4.1. Therapeutic indications

Micafungin is indicated for:

Adults, adolescent's ≥ 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 Micafungin should take into account a potential risk for the development of liver tumours (see section 4.4). Micafungin should therefore only be used if other antifungals are not appropriate.

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

4.2. Posology and method of administration

Treatment with Micafungin should be initiated by a physician experienced in the management of fungal infections.

Posology

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 depends on the body weight of the patient as given in the following tables:

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, the dose may be increased to 200 mg/day in patients weighing > 40 kg or 4 mg/kg/day in patients ≤ 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: Micafungin should be administered for at least one week after resolution of clinical signs and symptoms.

Prophylaxis of Candida infections: Micafungin should be administered for at least one week after neutrophil 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, the dose 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 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 (see section 5.2).

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: Micafungin should be administered for at least one week after neutrophil recovery. Experience with Micafungin in patients less than 2 years of age is limited.

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 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

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 established. Currently available data are described in section 4.8, 5.1, 5.2.

Method of administration

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 medicinal product, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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 clinical relevance of this finding is not known. 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.

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, anaphylactic/anaphylactoid reactions, including shock, may occur. If these reactions occur, micafungin infusion should be discontinued and appropriate treatment administered.

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 discontinued if lesions progress.

Haemolysis

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.

Renal effects

Micafungin 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 products

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).

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.

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 micafungin should be monitored for sirolimus, nifedipine or itraconazole toxicity and the sirolimus, nifedipine or itraconazole dosage should be reduced if necessary (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

Micafungin should not be used during pregnancy unless clearly necessary.

Breast-feeding

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 Micafungin should be made taking into account the benefit of breast-feeding to the child and the benefit of Micafungin therapy to the mother.

Fertility

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

Micafungin has no or negligible influence on the ability to drive or use machines. However, patients should be informed that dizziness has been reported during treatment with micafungin (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

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 phosphatase increased (2.7 %), phlebitis (2.5 %, primarily in HIV infected patients with peripheral lines), vomiting (2.5 %), and aspartate aminotransferase increased (2.3 %).

Tabulated list 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.

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

anaphylactic and anaphylactoid shock (see section 4.4)

Endocrine disorders

hyperhidrosis

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 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 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

Common:

thrombocytopenia

Cardiac disorders

Common:

tachycardia

Vascular disorders

Common:

hypertension, hypotension

Hepatobiliary disorders

Common:

hyperbilirubinaemia, hepatomegaly

Renal and urinary disorders

Common:

acute renal failure, blood urea increased

Reporting of suspected adverse reactions

Reporting 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, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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. In one spontaneous case, it was reported a dosage of 16 mg/kg/day was administered 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.