1. Name Of The Medicinal Product
Mycamine®
Mycamine®
2. Qualitative And Quantitative Composition
Each vial contains 50 mg micafungin (as sodium).
After reconstitution each ml contains 10 mg micafungin (as sodium).
Each vial contains 100 mg micafungin (as sodium).
After reconstitution each ml contains 20 mg micafungin (as sodium).
Excipients:
Each 50 mg vial contains 200 mg lactose.
Each 100 mg vial contains 200 mg lactose.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for infusion.
White compact powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Mycamine is indicated for:
Adults, adolescents
- 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.
4.2 Posology And Method Of Administration
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 fungal infections.
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
The dose regimen of Mycamine depends on the body weight of the patient as given in the following tables:
Use in adults, adolescents
| ||
|
|
|
|
|
|
|
|
|
|
|
|
*If the patient's response is inadequate, e.g. persistence of cultures or if clinical condition does not improve, the dose may be increased to 200 mg/day in patients weighing > 40 kg or 4 mg/kg/day in patients
Treatment duration
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 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
| ||
|
|
|
|
|
|
|
|
|
*If the patient's response is inadequate, e.g. persistence of cultures or if clinical condition does not improve, the dose may be increased to 200 mg/day in patients weighing > 40 kg or 4 mg/kg/day in patients weighing
Treatment duration
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 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/Race
No dose adjustment is necessary based on gender or race (see section 5.2).
Use in patients with hepatic impairment
No 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).
Use in patients with renal impairment
No dose adjustment is necessary in patients with renal impairment (see section 5.2).
After 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.
4.3 Contraindications
Hypersensitivity to the active substance, to other echinocandins or to any of the excipients.
4.4 Special Warnings And Precautions For Use
|
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 more severe 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).
During administration of micafungin, anaphylactic/anaphylactoid reactions including shock may occur. If these reactions occur, micafungin infusion should be discontinued and appropriate treatment administered.
Exfoliative 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.
Rare 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.
Micafungin may cause kidney problems, renal failure, and abnormal renal function test. Patients should be closely monitored for worsening of renal function.
Co-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).
The incidence of some adverse reactions was higher in paediatric patients than in adult patients (see section 4.8).
This medicinal product for intravenous use contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Micafungin has a low potential for interactions with medicines metabolised via CYP3A mediated pathways.
Drug interaction studies in healthy human subjects were conducted to evaluate the potential for interaction 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. No micafungin dose adjustments are necessary when these medicines are administered concomitantly. Exposure (AUC) of itraconazole, sirolimus and nifedipine was slightly increased in the presence of micafungin (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 monitoring of amphotericin B desoxycholate toxicities (see section 4.4).
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 4.4).
4.6 Pregnancy And Lactation
There 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.
It 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.
Testicular toxicity was observed in animal studies (see section 5.3). Micafungin may have the potential to affect male fertility in humans.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However, adverse reactions may occur, which may influence the ability to drive and use machines (see section 4.8).
4.8 Undesirable Effects
The 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.
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.
|
|
|
|
|
|
|
|
|
|
|
| |||
|
| |||
|
|
| ||
|
| |||
|
|
| ||
|
| |||
|
|
|
| |
|
| |||
|
|
| ||
|
|
|
| |
|
|
|
| |
|
|
| ||
|
|
| ||
|
|
Possible allergic-like symptoms
Symptoms 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 reactions
The 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 reactions
None of the injection-site adverse reactions were treatment limiting.
Paediatric patients
The 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).
| |
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
4.9 Overdose
Repeated daily doses up to 8 mg/kg (maximum total dose 896 mg) in adult patients have been administered in clinical trials with no reported dose-limiting toxicity. One case of mis-dosage of 7.8 mg/kg/day for 7 days was reported in a newborn patient. No adverse reactions associated with this high dose were noted.
There is no experience with overdoses of micafungin. In case of overdose, general supportive measures and symptomatic treatment should be administered. Micafungin is highly protein-bound and not dialysable.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other antimycotics for systemic use, ATC code: J02AX05
Mode of action
Micafungin 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 relationship
An additive or synergistic pharmacodynamic interaction of micafungin and amphotericin B was found in a mouse model of pulmonary aspergillosis (immunosuppression with hydrocortisone, intranasal infection with Aspergillus fumigatus).
Mechanism(s) of resistance
As 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 gene coding for a major subunit of glucan synthase.
Breakpoints
Susceptibility testing was performed with modifications according to the Clinical and Laboratory Standards Institute (CLSI) methods M27-A2 (Candida species) and M38-A (Aspergillus species), respectively. To date, standardised techniques for susceptibility testing for 1,3-β-D-glucan synthesis inhibitors have not been established and results of susceptibility testing do not necessarily correlate with clinical outcome.
Although no MIC breakpoints for echinocandins have been established, a MIC of Candida spp. without bisecting any species group and represents a concentration that is easily maintained throughout the dosing interval. Infections due to Candida spp. in this MIC range are likely to respond to therapy.
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information is only a guide to the probabilities of whether micro-organisms will be susceptible to micafungin or not. Where applicable the information on the European range of acquired resistance for the individual micro-organisms is indicated in brackets.
|
|
|
|
|
|
Information from clinical studies
Candidaemia 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 rate minus the liposomal amphotericin B rate, and 2-sided 95% confidence interval for the 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 in the first-line treatment of oesophageal candidiasis, 518 patients received at least a single dose of study drug. The median treatment duration was 14 days and the median average daily dose was 150 mg for micafungin (N=260) and 200 mg for fluconazole (N=258). An endoscopic grade of 0 (endoscopic cure) at the end of treatment was observed for 87.7% (228/260) and 88.0% (227/258) of patients in the micafungin and fluconazole groups, respectively (95% CI for difference: [-5.9%, 5.3%]). The lower limit 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 infections in a population of patients at high risk of developing a systemic fungal infection (patients undergoing haematopoietic 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 fungal infection through the end of therapy and absence of a proven or probable systemic fungal infection through the end of study. Most patients (97%, N=882) had neutropenia at baseline (< 200 neutrophils/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 was 19 days for micafungin and 18 days for fluconazole in the adult population (N=798) and 23 days for both treatment arms in the paediatric population (N=84).
The rate of treatment success was statistically significantly higher for micafungin than fluconazole (1.6%
No comments:
Post a Comment