Mygin 50 mg/100 mg Solution

MYGIN 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/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 2,0],
• 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 MYGIN should take into account a potential risk for the development of liver tumours (see section 4.4). MYGIN should therefore only be used if other antifungals are not appropriate. Principles of antibiotics stewardship should be adhered to.

Treatment with MYGIN should be initiated by a medical practitioner 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 MYGIN depends on the body mass of the patient as given in the following tables:

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

Indication

* 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.

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

Indication

*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.

Use in children (including neonates) < 4 months

Indication

*Micafungin 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 (see 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.

Oesophageal candidiasis: For the treatment of oesophageal candidiasis, MYGIN should be administered for at least one week after resolution of clinical signs and symptoms.

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

Special populations

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 MYGIN in patients with severe hepatic impairment and its use is not recommended in these patients (see sections 4.4 and 4.8).

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 in controlled clinical studies.

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 reconstitution instructions see section 6.6.

MYGIN is contraindicated in:

• Patients with hypersensitivity to micafungin, to other echinocandins or to any of the excipients listed in section 6.1.
• Pregnancy and breastfeeding (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 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 for the therapeutic use in patients cannot be excluded. Liver function should be carefully monitored during MYGIN 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. MYGIN 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, as in MYGIN, 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, as in MYGIN, anaphylactic/anaphylactoid reactions, including shock, may occur. If these reactions occur, micafungin 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) were 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 MYGIN discontinued if lesions progress.

Haemolysis

Cases of haemolysis, including acute intravascular haemolysis or haemolytic anaemia, have been reported in patients treated with micafungin, as in MYGIN. 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

MYGIN may cause kidney problems, renal failure, and abnormal renal function test. Patients should be closely monitored for worsening of renal function.

Paediatric population

The incidence of some adverse reactions was higher in paediatric patients than in adult patients (see section 4.8).

Excipients

Sodium MYGIN contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially u2018sodium-freeu2019.

MYGIN 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, as in MYGIN, 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 MYGIN 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 as in MYGIN. Co-administration of micafungin, as in MYGIN, 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. 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.

Women of childbearing potential/Contraception in males and females: The use of MYGIN in women of childbearing potential should only be given when appropriate contraceptive measures is taken. In animal studies micafungin crossed the placental barrier and reproductive toxicity was seen.

Pregnancy

MYGIN is contraindicated in pregnancy (see section 4.3).

Breastfeeding

Mothers receiving MYGIN should not breastfeed their infants (see section 4.3).

Fertility

Testicular toxicity was observed in animal studies. MYGIN may have the potential to affect male fertility in humans.

MYGIN may cause side effects, such as dizziness, which may affect the ability to drive and use machinery (see section 4.8). Caution is advised before driving a vehicle or operating machinery until the effects of MYGIN are known.

Summary of the safety profile

The most frequently reported adverse reactions were nausea, blood alkaline phosphatase increased, phlebitis (primarily in HIV infected patients with peripheral lines), vomiting and aspartate aminotransferase increased.

Tabulated list of adverse reactions

Blood and the lymphatic system disorders

• Frequent: leukopenia, neutropenia, anaemia
• Less frequent: pancytopenia, thrombocytopenia, eosinophilia, hypoalbuminaemia, haemolytic anaemia, haemolysis (see section 4.4)
• Frequency unknown: disseminated intravascular coagulation

Immune system disorders

• Less frequent: anaphylactic/anaphylactoid reaction (see section 4.4), hypersensitivity
• Frequency unknown: anaphylactic and anaphylactoid shock (see section 4.4)

Endocrine disorders

• Less frequent: hyperhidrosis

Metabolism and nutrition disorders

• Frequent: hypokalaemia, hypomagnesaemia, hypocalcaemia
• Less frequent: hyponatraemia, hyperkalaemia, hypophosphataemia, anorexia

Psychiatric disorders

• Less frequent: insomnia, anxiety, confusion

Nervous system disorders

• Frequent: headache
• Less frequent: somnolence, tremor, dizziness, dysgeusia

Cardiac disorders

• Less frequent: tachycardia, palpitations, bradycardia

Vascular disorders

• Frequent: phlebitis
• Less frequent: hypotension, hypertension, flushing
• Frequency unknown: shock

Respiratory, thoracic and mediastinal disorders

• Less frequent: dyspnoea

Gastrointestinal disorders

• Frequent: nausea, vomiting, diarrhoea, abdominal pain
• Less frequent: dyspepsia, constipation

Hepatobiliary disorders

• Frequent: increased blood alkaline phosphatase, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood bilirubin (including hyperbilirubinaemia), abnormal liver function test
• Less frequent: hepatic failure (see section 4.4), increased gamma-glutamyl transferase, jaundice, cholestasis, hepatomegaly, hepatitis
• Frequency unknown: hepatocellular damage including fatal cases (see section 4.4)

Skin and subcutaneous tissue disorders

• Frequent: rash
• Less frequent: urticaria, pruritus, erythema
• Frequency unknown: toxic skin eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (see section 4.4)

Renal and urinary disorders

• Less frequent: increased blood creatinine, increased blood urea, aggravated renal failure
• Frequency unknown: renal impairment (see section 4.4), acute renal failure

General disorders and administration site conditions

• Frequent: pyrexia, rigors
• Less frequent: injection site thrombosis, infusion site inflammation, injection site pain, peripheral oedema

Investigations

• Less frequent: increased blood lactate dehydrogenase

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) were less frequently reported during therapy with micafungin, as in MYGIN, and only in patients with serious underlying conditions (e.g., advanced AIDS, malignancies) requiring concomitant treatment with multiple medicines.

Hepatic adverse reactions

Reports have shown that the overall incidence of hepatic adverse reactions in the patients treated with micafungin in clinical studies was 8,6 %. The majority of hepatic adverse reactions were mild and moderate. Most frequent reactions were increase in AP, AST, ALT, blood bilirubin and abnormal liver function test. Few patients 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.

Paediatric population

The incidence of some adverse reactions (listed 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. It has been reported at the time of entering the study, that the proportion of paediatric patients with neutropenia was several-fold higher than in adult patients, as well as allogeneic HSCT and haematological malignancy.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of MYGIN is important. It allows continued monitoring of the benefit/risk balance of MYGIN. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRAu2019s website.

There is no experience with overdoses of MYGIN. In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). General supportive measures and symptomatic treatment should be administered. MYGIN is highly protein bound and not dialysable.