- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
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 cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count < 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 cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count < 500 cells / µl) for 10 or more days.The decision to use Mycamine should take into account a potential risk for the development of liver tumours (see section 4.4). Mycamine should therefore only be used if other antifungals are not appropriate.
PosologyThe dose regimen of Mycamine depends on the body weight of the patient as given in the following tables:
Use in adults, adolescents ≥ 16 years of age and elderly
|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|
Treatment durationInvasive 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 blood cultures have been obtained and after resolution of clinical signs and symptoms of infection.Oesophageal candidiasis:For the treatment of oesophageal candidiasis, Mycamine should be administered for at least one week after resolution of clinical signs and symptoms.Prophylaxis of Candida infections: For prophylaxis of Candida infection, Mycamine should be administered for at least one week after neutrophil recovery.
Use in children (including neonates) and adolescents < 16 years of age
|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|
Treatment durationInvasive 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 blood cultures have been obtained and after resolution of clinical signs and symptoms of infection.Prophylaxis of Candida infections: For prophylaxis of Candida infection, Mycamine should be administered for at least one week after neutrophil recovery. Experience with Mycamine in patients less than 2 years of age is limited.
Gender/raceNo dose adjustment is necessary based on gender or race (see section 5.2).
Patients with hepatic impairmentNo dose adjustment is necessary in patients with mild or moderate hepatic impairment (see section 5.2). There are currently insufficient data available for the use of Mycamine in patients with severe hepatic impairment and its use is not recommended in these patients (see section 4.4 and 5.2).
Patients with renal impairmentNo dose adjustment is necessary in patients with renal impairment (see section 5.2).
Method of administrationAfter reconstitution and dilution, the solution should be administered by intravenous infusion over approximately 1 hour. More rapid infusions may result in more frequent histamine mediated reactions.For reconstitution instructions see section 6.6.
|Hepatic effects: The development of foci of altered hepatocytes (FAH) and hepatocellular tumours after a treatment period of 3 months or longer were observed in rats. The assumed threshold for tumour development in rats is approximately in the range of clinical exposure. The relevance of this finding for the therapeutic use in patients can not be excluded. Liver function should be carefully monitored during micafungin treatment. To minimise the risk of adaptive regeneration and potentially subsequent liver tumour formation, early discontinuation in the presence of significant and persistent elevation of ALT/AST is recommended. Micafungin treatment should be conducted on a careful risk/benefit basis, particularly in patients having severe liver function impairment or chronic liver diseases known to represent preneoplastic conditions, such as advanced liver fibrosis, cirrhosis, viral hepatitis, neonatal liver disease or congenital enzyme defects, or receiving a concomitant therapy including hepatotoxic and/or genotoxic properties.|
Anaphylactic reactionsDuring administration of micafungin, anaphylactic/anaphylactoid reactions including shock may occur. If these reactions occur, micafungin infusion should be discontinued and appropriate treatment administered.
Skin reactionsExfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. If patients develop a rash they should be monitored closely and micafungin discontinued if lesions progress.
HaemolysisRare cases of haemolysis including acute intravascular haemolysis or haemolytic anaemia have been reported in patients treated with micafungin. Patients who develop clinical or laboratory evidence of haemolysis during micafungin therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing micafungin therapy.
Renal effectsMicafungin may cause kidney problems, renal failure, and abnormal renal function test. Patients should be closely monitored for worsening of renal function.
Interactions with other medicinal productsCo-administration of micafungin and amphotericin B desoxycholate should only be used when the benefits 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 Mycamine should be monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or itraconazole dosage should be reduced if necessary (see section 4.5).
Paediatric populationThe incidence of some adverse reactions was higher in paediatric patients than in adult patients (see section 4.8).
PregnancyThere are no data from the use of micafungin in pregnant women. In animal studies micafungin crossed the placental barrier and reproductive toxicity was seen (see section 5.3). The potential risk for humans is unknown.Mycamine should not be used during pregnancy unless clearly necessary.
Breast-feedingIt is not known whether micafungin is excreted in human breast milk. Animal studies have shown excretion of micafungin in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Mycamine should be made taking into account the benefit of breast-feeding to the child and the benefit of Mycamine therapy to the mother.
FertilityTesticular toxicity was observed in animal studies (see section 5.3). Micafungin may have the potential to affect male fertility in humans.
Summary of the safety profileThe safety profile of micafungin is based on 3028 patients treated with micafungin in clinical studies: 2.002 patients with Candida infections (including candidaemia, invasive candidiasis and oesophageal candidiasis), 375 with invasive aspergillosis (primarily refractory infections) and 651 for prophylaxis of systemic fungal infections.The patients treated with micafungin in clinical studies represent a critically ill patient population that requires multiple medicinal products including antineoplastic chemotherapy, potent systemic immunosuppressants and broad spectrum antibiotics. These patients had a wide variety of complex underlying conditions such as haematological malignancies and HIV-infection or were transplant recipients and/or treated in intensive care. Patients treated prophylactically with micafungin were those undergoing haematopoetic stem cell transplantation (HSCT) who were at high risk for fungal infections.Overall 32.2% of the patients experienced adverse drug reactions. The most frequently reported adverse reactions were nausea (2.8%), blood alkaline phosphatase increased (2.7%), phlebitis (2.5%, primarily in HIV infected patients with peripheral lines), vomiting (2.5%), and aspartate aminotransferase increased (2.3%). No clinically significant differences were seen when the safety data were analysed by gender or race.
Tabulated list of adverse reactionsIn 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 Class||Common≥ 1/100 to < 1/10||Uncommon≥ 1/1,000 to < 1/100||Rare≥ 1/10,000 to < 1/1,000||Not known(frequency cannot be estimated from available data)|
|Blood and lymphatic system disorders||leukopenia, neutropenia, anaemia||pancytopenia, thrombocytopenia, eosinophilia, hypoalbuminaemia||haemolytic anaemia, haemolysis (see section 4.4)||disseminated intravascular coagulation|
|Immune system disorders||anaphylactic / anaphylactoid reaction (see section 4.4), hypersensitivity|
|Metabolism and nutritional disorders||hypokalaemia, hypomagnesaemia, hypocalcaemia||hyponatraemia, hyperkalaemia, hypophosphataemia, anorexia|
|Psychiatric disorders||insomnia, anxiety, confusion|
|Nervous system disorders||headache||somnolence, tremor, dizziness, dysgeusia|
|Cardiac disorders||tachycardia, palpitations, bradycardia|
|Vascular disorders||phlebitis||hypotension, hypertension, flushing||shock|
|Respiratory, thoracic and mediastinal disorders||dyspnoea|
|Gastrointestinal disorders||nausea, vomiting, diarrhoea, abdominal pain||dyspepsia, constipation|
|Hepatobiliary disorders||blood alkaline phosphatase increased, aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased (including hyperbilirubinaemia), liver function test abnormal||hepatic failure (see section 4.4), gamma-glutamyltransferase increased, jaundice, cholestasis, hepatomegaly, hepatitis||hepatocellular damage including fatal cases (see section 4.4)|
|Skin and subcutaneous tissue disorders||rash||urticaria, pruritus, erythema||toxic skin eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (see section 4.4)|
|Renal and urinary disorders||blood creatinine increased, blood urea increased, renal failure aggravated||renal impairment (see section 4.4), acute renal failure|
|General disorders and administration site conditions||pyrexia, rigors||injection site thrombosis, infusion site inflammation, injection site pain, peripheral oedema|
|Investigations||blood lactate dehydrogenase increased|
Description of selected adverse reactions
Possible allergic-like symptomsSymptoms such as rash and rigors have been reported in clinical studies. The majority were of mild to moderate 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 serious underlying conditions (e.g. advanced AIDS, malignancies) requiring multiple co-medications.
Hepatic adverse reactionsThe overall incidence of hepatic adverse reactions in the patients treated with micafungin in clinical studies was 8.6% (260/3028). The majority of hepatic adverse reactions were mild and moderate. Most frequent reactions were increase in AP (2.7%), AST (2.3%), ALT (2.0%), blood bilirubin (1.6%) and liver function test abnormal (1.5%). Few patients (1.1%; 0.4% serious) discontinued treatment due to a hepatic event. Cases of serious hepatic dysfunction occurred uncommonly (see section 4.4).
Injection-site reactionsNone of the injection-site adverse reactions were treatment limiting.
Paediatric populationThe incidence of some adverse reactions (listed in the table below) was higher in paediatric patients than in adult patients. Additionally, paediatric patients < 1 year of age experienced about two times more often an increase in ALT, AST and AP than older paediatric patients (see section 4.4). The most likely reason for these differences were different underlying conditions compared with adults or older paediatric patients observed in clinical studies. At the time of entering the study, the proportion of paediatric patients with neutropenia was several-fold higher than in adult patients (40.2% and 7.3% of children and adults, respectively), as well as allogeneic HSCT (29.4% and 13.4%, respectively) and haematological malignancy (29.1% and 8.7%, respectively).
|Blood and lymphatic system disorders|
|Renal and urinary disorders|
|common||acute renal failure, blood urea increased|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Mode of actionMicafungin non-competitively inhibits the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall. 1,3-β-D-glucan is not present in mammalian cells.Micafungin exhibits fungicidal activity against most Candida species and prominently inhibits actively growing hyphae of Aspergillus species.
PK/PD relationshipIn animals models of candidiasis, a correlation was observed between exposure of micafungin divided by MIC (AUC/MIC) and efficacy defined as the ratio required to prevent progressive fungal growth. A ratio 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-type distribution of Candida spp.
Mechanism(s) of resistanceAs for all antimicrobial agents, cases of reduced susceptibility and resistance have been reported and cross-resistance with other echinocandins cannot be excluded. Reduced susceptibility to echinocandins has been associated with mutations in the Fks1 and Fks2 genes coding for a major subunit of glucan synthase.
|Candida species||MIC breakpoint (mg/L)|
|≤S (Susceptible)||>R (Resistant)|
|Candida tropicalis 1||Insufficient evidence|
|Candida krusei1||Insufficient evidence|
|Candida guilliermondii1||Insufficient evidence|
|Other Candida spp.||Insufficient evidence|
|1 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 significant and whether it translates into a relevant clinical difference is unknown. MICs for C. krusei are approximately 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 number of cases involved these species in the clinical trials. This means there is insufficient evidence to indicate whether the wild-type population of these pathogens can be considered susceptible to micafungin.|
Information from clinical studiesCandidaemia and Invasive Candidiasis: Micafungin (100 mg/day or 2 mg/kg/day) was as effective as and better tolerated than liposomal amphotericin B (3 mg/kg) as first-line treatment of candidaemia and 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 to 42 days in adults; 12 to 42 days in children).Non-inferiority was proven for adult patients, and similar findings were demonstrated for the paediatric subpopulations (including neonates and premature infants). Efficacy findings were consistent, independent of the infective Candida species, primary site of infection and neutropenic status (see Table). Micafungin demonstrated a smaller mean peak decrease in estimated glomerular filtration 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 Amphotericin B||% Difference[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 < 4 weeks)||7||7 (100)||5||4 (80)|
|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)|
|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)|
AbsorptionMicafungin is an intravenously administered medication.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 is generally reached within 4 to 5 days.
DistributionFollowing intravenous administration concentrations of micafungin show a biexponential decline. The drug 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.
BiotransformationUnchanged micafungin is the principal circulating compound in systemic circulation. Micafungin has been shown to be metabolised to several compounds; of these M-1 (catechol form), M-2 (methoxy form of M-1) and M-5 (hydroxylation at the side chain) of micafungin have been detected in systemic circulation. Exposure to these metabolites is low and metabolites do not contribute to the overall efficacy of micafungin. Even though micafungin is a substrate for CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for micafungin metabolism in vivo.
Elimination and excretionThe mean terminal half-life is approximately 10-17 hours and stays consistent across doses up to 8 mg/kg and after single and repeated administration. Total clearance was 0.15-0.3 ml/min/kg in healthy 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 the radioactivity was recovered in the urine and 71.0% in the faeces over 28 days. These data indicate that elimination of micafungin is primarily non-renal. In plasma, metabolites M-1 and M-2 were detected only at trace concentrations and metabolite M-5, the more abundant metabolite, accounted for a total of 6.5% relative to parent compound.
Special populationsPaediatric patients: In paediatric patients AUC values were dose proportional over the dose range of 0.5-4 mg/kg. Clearance was influenced by age, with mean values of clearance in younger children (2-11 years) being approximately 1.3 -fold greater than those in older children (12-17 years). Older children had mean clearance values similar to those determined in adult patients. Mean clearance in premature infants (gestational age approximately 26 weeks) is approximately 5-fold greater than in adults.Elderly: When administered as a single 1-hour infusion of 50 mg the pharmacokinetics of micafungin in the elderly (aged 66-78 years) were similar to those in young (20-24 years) subjects. No dose adjustment 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 from those in healthy subjects (n=8). Therefore, no dose adjustment is necessary for patients with mild to moderate 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 plasma concentrations of the hydroxide metabolite (M-5) were seen compared to healthy subjects (n=8). These data 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 dose adjustment is necessary for patients with renal impairment.Gender/Race: Gender and race (Caucasian, Black and Oriental) did not significantly influence the pharmacokinetic parameters of micafungin. No dose adjustment of micafungin is required based on gender or race.
Preparation of the solution for infusion
|Dose(mg)||Mycamine vial to be used(mg/vial)||Volume of sodium chloride (0.9%) or glucose (5%) to be added per vial||Volume (concentration) of reconstituted powder||Standard infusion (added up to 100 ml)Final concentration|
|50||1 x 50||5 ml||approx. 5 ml (10 mg/ml)||0.5 mg/ml|
|100||1 x 100||5 ml||approx. 5 ml (20 mg/ml)||1.0 mg/ml|
|150||1 x 100 + 1 x 50||5 ml||approx. 10 ml||1.5 mg/ml|
|200||2 x 100||5 ml||approx. 10 ml||2.0 mg/ml|
Astellas Pharma Ltd
2000 Hillswood Drive, Chertsey, Surrey, KT16 0RS, UK
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