot beestimated fromavailable data)

Blood and leukopenia, pancytopenia, haemolytic disseminatedlymphatic system neutropenia, anaemia thrombocytopenia, anaemia, intravasculardisorders eosinophilia, haemolysis coagulationhypoalbuminaemia (see section4.4)

Immune system anaphylactic/ anaphylacticdisorders anaphylactoid andreaction (see section anaphylactoid4.4), hypersensitivity shock (seesection 4.4)

System Organ Common Uncommon Rare Not known

Class ≥ 1/100 to < 1/10 ≥ 1/1,000 to < 1/100 ≥ 1/10,000 to (frequency< 1/1,000 cannot beestimated fromavailable data)

Endocrine hyperhidrosisdisorders

Metabolism and hypokalaemia, hyponatraemia,nutritional hypomagnesaemia, hyperkalaemia,disorders hypocalcaemia hypophosphataemia,anorexia

Psychiatric insomnia, anxiety,disorders confusion

Nervous system headache somnolence, tremor,disorders dizziness, dysgeusia

Cardiac disorders tachycardia,palpitations,bradycardia

Vascular disorders phlebitis hypotension, shockhypertension,flushing

Respiratory, dyspnoeathoracic andmediastinaldisorders

Gastrointestinal nausea, vomiting, dyspepsia,disorders diarrhoea, abdominal constipationpain

Hepatobiliary blood alkaline hepatic failure (see hepatocellulardisorders phosphatase section 4.4), gamma- damageincreased, aspartate glutamyltransferase including fatalaminotransferase increased, jaundice, cases (seeincreased, alanine cholestasis, section 4.4)aminotransferase hepatomegaly,increased, blood hepatitisbilirubin increased(includinghyperbilirubinaemia),liver function testabnormal

Skin and rash urticaria, pruritus, toxic skinsubcutaneous erythema eruption,tissue disorders erythemamultiforme,

Stevens-

Johnsonsyndrome,toxicepidermalnecrolysis (seesection 4.4)

Renal and urinary blood creatinine renaldisorders increased, blood urea impairmentincreased, renal (see sectionfailure aggravated 4.4), acuterenal failure

System Organ Common Uncommon Rare Not known

Class ≥ 1/100 to < 1/10 ≥ 1/1,000 to < 1/100 ≥ 1/10,000 to (frequency< 1/1,000 cannot beestimated fromavailable data)

General disorders pyrexia, rigors injection siteand thrombosis, infusionadministration site site inflammation,conditions injection site pain,peripheral oedema

Investigations blood lactatedehydrogenaseincreased

Possible allergic-like symptoms

Symptoms such as rash and rigors have been reported in clinical studies. The majority were of mild tomoderate intensity and not treatment limiting. Serious reactions (e.g. anaphylactoid reaction 0.2%,6/3028) were uncommonly reported during therapy with micafungin and only in patients with seriousunderlying conditions (e.g. advanced AIDS, malignancies) requiring multiple co-medications.

The overall incidence of hepatic adverse reactions in the patients treated with micafungin in clinicalstudies was 8.6% (260/3028). The majority of hepatic adverse reactions were mild and moderate. Mostfrequent reactions were increase in AP (2.7%), AST (2.3%), ALT (2.0%), blood bilirubin (1.6%) andliver function test abnormal (1.5%). Few patients (1.1%; 0.4% serious) discontinued treatment due to ahepatic event. Cases of serious hepatic dysfunction occurred uncommonly (see section 4.4).

Injection-site reactions

None of the injection-site adverse reactions were treatment limiting.

The incidence of some adverse reactions (listed in the table below) was higher in paediatric patientsthan in adult patients. Additionally, paediatric patients < 1 year of age experienced about two timesmore often an increase in ALT, AST and AP than older paediatric patients (see section 4.4). The mostlikely reason for these differences were different underlying conditions compared with adults or olderpaediatric patients observed in clinical studies. At the time of entering the study, the proportion ofpaediatric patients with neutropenia was several-fold higher than in adult patients (40.2% and 7.3% ofchildren and adults, respectively), as well as allogeneic HSCT (29.4% and 13.4%, respectively) andhaematological malignancy (29.1% and 8.7%, respectively).

Blood and lymphatic system disorderscommon thrombocytopenia

Cardiac disorderscommon tachycardia

Vascular disorderscommon hypertension, hypotension

Hepatobiliary disorderscommon hyperbilirubinaemia, hepatomegaly

Renal and urinarydisorderscommon acute renal failure, blood urea increased

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.

Repeated daily doses up to 8 mg/kg (maximum total dose 896 mg) in adult patients have beenadministered in clinical trials with no reported dose-limiting toxicity. In one spontaneous case, it wasreported a dosage of 16 mg/kg/day was administered in a newborn patient. No adverse reactionsassociated with this high dose were noted.

There is no experience with overdoses of micafungin. In case of overdose, general supportivemeasures and symptomatic treatment should be administered. Micafungin is highly protein-bound andnot dialysable.

Pharmacotherapeutic group: Antimycotics for systemic use, other antimycotics for systemic use, ATCcode: J02AX05

Micafungin non-competitively inhibits the synthesis of 1,3-β-D-glucan, an essential component of thefungal cell wall. 1,3-β-D-glucan is not present in mammalian cells.

Micafungin exhibits fungicidal activity against most Candida species and prominently inhibits activelygrowing hyphae of Aspergillus species.

PK/PD relationship

In animals models of candidiasis, a correlation was observed between exposure of micafungin dividedby MIC (AUC/MIC) and efficacy defined as the ratio required to prevent progressive fungal growth. Aratio of ~2400 and ~1300 was required for C. albicans and C. glabrata, respectively, in these models.

At the recommended therapeutic dosage of Mycamine, these ratios are achievable for the wild-typedistribution of Candida spp.

Mechanism(s) of resistance

As for all antimicrobial agents, cases of reduced susceptibility and resistance have been reported andcross-resistance with other echinocandins cannot be excluded. Reduced susceptibility to echinocandinshas been associated with mutations in the Fks1 and Fks2 genes coding for a major subunit of glucansynthase.

EUCAST breakpoints (version 10.0, valid from 2020-02-04)

Candida species MIC breakpoint (mg/L)≤S (Susceptible) >R (Resistant)

Candida albicans 0.016 0.016

Candida glabrata 0.03 0.03

Candida parapsilosis 2 2

Candida tropicalis1 Insufficient evidence

Candida krusei1 Insufficient evidence

Candida guilliermondii1 Insufficient evidence

Other Candida spp. Insufficient evidence1 MICs for C. tropicalis are 1-2 two-fold dilution steps higher than for C. albicans and C. glabrata.

In the clinical study, successful outcome was numerically slightly lower for C. tropicalis than for

C. albicans at both dosages (100 and 150 mg daily). However, the difference was not significantand whether it translates into a relevant clinical difference is unknown. MICs for C. krusei areapproximately 3 two-fold dilution steps higher than those for C. albicans and, similarly, those for

C. guilliermondii are approximately 8 two-fold dilutions higher. In addition, only a small numberof cases involved these species in the clinical trials. This means there is insufficient evidence toindicate whether the wild-type population of these pathogens can be considered susceptible tomicafungin.

Candidaemia and Invasive Candidiasis: Micafungin (100 mg/day or 2 mg/kg/day) was as effective asand better tolerated than liposomal amphotericin B (3 mg/kg) as first-line treatment of candidaemiaand invasive candidiasis in a randomised, double-blind, multinational non-inferiority study.

Micafungin and liposomal amphotericin B were received for a median duration of 15 days (range, 4 to42 days in adults; 12 to 42 days in children).

Non-inferiority was proven for adult patients, and similar findings were demonstrated for thepaediatric subpopulations (including neonates and premature infants). Efficacy findings wereconsistent, independent of the infective Candida species, primary site of infection and neutropenicstatus (see Table). Micafungin demonstrated a smaller mean peak decrease in estimated glomerularfiltration rate during treatment (p<0.001) and a lower incidence of infusion-related reactions (p=0.001)than liposomal amphotericin B.

Overall Treatment Success in the Per Protocol Set, Invasive Candidiasis Study

Micafungin Liposomal % Difference

Amphotericin B [95% CI]

N n (%) N n (%)

Overall Treatment Success 202 181 (89.6) 190 170 (89.5) 0.1 [-5.9, 6.1] †

Overall Treatment Success by Neutropenic Status

Neutropenia at baseline 24 18 (75.0) 15 12 (80.0) 0.7 [-5.3, 6.7] ‡

No neutropenia at baseline 178 163 (91.6) 175 158 (90.3)

Overall Treatment Success 48 35 (72.9) 50 38 (76.0) -2.7 [-17.3, 11.9] §< 2 years old 26 21 (80.8) 31 24 (77.4)

Premature Infants 10 7 (70.0) 9 6 (66.7)

Neonates (0 days to 7 7 (100) 5 4 (80)< 4 weeks)2 to 15 years old 22 14 (63.6) 19 14 (73.7)

Adults and Children Combined, Overall Treatment Success by Candida Species

Candida albicans 102 91 (89.2) 98 89 (90.8)

Micafungin Liposomal % Difference

Amphotericin B [95% CI]

N n (%) N n (%)

Non-albicans species ¶: all 151 133 (88.1) 140 123 (87.9)

C. tropicalis 59 54 (91.5) 51 49 (96.1)

C. parapsilosis 48 41 (85.4) 44 35 (79.5)

C. glabrata 23 19 (82.6) 17 14 (82.4)

C. krusei 9 8 (88.9) 7 6 (85.7)† Micafungin rate minus the liposomal amphotericin B rate, and 2-sided 95% confidence interval forthe difference in overall success rate based on large sample normal approximation.‡ Adjusted for neutropenic status; primary endpoint.§ The paediatric population was not sized to test for non-inferiority.¶ Clinical efficacy was also observed (< 5 patients) in the following Candida species: C. guilliermondii, C.famata, C. lusitaniae, C. utilis, C. inconspicua and C. dubliniensis.

Oesophageal Candidiasis: In a randomised, double-blind study of micafungin versus fluconazole inthe first-line treatment of oesophageal candidiasis, 518 patients received at least a single dose of studydrug. The median treatment duration was 14 days and the median average daily dose was 150 mg formicafungin (N=260) and 200 mg for fluconazole (N=258). An endoscopic grade of 0 (endoscopiccure) at the end of treatment was observed for 87.7% (228/260) and 88.0% (227/258) of patients in themicafungin and fluconazole groups, respectively (95% CI for difference: [-5.9%, 5.3%]). The lowerlimit of the 95% CI was above the predefined non-inferiority margin of -10%, proving non-inferiority.

The nature and incidence of adverse events were similar between treatment groups.

Prophylaxis: Micafungin was more effective than fluconazole in preventing invasive fungal infectionsin a population of patients at high risk of developing a systemic fungal infection (patients undergoinghaematopoietic stem cell transplantation [HSCT] in a randomised, double-blind, multicentre study).

Treatment success was defined as the absence of a proven, probable, or suspected systemic fungalinfection through the end of therapy and absence of a proven or probable systemic fungal infectionthrough the end of study. Most patients (97%, N=882) had neutropenia at baseline (< 200neutrophils/µL). Neutropenia persisted for a median of 13 days. There was a fixed daily dose of 50 mg(1.0 mg/kg) for micafungin and 400 mg (8 mg/kg) for fluconazole. The mean period of treatment was19 days for micafungin and 18 days for fluconazole in the adult population (N=798) and 23 days forboth treatment arms in the paediatric population (N=84).

The rate of treatment success was statistically significantly higher for micafungin than fluconazole(1.6% versus 2.4% breakthrough infections). Breakthrough Aspergillus infections were observed in 1versus 7 patients, and proven or probable breakthrough Candida infections were observed in 4 versus2 patients in the micafungin and fluconazole groups, respectively. Other breakthrough infections werecaused by Fusarium (1 and 2 patients, respectively) and Zygomycetes (1 and 0 patients, respectively).

The nature and incidence of adverse reactions were similar between treatment groups.

Pharmacokinetics are linear over the daily dose range of 12.5 mg to 200 mg and 3 mg/kg to 8 mg/kg.

There is no evidence of systemic accumulation with repeated administration and steady-state isgenerally reached within 4 to 5 days.

Following intravenous administration concentrations of micafungin show a biexponential decline. Thedrug is rapidly distributed into tissues.

In systemic circulation, micafungin is highly bound to plasma protein (> 99%), primarily to albumin.

Binding to albumin is independent of micafungin concentration (10-100 µg/ml).

The volume of distribution at steady state (Vss) was approximately 18-19 litres.

Unchanged micafungin is the principal circulating compound in systemic circulation. Micafungin hasbeen shown to be metabolised to several compounds; of these M-1 (catechol form), M-2 (methoxyform of M-1) and M-5 (hydroxylation at the side chain) of micafungin have been detected in systemiccirculation. Exposure to these metabolites is low and metabolites do not contribute to the overallefficacy of micafungin.

Even though micafungin is a substrate for CYP3A in vitro, hydroxylation by CYP3A is not a majorpathway for micafungin metabolism in vivo.

Elimination and excretion

The mean terminal half-life is approximately 10-17 hours and stays consistent across doses up to8 mg/kg and after single and repeated administration. Total clearance was 0.15-0.3 ml/min/kg inhealthy subjects and adult patients and is independent of dose after single and repeated administration.

Following a single intravenous dose of 14C-micafungin (25 mg) to healthy volunteers, 11.6% of theradioactivity was recovered in the urine and 71.0% in the faeces over 28 days. These data indicate thatelimination of micafungin is primarily non-renal. In plasma, metabolites M-1 and M-2 were detectedonly at trace concentrations and metabolite M-5, the more abundant metabolite, accounted for a totalof 6.5% relative to parent compound.

Paediatric patients: In paediatric patients AUC values were dose proportional over the dose range of0.5-4 mg/kg. Clearance was influenced by weight, with mean values of weight-adjusted clearance 1.35times higher in the younger children (4 months to 5 years) and 1.14 times higher in paediatric patientsaged 6 to 11 years. Older children (12-16 years) had mean clearance values similar to those determinedin adult patients. Mean weight-adjusted clearance in children less than 4 months of age isapproximately 2.6-fold greater than older children (12-16 years) and 2.3-fold greater than in adults.

PK/PD bridging study demonstrated dose-dependent penetration of micafungin into CNS with theminimum AUC of 170 µg*hr/L required to achieve maximum eradication of fungal burden in the CNStissues. Population PK modeling demonstrated that a dose of 10 mg/kg in children less than 4 month ofage would be sufficient to achieve the target exposure for the treatment of CNS Candida infections.

Elderly: When administered as a single 1-hour infusion of 50 mg the pharmacokinetics of micafunginin the elderly (aged 66-78 years) were similar to those in young (20-24 years) subjects. No doseadjustment is necessary for the elderly.

Patients with hepatic impairment: In a study performed in patients with moderate hepatic impairment(Child-Pugh score 7-9), (n=8), the pharmacokinetics of micafungin did not significantly differ fromthose in healthy subjects (n=8). Therefore, no dose adjustment is necessary for patients with mild tomoderate hepatic impairment. In a study performed in patients with severe hepatic impairment (Child-

Pugh score 10-12) (n=8), lower plasma concentrations of micafungin and higher plasmaconcentrations of the hydroxide metabolite (M-5) were seen compared to healthy subjects (n=8). Thesedata are insufficient to support a dosing recommendation in patients with severe hepatic impairment.

Patients with renal impairment: Severe renal impairment (Glomerular Filtration Rate[GFR] < 30 ml/min) did not significantly affect the pharmacokinetics of micafungin. No doseadjustment is necessary for patients with renal impairment.

Gender/Race: Gender and race (Caucasian, Black and Oriental) did not significantly influence thepharmacokinetic parameters of micafungin. No dose adjustment of micafungin is required based ongender or race.

The development of foci of altered hepatocytes (FAH) and hepatocellular tumours in rats wasdependent on both dose and duration of micafungin treatment. FAH recorded after treatment for 13weeks or longer persisted after a 13-week withdrawal period and developed into hepatocellulartumours following a treatment free period which covered the life span of rats. No standardcarcinogenicity studies have been conducted but the development of FAH was assessed in female ratsafter up to 20 and 18 months after cessation of a 3 and 6 month treatment, respectively. In both studiesincreased incidences/numbers of hepatocellular tumours were observed after the 18 and 20 monthtreatment free period in the high dose group of 32 mg/kg/day as well as in a lower dose group(although not statistically significant). The plasma exposure at the assumed threshold for tumourdevelopment in rats (i.e. the dose where no FAH and liver tumours were detected) was in the samerange as the clinical exposure. The relevance of the hepatocarcinogenic potential of micafungin for thehuman therapeutic use is not known.

The toxicology of micafungin following repeated intravenous dosing in rats and/or dogs showedadverse responses in liver, urinary tract, red blood cells, and male reproductive organs. The exposurelevels at which these effects did not occur (NOAEL) were in the same range as the clinical exposure orlower. Consequently, the occurrence of these adverse responses may be expected in human clinical useof micafungin.

In standard safety pharmacology tests, cardiovascular and histamine releasing effects of micafunginwere evident and appeared to be time above threshold dependent. Prolongation of infusion timereducing the plasma concentration peak appeared to reduce these effects.

In repeated dose toxicity studies in rat signs of hepatotoxicity consisted of increased liver enzymes anddegenerative changes of hepatocytes which were accompanied by signs of compensatory regeneration.

In dog, liver effects consisted of increased weight and centrilobular hypertrophy, no degenerativechanges of hepatocytes were observed.

In rats, vacuolation of the renal pelvic epithelium as well as vacuolation and thickening (hyperplasia)of the bladder epithelium were observed in 26-week repeat dose studies. In a second 26-week studyhyperplasia of transitional cells in the urinary bladder occurred with a much lower incidence. Thesefindings showed reversibility over a follow-up period of 18 months. The duration of micafungindosing in these rat studies (6 months) exceeds the usual duration of micafungin dosing in patients (seesection 5.1).

Micafungin haemolysed rabbit blood in vitro. In rats, signs of haemolytic anaemia were observed afterrepeated bolus injection of micafungin. In repeat dose studies in dogs, haemolytic anaemia was notobserved.

In reproductive and developmental toxicity studies, reduced birth weight of the pups was noted. Oneabortion occurred in rabbits at 32 mg/kg/day. Male rats treated intravenously for 9 weeks showedvacuolation of the epididymal ductal epithelial cells, increased epididymis weights and reducednumber of sperm cells (by 15%), however, in studies of 13 and 26 weeks duration these changes didnot occur. In adult dogs, atrophy of seminiferous tubules with vacuolation of the seminiferousepithelium and decreased sperm in the epididymides were noted after prolonged treatment (39 weeks)but not after 13 weeks of treatment. In juvenile dogs, 39 weeks treatment did not induce lesions in thetestis and epididymides in a dose dependent manner at the end of treatment but after a treatment freeperiod of 13 weeks a dose dependent increase in these lesions were noted in the treated recoverygroups. No impairment of male or female fertility was observed in the fertility and early embryonicdevelopment study in rats.

Micafungin was not mutagenic or clastogenic when evaluated in a standard battery of in vitro and invivo tests, including an in vitro study on unscheduled DNA synthesis using rat hepatocytes.

Lactose monohydrate

Citric acid anhydrous (to adjust the pH)

Sodium hydroxide (to adjust the pH)

This medicinal product must not be mixed or co-infused with other medicinal products except thosementioned in section 6.6.

Unopened vial: 3 years.

Reconstituted concentrate in vial

Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25°C whenreconstituted with sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%)solution for infusion.

Diluted infusion solution

Chemical and physical in-use stability has been demonstrated for 96 hours at 25°C when protectedfrom light when diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose50 mg/ml (5%) solution for infusion.

Mycamine contains no preservatives. From a microbiological point of view, the reconstituted anddiluted solutions should be used immediately. If not used immediately, in-use storage times andconditions prior to use are the responsibility of the user and would normally not be longer than 24hours at 2 to 8°C, unless the reconstitution and dilution have taken place in controlled and validatedaseptic conditions.

This medicinal product does not require any special storage conditions.

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

10 ml Type I glass vial with an isobutylene-isoprene (Fluoro resin film laminated) rubber stopper anda flip-off cap. The vial is wrapped with an UV-protective film.

Pack size: packs of 1 vial.

Any unused product or waste material should be disposed of in accordance with local requirements.

Mycamine must not be mixed or co-infused with other medicinal products except those mentionedbelow. Using aseptic techniques at room temperature, Mycamine is reconstituted and diluted asfollows:

1. The plastic cap must be removed from the vial and the stopper disinfected with alcohol.

2. Five ml of sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose 50 mg/ml (5%)solution for infusion (taken from a 100 ml bottle/bag) should be aseptically and slowly injectedinto each vial along the side of the inner wall. Although the concentrate will foam, every effortshould be made to minimise the amount of foam generated. A sufficient number of vials of

Mycamine must be reconstituted to obtain the required dose in mg (see table below).

3. The vial should be rotated gently. DO NOT SHAKE. The powder will dissolve completely. Theconcentrate should be used immediately. The vial is for single use only. Therefore, unusedreconstituted concentrate must be discarded immediately.

4. All of the reconstituted concentrate should be withdrawn from each vial and returned into theinfusion bottle/bag from which it was originally taken. The diluted infusion solution should beused immediately. Chemical and physical in-use stability has been demonstrated for 96 hours at25°C when protected from light and diluted as described above.

5. The infusion bottle/bag should be gently inverted to disperse the diluted solution but NOTagitated in order to avoid foaming. The solution must not be used if it is cloudy or hasprecipitated.

6. The infusion bottle/bag containing the diluted infusion solution should be inserted into aclosable opaque bag for protection from light.

Preparation of the solution for infusion

Dose Mycamine Volume of sodium Volume Standard infusion(mg) vial chloride (0.9%) or (concentration) (added up toto be used glucose (5%) to be of reconstituted 100 ml)(mg/vial) added per vial powder Finalconcentration50 1 x 50 5 ml approx. 5 ml 0.5 mg/ml(10 mg/ml)100 1 x 100 5 ml approx. 5 ml 1.0 mg/ml(20 mg/ml)150 1 x 100 + 1 x 5 ml approx. 10 ml 1.5 mg/ml200 2 x 100 5 ml approx. 10 ml 2.0 mg/ml

After reconstitution and dilution, the solution should be administered by intravenous infusion overapproximately 1 hour.

Sandoz Pharmaceuticals d.d.

Verovškova ulica 571000 Ljubljana

Slovenia

EU/1/08/448/001

EU/1/08/448/002

Date of first authorisation: 25 April 2008

Date of latest renewal: 19 February 2018

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

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