Levuspoz 50 & 100 50 mg, 100 mg Powder for solution for infusion

LEVUSPOZ is indicated for:

• Adults, adolescents u226516 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/u03bcl) 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/u03bcl) for 10 or more days.

Commonly susceptible species [MIC ranges in Europe, mg/L] in vitro:

• Candida albicans [0,007 u2013 0,25],
• Candida glabrata [0,007 u2013 0,12],
• Candida tropicalis [0,007 u2013 0,12],
• Candida krusei [0,015 u2013 0,12],
• Candida kefyr [0,03 u2013 0,06],
• Candida parapsilosis [0,12 u2013 2],
• Candida guilliermondii [0,5],
• Candida lusitaniae [0,12 u2013 0,25],
• Candida spp. [0,015 u2013 0,5], (incl. C. famata, C. dubliniensis, C. lipolytica, C. pelliculosa, C. rugosa, C. stellatoidea and C. zeylanoides),
• Aspergillus fumigatus,
• Aspergillus flavus,
• Aspergillus niger,
• Aspergillus terreus,
• Aspergillus nidulans,
• Aspergillus versicolor

The mycelial form of dimorphic fungi (e.g. Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis).

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

Treatment with LEVUSPOZ 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.

Posology

The dose regimen of LEVUSPOZ depends on the body weight of the patient as given in the following tables:

Table 1: Use in adults, adolescents u2265 16 years of age and elderly

*If the patientu2019s 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.

Special populations

Use in patients with hepatic impairment: No dose adjustment is necessary in patients with mild or moderate hepatic impairment. There are currently insufficient data available for the use of micafungin in patients with severe hepatic impairment and its use is not recommended in these patients (See Section 4.4 and 4.8).

Use in patients with renal impairment: No dose adjustment is necessary in patients with renal impairment.

Paediatric population

Table 2: Use in children u2265 4 months of age up to adolescents < 16 years of age

*If the patientu2019s 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 u2264 40 kg.

Table 3: Use in children (including neonates) < 4 months

*Micafungin as contained in LEVUSPOZ, dosed at 4 mg/kg in children less than 4 months approximates medicine exposures achieved in adults receiving 100 mg/day for the treatment of invasive candidiasis. If central nervous system (CNS) infection is suspected, a higher dosage (e.g. 10 mg/kg) should be used due to the dose-dependent penetration of micafungin into the CNS. The safety and efficacy in children (including neonates) less than 4 months of age of doses of 4 and 10 mg/kg for the treatment of invasive candidiasis with CNS involvement has not been adequately reported in controlled clinical studies.

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

Prophylaxis of Candida infections: For prophylaxis of Candida infection, LEVUSPOZ should be administered for at least one week after neutrophil recovery. Experience with micafungin in patients less than 2 years of age is limited.

• Hypersensitivity to the active substance micafungin, to other echinocandins or to any of the excipients of LEVUSPOZ (see section 6.1).
• Pregnancy and lactation (see section 4.6).

Hepatic effects: The development of foci of altered hepatocytes (FAH) and hepatocellular tumours after a treatment period of 3 months or longer were reported 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 LEVUSPOZ 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. LEVUSPOZ 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 (as contained in LEVUSPOZ) treatment is reported to be 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.

Anaphylactic reactions: During administration of LEVUSPOZ, anaphylactic/anaphylactoid reactions including shock may occur. If these reactions occur, LEVUSPOZ infusion should be discontinued and appropriate treatment administered. 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 %) were commonly reported during therapy with micafungin as contained in LEVUSPOZ 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 LEVUSPOZ discontinued if lesions progress.

Haemolysis: Cases of haemolysis including acute intravascular haemolysis or haemolytic anaemia have been reported in patients treated with micafungin as contained in LEVUSPOZ. Patients who develop clinical or laboratory evidence of haemolysis during LEVUSPOZ therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing LEVUSPOZ therapy.

Renal effects: LEVUSPOZ may cause kidney problems, renal failure, and abnormal renal function tests. Patients should be closely monitored for worsening of renal function.

A total of 14 clinical interaction studies conducted in healthy volunteers to evaluate the potential for interaction between micafungin and mycophenolate mofetil, ciclosporin, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, amphotericin B, itraconazole and voriconazole were reported. In these reported studies, no interaction that altered the pharmacokinetics of micafungin as contained in LEVUSPOZ was reported. Exposure (AUC) of sirolimus was reported to be increased in the presence of micafungin (21 %). Patients receiving sirolimus in combination with LEVUSPOZ should be monitored for sirolimus toxicity and the sirolimus dosage should be adjusted if necessary.

Human reproduction: LEVUSPOZ must not be used during pregnancy and lactation. Mothers receiving LEVUSPOZ must not breastfeed their infants (see section 4.3 and 4.6).

Excipients: Lactose Monohydrate LEVUSPOZ 50 and 100 contains 223,15 mg lactose monohydrate per vial. Patients with rare hereditary problems of galactose intolerance total lactase deficiency or glucose-galactose malabsorption should not take LEVUSPOZ. This should be taken into account in patients with diabetes mellitus.

Paediatric population: The incidence of some adverse reactions was reported to be higher in paediatric patients than in adult patients (See section 4.8).

Pregnancy: LEVUSPOZ is contraindicated in pregnancy (see section 4.3). In reported animal studies, micafungin crossed the placental barrier and reproductive toxicity was reported.

Breast-feeding: LEVUSPOZ is contraindicated in lactation (See section 4.3). Mothers receiving LEVUSPOZ must not breastfeed their infants.

Fertility: Testicular toxicity was reported in animal studies. LEVUSPOZ may have the potential to affect male fertility in humans.

Adverse reactions such as dizziness may occur, which may influence the ability to drive and use machines (see section 4.8).

a) Summary of the safety profile: Overall 32,2 % of the patients have been reported to experience adverse drug reactions. The most frequently reported adverse reactions were nausea, blood alkaline phosphatase increased (2,7 %), phlebitis (primarily in HIV infected patients with peripheral lines), vomiting and aspartate aminotransferase increased. No clinically significant differences were reported when the safety data were analysed by gender or race.

b) Tabulated summary of adverse reactions: 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.

c) Description of selected adverse reactions: Hepatic adverse reactions: The overall incidence of hepatic adverse reactions in the patients treated with micafungin, in reported clinical studies was 8,6 %. The majority of hepatic adverse reactions were reported as mild and moderate. Most frequent reactions were reported to be 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 reported less frequently.

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 %) 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.

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

Paediatric patients: The incidence of some adverse reactions (listed below) was reported to be 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. The most likely reason for these differences were different underlying conditions compared with adults or older paediatric patients reported 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

There is no experience reported 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.