Micafungin 100 Mg/50 mg Solution

MICAFUNGIN ADCO is indicated for:

Adults, adolescents u2265 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/u03bcI) 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/u03bcI) for 10 or more days.

The decision to use MICAFUNGIN ADCO should take into account a potential risk for the development of liver tumours. MICAFUNGIN ADCO should therefore only be used if other antifungals are not appropriate (See section 4.4)

Posology

Treatment with MICAFUNGIN ADCO should be initiated by a medical practitioner 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 MICAFUNGIN ADCO depends on the body weight of the patient as given in the following table:

*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 u2264 40 kg.

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, MICAFUNGIN ADCO should be administered for at least one week after resolution of clinical signs and symptoms.

Prophylaxis of Candida infections: For prophylaxis of Candida infection, MICAFUNGIN ADCO should be administered for at least one week after neutrophil recovery.

Special population

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 MICAFUNGIN ADCO in patients with severe hepatic impairment and its use is not recommended in these patients (see sections 4.4 and 5.2).

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

Paediatric population: Experience with MICAFUNGIN ADCO in patients less than 2 years of age is limited.

Method of administration

Precaution to be taken before manipulating or administering the product. For intravenous use.

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 instructions on reconstitution of the medicine before administration, see section 6.6.

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

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 cannot be excluded. Liver function should be carefully monitored during MICAFUNGIN ADCO 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 ADCO 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.

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).

Anaphylactic reactions: During administration of MICAFUNGIN ADCO, anaphylactoid reactions, including shock, may occur. If these reactions occur, MICAFUNGIN ADCO infusion should be discontinued, and appropriate treatment administered. Symptoms such as rash and rigors may occur. They may be mild to moderate in intensity and not treatment limiting. Serious reactions (e.g., anaphylactoid reaction) were commonly reported during therapy with micafungin and only in patients with serious underlying conditions (e.g., advanced AIDS, malignancies) requiring multiple co-medications.

Skin reactions: 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 ADCO discontinued if lesions progress.

Haemolysis: Cases of haemolysis, including acute intravascular haemolysis or haemolytic anaemia, may occur in patients treated with MICAFUNGIN ADCO. Patients who develop clinical or laboratory evidence of haemolysis during MICAFUNGIN ADCO therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing MICAFUNGIN ADCO therapy.

Renal effects: MICAFUNGIN ADCO 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 micafungin 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 population: The incidence of some adverse reactions was higher in paediatric patients than in adult patients (See section 4.8).

MICAFUNGIN ADCO has a low potential for interactions with medicines metabolised via CYP3A mediated pathways. 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 ADCO dose adjustments are necessary when these medicines are administered concomitantly. Exposure (AUC) of itraconazole, sirolimus and nifedipine may be slightly increased in the presence of MICAFUNGIN ADCO. Patients receiving sirolimus, nifedipine or itraconazole in combination with MICAFUNGIN ADCO 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). Co-administration of MICAFUNGIN ADCO and amphotericin B desoxycholate may be 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).

Women of childbearing potential/ Contraception in males and females: The use of MICAFUNGIN ADCO in women of childbearing potential should be given when appropriate contraceptive measures is taken.

Pregnancy: There are no data from the use of MICAFUNGIN ADCO in pregnant women. In animal studies micafungin crossed the placental barrier and reproductive toxicity was seen. The potential risk for humans is unknown. MICAFUNGIN ADCO should not be used during pregnancy.

Breast-feeding: MICAFUNGIN ADCO should not be used during breastfeeding. It is not known whether micafungin is excreted in human breast milk. Animal studies have shown excretion of micafungin in breast milk.

Fertility: Testicular toxicity was observed in animal studies. MICAFUNGIN ADCO may have the potential to affect male fertility in humans.

MICAFUNGIN ADCO has no or negligible influence on the ability to drive and use machines. However, adverse reactions, such as dizziness has been reported during treatment which may influence the ability to drive and use machines (see section 4.8).

a. Summary of the safety profile

The most frequent adverse reactions may be nausea, blood alkaline phosphatase increase, phlebitis (primarily in HIV infected patients with peripheral lines), vomiting and aspartate aminotransferase increased.

b. Tabulated summary of adverse reactions

c. Description of selected adverse reactions

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 less frequently 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 less frequently (see section 4.4).

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

d. Paediatric population: 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).

Blood and lymphatic system disorders: Frequent: thrombocytopenia

Cardiac disorders: Frequent: tachycardia

Vascular disorders: Frequent: hypertension, hypotension

Hepatobiliary disorders: Frequent: hyperbilirubinaemia, hepatomegaly

Renal and urinary disorders: Frequent: acute renal failure, blood urea increased

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. There is no experience with overdoses of MICAFUNGIN ADCO. In case of overdose, general supportive measures and symptomatic treatment should be administered. MICAFUNGIN ADCO is highly protein-bound and not dialysable.